Evidence Report/Technology Assessment
Number 200
Safety of Probiotics to
Reduce Risk and Prevent
or Treat Disease
Agency for Healthcare Research and Quality
Advancing Excellence in Health Care • www.ahrq.gov
EvidenceBased
Practice
Evidence Report/Technology Assessment
Number 200
Safety of Probiotics to Reduce Risk and Prevent or
Treat Disease
Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
540 Gaither Road
Rockville, MD 20850
www.ahrq.gov
Contract No. HHSA 290-2007-10062-I
Prepared by:
Southern California Evidence-based Practice Center, Santa Monica, CA
Investigators:
Susanne Hempel, Ph.D.
Sydne Newberry, Ph.D.
Alicia Ruelaz, M.D.
Zhen Wang, M.S.
Jeremy N. V. Miles, Ph.D.
Marika J. Suttorp, M.S.
Breanne Johnsen, B.S.
Roberta Shanman, M.L.S.
Wendelin Slusser, M.D., M.P.H.
Ning Fu, M.P.P.
Alex Smith, M.P.H.
Beth Roth, M.A.
Joanna Polak, B.S.
Aneesa Motala, B.A.
Tanja Perry, B.H.M.
Paul G. Shekelle, M.D., Ph.D.
AHRQ Publication No. 11-E007
April 2011
This report is based on research conducted by the Southern California Evidence-based Practice
Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ),
Rockville, MD (Contract No. HHSA 290-2007-10062-I). The findings and conclusions in this
document are those of the author(s), who are responsible for its content, and do not necessarily
represent the views of AHRQ. No statement in this report should be construed as an official
position of AHRQ or of the U.S. Department of Health and Human Services.
The information in this report is intended to help clinicians, employers, policymakers, and others
make informed decisions about the provision of health care services. This report is intended as a
reference and not as a substitute for clinical judgment.
This report may be used, in whole or in part, as the basis for the development of clinical practice
guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage
policies. AHRQ or U.S. Department of Health and Human Services endorsement of such
derivative products may not be stated or implied.
This document is in the public domain and may be used and reprinted without permission except
those copyrighted materials noted for which further reproduction is prohibited without the
specific permission of copyright holders.
No investigators have any affiliations or financial involvement (e.g., employment, consultancies,
honoraria, stock options, expert testimony, grants or patents received or pending, or royalties)
that conflict with material presented in this report. Service as a Technical Expert Panel member
or peer reviewer should not be construed as agreeing with or endorsing the content of the report.
Suggested citation: Hempel S, Newberry S, Ruelaz A, Wang Z, Miles JNV, Suttorp MJ,
Johnsen B, Shanman R, Slusser W, Fu N, Smith A, Roth E, Polak J, Motala A, Perry T, Shekelle
PG. Safety of Probiotics to Reduce Risk and Prevent or Treat Disease. Evidence
Report/Technology Assessment No. 200. (Prepared by the Southern California Evidence-based
Practice Center under Contract No. 290-2007-10062-I.) AHRQ Publication No. 11-E007.
Rockville, MD: Agency for Healthcare Research and Quality. April 2011. Available at:
www.ahrq.gov/clinic/tp/probiotictp.htm.
ii
Preface
The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based
Practice Centers (EPCs), sponsors the development of evidence reports and technology
assessments to assist public- and private-sector organizations in their efforts to improve the
quality of health care in the United States. This review was jointly sponsored by the National
Institutes of Health (NIH) Office of Dietary Supplements (ODS), the NIH National Center for
Complementary and Alternative Medicine (NCCAM), and the Food and Drug Administration
(FDA) Center for Food Safety and Applied Nutrition (CFSAN). The reports and assessments
provide organizations with comprehensive, science-based information on common, costly
medical conditions and new health care technologies. The EPCs systematically review the
relevant scientific literature on topics assigned to them by AHRQ and conduct additional
analyses when appropriate prior to developing their reports and assessments.
To bring the broadest range of experts into the development of evidence reports and health
technology assessments, AHRQ encourages the EPCs to form partnerships and enter into
collaborations with other medical and research organizations. The EPCs work with these partner
organizations to ensure that the evidence reports and technology assessments they produce will
become building blocks for health care quality improvement projects throughout the Nation. The
reports undergo peer review prior to their release.
AHRQ expects that the EPC evidence reports and technology assessments will inform
individual health plans, providers, and purchasers as well as the health care system as a whole by
providing important information to help improve health care quality.
We welcome comments on this evidence report. They may be sent by mail to the Task Order
Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road,
Rockville, MD 20850, or by e-mail to epc@ahrq.gov.
Carolyn M. Clancy, M.D.
Director
Agency for Healthcare Research and Quality
Jean Slutsky, P.A., M.S.P.H.
Director, Center for Outcomes and Evidence
Agency for Healthcare Research and Quality
Paul Coates, Ph.D.
Director
Office of Dietary Supplements
National Institutes of Health
Stephanie Chang, M.D., M.P.H.
Director, EPC Program
Agency for Healthcare Research and Quality
Josephine P. Briggs, M.D.
Director
National Center for Complementary
Margaret Coopey, R.N., M.G.A., M.P.S.
EPC Program Task Order Officer
Agency for Healthcare Research and Quality
and Alternative Medicine
National Institutes of Health
Carmen Kelly, Pharm.D.
EPC Program Task Order Officer
Agency for Healthcare Research and Quality
Marguerite Klein, M.S.
Health Science Administrator
Office of Dietary Supplements
National Institutes of Health
iii
Linda Duffy, Ph.D.
Health Science Administrator/Program Officer
National Center for Complementary and Alternative Medicine
National Institutes of Health
Dan D. Levy, Ph.D.
Microbiologist and Project Officer
Office of Nutrition, Labeling, and Dietary Supplements
Center for Food Safety and Applied Nutrition
Food and Drug Administration
iv
Acknowledgments
We wish to thank Marguerite Klein, M.S. (National Institutes of Health [NIH] Office of
Dietary Supplements [ODS]); Linda Duffy, Ph.D. (NIH National Center for Complementary and
Alternative Medicine); Dan D. Levy, Ph.D. (Food and Drug Administration Center for Food
Safety and Applied Nutrition); and Anne Thurn, Ph.D. (ODS) for their guidance and support. We
wish to thank the members of the Technical Expert Panel: Michael Cabana, M.D., M.P.H.; Cara
Fiore, Ph.D.; Barry Goldin, Ph.D.; Patricia L. Hibberd, M.D., Ph.D.; David Mills, Ph.D.; Mary
Ellen Sanders, Ph.D.; Maija-Liisa Saxelin, Ph.D.; Alain L Servin, Ph.D.; and Jon A. Vanderhoof,
M.D., for their helpful suggestions and recommendations. We also would like to thank Louis
M.A. Akkermans, Ph.D.; Marc Besselink, M.D.; Daniel Buijs, M.Sc., and Ger Rijkers, Ph.D.,
who provided peer reviews of the draft report.
v
Safety of Probiotics to Reduce Risk and Prevent or
Treat Disease
Structured Abstract
Objectives. To catalog what is known about the safety of interventions containing Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus strains used as
probiotic agents in research to reduce the risk of, prevent, or treat disease.
Data Sources. We searched 12 electronic databases, references of included studies, and pertinent
reviews for studies addressing the safety of probiotics from database inception to August 2010
without language restriction.
Review Methods. We identified intervention studies on probiotics that reported the presence or
absence of adverse health outcomes in human participants, without restriction by study design,
participant type, or clinical field. We investigated the quantity, quality, and nature of adverse
events.
Results. The search identified 11,977 publications, of which 622 studies were included in the
review. In 235 studies, only nonspecific safety statements were made (“well tolerated”); the
remaining 387 studies reported the presence or absence of specific adverse events. Interventions
and adverse events were poorly documented.
A number of case studies described fungemia and some bacteremia potentially associated
with administered probiotic organisms. Controlled trials did not monitor routinely for such
infections and primarily reported on gastrointestinal adverse events. Based on reported adverse
events, randomized controlled trials (RCTs) showed no statistically significantly increased
relative risk (RR) of the overall number of experienced adverse events (RR 1.00; 95%
confidence interval [CI]: 0.93, 1.07, p=0.999); gastrointestinal; infections; or other adverse
events, including serious adverse events (RR 1.06; 95% CI: 0.97, 1.16; p=0.201), associated with
short-term probiotic use compared to control group participants; long-term effects are largely
unknown. Existing studies primarily examined Lactobacillus alone or in combination with other
genera, often Bifidobacterium.
Few studies directly compared the safety among different intervention or participant
characteristics. Indirect comparisons indicated that effects of delivery vehicles (e.g., yogurt,
dairy) should be investigated further. Case studies suggested that participants with compromised
health are most likely to experience adverse events associated with probiotics. However, RCTs
in medium-risk and critically ill participants did not report a statistically significantly increased
risk of adverse events compared to control group participants.
Conclusions. There is a lack of assessment and systematic reporting of adverse events in
probiotic intervention studies, and interventions are poorly documented. The available evidence
in RCTs does not indicate an increased risk; however, rare adverse events are difficult to assess,
and despite the substantial number of publications, the current literature is not well equipped to
answer questions on the safety of probiotic interventions with confidence.
vi
Contents
Executive Summary...................................................................................................................ES-1
Introduction ......................................................................................................................................1
Background ..........................................................................................................................1
Project Purpose ....................................................................................................................3
Scope....................................................................................................................................4
Analytic Framework ............................................................................................................6
Methods............................................................................................................................................8
Electronic Search for Literature Review..............................................................................8
Inclusion Screening..............................................................................................................9
Data Abstraction and Quality Assessment.........................................................................11
Analysis..............................................................................................................................13
Rating the Strength of the Evidence ..................................................................................15
Results............................................................................................................................................16
Potentially Relevant Studies Not Addressing Safety.........................................................18
Included Studies With Nonspecific Safety Statements......................................................18
Included Studies Addressing Specific Harms....................................................................20
Discussion ....................................................................................................................................102
Results Summary .............................................................................................................102
Scope and Limitations......................................................................................................103
Key Questions..................................................................................................................107
Future Research ...........................................................................................................................115
Conclusions..................................................................................................................................117
References....................................................................................................................................118
Included Studies...........................................................................................................................138
Acronyms and Abbreviations ......................................................................................................182
Figures
Figure 1. Included Studies ...............................................................................................................7
Figure 2. PubMed Search Strategy ..................................................................................................9
Figure 3. Literature Volume ..........................................................................................................16
Figure 4. Literature Flow ...............................................................................................................17
Figure 5. Included Strains by Genus in Studies With Nonspecific Safety Statements..................19
Figure 6. Number of Participants in Included Studies...................................................................21
Figure 7. Included Strains by Genus..............................................................................................23
Figure 8. Intervention Duration in Months ....................................................................................24
Figure 9. Quality of the Reporting and Risk of Bias in Included Studies .....................................26
Figure 10. Adverse Events per CTCAE Category for Participants Using Probiotics and Control
Participants (up to 3 Probiotics Intervention Groups, 1 Control Group).......................................47
Figure 11. Graphical Representation of the RR of the Number of Gastrointestinal Adverse Events
Across RCTs ..................................................................................................................................49
Figure 12. Graphical Representation of the RR of the Number of Infection and Infestation
Adverse Events Across RCTs........................................................................................................51
Figure 13. Graphical Representation of the RR of the Number of Other Adverse Events
Across RCTs ..................................................................................................................................53
Figure 14. RR Number of Participants With Adverse Events Lactobacillus RCTs ......................60
vii
Figure 15. RR Number of Participants With Adverse Events Bifidobacterium RCTs..................61
Figure 16. RR Number of Participants With Adverse Events Saccharomyces RCTs ...................62
Figure 17. RR Number of Participants With Adverse Events Streptococcus RCTs .....................63
Figure 18. RR Number of Participants With Adverse Events Enterococcus RCTs ......................64
Figure 19. RR Number of Participants With Adverse Events Bacillus RCTs...............................65
Figure 20. Comparison of Adverse Events Across Genera (RR Log Scale) .................................66
Figure 21. RR Number of Participants With Adverse Events in Long-Term use RCTs ...............76
Figure 22. RR Number of Children With Adverse Events ............................................................82
Figure 23. RR Number of Adults With Adverse Events ...............................................................83
Figure 24. RR Number of Elderly Participants With Adverse Events ..........................................85
Figure 25. RR Number of Critically Ill or High-Risk Participants With Adverse Events.............88
Figure 26. Number of Participants With Serious Adverse Events.................................................94
Appendixes
Appendix A. Exact Search Strings and List of Manufacturers
Appendix B. Sample Data Abstraction Forms
Appendix C. Evidence Tables
Appendix D. Excluded Studies
Appendix E. Technical Expert Panel and Peer Reviewers
viii
Executive Summary
Introduction
The Agency for Healthcare Research and Quality (AHRQ) commissioned the Southern
California Evidence-based Practice Center based at RAND to carry out a systematic review on
the safety of probiotics used in research to reduce the risk of, prevent, or treat disease. The
evidence report was jointly sponsored by the National Institutes of Health (NIH) Office of
Dietary Supplements, the NIH National Center for Complementary and Alternative Medicine,
and the Food and Drug Administration Center for Food Safety and Applied Nutrition.
Probiotics (literally, “for life”) are bacteria or yeasts considered to confer a health benefit on
the host organism. The review objective was to catalog what is known about the safety of
interventions containing organisms from six different genera used as probiotic agents
(Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus),
alone or in combination, used to reduce the risk of, prevent, or treat disease in research studies.
This evidence report has a broad scope and was not restricted to specific interventions,
specific patient groups, or specific clinical outcomes. The large number of included studies
allowed unique analyses to explore adverse events reported to date in research on probiotics.
Methods
We searched 12 electronic databases (DARE, Cochrane Database of Systematic Reviews,
CENTRAL, PubMed, Embase, CINAHL, AMED, MANTIS, TOXLINE, ToxFile, NTIS, and
AGRICOLA) and scanned the references of included studies and pertinent reviews for studies
addressing the safety of interventions using products containing microorganisms purported to
have probiotic properties (henceforth called “probiotics”) from database inception to August
2010 without language restriction.
We systematically identified studies monitoring the presence or absence of participants’
adverse health outcomes, without restriction due to study design, participant, or clinical field.
Any studies that assessed the effect of microorganisms used as probiotic agents and reported on
an adverse health outcome (its presence or absence) were included. Two reviewers
independently screened studies for inclusion, extracted data, and assessed their quality. We
differentiated studies that addressed a specific adverse event from those with nonspecific safety
statements.
We investigated the quantity of adverse events (number of participants with adverse events
per treatment group, number of adverse event incidences per treatment group), the quality of the
adverse events (all adverse events, serious adverse events), and the nature of adverse events (e.g.,
gastrointestinal events, infections). The review aims to answer a large number of questions
pertaining to product and participant factors. Studies reporting direct comparisons (e.g., between
two different probiotic organisms) were primarily sought; in addition, indirect evidence was
analyzed in stratified analyses and meta-regressions.
Results
The review demonstrates that there is a large volume of literature on probiotics. However, the
literature provided only limited evidence to address the questions the review set out to answer.
ES-1
The literature search identified 11,981 publications, of which 2,189 were ordered as full-text
publications after title and abstract screening and 622 studies were included in the review. Of
these, 235 studies made only nonspecific safety statements (e.g., “the intervention was well
tolerated”) without indicating what kind of adverse events were monitored. The remaining 387
studies reported the presence or absence of one or more specific adverse events; these studies
were abstracted in detail and used to answer the Key Questions. Across all included studies and
treatment arms, 24,615 participants used a probiotic product.
The review considered reports without study design restrictions and included a large number
of randomized controlled trials (RCTs); however, the majority were not designed to address
safety. The quality of included studies varied greatly within study design categories. Adverse
events were poorly documented, and the parameters that were monitored were often not stated.
Interventions were poorly documented, lacking detail, for example, on the specific probiotic
strain administered. Very few of the identified studies investigated Saccharomyces or
Streptococcus, and even fewer Enterococcus or Bacillus; the majority of identified studies used
Lactobacillus, alone or in combination with other genera, most often Bifidobacterium.
To estimate the proportion of existing studies of probiotic organisms found in the literature
that are included in this safety review, we noted all RCTs of probiotics that were found in our
searches that reported on patient outcomes. Of this pool of potentially relevant RCTs, 58 percent
met inclusion criteria for the review (i.e., made a nonspecific safety statement or reported the
presence or absence of a specific adverse event). The remaining RCTs did not address the safety
of probiotics as defined in this evidence review.
Key Questions
Key Question 1. What is the evidence that the active and lyophilized forms
of probiotics (Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus) as single ingredients or in
combination with other probiotics or prebiotics in all delivery vehicles (and
formulations) when used to cure, treat, mitigate, or prevent a disease or
reduce disease risk are safe in the short term? In the long term?
Case studies indicated that fungemia, bacteremia, sepsis, and other infections may be
associated with administered probiotic organisms; the ability to reliably determine whether
administered strains match the clinical isolate is now possible through DNA-based methods.
None of the identified case series, controlled clinical trials, or parallel and crossover RCTs
reported an infection caused by the administered probiotic organisms. However, studies seldom
reported that they monitored for infections of the types identified in case reports. In fact, most
did not state what adverse events were monitored and did not systematically address the safety of
the probiotic products.
Across parallel RCTs there was no indication that the quantity of reported adverse events was
increased in short-term probiotic intervention arms compared to control groups, based on the
relative risk (RR) of the number of participants with adverse events (RR 0.98; 95% confidence
interval [CI]: 0.93, 1.04, p=0.537; 121 RCTs) as well as the number of adverse-event incidences
reported in each treatment group (RR 1.00; 95% CI: 0.93, 1.07, p=0.999; 208 RCTs). The
current available evidence does not suggest a widespread risk of adverse events associated with
ES-2
probiotics, but future studies that explicitly monitor for the issues of concern are needed to
quantify the actual risk of specific adverse events in intervention studies.
Key Question 2. What are characteristics and associations of the reported
harms in Question 1?
Across all included studies, the most commonly reported adverse events were gastrointestinal
in nature. This was followed by reported infections and infestations. The third most common
category was the “other” category for symptoms that could not be assigned to a specific organ
system or type of adverse event.
Across identified RCTs, there was no indication that participants using probiotic organisms
experienced statistically significantly more gastrointestinal (RR 1.03; 95% CI: 0.89, 1.18,
p=0.693; 126 RCTs), infections (RR 1.00; 95% CI: 0.87, 1.16, p=0.967; 65 RCTs), or other
adverse events (RR 1.01; 95% CI: 0.91 1.12, p=0.923, 131 RCTs) compared to control group
participants.
Studies rarely reported efforts to monitor adverse events specific to probiotic products.
Hence, safety evaluations may change with future, more targeted assessment of adverse events in
intervention studies.
Key Question 3. What is the evidence that harms of Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus differ by product and delivery characteristics?
The lack of detail in the description of administered probiotic organisms in most studies
hindered evaluations of the safety. Many studies did not specify which probiotic strains were
investigated, nor was there indication that intervention preparations were tested for identity of
the included organisms, quantity, viability, or contaminants.
Stratified analyses by probiotic genus showed no increased risk of adverse events among the
probiotic group compared to a control group in RCTs using interventions reported to contain
exclusively Lactobacillus (RR 0.98; 95% CI: 0.87, 1.11; p=0.785), Bifidobacterium (RR 0.92;
95% CI: 0.82, 1.03; p=0.141), Saccharomyces (RR 1.00; 95% CI: 0.46, 2.18; p=0.993),
Streptococcus (0.99; 95% CI: 0.78, 1.25; p=0.907), Enterococcus (RR 0.85; 95% CI: 0.47, 1.54;
p=0.588), or Bacillus (0.99; 95% CI: 0.44, 2.22; p=0.973) strains. A meta-regression comparing
the relative risk ratio associated with the genera indicated a statistically significantly higher risk
for Streptococcus strains compared with the other genera; however, this indirect comparison is
based on a small number of studies that investigated Streptococcus, Enterococcus, or Bacillus
interventions. Direct (head-to-head) comparisons of genera, species, strains, or delivery vehicles
are largely absent in the literature.
There was some indication across studies that safety findings may differ by delivery vehicle.
Intervention participants in studies in which yogurt or other dairy products were administered
were more likely to experience adverse events compared with control group participants (RR
1.37; 95% CI: 1.05, 1.79; p=0.022) based on the number of adverse event incidences reported
across groups in a subgroup analysis. However, studies directly comparing delivery vehicles are
missing.
We did not find conclusive evidence in the existing literature that interventions with a
mixture of different organisms reported more adverse events than studies using one probiotic
strain only or evidence that synbiotics (mixtures of prebiotics and probiotics) differ from
probiotics; however, there is a lack of direct comparisons.
ES-3
Key Question 4. How do the harms of Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus vary based on
(a) dose; (b) timing; (c) mode of administration; (d) age, gender, ethnicity,
disease or immunologic status; (e) relationship to efficacy?
Very few studies overall explored the effect of intervention or participant characteristics on
safety. To summarize, in the few studies that reported on the time of onset of gastrointestinal
effects, most effects were observed in the first 3 days of treatment. The onset of infections tended
to occur 1 week to several weeks after initiation of probiotics use; however, this information is
primarily derived from case studies and was not systematically reported.
In indirect comparisons across studies, we found no evidence that a particular mechanism or
route of administration of probiotic organisms was associated with an increased risk of an
adverse event in intervention participants relative to control group participants. Stratified
analyses and meta-regressions showed no increased risk of adverse events for children (RR 0.96;
95% CI: 0.88, 1.04; p=0.296, 35 RCTs), adults (RR 0.97; 95% CI: 0.79, 1.19; p=0.745, 40
RCTs), or elderly (RR 0.94; 95% CI: 0.82, 1.08; p=0.367, 4 RCTs) participants compared with
adverse events observed in corresponding control groups; however, it has to be noted that only
very few studies were identified that reported on elderly participants.
There was some indication that health status is associated with the experience of an adverse
event when using probiotics. Case studies reporting serious adverse events described healthcompromised, not generally healthy participants who contracted (most often) a serious infection
potentially caused by probiotic organisms. However, subgroup analyses of RCTs in medium
health-compromised participants (RR 1.03; 95% CI: 0.94, 1.13; p=0.491) and critically ill
patients (RR 0.79; 95% CI: 0.51, 1.22; p=0.286) did not show a statistically significantly
increased risk of experiencing adverse events for intervention participants compared with control
group participants with similar patient characteristics.
Key Question 5. How often does harm associated with Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus lead to hospital admission or lengthened hospitalization?
While several case studies reported hospitalizations associated with the consumption of a
product including Saccharomyces, Lactobacillus, or Bacillus strains, none of the case series or
controlled trials reported that a probiotics intervention led to a hospitalization in the intervention
participants. However, the number of hospitalizations due to adverse events was only explicitly
reported on in a few of the included studies, and older publications may not have associated a
hospitalization with probiotics intake.
RCTs reporting on the presence or absence of serious adverse events showed that differences
across probiotic and control group participants were not statistically significant (RR 1.06; 95%
CI: 0.97, 1.16; p=0.201, 66 RCTs). However, this result is primarily based on Lactobacillus
interventions, and a few studies investigating Saccharomyces and Bifidobacterium; there was a
lack of studies reporting on the presence or absence of serious adverse events for other genera.
ES-4
Key Question 6. How does harm associated with Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus relate to use of concomitant antibiotics, confounding diet therapies,
corticosteroid use, immune suppressants, or other potential confounders?
We did not identify studies that addressed possible interactions or confounders of probiotics
interventions. Although the risk of adverse events in general might be higher in individuals
taking multiple medications, subgroup analyses of studies in which the intervention participants
as well as the control group participants received antibiotics (RR 1.07; 95% CI: 0.94, 1.23;
p=0.271) or corticosteroids (RR 1.04; 95% CI: 0.88, 1.22; p=0.650) found no statistically
significant increased risk of adverse effects among intervention participants. There were too few
studies to explore interactions with concomitant diet therapies, and studies in participants using
immune suppressants were also largely absent from the existing literature.
Future Research
Future studies need to characterize the intervention preparations in more detail. As
identification methods progress, the reporting should include verification with DNA-based
methods to identify the individual strains included in preparation, their potency and viability, and
any potential confounders. The majority of existing studies report on Lactobacillus, alone or in
combination with other genera, most commonly Bifidobacterium strains, and more studies are
needed to explore potential adverse events associated with interventions that include the genera
Enterococcus and Bacillus, in addition to studies on Streptococcus species selected for their
probiotic properties, as well as studies on the use of Saccharomyces in some patient groups.
Studies should describe which adverse events were monitored to allow a clearer
understanding of the presence and absence of adverse events in probiotics intervention studies.
The reporting of adverse events should follow reporting guidelines such as the extension of the
CONSORT statement for harms. In addition, there are comprehensive systems for cataloging
adverse events, such as the Common Terminology Criteria for Adverse Events system.
Monitored harms should include infections with probiotics organisms as well as treatment
failures in order to be able to quantify the risk for participants in intervention studies. Critical
outcomes, such as all-cause mortality, should be assessed and reported in primary studies, and
reviews should consider all studies measuring the outcome regardless of whether the study was
conducted to evaluate the efficacy of the intervention or the occurrence of adverse events.
Long-term effects of probiotic interventions are largely unknown, and there is a need to
evaluate long-term interventions. In addition, large cohort studies following self-selected use of
probiotic organisms are needed to fully understand the efficacy and safety of probiotics among
representative populations.
Currently, few studies address complex questions about probiotic safety, such as interactions
of participant or intervention characteristics with the use of probiotic products. The effect of
product, intervention, or participant characteristics should be addressed with appropriate
multivariate analyses. There is also indication that participants with compromised health should
be monitored closely for potential adverse events associated with the use of probiotic products.
Studies evaluating effects on elderly participants are largely absent from the literature, and the
effects of delivery vehicles should be investigated systematically.
ES-5
Conclusions
There is a lack of assessment and systematic reporting of adverse events in probiotic
intervention studies, and interventions are poorly documented. RCTs and case studies diverge in
the outcomes they report. The available evidence in RCTs does not indicate an increased risk;
however, rare adverse events are difficult to assess, and despite the substantial number of
publications, the current literature is not well equipped to answer specific questions on the safety
of probiotic interventions with confidence.
ES-6
Introduction
The Agency for Healthcare Research and Quality (AHRQ) has commissioned the Southern
California Evidence-based Practice Center based at RAND to carry out a systematic review on
the safety of products containing microorganisms believed to have probiotic properties
(henceforth called probiotics or products containing probiotics). This review was jointly
sponsored by the National Institutes of Health (NIH) Office of Dietary Supplements, the NIH
National Center for Complementary and Alternative Medicine, and the Food and Drug
Administration Center for Food Safety and Applied Nutrition.
Background
Probiotics (literally, “for life”) are microorganisms purported to have a health benefit on the
host organism. The definition of what is a probiotic has evolved as the sciences of microbiology,
medicine, and the manufacturing industries have matured. According to one definition offered by
an expert committee convened by the Food and Agriculture Organization of the United Nations
and the World Health Organization, probiotic organisms are live microorganisms that when
administered in adequate amounts confer a health benefit on the host (FAO/WHO, 2001). This
definition explicitly restricts what can be considered a probiotic to live organisms. Other
definitions do not emphasize the viability of the microorganisms and would include heat-killed
preparations (e.g., Salminen, Ouwehand, Benno, & Lee, 1999). Defining probiotics is
challenging because of the limits in our understanding of how organisms benefit the human host,
the apparent variation in what may constitute a beneficial balance for digestion and other
physiological processes, the effects of probiotic organisms on the normal gut environment, and
our limited understanding of the gut ecosystem (Schmid, 2006).
The genera of bacteria and fungi that have been employed for their probiotic properties are
most commonly species of Lactobacillus and Bifidobacterium; other bacterial genera, such as
Streptococcus, Enterococcus, and Bacillus, and species of the yeast genus Saccharomyces have
also been studied. Probiotic properties of genera, species, and strains may vary according to the
indication. Related to probiotic organisms, prebiotics are food products defined as nondigestible
food ingredients that benefit the host by selectively stimulating the growth and/or activity of one
or a limited number of bacteria in the colon and thus improve host health. Synbiotics are
preparations in which probiotic organisms and prebiotics are combined, presumably to form a
synergistic relationship.
The intentional use of microorganisms in the preparation of foods as well as the belief in
their health-promoting properties has a long history. Species of the lactic acid bacterium genus
Lactobacillus have been used for thousands of years to preserve dairy products by converting
milk to yogurt; likewise, the yeast, Saccharomyces cerevisiae, has long been used for leavening
bread and for fermenting grains and fruits to make spirits. Various other fungi (molds) have long
been known for their use in cheesemaking. Bacillus subtilis, a soil bacterium, has long been used
to ferment soy beans to make the Japanese staple food natto. Mixtures of microorganisms have
been used to treat infections topically and systemically since ancient times. The use of probiotics
to prevent and treat gastrointestinal disorders in particular has been proposed, for example, by
Metchnikoff in the 1890s, using Lactobacillus strains to restore normal gastrointestinal microbial
balance. The use of Lactobacillus strains to treat urogenital infections is often attributed to
Newman, who published a paper in 1915 on this topic (McGroarty, 1993). More recently, the use
1
of the commensal bacterium, Bifidobacterium, has been advocated to promote immune and
gastrointestinal function in infants. Probiotic strains of Streptococcus have been used in an
attempt to prevent and treat dental disease and gastrointestinal disorders. Probiotic strains of
Enterococcus have also been used to treat gastrointestinal infections. Bacillus subtilis has
fungicidal properties and, for example, was used as a treatment for gastrointestinal complaints
prior to the introduction of sulfur-based antibiotics. Regarding these last two examples, particular
concerns have been raised about the safety of the genera Enterococcus and Bacillus, both of
which include pathogenic species.
Depending on the form and the country in which they are administered or used, probiotic
products are classified as any one of several different entities: dietary supplements, foods, food
components, or pharmaceuticals. Each of these categories is subject to entirely different
regulations and burdens of proof regarding the demonstration of a health benefit as well as
safety, and these regulations and guidelines differ by country (Sanders, 2010; Venugopalan,
2010). Further complicating the current picture is that very little is known about the quantities
required for the various genera, species, and strains to show probiotic properties.
The scientific and popular literature includes numerous reviews on the efficacy or
effectiveness of probiotic organisms for treating or preventing a variety of conditions. However,
despite their popularity, questions remain about the efficacy and effectiveness of probiotics;
published reports for specific conditions often provide conflicting results, and the efficacy and
effectiveness of probiotics is quite likely to be strain and indication specific. In 2010, the
European Food Safety Authority denied the merit of multiple health claims filed on behalf of
probiotic products, citing lack of scientific basis (EFSA, 2010).
Regardless of the evidence base for the efficacy and effectiveness of products containing
probiotics, the widespread availability and popularity of products promoted as containing
probiotic organisms indicate that their safety warrants further investigation. Probiotic organisms
added to foods (i.e., yogurt and some infant formulas) have been described by some authors as
“generally recognized as safe” (GRAS). Food ingredients considered GRAS are those affirmed
or apparently affirmed by their manufacturers as meeting the requirements for the GRAS
exemption from the requirement for regulation as a food additive. This term, defined in sections
201(s) and 409 of the Federal Food, Drug, and Cosmetic Act, applies to any substance that is
intentionally added to food and has been exempted from premarket approval because it is
“generally recognized, among qualified experts, as having been adequately shown to be safe
under the conditions of its intended use.” Authors often cite the fact that lactic acid bacteria have
been used for preservation of food by fermentation for thousands of years as evidence of their
safety (World Gastroenterology Organisation, 2008). However, the GRAS designation can be
applied only to specified uses of a specific ingredient. Other uses, particularly if they are based
on higher exposure or exposure to an ingredient with very different properties, may not be
included in the original GRAS designation.
Advances in microbiology and molecular biology, along with the adoption of organisms not
previously used as probiotics, have contributed to a growing concern about the potential safety of
these microorganisms. Specific concerns include the isolation of administered probiotic
organisms from infection sites, and the possibility of gene transfer between probiotic organisms
and bacteria or fungi dwelling in the digestive tract and antibiotic resistance shown in in vitro
studies. A number of cases of infection have been documented that resemble closely the strains
given as probiotic agents to the infected individuals or persons in their vicinity. Such concerns
suggest that the pathogenicity, infectivity, toxicity, and intrinsic properties of the organisms may
2
require closer study (Ishibashi, 2001). Liong (2008) concluded from a review of the literature
that translocation and infection reports associated with use of probiotics deserve further
investigation and should become a part of safety assessments so that the negative effects of
probiotics do not outweigh the benefits. Recent trials and reviews that failed to show the efficacy
of probiotics and in some cases report an increased risk of undesirable effects associated with
probiotic interventions (Besselink, 2008; Whelan, 2010) also point to a closer look into the safety
of probiotics, in particular for patients with compromised health.
In order to make informed decisions about the use of probiotic organisms, it would thus
appear helpful at this point to assess the evidence for their safety across clinical areas. To date,
no comprehensive systematic review has synthesized the available evidence of adverse
symptomatic health outcomes in human participants.
Project Purpose
The review set out to answer a number of research questions posed by the sponsors of the
evidence review.
Key Questions
1. What is the evidence that the active (e.g., live or viable) and lyophilized forms of probiotics
(Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus)
as single ingredients or in combination with other probiotics or prebiotics in all delivery
vehicles (and formulations) when used to cure, treat, mitigate, or prevent a disease or reduce
disease risk are safe in the short term? Long term?
a. What safety parameters are collected in clinical studies (Phases I-IV)?
b. What harms are reported in clinical studies (Phases I-IV)?
c. What harms are reported in case reports?
d. What safety parameters are collected in population surveillance studies and other
observational studies, and do these include only standard clinical safety parameters (e.g.,
standard blood chemistry profiles) or also expanded laboratory or clinical testing unique
to the use of probiotics?
e. What harms are reported in population surveillance studies and other observational
studies?
f. What harms are reported in human mechanistic studies?
g. Do the studies describe an antibiotic therapy designed to treat unintended pathology
caused by the administered organism?
h. Do the studies describe methods for recovery of the administered organism from either
the gastrointestinal tract or serum?
2. What are characteristics and associations of the reported harms in Question 1?
a. What interactions between probiotics and medications are reported?
b. What harms related to acquired antibiotic resistance and/or transferability are reported?
c. What is the nature of harms (e.g., toxicogenic, immunologic, hematologic, deleterious
physiologic or metabolic activity, allergic, blood infections, hematocytometric values,
liver and renal function enterotoxin, production, proteases, or opportunistic infection,
etc.), and do these include only standard harms or also harms that might be uniquely
applicable to the use of a probiotic?
3
3. What is the evidence that harms of Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus differ by product and delivery characteristics?
a. What is the scientific evidence that harms differ by delivery vehicle including excipients
or novel delivery vehicles?
b. What is the scientific evidence that harms differ by genus, species, and strain (including
intraspecies strain variations)?
c. What is the scientific evidence that harms differ between active and lyophilized forms of
probiotics?
d. Does harm differ by products containing a single probiotic versus a mixture of
probiotics?
e. Does harm differ by products containing only probiotics and those containing a mixture
of probiotics and prebiotics?
4. How do the harms of Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus,
Enterococcus, and Bacillus vary based on (a) dose (cfu); (b) timing; (c) mode of
administration (e.g., catheter); (d) age (all ages, including infants), gender, ethnicity, disease
or immunologic status of the patient; (e) relationship to efficacy?
a. Is there a threshold or dose-response relationship between probiotics and harm? Does the
duration of intervention relate to harm?
b. Is there a relationship between time of onset of harm and time of probiotic administration
(e.g., prior to onset of disease under study, after disease onset)? How does time of
exposure affect harm? Is harm sustained after the intervention or exposure stops?
c. Does the route of administration (e.g., orally, jejunostomy tube, central venous catheter)
relate to harm?
d. How does harm relate to subpopulations, including different age groups (specifically
including neonates and infants under age 24 months), men and women, ethnic/race
subgroups, or health status (healthy to high risk) individuals?
e. Do randomized controlled studies that report harm show efficacy or no efficacy?
5. How often does harm associated with Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus lead to hospital admission or lengthened
hospitalization?
6. How does harm associated with Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus relate to use of concomitant antibiotics,
confounding diet therapies, corticosteroid use, immune suppressants, or other potential
confounders?
Scope
This review on the safety of probiotics is explicitly exploratory in nature. Therefore, a
number of clarifications are warranted regarding what the review set out to achieve and what
questions may have to be addressed in future research.
First, because little evidence currently suggests the kinds of potential harms that should be
investigated in a review on the safety of probiotics, the safety outcomes considered for this
review were explicitly not specified a priori; instead, all reported adverse events were included in
the review. Theoretically, a selection of particular kinds of harms could be guided by the nature
of the intervention—for example, the exposure to bacteria and yeasts suggests monitoring
infections—and as a general research approach, serious adverse events should have priority. But
given the lack of any prior synthesis on the specific risks of probiotic organisms for human
4
participants, a broad, unrestricted overview of what has been assessed in the literature and what
has been reported appeared most informative. Thus, the review aimed to identify the adverse
events reported in the literature, without restriction to specific outcomes of interest, as further
outlined in the inclusion criteria, with one limitation: The focus was on health outcomes, that is,
symptomatic outcomes and/or clinically relevant outcomes, rather than on intermediate outcomes
or in vitro results. In this review we explore the quantity, the quality, and the nature of the
adverse events as outlined in the methods section.
This report is not an efficacy or effectiveness review investigating the usefulness of probiotic
organisms for preventing adverse events caused by other treatments such as antibiotic treatment.
That is, studies in which efficacy outcomes were identical with adverse events (e.g., prevention
of antibiotic-induced diarrhea) were not considered for this review, as further outlined in the
inclusion criteria. This restriction required careful review of individual studies, but has also been
imposed in other safety reviews (e.g., Pitrou, Boutron, Ahmad & Ravand, 2009), and an
overview of the efficacy and effectiveness of probiotic organisms for the prevention of adverse
events from other treatments was outside the resources and scope of this project. We considered
failed effectiveness outcomes only in those cases where this was explicitly highlighted by the
study authors as one of the main results of the study.
Throughout this report we use the term “harm” and “adverse event” interchangeably. We
explicitly avoid the term “adverse effects,” as it implies a causal relationship between harm and
intervention. In most included studies, there are multiple alternative explanations for the
encountered adverse events; hence we only list the encountered events per treatment group.
This review focuses on published literature. A substantial number of peer-reviewed articles
reporting on studies of probiotics have been published in scientific journals. Although the pursuit
of unpublished data (for example through approaching manufacturers of probiotic products)
might be desirable, the approach taken for this exploratory review was to summarize the existing
literature in the public domain to develop a clear picture of the readily available body of
evidence. The data sources are outlined in the search strategy, and the implications of the search
strategy are further addressed in the discussion section.
Furthermore, the review aimed to capture the safety of organisms—Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus—when used as
probiotic agents, rather than the safety of any exposure to any member of these genera of
microbiological organisms. The search strategy primarily aimed to identify studies of probiotics,
rather than aiming to identify every study that investigated the effects of the above bacterial or
fungal organisms, such as exposure to Streptococcus bacteria strains. Studies were included in
the review if they were described as probiotic studies, without further restriction to particular
dose; demonstrated health benefits; genera, species, or strains of known quality; rather, all
studies investigating the effect of purposeful intake of probiotic organisms of the genera of
interest were considered.
However, a reported intervention was part of the inclusion criteria for this review as outlined
in detail in the inclusion criteria section. Publications reporting incidences of infections, such as
documented cases of Lactobacillus infections, were included in the review only if an intervention
prior to the infection was reported, e.g., the probiotic organisms were purposefully consumed or
administered. Studies were not restricted to investigator-controlled studies; observational studies
of participants using probiotic organisms were also eligible for inclusion. We also did not restrict
the review to products that would be classified as dietary supplements, foods, food ingredients,
or pharmaceuticals.
5
Finally, the review summarizes the existing evidence from studies in human participants
only; animal studies and in vitro studies were outside the scope of the review. As outlined, the
focus was on adverse events encountered in research studies that used probiotics to reduce the
risk, prevent, or treat disease in human participants.
In summary, the review aimed to document what is currently known about the safety of
probiotics in the existing published research literature on interventions, assuming an inclusive
definition of safety and inclusive definition of probiotics. The purpose of the project was to
catalog what is known about the safety of probiotics, in particular Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus organisms, used in
research to reduce the risk of, prevent, or treat disease. The literature review also assessed the
quality and completeness of the available information and our confidence in interpreting this
information. The overview aimed to provide information relevant to practitioners, researchers,
and regulators for assessing the safety of probiotic administration as well as to identify priorities
or needs for future research.
Analytic Framework
Figure 1 shows the universe of studies from which the studies included in this review stem
were drawn. Only studies in human participants; studies that used the genera Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus as probiotic
agents to cure, treat, mitigate, or prevent a disease or reduce the risk of a disease; and studies that
addressed health outcomes were sought. Within these studies, we included those studies that
addressed the safety of probiotics. All studies that contained vague safety statements as well as
those that addressed specific harms, adverse events, adverse effects, side effects, or unintended
effects were considered.
6
Figure 1. Included studies
Genera Lactobacillus,
Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus,
and/or Bacillus as probiotic agents
Given to cure, treat,
mitigate, or prevent a
disease or reduce
disease risk
Addressing health
outcomes
Addressing safety
Human participants
All Key Questions were answered with studies within the above outlined universe of studies
7
Methods
Electronic Search for Literature Review
A pilot literature search undertaken at the outset of the project revealed that whereas safety
aspects are not a research priority in the existing probiotics literature, many studies undertake a
limited safety analysis as part of assessing efficacy. However, the inclusion of safety results in a
publication was rarely indicated in the title or abstract of the publication or referred to in the
keywords assigned by the individual electronic database (a finding that is not unique to the
research field of probiotics). Although search filters exist for effectiveness studies in some
clinical areas, filters to address adverse events tend not to be successful in reliably identifying
relevant studies. And because the volume of literature on the efficacy of probiotics, both original
research and reviews, was vast, it was necessary to conduct a careful review of the full text of a
large number of publications to identify the relevant body of research results on the safety of
probiotics.
The chosen search strategy was very inclusive in order not to miss potentially relevant
publications. The truncated term “probiotic” and the term “synbiotic” were used to adequately
reflect the scope of this project (see Appendix A). The term “prebiotic” also appeared initially
useful and was added to the search strategy. The electronic search was not restricted to the
genera specified in the key questions in order not to miss articles that did not mention the genus
in the title, abstract, or keywords of the publication. The genera alone (without reference to their
use as probiotics) were not useful search terms, as their inclusion added a very large number of
irrelevant publications (e.g., all studies on Bacillus infections). Given the large number of
probiotic and synbiotic products marketed as dietary supplements, foods, food ingredients, or
drugs, the search also did not rely on product names. Many studies used mixtures that were not
commercially obtained or available. Thus, an incomplete list of commercial product names might
have introduced bias into the selection of studies for review. The identified manufacturers of
probiotic products are listed in Appendix A.
The searches were performed without restriction by publication year or language, taking into
consideration that a substantial proportion of research is published in Asian language
publications. While uncertainty exists regarding whether the strains investigated in these studies
are similar to those common in the U.S. market, these studies need to be assessed. The review
also was not restricted with regard to study design; hence, no methodological search filter was
applied. The review was restricted to studies in human participants. Rather than searching for
studies that were indexed as studies in human participants, the electronic search was designed to
exclude only publications that were indexed by the individual databases as studies in animals
(where possible). The intent was to avoid missing studies that were not yet indexed accordingly
or were misclassified.
Databases
The following databases were searched as sources for safety data on probiotics:
• DARE (Database of Abstracts of Reviews of Effects)
• Cochrane library of systematic reviews
• CENTRAL (Cochrane Central Register of Controlled Trials)
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•
•
•
•
•
•
•
•
•
PubMed (National Library of Medicine, includes MEDLINE) (Figure 2 depicts the
PubMed search strategy)
Embase (Biomedical and pharmacological bibliographic database)
CINAHL (Cumulative Index to Nursing and Allied Health Literature)
AMED (Allied and Complementary Medicine)
MANTIS (Manual, Alternative and Natural Therapy Index System)
TOXLINE (biochemical, pharmacological, physiological, and toxicological effects of
drugs and other chemicals)
ToxFile (biochemical, pharmacological, physiological, and toxicological effects of drugs
and other chemicals)
NTIS (National Technical Information Service)
AGRICOLA (agricultural journals)
Figure 2. PubMed search strategy
PubMed – 1966-2010
probiotic* OR prebiotic* OR synbiotic*
NOT
animals NOT humans
Other Sources
The electronic search was complemented by screening the references of included studies and
the references of relevant reviews. In addition, we hand searched the International Journal of
Probiotics and Prebiotics. Clinicaltrials.gov was searched during the update searches. The
database lists a number of registered probiotic trials. Personal files from Evidence-based Practice
Center projects on related topics were also scanned to identify additional relevant studies. The
safety data from MedWatch; the Web pages of the Food and Drug Administration (FDA),
including Center for Food Safety and Applied Nutrition CFSAN and the Center for Biologics
Evaluation and Reasearch; and the CFSAN Adverse Event Reporting System database were also
explored but did not contribute studies eligible for inclusion in the review.
Inclusion Screening
This section describes the inclusion criteria for the review.
Inclusion Criteria
•
•
•
Participants:
o Studies in human participants were eligible for inclusion in the review; animal and in
vitro studies were excluded
Intervention:
o Studies using probiotics or synbiotics to cure, treat, mitigate, or prevent a disease or
reduce disease risk (including probiotic drinks or supplements “to boost immunity” or
similar) were eligible for inclusion in the review. The organisms had to be taken
purposefully, and documented cases of infections were included only if use of a
probiotic or synbiotic intervention was reported
Comparator and Study Design:
9
•
•
o Original research studies were considered without study design restriction, but
uncontrolled studies were included only when they explicitly addressed the effect of
probiotic or synbiotic intake. Studies primarily testing the effects of a combination of
a probiotic and another medication that could also result in adverse events were
included only if the study also reported on a group receiving that medication without
probiotics or the study explicitly addressed the safety of probiotic intake:
Randomized controlled trials (RCTs), clinical controlled trials, and cohort
studies with at least two arms comparing the use of probiotics or synbiotics to
placebo, other treatment, or other types of probiotics or synbiotics
Before–after studies and time series with measurements before and after
introducing probiotics or synbiotics
Case series (no comparator) that address the effects of probiotics or synbiotics
Case reports that explicitly address the effects of probiotics or synbiotics
Mechanistic probiotics or synbiotics studies of all designs addressing patient
health outcomes
Case-control studies that focus on probiotics or synbiotics as predictors of an
adverse event in participants
Outcomes:
o Studies that addressed adverse patient health outcomes, particularly symptomatic
outcomes, were included in the review. Studies that reported only intermediate
outcomes such as gene transfer or gastric colonization without reference to
participants’ negative health status were not eligible for inclusion in the review.
Dislike or the taste of the product was not considered eligible adverse events. Studies
where efficacy outcomes were identical to adverse events (e.g., efficacy of probiotics
in the treatment of diarrhea; efficacy of probiotics in the prevention or reduction of
negative health outcomes caused by antibiotic treatment) were excluded unless the
safety of the probiotics was also explicitly addressed in the publication. As no
effectiveness review was undertaken in conjunction with the safety review
exacerbations of primary outcomes, such as exacerbation instead of improvement in
allergy symptoms in some participants, compared to baseline or in comparison to a
control group (treatment failures), were also not included in the review unless these
results were one of the main findings of the publication and highlighted in the abstract
of the publication
Genus:
o Studies investigating Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus,
Enterococcus, and/or Bacillus as probiotic agents alone or in combination with other
ingredients were eligible for inclusion in the review. Studies were excluded if the
genera used could not be verified. Studies administering yogurt or milk products
containing only Lactobacillus and/or Streptococcus organisms as starter cultures were
not included unless an additional probiotic strain was added to the product. We
included studies regardless of whether authors stated that viable organisms were used
but interventions of explicitly heat-killed or inactivated organisms were excluded, as
the criterion of viability is part of the established definitions of probiotics and
interventions using heat-killed forms rarely labeled these preparations “probiotics.”
10
Title and Abstract Inclusion Screening
The initial relevance screening was performed using the reference manager software
Endnote. Endnote allows the import of titles, abstracts, and keywords for each reference
identified through electronic searches. All identified records were screened independently by two
reviewers in order not to miss potentially relevant studies. Records deemed by at least one
reviewer to potentially report safety information were ordered as full text copies for further
scrutiny.
Identifying safety data is challenging since most publications focus on the clinical efficacy of
the intervention in question with either no, sparse, or incomplete and nonsystematic reporting of
safety aspects. The review team followed inclusive decision rules for ordering full paper copies
of publications in order not to miss studies that might report on adverse events in the full
publication but did not indicate so in the title, abstract, or keywords of the publication. In
summary, we ordered all publications that targeted the safety of probiotics as full-text articles. In
addition, all empirical studies on probiotics in humans that addressed health outcomes were
ordered to check the full text publication for data on the safety of probiotics.
Publications that clearly addressed animal studies or in vitro studies, comments, opinion
pieces without data, unsystematic reviews not specific to safety, and publications that did not
address health topics were excluded.
Full Text Inclusion Screening
Two reviewers independently screened the selected full text publications using a
standardized form outlining the inclusion criteria. Any disagreement was resolved through
discussion, through consultation with the review team, or with other input such as the local
content expert or the technical expert panel (TEP).
Studies identified through reference mining were included in the review if they met all the
above mentioned inclusion criteria.
The inclusion screening process also identified all RCTs reporting patient health outcomes in
human participants using probiotics or synbiotics of the genus Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, or Bacillus to cure, treat, mitigate, or prevent a
disease or reduce disease risk compared to placebo, another probiotic, prebiotic or synbiotic,
other, or no intervention. The number of such relevant RCTs was determined as a denominator
for assessing the proportion of those that addressed safety.
Data Abstraction and Quality Assessment
This report considered two different kinds of publications. Our primary interest was in
identifying publications that addressed specific adverse events. However, a number of
publications were found that addressed the safety of probiotics but did not report the presence or
absence of specific adverse events.
For papers that did not address specific adverse events but instead provided only general
statements such as “well tolerated,” “no adverse events,” or “two participants dropped out due to
adverse events” without specifying which adverse events were assessed, the data abstraction was
minimal. These studies were included for reasons of completeness but their informational value
for this evidence review is minimal due to the lack of outcome determination.
For studies addressing specific adverse events, detailed information was extracted regarding
the type of study, the participants, the product containing probiotics or synbiotics, the assessed
11
adverse events, and the results of the study regarding the safety of the intervention (see
abstraction form in Appendix B). The data were abstracted using defined categories where
possible and appropriate, and, if not, using free text. These studies were the primary basis for
answering the research question addressed in this review. All extracted information is
documented for each study in the evidence tables (Appendix C).
Multiple publications of the same study were counted (and extracted, quality assessed and
analyzed) as one study to ensure that the same participants did not enter the analyses multiple
times. Publications of a particular study were defined by the investigated participant population.
Publications that reported the results of two different studies were counted as different studies if
both studies met the inclusion criteria of the review (human participants; eligible study design;
report of an intervention; Lactobacillus, Bifidobacterium, Saccharomyces, Enterococcus,
Streptococcus, and Bacillus used as probiotic agents; adverse health outcome addressed).
For studies with more than one arm, we selected a main treatment arm (arm 1 in evidence
tables) and a control group that was most similar to the main treatment arm but did not receive
probiotics or synbiotics if available (arm 2 in evidence tables). If additional probiotic and
synbiotic groups (arms) were included in the study (including interventions of heat-killed or
inactivated organisms), those data are shown as arm 3 and 4 in the evidence tables.
We extracted data on all Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus,
Enterococcus, or Bacillus strains contained in the intervention preparations regardless of the
probiotic qualities of the strain. If an intervention included a yogurt starter culture with a
probiotic strain added, we listed the starter cultures alongside the probiotics strain, if that
information was provided. Studies were inconsistent in differentiating strains with assumed
probiotic properties from strains without assumed probiotics properties (the product was
assumed to have probiotic effects, without attributing these effects to individual strains); hence,
we recorded all reported strains. Initially, we had considered contacting authors of primary
studies for missing information on the identity of probiotic organisms, that is, whether the
administered probiotics strains were verified in the study. However, the quality of reporting on
the administered probiotic organisms was rather poor overall, and our resources did not permit
contacting what would have been the majority of study authors for this extensive literature
review. Therefore, study details were extracted as reported.
Adverse events. Regarding safety data, we extracted any adverse event reported in the
publication and assessed the quantity, quality, and nature of the adverse events. We considered
reasons for dropouts as well as adverse events reported for participants finishing the study. We
extracted all adverse events for all treatment groups, including those that study authors did not
consider related to the intervention. Because such judgments are difficult to make and may
depend on the development of the clinical field, we report the complete set of adverse events.
Reports of individual treatment failures were not extracted, as these outcomes should be
addressed systematically in an effectiveness review extracting all data for the selected outcome.
We extracted the number of incidences of the individual adverse events and the number of
participants with an adverse event per group if this information was clearly provided in the
publication or could be derived with confidence from the reported information.
We extracted the number of participants with adverse events per group and the number of all
individual incidences of adverse events per treatment arm.
The nature of the reported adverse events was explored by categorizing events with the
Common Terminology Criteria for Adverse Events (CTCAE) classification system. The reported
12
adverse events and reasons for dropping out were classified according to the 27 areas specified in
the CTCAE and, where possible, graded in their severity on a scale from 1 (mild; asymptomatic
or mild symptoms; clinical or diagnostic observations only; intervention not indicated) to 5
(death from adverse event) according to the CTCAE system.
The reported adverse events were also assessed as to whether they constituted serious
adverse events following the FDA definitions. Serious adverse events were defined as death, a
life-threatening event, hospitalization, a disability-causing event, a congenital anomaly, or events
requiring an intervention to prevent permanent impairment or damage. Sepsis was classified as a
serious adverse event.
In trials where mothers and their children received probiotic interventions, only the adverse
events for children were considered for pooled analyses because studies reported inconsistently
on children and their mothers. The number of participants was calculated as the number of
mother–child dyads randomized to the treatment groups.
Quality. Each study was also assessed regarding its quality. We considered a wide range of study
designs in this review, and some quality dimensions were specific to the individual study design
(e.g., concealment of treatment allocation for RCTs), while others were sources of bias that apply
to all study designs (e.g., blinding of outcome assessors). The quality assessment incorporated
the quality of the reporting of the product and probiotic genus, species, and strain; the methods;
and the reporting of the assessment and the documentation of observed adverse events. Each
quality indicator was scored using a three-point scale (0 = high risk of bias, 1 = unclear or
possible risk of bias, 2 = low risk of bias).
The specific markers of quality were the quality of the probiotic description (genus, species,
and strain), the quality of the reporting of the assessment of adverse events, the quality of the
reporting of the adverse events themselves, selection bias, baseline comparability of groups,
power calculation for harms, ascertainment of compliance and exposure, method of ascertaining
adverse events, random treatment allocation, concealment of allocation, participant blinding,
outcome assessor blinding, rate and description of dropouts, intention to treat analysis, presence
or handling of confounders, and the potential conflict of interest.
Procedure. The data abstraction and quality assessment were performed in duplicate with two
reviewers independently reviewing the publications using a standardized form. The numerical
results for the eligible outcomes were abstracted and checked by a statistician. Any
disagreements were resolved through discussion, through consultation with the review team, or
with other input such as from the local content expert or the TEP.
Analysis
Several of the questions the review set out to address required only descriptive data (e.g.,
number of studies reporting adverse events, type of harms, etc.). For studies that reported the
presence or absence of a specific adverse event, we extracted two different measures of the
quantity of adverse events where possible: the number of participants who experienced adverse
events and the number of incidences of individual, reported adverse events. For controlled
studies, we extracted the number of participants with adverse events and the number of
individual incidences for each intervention arm. In cases where the number of events was
reported for one group within a study but not explicitly for the other group, we assumed that zero
events occurred for this second group.
13
For each study, we extracted the total number of participants entering the study and the
number of participants per treatment arm. The latter was the number of participants per group as
randomized or initially entering the treatment group where stated; in nonrandomized and single
group studies we used the number of participants in the treatment group as reported. In addition,
we extracted the number of dropouts and the number of dropouts due to adverse events per
group.
Where appropriate, we pooled results across studies in a meta-analysis to obtain a summary
estimate. Studies were included in pooled analyses if they reported complete information on the
total number of participants in each treatment group, as well as the number of participants with
events in each group or the number of adverse event incidences per group. We identified a large
number of RCTs and restricted the pooled analyses to parallel RCTs. Trials that did not
randomize participants or that used a crossover design were used only for sensitivity analyses,
where appropriate. When pooling studies with adverse event incidences, we excluded those trials
where the total number of adverse events incidences exceeded the number of participants per
treatment arm (this was very rare but not impossible as participants can experience more than
one adverse event).
For parallel RCTs, we computed the relative risk for adverse events, comparing treatment
and control groups, and the absolute risk per group and compared risk differences across groups.
Where the number of cases with an adverse event for a treatment arm was zero, an increment of
0.5 was added, where required for the specific statistical analysis. Studies were pooled with
random effects analysis using the DerSimonian-Laird procedure, using the metafor package, v1.4
(Viechtbauer, 2010) within R 2.10.2. We report the pooled relative risk and risk differences
together with a 95% confidence interval (CI).
Pertinent results were depicted graphically in forest plots. Each forest plot indicates the point
estimate and confidence interval associated with the data reported for each included study. The
area of each square is proportional to the study's weight in the meta-analysis. Throughout, the
forest plots show the log of the relative risk on the horizontal axis.
The evidence report set out to answer a large number of Key Questions pertaining to product
and participant factors. We primarily sought studies that reported direct comparisons to answer
Key Questions. For example, studies comparing two different delivery vehicles within the same
study were used to address differences associated with the delivery vehicle. Where no direct
comparisons or only few comparisons were identified, or where comparisons were unusual or
inappropriate (e.g., comparing effects in children and in adults), we used subgroup analyses and
metaregressions to investigate the factor in question. Subgroup analyses stratified RCTs by the
factor in question. For example, a separate pooled analysis comparing intervention and control
groups was undertaken for studies in children, in adults, and in elderly participants to investigate
whether safety results vary by age. Metaregressions were undertaken to investigate the potential
predictors (or moderators) of effects such as the age of the participants. In the metaregressions,
we incorporated additional predictors into the model, assessing the 95% CI and p-value
associated with the ratio of relative risk for the particular predictor. This type of analysis can
identify interaction effects, that is, whether the risk compared to control is statistically
significantly higher than compared to the risk seen in other study types. Where a categorical
moderator had more than two levels, we first assessed the joint significance of the predictor
before examining the univariate effects. Metaregressions and subgroup analyses are indirect
comparisons across studies and were interpreted with caution, as they are confounded by many
factors.
14
The proportion of RCTs that addressed adverse events was also determined relative to the
total number of identified RCTs reporting patient health outcomes in human participants using
probiotics or synbiotics of the genera Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, or Bacillus to cure, treat, mitigate, or prevent a disease or reduce
disease risk compared to placebo, another probiotic or synbiotic, other intervention, or no
intervention. This assessment answers the question of what proportion of high evidence level
studies do and do not address the safety of using probiotics or synbiotics. This analysis is based
on a literature scoping approach of the excluded literature and is an estimate only.
Rating the Strength of the Evidence
For each of the key research questions, a synopsis of the evidence was undertaken. The body
of evidence consisting of all studies that were identified that contribute to answering the research
question was rated according to the following criteria: risk of bias, consistency, directness, and
precision.
The risk of bias was assessed for each study by taking the study design and the results of the
quality assessment of the individual study into account. The quality criteria are outlined above.
In addition, the consistency of results across studies was considered. For this dimension, we
checked whether the direction of results was similar across comparable studies. The directness of
the evidence takes into account whether any head-to-head trials were identified that allowed a
direct comparison (between two probiotic genera, for example) within the same study rather than
having to rely on indications across studies. Across-study comparisons are confounded by many
factors, results may be misleading, and conclusions from indirect comparisons have to be
regarded with caution. The precision relates to the confidence intervals around a summary
estimate, the range of values that have to be considered true based on the given data. In addition,
this dimension considers, for example, whether the risk of adverse events in the intervention
group is statistically significantly different from the risk of adverse events in a control group.
Finally, for each question we graded the strength of the evidence that was identified for the
particular topic. The strength of evidence reflects the confidence in answering each Key
Question. The following categories were used: high, moderate, low, or insufficient. High
indicates that we have confidence that the evidence reflects the true effect; the research question
can be sufficiently answered with the available evidence. Moderate indicates that we have only
moderate confidence that the identified evidence reflects the true effect. A rating of low indicates
that we have only low confidence that the identified evidence reflects the true effect and that it is
likely that future research will change currently available estimates of effects. When the strength
of evidence is rated as insufficient, it indicates that evidence to answer the research question is
unavailable. The absence of evidence does not equal the absence of an effect; it indicates that
there is insufficient evidence to answer the research question. A summary of the general
approach is outlined in the Methods Guide for Effectiveness and Comparative Effectiveness
Reviews (AHRQ, 2007).
15
Results
The literature search revealed a large research volume on the topic of probiotics, with a
particular increase in research publications shown in recent years. All databases were searched
from inception. Figure 3 plots the identified publications by the year of publication.
Figure 3. Literature volume
1800
1600
1400
1200
1000
800
600
400
200
0
2007
2005
2003
2001
1999
1997
1995
1993
1991
1989
1987
1985
1983
1981
1979
1977
1975
1973
1971
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1967
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1941
The literature search for the systematic review identified 11,977 publications. Of these,
11,201 publications were identified through searching electronic databases, and the remaining
776 came from reference mining included studies and background papers and hand searches. The
literature flow for the review is shown in Figure 4.
16
Figure 4. Literature flow
Electronic Database Search
n = 11,201
Reference Mining,
Expert Identified,
and Hand Search
n = 776
Excluded based on title and
abstract (animal study, in vitro, no
data, unsystematic reviews not
specific to safety, not health)
Full Text Articles Screened
n = 2,189
Subsequently Excluded n = 1,252; Reasons:
Background
(not included in analyses)
n = 315
636
243
141
101
86
Adverse events / safety not addressed
No Intervention
Ineligible Participants
Ineligible Design
Not probiotic intervention or ineligible genus
45
Duplicate
Included in the review
(meeting all inclusion criteria) n = 622
Specific harm addressed, thus
selected for detailed data
extraction and quality assessment
n = 387
291
RCTs
and
CCTs
53
Case
Series
Nonspecific safety
statements only
n = 235
43
Case
Studies
Of all identified publications, 9,788 were excluded on title and abstract level where
publications clearly addressed animal studies, in vitro studies, comments and opinion pieces
without data, unsystematic reviews not specific to safety, and publications that did not address
health topics. We ordered 2,189 full text articles for further scrutiny.
Applying the standardized form to inclusion screen full text papers by two independent
reviewers, 1,252 publications were excluded. Excluded publications are listed in Appendix D
with the primary reason for exclusion. The screening process considered, in this order,
17
monitoring and/or reporting of adverse events, participants, genus, design, intervention, and
duplicates. Only one reason for exclusion was recorded, although most publications would have
not passed two or three exclusion criteria. Also listed in the appendix are 315 studies that were
classified as background papers. These were mostly reviews used for further reference mining or
multiple publications of included studies.
Overall, 622 studies met inclusion criteria. The full list of included studies is shown in the
appendix together with the source the publication was identified from. The electronic databases
were searched in a particular order, starting with PubMed as outlined in the search strategy. The
majority of included studies were indexed in PubMed. A substantial number of studies were
identified through reference screening of included studies and background papers.
The included studies were then screened again in a further step to differentiate studies that
addressed a specific adverse event from those that did not (nonspecific safety statements).
Potentially Relevant Studies Not Addressing Safety
To estimate the proportion of existing probiotics studies currently found in the literature that
are included in this safety review, we enumerated the probiotics randomized controlled trials
(RCTs) reporting on patient outcomes that were found in our searches. We then calculated the
proportion of RCTs included in this review as an estimate of the proportion of currently available
studies that were included.
RCTs are regarded as high evidence level studies, and of all published research studies, these
should be more likely to adhere to good reporting practices, which include the reporting of
adverse events. We have identified 774 RCTs in our literature searches that were potentially
relevant for the Key Questions and were theoretically eligible to be included in this review based
on the participant, intervention, genus, and study design criteria of this review.
Of these relevant RCTs, 446 (58 percent) met inclusion criteria for this review because they
addressed the safety of probiotics. All other RCTs reported on relevant interventions, in relevant
participant groups, but they did not address adverse patient health outcomes as defined in this
evidence review. Of all published RCTs that we identified in our searches, 279 (36 percent)
reported on the presence or absence of a specific adverse event.
Included Studies With Nonspecific Safety Statements
Evidence Table C6, Nonspecific Safety Statements,in Appendix C summarizes the 235
identified studies that made only vague safety statements indicating that “there were no adverse
events” or that the intervention was “well tolerated” but gave no indication what kind of adverse
events were screened for or did occur. The evidence table shows what the publication reported
regarding the assessment of adverse events and the safety results.
The majority of these studies were RCTs. Very few included studies were “mechanistic
studies,” that is, specifically investigating the mechanism of action with which probiotic
organisms potentially achieve effects. Mechanistic studies rarely addressed patient health
outcomes, including adverse events.
Only few studies (67/235) provided details about the assessment procedure (e.g. “any side
effects were also recorded,”), but no specific outcomes that were monitored in the study were
reported. The large majority of studies did not refer to the assessment of adverse events.
The table also shows the investigated genus, species, strain, and form of probiotic organisms
given, as well as the potency and the administered dose, and the product name, where applicable,
for these studies. Lactobacillus was by far the most commonly investigated genus, and about
18
three-fourths of the identified studies used products that included Lactobacillus alone or in
combination with other genera. Enterococcus and Bacillus studies accounted for less than 5
percent of the sample. Figure 5 shows the frequency of the genera of all strains used in the
studies.
Figure 5. Included strains by genus in studies with nonspecific safety statements
300
250
200
150
100
50
0
Several publications reported the species and in some cases subspecies that were
investigated. Common in this sample were Lactobacillus rhamnosus, casei, and acidophilus;
Bifidobacterium bifidum, lactis, and longum; Saccharomyces boulardii/cerevisiae;
Streptococcus/Enterococcus faecium; or Bacillus coagulans. One-third of the studies did not
report the investigated strain. These studies provided no information on what exactly was studied
or at least what was supposed to be studied. In addition, most studies did not state that any efforts
were made to test the administered microorganism(s).
In more than half of the identified publications, the form of the organism was not described,
such as whether the organism was active, lyophilized (freeze-dried), or heat killed. Most
common was the description “live,” “active,” or “viable” (32 percent); reference to freeze-dried
stored organisms was made in a quarter of the publications. No studies that employed heat-killed
organisms and provided vague safety statements were identified using the search algorithm.
The potency of the studied probiotic strain was reported for a third of the articles (expressed
as colony-forming units [cfu] for bacterial strains), although with rare exceptions, the potency
does not appear to have been tested as part of the study. Thus, the reported potency information
may have been that provided by the manufacturer of the product. The actual potency can deviate
from the product label and can be influenced by the delivery vehicle that is employed in the
study so the stated potency information is only a rough indicator. In addition, the dose
information was usually not clearly documented or not linked to the potency information, or the
potency and dose were reported only on the product, not at the individual organism level, so that
in most cases the daily amount of exposure of the probiotic organisms remained unknown.
A third of these publications stated that the investigated intervention had “no side effects.”
The statements “no adverse effects,” “well tolerated,” and “no adverse events” were also, and all
equally, common, each found in about 20 percent of the identified publications. The statement
“safe” was a rarely used expression, accounting for fewer than 5 percent of the publications,
19
presumably acknowledging that this statement is very difficult to ascertain with a single study.
The remaining studies used other expressions.
None of these publications clearly reported their basis for the conclusions related to the
absence of harms. That is, they did not state the specific parameters they monitored, or
characterize the encountered adverse events further. A small number of publications monitored
specific harms according to the methods section but the results were not reported. Studies
describing the presence or absence of a specific adverse event were eligible for detailed data
extraction, are described in the next section, and were used to answer the Key Questions.
Included Studies Addressing Specific Harms
A total of 387 studies were identified that addressed a specific adverse event. These studies
were used to answer the Key Questions posed by the sponsors.
Evidence Tables
Detailed information on the included studies is shown in five evidence tables in Appendix C.
Table C1 lists the study details and participant information, table C2 shows the intervention
details, Table C3 outlines the assessment and analyses, Table C4 summarizes the reported results
and Table C5 shows the quality assessment. Studies appear in alphabetical order (by name of the
first author) within study design categories. For this categorization, we differentiated three study
design groups: controlled trials, observational studies, and case studies. The nonrandomized
controlled trials and the crossover and parallel randomized controlled trials were extracted in the
same category; the observational study design group included only uncontrolled case series.
Study and Participant Details
Table C1: Study and Participant Details provides an overview of the type of study and the
included participants. Almost all included studies were published as articles. Although abstracts
and letters with data were eligible for inclusion in the review, these publications accounted for
fewerthan 5 percent of the included publications. Multiple publications about the same study
were extracted as one study, regardless of the number of publications employed to report the
data. Publications reporting more than one study, in particular with different research designs,
are shown as multiple studies. Fewer than one-third of studies reported that safety was one of the
main aims of the publication. The efficacy of the intervention was the most common research
question addressed by the included studies.
In all, 49 percent of included studies were conducted in European countries; Italian
publications alone accounted for 10 percent of the sample. Studies were included regardless of
the language of the publication. The number of U.S. studies included (11 percent) was similar to
the number of Asian studies (16 percent). We determined the country by the study participants,
not the authors of the publication. The individual countries are shown in the evidence table.
The majority of included studies employed a modest number of participants, that is, ranging
between 11 and 100 participants. However, we also identified 111 larger studies (29 percent of
all included studies) with more than 100 participants. Small studies with between 1 and 10
participants constituted 14 percent of the entire sample of included studies; most, but not all,
were case studies. Figure 6 shows the number of participants included in the identified studies.
20
Figure 6. Number of participants in included studies
Across all studies and treatment arms, 24,615 intervention participants used a probiotics
product, of which 21,403 were in the main treatment group. Across all studies, 16,574
participants were allocated to a nonprobiotic control group.
In terms of study design, parallel RCTs accounted for two-thirds of the entire sample
addressing specific adverse events. We only classified those studies as RCTs that explicitly
stated the random allocation to treatment and control group. All other trials were categorized as
clinical controlled trials (CCT). We distinguished parallel and crossover RCTs, because with a
crossover design, a carryover effect from the intervention phase cannot be ruled out and may
lead to misinterpretation of the data. These trials included all studies where the intervention was
under the control of the investigator. Cohort studies comparing two cohorts or case-control
studies that addressed the safety of probiotics were not found. Cohort studies compare groups of
participants using probiotic organisms with a group of participants not using probiotics; the
intervention, that is, the use of probiotic organisms, is not controlled by the investigator but selfselected by the participant, and the data obtained are purely observational. Case-control studies
are defined by the outcome, that is, a specific harm, and the intervention, the use of probiotic
organisms, is investigated as a possible risk factor for the outcome in question. The remaining
studies we included were case series and case studies, which represented 14 percent and 11
percent respectively. Case series report on a number of patients receiving the same intervention
without a control group. Some case series were before–after studies, but for this safety analysis,
these studies were not differentiated from other case series, because the preintervention data for
safety aspects were typically missing so there was no baseline that allowed a comparison. The
included case studies reported on one or more cases of adverse events attributed to probiotic
organisms.
We also categorized the health status of the participants taking part in the included studies.
We differentiated generally healthy, critically ill or high-risk patients, and participants with
medium or indeterminate risk on the continuum from generally healthy to critically ill. Twothirds of studies were in participants who were neither generally healthy nor critically ill. These
participants were suffering from a variety of health complaints such as diarrhea, ulcerative
colitis, or bacterial vaginosis. Some of the participant samples were generally healthy
21
participants (81/387). The smallest group of included participants was critically ill or high-risk
patients, for example patients currently being treated in an intensive care unit or babies with very
low birth weight. The participants’ specific health problems were also extracted. We also noted
whether participant groups of interest to the Key Questions were systematically excluded from
each study, such as newborn and very young children; elderly participants; or immunecompromised, critically ill, or high-risk patients. In all, 52 studies explicitly reported that
immunocompromised patients were excluded from the study. Another 73 studies excluded
pregnant women, and 36 excluded breastfeeding or lactating women.
For each study, we noted the reason for which the probiotic organisms were given. Seventynine percent of studies used probiotic organisms in an attempt to either treat or prevent a specific
condition. Although probiotic organisms can be administered in the form of a food or food
ingredient, a drug, or a dietary supplement, and our search or inclusion criteria did not favor one
particular form over another, the probiotic organisms were administered in a clinical context in
the vast majority of identified studies, that is, testing the efficacy or effectiveness of the
preparation to treat or prevent a clinical indication. On a related note, although definitions of
drugs vary across countries (as reflected in the international literature), the vast majority of
interventions were not commercial food or dietary supplement products (see also Evidence Table
C2, Intervention). The evidence table also lists pertinent cotreatments such as antibiotics,
immunosuppressants, steroids, or dietary therapies. Of all included studies, 28 percent reported
that participants also took antibiotics while participating in the probiotics study.
Intervention
The Evidence Table C2, Intervention presents an overview of the specific interventions
evaluated in the included studies. When provided, the name of the product under evaluation was
extracted. Furthermore, we extracted the delivery vehicle for the probiotic organisms where
reported: in one-quarter of all included studies, the delivery vehicle was a pill or capsule. We
also extracted the target of the intervention, since we identified somestudies that gave probiotic
organisms to pregnant women, their babies after delivery, or both.
We also categorized the studies as to whether they investigated only one probiotic strain or
several (i.e., a mixed product). A single-genus product was investigated in 55 percent of studies.
In 39 percent of studies, more than one strain was included in the intervention preparation. The
latter studies included those in which the probiotic agents were given in yogurt or other milk
products, and we have included Lactobacillus and Streptococcus in this evaluation where
reported, even when the study did not claim any probiotic characteristics for the yogurt strains
(studies were inconsistent in differentiating strains with assumed probiotic properties or
attributing probiotic properties to the studied product in its entirety).
We carefully avoided searching by the names of particular strains, species, or genera.
However, the majority of identified studies targeted at least one Lactobacillus strain (73 percent).
In all, 34 percent of studies included at least one Bifidobacterium strain. The other genera of
interest to the report were represented in only 18 percent (Streptococcus), 12 percent
(Saccharomyces), 4 percent (Enterococcus), and 3 percent (Bacillus) of studies, respectively.
Figure 7 shows the number of strains by genus that were investigated in the included studies in
the various treatment groups. Many studies used exclusively one Lactobacillus strain and many
studies included more than one Lactobacillus strain but no other genera in the intervention.
22
Figure 7. Included strains by genus
600
500
400
300
200
100
0
We also categorized studies according to whether the intervention included only probiotics,
or a combination of probiotics and prebiotics, that is, synbiotics. Fewer than 10 percent of studies
stated clearly that they used a synbiotic product or reported the addition of ingredients with
assumed prebiotic properties.
Details of the interventions were documented only sketchily. Studies reported the
investigated genus and often the species but strain information was often not reported, as
indicated by the large number of “not available (n/a)” entries in the evidence table. The evidence
tables include the species as reported regardless of reclassifications on genus, species, or strain
level based on new evidence. Apart from the genera Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus, some intervention products also
included the genera Clostridium, Lactococcus, Leuconostoc, Pediococcus, and
Propionibacterium. The studied intervention products included the Lactobacillus species
acidophilus, bifidum, brevis, buchneri, bulgaricus, casei, caucasicus, coryniformis, crispatus,
delbrueckii, fermentum, gasseri, (GG), helveticus, johnsonii, lactis, leichmannii, paracasei,
plantarum, reuteri, rhamnosus, and salivarius as reported by the authors. The reported
Bifidobacterium species were animalis, bifidum, breve, clausii, infantis, lactis, and longum. The
Saccharomyces interventions were described as boulardii, cerevisiae, or cerevisiae boulardii,
and one study used the Saccharomyces florentinus. The reported Enterococcus species were
faecalis and faecium. The reported Streptococcus species were described as mitis, oralis, rattus,
salivarius, sanguis, and thermophilus, and some organisms were described as Streptococcus
faecium. The studied Bacillus species were described as clausii, coagulans, IP, licheniformis,
oligonitrophilus, stearothermophilus, and subtilis. Of all included studies, 43 percent did not
report on included strains.
The form of the probiotic strain was also often not reported: 62 percent of studies did not
report whether the organisms in the various intervention arms were in active, lyophilized, or
heat-killed form, and/or whether the tested organisms were viable.
For studies that reported using a commercial product, we extracted only the intervention
detail as reported by the authors, that is, we did not search for information from manufacturers to
determine the composition of the product. The review covers the international literature and was
23
searched without restriction by publication year; it is possible that the product compositions vary
across countries and have also changed over time. Fewer than 10 percent of studies clearly
reported that they verified the probiotic strains that were given to participants as part of the
study. The verification checked for the included strains, whether any contaminants were
identified, and/or the number of active organisms.
The evidence table also shows the dose information as reported by the individual study
authors. For each study, we extracted the daily intake of probiotic products where possible. The
dose information was often incomplete, that is, the information provided was insufficient to
calculate participants’ actual daily or overall study exposure.
The evidence table also reports the length of the intervention in months. Many intervention
periods in the included studies were of short duration, often lasting for only 1 week. We
categorized studies by short-term, medium, and long-term use. Defining short-term use as 1
month or less and long-term use as 1 year or longer, we note that almost half of the included
studies (46 percent) reported an intervention period of 1 month or less, and only 5 percent of
studies explicitly investigated the long-term use of probiotic organisms, that is, use of probiotic
products for 1 year or longer. In the remaining studies, medium intervention durations were
studied (more than 1 month but less than 12 months) or in some cases, it could not be established
how long the probiotic product was taken. Figure 8 shows the individual study durations in
months.
Figure 8. Intervention duration in months
We also differentiated the route of administration of the probiotic product. In two-thirds of
studies, probiotic organisms were administered orally. In 10 percent of these studies, enteral
feeding tubes were used, owing to the fact that a number of studies evaluated probiotics in
critically ill patients (see Evidence Table C1, Study and Participant Details).
In controlled studies, the probiotic intervention was most commonly compared to a placebo,
or a group receiving probiotic organisms in addition to another medication, product, or treatment
(the standard intervention) was compared to a group receiving only the standard intervention
without the probiotic addition. For studies with multiple interventions, we chose as the primary
intervention arm the one that differed from the control group only in the administration of a
probiotic.
24
Assessment
We distinguished descriptions of the assessment of adverse events from the reported events.
Evidence Table C4, Results lists all reported events; however, the Evidence Table C3,
Assessment lists the specific adverse events that were reportedly assessed according to the
methods section of the publication. We noted all reported published systems used to record,
categorize, and grade adverse events; however, this information was not very common in the
included studies. The assessed safety parameters of controlled trials are summarized in Key
Question 1a. The information on observational studies is summarized in Key Question 1d.
We also categorized the duration of followup. In particular, in studies with multiple
publications, this categorization was based on the longest reported followup period. In terms of
short-, medium-, or long-term effects of probiotics use, outcomes were often elicited
immediately after the end of the intervention period. The use of the probiotic product had either
recently stopped, or in some instances was still ongoing at the time of the followup assessment.
One-third of included studies assessed the effects of a probiotic intervention within 6 months
after the intervention. Very few studies assessed long-term effects of probiotic use, i.e., effects
reported more than 1 year after the treatment had stopped.
Results
Evidence Table C4, Results lists the reported results separately for each treatment group in
the included studies (arm 1 to 4). The table documents the quantity, the quality, and the nature of
the reported adverse events. For each study, we also extracted the total number of participants
per study, the number of participants in each group at the time of randomization where
applicable, the specific reported adverse events, the number of dropouts, and the number of
dropouts due to adverse events.
In terms of the quantity of adverse events, we extracted the number of adverse event
incidences separately for each treatment arm. In addition, we extracted the number of
participants who experienced one or more adverse events per treatment arm. Since participants
could experience multiple adverse events, the number of participants with adverse events and the
total number of individual adverse events do not coincide and were extracted individually.
In terms of the nature of the adverse events, as outlined in the Methods section, we extracted
the exact adverse events as reported by the authors of the publication, and in addition, we applied
the Common Terminology Criteria for Adverse Events (CTCAE) system and categorized the
events according to 27 categories. The Roman numerals in the evidence table refer to the
CTCAE category, e.g., VII is gastrointestinal disorders, XII is infections and infestations, and
XXVII is a miscellaneous category for events not covered by the CTCAE system or where
adverse events were reported in a way that did not allow the assignment to a single category. In
brackets after the individual adverse event, we added a characterization where possible (e.g.
mild, or classified as 1 according to the CTCAE system). However, this information was usually
not available. For each individual adverse event, we extracted the reported number of instances
of the event.
In terms of the quality of the adverse events, we assessed for each reported adverse event
whether it represents a serious adverse event (SAE) as outlined in the Methods section to
distinguish the large number of minor complaints from the serious events. In the evidence table,
the latter are noted as “(SAE)” for each applicable adverse event.
We also extracted a number of additional variables pertinent to the Key Questions such as the
number of hospitalizations and the duration of hospitalization, where reported. Whether the
25
administered organism was recovered from the gastrointestinal tract, serum, mouth, or vagina
(indicator of efficacy or safety); the need for antibiotic therapy to treat an infection; and
occurrences of antibiotic resistance were also extracted and are explained in detail in the
following sections.
We noted that the quality of the reporting seems to have increased in recent years; however,
it is challenging to quantify this subjective observation. A logistic regression of the number of
individual adverse events (including zero events, i.e., reporting on the presence or absence of
adverse events) showed that the reporting of gastrointestinal events increased (B=0.048;
p=0.010), however, there was a larger increase in the reporting of infections and infestations
(B=0.014; p<0.0010).
Quality
Evidence Table C5, Quality summarizes the quality of the individual included studies, as judged
by two independent reviewers. We applied a number of quality criteria covering the quality of
the reporting as well as internal validity criteria for the study design. Only “met criteria” or
“possibly met/not enough information to judge the quality” are displayed in the table, to allow an
easy overview of the entire sample. Figure 9 synthesizes the quality of the reporting and the risk
of bias for all assessed variables for the included 387 studies meeting all inclusion criteria.
Figure 9. Quality of the reporting and risk of bias in included studies
350
300
250
200
150
100
50
0
AE=adverse event; ITT=intention-to-treat
26
For each study, we evaluated the quality of the intervention reporting: Only studies reporting
the administered strain as well as the genus and species met the criterion (211/387 studies). The
assessment of adverse events was judged as clear and well reported by the two independent
reviewers in 93/387 studies. The reporting of the adverse events themselves was judged adequate
in 229/387 studies.
We also assessed the selection of the sample: 27/387 studies were judged to protect
adequately against selection bias, for example, through the use of consecutive patients or
explicitly representative samples drawn from the study population. Also, for controlled trials, we
assessed the comparability of the groups allocated to the probiotics and to the control
interventions. Of all controlled trials, 195/291 relevant studies were classified as adequate; these
studies reported basic baseline information on both groups, and the data were considered
comparable. As a quality measure for the study, we also judged whether the study reported a
power calculation that considered any adverse event. Of all included studies, six studies assessed
in advance whether their study would be adequately powered to show a statistically significant
difference in adverse events between treatment arms, should they occur. Because we expected to
find a number of case-control studies, we also assessed the studies for exposure ascertainment. In
194/387 studies, the reviewers were relatively certain that the probiotics were used as described,
for example, because studies reported on the compliance of the participants, or it was assumed
that the probiotic organisms were taken as indicated because studies took place in a controlled
hospital environment (i.e., most likely administered by hospital staff).
The reviewers also judged the method of harms surveillance. Reported adverse events can
differ across studies due to the method used to elicit adverse events. We differentiated passive
surveillance, such as health care providers recording adverse events when spontaneously
disclosed by participants, from active surveillance, for example, mention of a structured
assessment of harms that was part of the study protocol as evidence that participants were
explicitly prompted to report adverse events. In total, 172/387 studies were classified as using
active surveillance, while for the other studies only passive surveillance could be assumed, or it
was unclear from the reporting of the study.
Among the included studies were a large number of RCTs. In total, 121 studies described as
randomized had a randomization sequence approach that was described and considered adequate
(e.g., use of table of random numbers, computer generated sequences). We also judged the
concealment of treatment allocation—whether study personnel were able to predict the study arm
in which the participant would end up or whether the allocation to treatment groups was
concealed. Only 56 out of all 266 parallel RCTs reported treatment allocation concealment.
Finally, we assessed participant and outcome assessor blinding. In 223 studies, the participants
were blinded to the treatment they received; they did not know whether they consumed or were
exposed to the probiotic organisms in question, a placebo, or another control preparation. In a
similar number of studies (221/387), the outcome assessor was described as blinded: it was
assumed that the person eliciting the study outcomes was not aware whether the participant was
taking probiotic organisms or not.
When assessing the risk for adverse events in a particular study, it is important to identify the
number of dropouts (withdrawals). Whereas participants completing the intervention may report
no adverse events, adverse events can lead to withdrawal (and might or might not be accounted
for). In 290/387 studies, the numbers of withdrawals and dropouts were reported and the reasons
for dropping out were described, or it was clearly reported that there were no dropouts and all
participants were followed up. Of all parallel RCTs, 75 percent were judged by two independent
27
reviewers to report adequately on withdrawals. As a general quality measure, we also assessed
whether studies reported an intention-to-treat analysis. In all, 99 included trials reported that they
analyzed participants according to the treatment group to which they were originally assigned
regardless of whether they completed the intervention or switched to another treatment. We also
assessed whether studies reported any attempts to investigate or to avoid upfront confounding
factors. Of all included studies, 126 were classified as attempting to address confounders, either
through statistical analyses (e.g., multivariate analyses) or by features of the study design (e.g.,
matching control groups).
We also assessed the potential for conflicts of interest. We differentiated studies that were
funded by a manufacturer of probiotics and studies where the conflict of interest was somewhat
unclear because of lack of reporting or because the researcher’s affiliation indicated no conflict
of interest but the article reported that the study products were donated by a manufacturer. In
61/387 included studies, the authors explicitly stated in the publication that they had no conflict
of interest.
Key Question 1. What is the evidence that the active (e.g., live or viable)
and lyophilized forms of probiotics (Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus) as single
ingredients or in combination with other probiotics or prebiotics in all
delivery vehicles (and formulations) when used to cure, treat, mitigate or
prevent a disease or reduce disease risk are safe in the short term? Long
term?
All 387 studies meeting criteria for full data abstraction were considered to answer Key
Question 1. Studies were considered, regardless of the genus, species, or strain; form; and
delivery vehicles. Probiotics as well as synbiotics are included in the summary.
We have identified only very few studies that investigated Enterococcus or Bacillus strains
and that could be included in this review, despite an extensive and unrestricted search. The
following results primarily pertain to Lactobacillus, alone or in combination with other genera,
most often Bifidobacterium strains.
Very few included studies (nine in total) investigated long-term effects defined as reporting
on followup periods of one or more years.
(1a) What safety parameters are collected in clinical studies (Phases I–IV)?
The monitored safety parameters of the included CCTs and parallel and crossover RCTs are
shown in Evidence Table C3, Assessment in Appendix C. We distinguished assessed harms from
actually reported adverse events. Evidence Table C3, Assessment lists only outcomes that were
explicitly monitored according to the publication.
The majority of publications reported little information on the assessment of adverse events,
including what adverse events were monitored. Safety was one of the primary outcomes in only
55 publications out of all 291 identified CCTs, and parallel and crossover RCTs.
Often, adverse events were not specified a priori. Many trials did not mention safety or
adverse events in the study outcome section (103 trials). A substantial number of publications
reported in the methods section of the publication that ‘adverse events’ were monitored but did
not define these outcomes further and reported no examples of what kind of events would be
monitored (55 studies). The “AE Non-specific” category in Evidence Table C3, Assessment
28
includes those studies that explicitly monitored for any adverse event that occurred during the
study period.
The trials rarely reported the use of a protocol or a systematic approach for the assessment of
adverse events. Some publications used published tools to categorize adverse events. Allen
(2010) recorded all untoward medical occurrences and these were then independently reviewed.
The authors referred to the Directive 2001/20/EC and the ICD10 criteria. Aso (1992 and 1995)
evaluated adverse reactions according to the criteria of the Japan Society for Cancer Therapy
(Furue et al., 1986). Chouraqui (2008) and Dylewski (2010) reported that adverse events were
coded using the Medical Dictionary for Regulatory Activities (MedDRA). Hemmerling (2009)
used the DAIDS Toxicity Table Addendum for Vaginal Microbicide Studies, WHO/CONRAD
colposcopy manual 1994, and DAIDS Adult Toxicity Table (Division of AIDS, 2007) . The
severity of adverse reactions was assessed using the CTCAE, version 2.0 in the trial by Naito
(2008). The Common Toxicity Criteria of the National Cancer Institute of Canada scale version
2 was used by Osterlund (2007) to assess and grade any adverse events. Sykora (2005) used a
tool for H. pylori treatment side effects (de Boer, 1996) and assessed the causal relationship of
the encountered side effects to the treatment. Wind (2010) also used published tools to assess
safety (Gastrointestinal symptom rating scale, Svedlund et al., 1988; King's stool chart, Whelan
et al., 2004).
When specified, the assessment of adverse events was either by provider assessment at the
time of clinical examination (165 trials), by patient diary (68 trials), by questionnaire (24 trials),
or explicitly by telephone interview (21 trials), and some trials used lab tests (24 trials), but a
substantial number of trials (52 trials) did not specify how adverse events were elicited. In
studies with provider assessment, it was usually unclear whether participants were prompted to
report adverse events, whether clinicians routinely checked for particular events, or whether it
was left up to the participants to mention events that they noticed. We suspected that studies that
completed an Investigational New Drug (IND) application were more likely to report a
systematic approach to assessing harms, but only one publication (McFarland, 1994) reported on
the completion of an IND application.
Individual outcomes that were frequently explicitly monitored were “diarrhea” (37 trials),
“vomiting” (27 trials), “constipation” (22 trials), “flatulence” (13 trials), “abdominal pain” (12
trials), “bloating” (10 trials), and “nausea” (9 trials) (see Evidence Table C3, Assessment in
Appendix C). Signs of infections were rarely explicitly monitored in the included trials. The
outcome “sepsis” or signs of sepsis was assessed in 11 of the included trials. Nine trials reported
that “infections” were monitored, two trials explicitly monitored for bacteremia, and none of the
trials stated in the methods section that fungemia was monitored. The outcome “death” was
specified as a monitored adverse event in nine trials (this number does not include studies
assessing mortality as an efficacy or effectiveness measure). Data on hospitalizations are
presented in detail in Key Question 5.
All studies eligible for full data extraction had to report on a specific adverse event. All
specific adverse events that were recorded are presented in Evidence Table C4, Results in
Appendix C. These adverse events were reported in the publication, even though the study might
not have stated upfront that safety was assessed or defined what would be considered an adverse
event. The table covers the presence as well as the absence of adverse events (zero events). In
other words, the publications that reported identified no instances of a particular harm.
The specific outcome most commonly reported on across studies was “diarrhea.” In total, 59
studies reported the absence or presence of diarrhea incidences in the treatment arms. This was
29
followed by “vomiting” (39 studies). Incidences of “death” or the absence of incidences was
reported in 36 studies. The outcome “nausea” was recorded in 24 studies. “Sepsis” or
“septicemia” was reported on in 21 studies. Twenty-three studies reported on “abdominal pain”
and 30 on “constipation.” “Headache” was reported on in 22 studies. Flatulence was reported on
in 19 studies, and 16 studies reported on the presence or absence of “bloating” incidences. All
other outcomes were addressed in fewer than 10 studies.
In almost all included studies, the outcome assessment took place shortly after probiotic
organisms were given (assessing short- and medium-term effects), and the intervention period
was less than one year long (studying short- and medium-term use).
(1b) What harms are reported in clinical studies (Phases I–IV)?
For all CCTs and parallel and crossover RCTs, we recorded which adverse events were
reported and how many participants per treatment group experienced the presence or absence of
this particular outcome. In the evidence tables, the study arms appear in this order: main
treatment group, control group, and additional treatment groups to which probiotics were given.
Exact adverse events as reported were extracted and are shown in Evidence Table C4,
Results, in Appendix C. We extracted all reported results, including zero events (e.g., zero cases
of sepsis). We classified the adverse events according to the CTCAE system and added the
corresponding codes I to XXVII. Where possible, we graded the severity of the symptom on a
scale from 1 to 5 or characterized the adverse event further if additional information was
provided (in brackets after the harm). Studies reported on the presence or absence of a very large
number of individual outcomes.
The number of reported adverse events per study varied greatly, presumably depending in
part on the thoroughness of the adverse event recording and potentially in part on the type of
study; for example, most studies whose primary aim was to assess the efficacy of probiotics
reported one or more cases of each of a small number of adverse events encountered. Other
studies, the primary aim of which was to specifically investigate the safety of probiotics in
substantial participant samples, compared the incidence of relatively common occurrences such
as colic in infants. Finally, this review also considered studies of “failed effectiveness,” that is,
studies that assessed the efficacy or effectiveness of probiotics in preventing a particular
condition (e.g., antibiotic-induced diarrhea or allergic dermatitis), where, unexpectedly, the risk
for the condition actually increased in the probiotics group (rather than decreasing, as was
hoped); thus, the primary outcome (efficacy, or lack thereof) became the safety issue.
Frequent Individual Adverse Events
The most commonly reported individual adverse events were “death,” “‘diarrhea,”
“constipation,” “nausea,” “respiratory infections,” “spitting up,” “abdominal discomfort,”
“dyspepsia,” “colic,” “abdominal fullness,” “allergy sensitization,” and “pain on micturition.”
This analysis considers only the exact wording; similar symptoms or syndromes were not
grouped. A categorization of reported adverse events is undertaken in response to Key Question
2c. Only data that indicated the treatment group in which the adverse event occurred were
considered.
Across all trials, 177 incidences of “deaths” were reported in probiotic treatment groups, and
174 incidences were reported in a control group. Mortality was recorded in 32 trials, and each
contributed one or two cases to the total number, with the exception of Kerac (2009), Besselink
(2008), and Awad (2010). Kerac (2009) monitored deaths in children with severe acute
30
malnutrition and reported 108/399 deaths in a group receiving synbiotics compared to 119/396 in
children using a control formula. The PROPATRIA trial reported by Besselink et al. (2008), a
study of failed effectiveness, reported on 24 deaths in a treatment group compared to 9 cases in
the control group in patients with acute pancreatitis. The deaths were not directly associated with
cases of sepsis caused by the administered organism (0 incidences). Awad (2010) reported 5/60
deaths in a Lactobacillus acidophilus intervention group for the prevention of necrotizing
enterocolitis and sepsis compared to 6/30 neonates receiving placebo; however mortality was
14/60 in the heat-killed Lactobacillus acidophilus group.
Of the other trials that reported on the group the deceased participant was originally allocated
to, eight recorded more death incidences in one or more probiotic or synbiotic treatment groups
compared to a control group (Bajaj, 2008; Beausoleil, 2007; Correa, 2005; Frohmader, 2010;
Ishikawa, 2005; Manley, 2007; Naito, 2008; Puccio, 2007). Nine trials reported more deaths in
control groups (Alberda, 2007; Basu, 2007; Chui, 2009; Dylewski, 2010; Honeycutt, 2007;
Klarin, 2008; McFarland, 1994; Reuman, 1986; Sazawal, 2010). Three trials reported an equal
number of deaths across groups (Dewan, 2007; Klarin, 2005; Tempe, 1985). Several studies
reported that no deaths occurred in either treatment group of the trial (Anukam, 2008; Delia,
2002; Gibson, 2008; Knight, 2007; Lata, 2009; Luoto, 2010; Merenstein, 2009; Merenstein,
2009; Rio, 2002).
In total, 130 cases of diarrhea were reported in probiotics treatment groups, compared to 126
cases in a control group; the outcome was assessed in a large number of studies. Individual study
results varied, sometimes favoring the probiotics treatment group, sometimes the control group,
or reporting an equal number of incidences as documented in the Evidence Table C4, Results.
Constipation was assessed in a large number of studies that contributed 1 or 2 cases of
constipation in each of the treatment groups to the total number of 78 cases in a probiotics
intervention and 73 cases in a control group. McFarland (1994) reported eight cases of
constipation in the treatment group and two in the placebo group. Nausea was assessed in many
studies, and several contributed 1 or 2 cases to the total number of 58 in probiotics users and 52
across control groups. However, Besselink (2008) reported 20 cases of nausea in the treatment
group and 23 in the control group.
Respiratory infections were assessed in a number of studies, but 47 out of all 58 reported
infections in a treatment group, and 49 out of all 59 control group incidences were reported by
Gibson (2008), investigating the safety of a probiotic infant formula.
The 52 cases of “spitting up” in participants taking probiotics compared to 45 control group
cases were almost all reported in a study by Abrahamsson (2007) (2 control group cases were
reported by Maldonado (2009) investigating a probiotics intervention in the prevention of
eczema).
There were 46 cases of “dyspepsia” in the probiotics group across studies and 3 in control
group participants. As 45 cases came from one study that did not explicitly report on the control
group (Turchet, 2003), the interpretation of the difference in results has to be regarded with
caution. The adverse event with the next highest incidence was that of “constipation” (76 cases
vs. 71 cases among control). In all, 44 cases of “abdominal discomfort” were reported across
probiotics intervention groups (compared to the same number in a control group) where the
number of adverse events was clearly stated. The symptom was assessed in a number of studies
but the cases primarily came from one study (Kukkonen, 2007) that evaluated a synbiotic infant
formula (35 cases in treatment, 37 in control group).
31
Colic was assessed in a number of studies, but 17 out of the 38 treatment group cases and 15
out of all 33 incidences of colic in control group infants were reported in Vlieger (2009), who
investigated the tolerance and safety of a probiotic infant formula. There were 36 recorded
incidences of abdominal fullness in a probiotics intervention group and 43 incidences across the
control groups, all reported in one study (Besselink, 2008). All 35 cases of ‘allergy sensitization’
in the treatment group compared to 21 cases in the control group were identified in a failed
effectiveness study (Taylor, 2007) that investigated the role of probiotic infant formula in the
prevention of atopic dermatitis. The 31 cases of pain on micturition compared to 42 control
group incidences were reported by Naito (2008) investigating adverse events in patients with
transurethral resection of bladder cancer. All other events occurred in fewer than 30 participants
across the 291 trials; all individual study results are shown in the Evidence Table C4, Results.
Number of Adverse Events
To quantify the risk of adverse events, we extracted two measures from individual studies,
the number of participants with adverse events and the number of incidences of adverse events.
This review included studies in generally healthy as well as critically ill participants with
multiple morbidities. The listed adverse events are primarily of interest only in relation to a
control group. Only controlled studies allow a comparison of the natural occurring rate of
adverse events, the rate that can be expected with patients suffering from a particular condition,
or that are caused by cointerventions.
Number of participants with adverse events. For each included study, we extracted the number of
participants who experienced an adverse event in each group, where available. There were 121
studies that reported this number for a group with probiotics intake and a control group not
receiving probiotic organisms as part of the intervention. The pooled relative risk effect for the
number of adverse events was 0.98 (95% confidence interval [CI]: 0.93, 1.04, p=0.537)
indicating that the risk to experience any adverse event was not higher in the probiotic group
than in a control group not taking probiotics. The pooled risk difference was -0.001 (95% CI:
0.005, 0.003, p=0.993), indicating no difference between treatment and control groups.
The included controlled trials used a variety of control interventions. For comparisons
between treatment groups, we considered all control interventions that were characterized by the
absence of probiotics use. In a further sensitivity analysis, we restricted the comparison to
parallel placebo-controlled RCTs. There was also no indication of an increased risk of adverse
events relative to placebo control group participants (relative risk [RR]: 0.98; 95% CI: 0.92,
1.05; p=0.654; risk difference [RD] -0.003; 95% CI: -0.009, 0.004; p=0.386.
Number of incidences of adverse events. Not all studies reported explicitly the total number of
participants who experienced any adverse event in each treatment group. The majority of studies
reported one or more instances of adverse events that occurred in each group. From the
publication it was not always clear whether these events were the only adverse events
encountered and how many participants experienced an adverse event, as a participant can
experience more than one adverse event. An alternative way to approach the risk for adverse
events is to synthesize across all mentioned adverse event incidences. Studies where the total
number of adverse event incidences exceeded the number of participants were excluded from
this analysis, but 208 studies entered the analyses. The pooled relative risk for probiotics groups
relative to control groups was 1.00 (95% CI: 0.93, 1.07, p=0.999) in this analysis, indicating an
32
equal risk of adverse events in the intervention group and the control group. The risk difference
between intervention and control groups was 0.002 (95% CI: -0.002, 0.007, p=0.303). The small
difference was not statistically significant; despite the large number of RCTs, no difference
across treatment arms in the quantity of adverse events could be observed.
Considering only parallel placebo-controlled trials, there was also no evidence for a
statistically significantly increased risk of adverse events based on the number of adverse event
incidences (RR 1.02; 95% CI: 0.94, 1.10; p=0.659; RD 0.0010; 95% CI: -0.004, 0.006; p=0.659).
These quantitative analyses consider only the total number of adverse events reported in the
main treatment group and the main control group, regardless of the type of outcome, including
mild side effects such as bloating as well as serious adverse events such as sepsis and death. In
section 2c we explore the nature of reported adverse events further, and Key Question 5
summarizes the evidence on serious adverse events.
A detailed analysis of the genera-specific safety reported in controlled trials is provided in
Key Question 3b, additional intervention factors are also explored in Key Question 3.
Long-Term Effects
Of all included controlled trials, six addressed long-term effects of probiotics intake, meaning
the studies reported followup assessments of one year or more. All investigated Lactobacillus
strain interventions, alone or in combination with Bifidobacterium.
Abrahamsson (2007) investigated a short prenatal exposure and then 1 year of intake of
probiotic organisms (Lactobacillus reuteri ATCC 55730) in infants to prevent eczema and found
no differences in gastrointestinal problems between groups (spitting up, colic, or constipation),
the last followup was at two years, one year after the original treatment had stopped, and no
other adverse events were reported. Kopp (2008) investigated a short prenatal exposure and then
six months of probiotics intake (Lactobacillus rhamnosus GG ATCC 53103) in infants to
prevent atopic dermatitis and pointed out that children with recurrent episodes of wheezing
bronchitis were more frequent in the probiotics treatment group (13 vs. 4 cases, p=0.03) at the 2
year followup, 1.5 years after the original treatment had stopped; the authors reported that no
other notable adverse effects attributable to the probiotics supplementation were observed.
Kuitunen (2009) (see also Kukkonen, 2007) investigated a short prenatal exposure and then 6
months of probiotics intake (Lactobacillus rhamnosus GG ATCC-55 103) in infants to prevent
allergic diseases and found similar rates of abdominal discomfort, vomiting, excessive crying,
and difficulty swallowing the product across groups, but infants in the probiotic group had
significantly lower hemoglobin values than the placebo group. The followup period was 2 years;
the last followup was 1.5 years after the intervention had stopped. Ljungberg (2006) followed
children with genetic risk for type 1 diabetes mellitus for two years to evaluate the feasibility of
using Lactobacillus rhamnosus GG in the first 6 months of life to decrease the appearance of
Type 1 diabetes-associated autoantibodies. At the 2-year followup, the study found two samples
positive for autoantibodies (3 across all followup periods), but the treatment group allocation was
not specified, and other adverse event results were not reported. Naito (2008) investigated a 1
year probiotic supplementation (Lactobacillus casei Shirota) of participants on chemotherapy
and reported no statistically significant differences between pain on micturition, urinary
frequency, gross hematuria, constipation, or diarrhea across groups in the 3-year followup
period, 2 years after the intervention stopped.
Niers (2009) investigated a short prenatal exposure and then 1 year of Bifidobacterium and
Lactobacillus intake of mothers and their high-risk children to prevent allergic disease and
33
followed these dyads for 2 years. The flow diagram shows that the rate of dropouts for health
problems of the child or the mother, feeding difficulties, or gastrointestinal colic were similar
across groups.
No other trials were identified that reported on long-term effects of probiotics. The effects of
long-term use of probiotics (defined as intervention durations of 1 year or more) are described in
Key Question 4a.
(1c) What harms are reported in case reports?
In total, 43 case studies were identified that reported 1 case (Barton, 2001; Bassetti, 1998;
Burkhardt, 2005; Cesaro, 2000; Cherifi, 2004; Conen, 2009; De Groote, 2005; Fredenucci, 1998;
Henry, 2004; Hwang, 2009; Jensen, 1976; Ku, 2006; Ledoux, 2006; Lestin, 2003; Lolis, 2008;
Lungarotti, 2003; Mackay, 1999; Munakata, 2010; Niault, 1999; Oggioni, 1998; Oh, 1979;
Ohishi, 2010; Perapoch, 2000; Piarroux, 1999; Piechno, 2007; Pletinex, 1995; Presterl, 2001;
Rautio, 1999; Rijnders, 2000; Tommasi, 2008; Trautmann, 2008; Viggiano, 1995; Zein, 2008;
Zunic, 1991), 2 cases (Force, 1995; Kunz, 2004; Land, 2005; Riquelme, 2003), 3 cases (Kniehl,
2003; Munoz, 2005), 4 cases (Hennequin, 2000; Richard, 1988) or 6 cases (Lherm, 2002) of
individuals who experienced an adverse event potentially associated with administered probiotic
organisms. Only patients reported to have taken probiotic organisms purposefully (intervention
study criterion) were eligible for inclusion in the review; hence, Perapoch et al. (2000) and
Piarroux et al. (1999) contributed only one case each to the evidence tables, Munoz (2005) three
cases, and Lherm (2002) six out of seven discussed cases. The identified case studies reported on
62 cases in total.
The participant details are abstracted in Evidence Table C1, Study and Participant Detail; the
product details are abstracted in Evidence Table C2, Intervention. We extracted details for all
included case studies that reported adverse events. We extracted the exact reported adverse
event(s) and classified them using the CTCAE classification system. Although the reporting of
adverse events tended to be more detailed in case studies, it was nonetheless rarely possible to
grade the severity of the individual symptoms. The adverse events are shown in Evidence Table
C4, Results.
The safety of probiotics was the main aim of all included case studies; the topic was an
adverse event potentially associated with the intake of probiotic organisms. The case reports
considered the adverse event to have potentially been caused by the intake of probiotic
organisms.
The majority of publications presented the finding as a rare event of clinical importance
encountered in clinical practice (Barton, 2001; Bassetti, 1998; Burkhardt, 2005; Cesaro, 2000;
Cherifi, 2004; Conen, 2009; De Groote, 2005; Force, 1995; Fredenucci, 1998; Hennequin, 2000;
Henry, 2004; Hwang, 2009; Jensen, 1976; Ku, 2006; Kunz, 2004; Land, 2005; Ledoux, 2006;
Lestin, 2003; Lolis, 2008; Lungarotti, 2003; Mackay, 1999; Munakata, 2010; Niault, 1999;
Oggioni, 1998; Oh, 1979; Ohishi, 2010; Perapoch, 2000; Piechno, 2007; Pletinex, 1995; Presterl,
2001; Rautio, 1999; Rijnders, 2000; Riquelme, 2003; Tommasi, 2008; Trautmann, 2008;
Viggiano, 1995; Zein, 2008; Zunic, 1991).
Other cases were identified by following up a particular infection and then investigating
whether it might be linked to exposure to probiotics. Lherm (2002) describe seven cases of
fungemia in an intensive care unit, 6 of which could be linked to pretreatment with
Saccharomyces boulardii [cerevisiae]. Munoz (2005) observed three patients with
Saccharomyces cerevisiae fungemia in an intensive care unit for whom a review of the medical
34
records identified the treatment with Ultralevura as a risk factor. Piarroux (1999) retrospectively
analyzed case histories of 437 observed cases of fungemia and concluded that Saccharomyces
accounted for 16 cases. The authors described a Saccharomyces boulardii [cerevisiae]
intervention for one patient but provided no further details on the other cases. Richard (1988)
followed up all encountered cases of bacteremia caused by a Bacillus strain in a 6-year period
and concluded that four of eight cases of Bacillus subtilis bacteremia were associated with the
absorption of an oral preparation containing Bacillus subtilis spores.
The most commonly reported single outcome in the case studies was fungemia. Fungemia or
presence of Saccharomyces cerevisiae/boulardii in blood cultures was reported for 33 cases in
21 publications (Bassetti, 1998; Cesaro, 2000; Cherifi, 2004; Force, 1995; Fredenucci, 1998;
Hennequin, 2000; Henry, 2004; Lherm, 2002; Lolis, 2008; Lungarotti, 2003; Munoz, 2005;
Niault, 1999; Perapoch, 2000; Piarroux, 1999; Piechno, 2007; Pletinex, 1995; Rijnders, 2000;
Riquelme, 2003; Trautmann, 2008; Viggiano, 1995; Zunic, 1991). In addition, one publication
reported the spread of fungemia to another infant who had not consumed probiotic organisms
(Perapoch, 2000). All studies reported that the infection was associated with the administered
organism Saccharomyces boulardii [cerevisiae]; however more details on the reliability and
validity of the recovery methods are given in section 1h.
Eight cases of bacteremia associated with Lactobacillus acidophilus, Lactobacillus casei,
Lactobacillus GG, and Bacillus subtilis were reported in six publications (Barton, 2001; De
Groote, 2005; Ledoux, 2006; Richard, 1988; Tommasi, 2008).
Sepsis was reported for nine cases described in seven publications (Burkhardt, 2005; Kunz,
2004; Land, 2005; Lestin, 2003; Oggioni, 1998; Ohishi, 2010; Zein, 2008). The authors
associated the outcome with the intake of Saccharomyces boulardii [cerevisiae], Lactobacillus
GG, Bacillus subtilis, Bifidobacterium breve, or a blend of Bifidobacterium and Lactobacillus
strains, but more details are reported in section 1h.
D-lactic acidosis was reportedly associated with Lactobacillus acidophilus in one case, a
blend of Lactobacillus acidophilus and Bifidobacterium infantis in one other, and a product
containing Lactobacillus acidophilus, Lactobacillus bulgaricus, Streptococcus faecalis, and
Streptococcus faecium in three publications (Ku, 2006; Munakata, 2010; Oh, 1979). Endocarditis
was reported in two publications reporting on two total cases (Mackay, 1999; Presterl, 2001),
associated with a blend of Lactobacillus and Streptococcus strains. The development of an
abscess associated with Lactobacillus rhamnosus was reported in two publications describing
one case each (Conen, 2009; Rautio, 1999). Fever as the main adverse event after
Saccharomyces boulardii [cerevisiae] use was described in one publication describing one
patient (Jensen, 1976). One case of food protein-induced enterocolitis syndrome was associated
with a Saccharomyces boulardii [cerevisiae] intervention (Hwang, 2009). Kniehl et al. (2003)
reported 3 cases of diarrhea in patients who took a Bacillus product, but concluded that
probiotics medication may result in diagnostically misleading results when stool specimens are
taken (pseudo-outbreak of Bacillus cereus).
Twelve of the 59 patients described above died: 1 patient due to neurological complications
(Richard, 1988), 1 due to pulmonary infection (Richard, 1988), 1 due to complications of
anorexia nervosa (Cherifi, 2004), 1 due to multiple organ failure after bypass operation (Lestin,
2003), 2 presumably primarily sepsis related (Oggioni, 1998; Rijnders, 2000), and 6 patients due
to causes not further specified (Lherm, 2002; Munoz, 2005).
35
Long-Term Effects
Three studies reported on the clinical course of the presented case studies and followed the
patient for 1 year or more.
Oh (1979) reported on an incidence of d-lactic acidosis in a patient with short-bowel
syndrome taking Lactobacillus acidophilus. After treatment with neomycin, the patient remained
free of acidosis and neurologic dysfunction in the reported 1-year followup period. Presterl
(2001) reported on a case of endocarditis initially associated with the intake of Lactobacillus
rhamnosus after possible long-term consumption of probiotic yogurt (exact duration not
reported, DNA-based methods showed no match of organisms). After treatment with penicillin
for the infection and other medical procedures for further morbidities, the patient was well at the
3-, 6-, and 12-month checkups.
Cesaro (2000) reported on a case of Saccharomyces cerevisiae fungemia in a neutropenic
patient. After treatment with amphotericin-B, bone marrow transplantation, and chemotherapy to
treat leukemia, the patient was well at least 3 years after the fungemia incidence.
(1d) What safety parameters are collected in population surveillance
studies and other observational studies, and do these include only standard
clinical safety parameters (e.g., standard blood chemistry profiles) or also
expanded laboratory or clinical testing unique to the use of probiotics?
None of the included studies in this review is a traditional population surveillance study.
None of the screened studies followed participants who chose to take probiotics or synbiotics,
and hence would have been a self-selected intervention group. With the exception of some case
studies, all of the included studies were part of a research study investigating the effects of
probiotics or synbiotics chosen by the study investigators. We identified no cohort study
comparing a group of participants who used probiotics with a group of people who did not. We
also did not identify case-control studies that met all our inclusion criteria, that is, studies that
identify cases by the outcome and look for potential risk factors, of which taking probiotics
might be one. Hence there is no evidence from traditional population surveillance studies.
We identified 53 case series, studies that followed a group of participants who were given
probiotics or synbiotics. Case series do not compare the results of the treatment sample to a
control group, so this evidence is typically classified as observational and limited in its power to
allow inferences from observed adverse events to the received intervention. Two thirds of the
identified studies used medium sample sizes. Only 8 large studies (reporting on 100 or more
participants) were identified (Bellomo, 1979; Cobo Sanz, 2006; Colecchia, 2006; Di Pierro,
2009; Dughera, 2007; Fukuda, 2008; Gniwotta, 1977; Luoto, 2010). Eight studies reported on 10
or fewer participants (Benchimol, 2004; Berman, 2006; Bruce, 1988; Elmer, 1995; Garrido,
2005; Hensgens, 1976; Malkov, 2006; Reid, 2001; Weiss, 2010).
Nineteen of the case series indicated that investigating the safety of the intervention was one
of the main aims of the publication (Bibiloni, 2005; Bruni, 2009; Colecchia, 2006; Elmer, 1995;
Fukuda, 2008; Gabrielli, 2009; Huynh, 2009; Karimi, 2005; Kitajima, 1997; Lamiki, 2010;
Lombardo, 2009; Luoto, 2010; Mego, 2005; Nobuta, 2009; Rosenfeldt V, 2003; Uehara, 2006;
Yim, 2006; Zahradnik, 2009). However, almost half of the case series did not report that they
assessed adverse events as part of their treatment evaluation, as can be seen in Evidence Table
C3, Assessment.
36
Where studies stated that adverse events were monitored, they typically did not define what
would be considered an adverse event and what exactly was monitored. Where specified, studies
mentioned that they monitored gastrointestinal symptoms or blood chemistry results.
To assess any adverse events that may occur during the treatment period, some studies used a
patient diary (Barrett, 2008; Bekkali, 2007; Gionchetti, 2007; Huynh, 2009; Lamiki, 2010;
Lombardo, 2009; Zahradnik, 2009) or a questionnaire (An, 2010; Barrett, 2008; Cobo Sanz,
2006; Colecchia, 2006; Dughera, 2007; Gruenwald, 2002; Nobuta, 2009), but in most cases, the
assessment was done by a health care professional. It was often not clear whether the assessment
of adverse events was prompted or whether the health care professionals recorded only adverse
events that participants chose to mention. Colechia (2006) reported the use of a published
questionnaire (Neri, 2000) for the harms assessment. The measure was designed to discriminate
irritable bowel syndrome and gastrointestinal diseases from food allergies; however it also
covered drug tolerance. Mego (2005 and 2006) graded toxicity according to the National Cancer
Institute Common Toxicity Criteria (version 2.0), designed to report results of cancer treatment.
We also extracted which adverse events were reported on by the authors, regardless of
whether the harm occurred or it was reported that no incidence of the harm was found. The most
frequently recorded individual adverse event was diarrhea or watery stool (recorded in nine
studies); gas, meteorism, or flatulence (nine studies); bloating or fullness (seven studies);
abdominal pain or gastralgia (five studies); and nausea (six studies).
(1e) What harms are reported in population surveillance studies and other
observational studies?
As described under Key Question 1d, we did not identify conventional population
surveillance studies that met our inclusion criteria. The only evidence that can be described here
stems from case series. In this review, a case series was defined as a study reporting on a single
group of participants using probiotics or synbiotics. In total, 53 case series were identified
reporting on 3,473 participants. The majority investigated Lactobacillus strain interventions,
mainly alone or in some cases in combination with strains of other genera. Five studies
investigated an intervention including Bifidobacterium, four used Saccharomyces, three
Enterococcus, two Streptococcus, and two Bacillus organisms. All included genera are indicated
in the Evidence Table C4, Results, details of the individual interventions are shown in Evidence
Table C2, Intervention.
For all case series, we extracted which adverse events were reported in the publication, using
the exact wording from the articles. In addition we classified the adverse events using the
CTCAE classification system and graded events where possible; however the reported detail of
adverse events rarely permitted grading the severity. We also indicated for each outcome
whether it was considered an SAE. The details of each study can be seen in Evidence Table C4,
Results.
The most frequently reported incidence of an individual symptom across the case series was
bloating or fullness (25 participants, recorded in 7 studies) followed by diarrhea or watery stools
(22 participants across studies, 16 studies recorded the outcome). Flatulence or gas (20
participants, 9 studies recorded the outcome) and nausea (18 participants, recorded in 13 studies)
were also recorded in more than 10 participants.
In total, the case series reported 12 deaths across studies, and the outcome was recorded in 3
studies. During the study reported by Carlsson (2009), two dementia patients using Lactobacillus
and Lactococcus among other medications died. Malkov (2006) reporting on a sample of 10
37
cancer patients using, among other medication, a Bacillus oligonitrophilus KU-1 containing
product, all of whom died from unspecified causes, liver failure, pulmonary edema, and stroke.
Mego (2006) reported that no deaths occurred (Enterococcus faecium M-74 containing
intervention).
In the absence of a control group and multiple alternative explanations for the reported
adverse events, it is not possible to attribute the events to the probiotics intervention.
Long-Term Effects
None of the included case series reported on long-term treatment effects (a followup of 1 or more
years after the administration of probiotic organisms).
(1f) What harms are reported in human mechanistic studies?
Of the included studies that reported a specific adverse event, none could clearly be
described as a mechanistic study. Studies primarily investigating possible mechanisms of action
of probiotics are either not published in the peer-reviewed literature and databases we searched,
which concentrated on health research, or they do not consider patient health outcomes, the focus
of this review. We also identified only a very small number of studies that reported nonspecific
safety statements and that could be described as mechanistic studies (see Appendix C, Evidence
Table C6, Nonspecific Safety Statements).
A study focusing in part on a mechanistic question (Garrido, 2005) investigated how the
ingestion of different amounts of Lactobacillus johnsonii La1 influences the main bacterial
populations of the fecal microbiota in eight symptomatic volunteers. The study stated that the
participants showed good tolerance for the product and noted only mild increases of borborygmi.
Johansson (1998) investigated the survival of Lactobacillus plantarum DSM 9843 (299v) after
ingestion in a RCT and reported that five participants in the probiotic and (the rose-hip drink)
control group experienced transient abdominal discomfort, nausea, or flulike symptoms.
Songisepp (2005) studied the fecal lactoflora composition, Lactobacillus fermentum ME-3
recovery, intestinal lactoflora, and oxidative stress markers of blood in healthy volunteers and
reported one acute respiratory viral infection (treatment group unclear) and no changes in
gastrointestinal functions or other adverse effects on general welfare.
A case series by Biblioni (2005) that investigated the composition of biopsy-associated
microbiota in patients with ulcerative colitis among other questions reported that no biochemical
adverse events occurred with VSL#3, but 29 percent of participants reported increased bloating.
Satokari (2001) published an additional article on polymerase chain reaction and denaturing
gradient gel electrophoresis monitoring of fecal Bifidobacterium populations in a prebiotic and
probiotic trial, and reported one incident of abdominal discomfort in the control group and one
control group participant who did not complete the study due to antibiotic treatment.
(1g) Do the studies describe an antibiotic therapy designed to treat
unintended pathology caused by the administered organism?
Of the 387 included studies, 40 case studies (of all 43 case studies) described an antibiotic or
antifungal therapy designed to treat unintended pathology potentially caused by the administered
organism (Barton, 2001; Bassetti, 1998; Burkhardt, 2005; Cesaro, 2000; Cherifi, 2004; Conen,
2009; De Groote, 2005; Force, 1995; Fredenucci, 1998; Hennequin, 2000; Henry, 2004; Ku,
2006; Kunz, 2004; Land, 2005; Ledoux, 2006; Lestin, 2003; Lherm, 2002; Lolis, 2008;
Lungarotti, 2003; Mackay, 1999; Munakata, 2010; Munoz, 2005; Niault, 1999; Oggioni, 1998;
38
Oh, 1979; Ohishi, 2010; Perapoch, 2000; Piarroux, 1999; Piechno, 2007; Pletinex, 1995;
Presterl, 2001; Rautio, 1999; Richard, 1988; Rijnders, 2000; Riquelme, 2003; Tommasi, 2008;
Trautmann, 2008; Viggiano, 1995; Zein, 2008; Zunic, 1991). Details of the case studies are
described in section 1c.
None of the other studies (i.e., case series, CCTs, parallel and crossover RCTs) reported the
use of antibiotics to treat unintended effects of the probiotics treatment.
However, causes for antibiotic or antifungal therapy were neither always clearly stated nor
easy to establish, and authors might not have associated the treatment with the probiotic
intervention. Hence, we extracted any mention of antibiotic treatment in the included studies.
This summary does not include studies where all participants received antibiotics as a
cotreatment or studies where the reduction or prevention of antibiotics use was an efficacy
outcome. Only studies were considered that reported that a course of antibiotic or antifungal
treatment was required to treat an adverse event of individual participants during or after the
intervention period.
Two case series reported that a participant required antibiotic treatment during a probiotic
intervention. One study reported antibiotic treatment for febrile neutropenia (Mego, 2006). The
other study reported treatment for a case of bronchitis (Reid, 2001).
Seventeen RCTs in total reported explicitly that a participant required antibiotic treatment
during or after the intervention. In none of the RCTs did the authors relate the infections
requiring antibiotic treatment to the probiotic, and antibiotic treatment was required in treatment
and control group participants.
One study reported that participants receiving the probiotic had more otitis media, and it was
then treated with an antibiotic (Abrahamsson, 2007). Allen (2010) reported more respiratory
infections in the probiotic treatment group compared to placebo, and nine cases across arms were
treated with antibiotics. Basu (2007) reported that two participants in each group were treated for
septicemia (presumably with antibiotics, although not explicitly stated). Another study reported
that two participants received antibiotics for abscesses that the authors attributed to Crohn’s
disease, specifically stating that they were “not caused by LGG,” or Lactobacillus GG
(Bousvaros, 2005). Gerasimov (2010) reported that three preschool children (two treatment
group and one control group) treated for atopic dermatitis were lost to followup due to
respiratory tract infections requiring antibacterial therapy. Two of the RCTs reported
unanticipated antibiotic use required during probiotic and placebo treatment but did not specify
what it was treating (Chouraqui, 2008; Krasse, 2006). Haschke-Becher (2008) reported that one
child in a probiotic intervention and three children in control groups withdrew due to antibiotic
intake. One of the RCTs reported a gastrointestinal infection in the probiotics treatment group,
without identification of the causative organism (Mimura, 2004). In another study, one case of
perineal Candida was found in both arms and was treated with antibiotics (Millar, 1993). Niers
(2009) reported that three mother-child pairs out of each treatment group discontinued a trial on
prevention of allergic diseases due to use of antibiotics. Satokari (2001) reported that one control
group participant did not complete the study because of an antibiotic treatment (details not
reported). Sullivan (2003) reported that one participant in the probiotics group developed
diarrhea, with no causative organism confirmed and was later treated with antibiotics. Tursi
(2006 and 2008) reported that one case in a probiotics group was admitted to a hospital due to
acute bronchial pneumonia and treated with antibiotics.
Larsson (2008) reported that 10 participants received antibiotics for upper respiratory
infections or other reasons, at least 4 of whom were in the probiotic group. De Preter (2006)
39
reported that 1 participant withdrew from a crossover trial comparing Saccharomyces boulardii
[cerevisiae], lactulose, and placebo intake but the group to which the participant was assigned
was not reported.
(1h) Do the studies describe methods for recovery of the administered
organism from either the gastrointestinal tract or serum?
To be included in the review, studies had to report an adverse patient health outcome; the
recovery of the administered organism alone was not a sufficient outcome to be eligible for
inclusion in the review. Nonetheless, a large number of included studies reported recovery of
Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus in
the gastrointestinal tract, serum, mouth, or vagina. In most cases, the attempt to recover the
organism was used as an efficacy measure, an indicator of a successful intervention and quality
check that the organism was indeed consumed.
None of the case series, CCTs, or parallel or crossover RCTs reported an infection or other
significant clinical signs and the recovery of the administered organism. Some of the trials
reported that infections and/or the recovery of the administered organisms in the blood were
monitored but that no cases occurred. A description of the methods was not reported; however,
any suspected positive identification may have changed that.
Evidence From Controlled Trials
In total, 36 trials reported that sepsis, bacteremia or fungemia, infections, or blood cultures
were monitored to investigate associations with the administered organism as a safety
precaution.
A small number of trials reported explicitly on the absence of probiotics-associated sepsis,
bacteremia or fungemia. Alberda (2007) reported no cases of Lactobacillus-induced sepsis. BinNun (2005) reported no cases of sepsis due to administered probiotics (Bifidobacterium and
Streptococcus strains). Forestier (2008) reported no cases of Lactobacillus-related sepsis.
Jirapinyo (2002) reported no cases of sepsis due to Lactobacillus or Bifidobacterium. Kerac
(2009) reported no cases of probiotics-related sepsis (Lactobacillus, Leuconostoc, and
Pediococcus). Li (2004) reported no cases of sepsis due to Bifidobacterium. Lin (2005) reported
no cases of sepsis due to probiotics (Lactobacillus and Bifidobacterium). Lin (2008) reported no
cases of sepsis due to probiotics (Lactobacillus and Bifidobacterium). Manzoni (2006) reported
no cases of sepsis due to LGG. Millar (1993) reported no cases of sepsis or infections
attributable to LGG. Rouge (2009) reported no cases of sepsis due to Lactobacillus and
Bifidobacterium. Barraud (2010) reported no cases of bacteremia due to Lactobacillus.
Honeycutt (2007) reported no cases of Lactobacillus bacteremia. Morrow (2010) reported no
cases of Lactobacillus bacteremia. Song (2010) reported no cases of fungemia due to
Saccharomyces.
A small number of trials reported on the absence of probiotic-associated infections or signs
of infections. Allen (2010) reported no infections due to Lactobacillus or Bifidobacterium. The
PROPATRIA trial (Besselink, 2008) reported no infections caused by the administered
probiotics (Lactobacillus and Bifidobacterium strains). Frohmader (2010) reported no infections
due to probiotic strains (Lactobacillus, Bifidobacterium, and Streptococcus strains). Kotzampassi
(2006) reported no cases of infections due to Lactobacillus species contained in formula.
Lawrence (2005) reported no cases of Lactobacillus infections. Salminen (2004) reported no
cases of infections due to Lactobacillus. Awad (2010) reported no probiotic bacteria were found
40
in blood (Lactobacillus). Osterlund (2007) reported no cases of Lactobacillus growth in blood.
Peral (2009) reported that the administered Lactobacillus organism was not recovered in
peripheral blood or wound samples. Samanta (2008) reported no blood cultures grew
Lactobacillus or Bifidobacterium. Wolf (1998) reported that all cultures for bacteria in blood
samples showed no growth after seven days of incubation (Lactobacillus).
Finally, some studies reported on the absence of infectious incidences without reference to
the administered probiotic. Anukam (2008) reported no cases of bacteremia (Lactobacillus and
Streptococcus strain intervention). Delia (2007) reported no cases of bacteremia or sepsis
(intervention with Lactobacillus, Bifidobacterium, and Streptococcus strains). Kianifar (2009)
reported no cases of bacteremia or fungemia (Lactobacillus and Bifidobacterium intervention).
Luoto (2010) reported no cases of sepsis (Lactobacillus and Bifidobacterium intervention).
Merenstein (2010) reported no cases of viral infections causing fever in the treatment group
(Lactobacillus and Streptococcus strains). Panigrahi (2008) reported no cases of sepsis
(Lactobacillus intervention). Reid (1992) reported no cases of superinfections (Lactobacillus
strains). Saint-Marc (2010) reported no cases of infections (Saccharomyces intervention).
Songisepp (2005) reported no infections (Lactobacillus intervention). Wada (2010) reported no
cases of bacteremia (Bifidobacterium intervention). Knight (2007) reviewed whether any deaths
in the samples were attributable to probiotic organisms and reported also on colonization of
Leuconostoc in tracheal aspirate which may indicate that they also looked for the administered
organisms. McFarland (1994) reported no cases of Staphylococcus sepsis, which may indicate
that they also looked for the administered organisms.
Evidence From Case Series
Of the case series, Luoto (2010) reported no cases of LGG sepsis. Mego (2005) reported that
the seven cases of bacteremia were mainly caused by coagulase-negative Staphylococcus and
concluded that no infection was induced by the tested strain (Enterococcus faecium M-74). In a
second study, Mego (2005) described a test for colonization of the gut by Enterococcus bacteria
and in addition stated that bacteremia or infection caused by the tested probiotic strain
(Enterococcus faecium M-74) was not found. Schneider (2005) described stool analyses and
reported that no fever or fungemia occurred but did not mention a specific test (Saccharomyces
boulardii [cerevisiae] intervention. Srinivasan (2006) explicitly stated that cultures did not show
a pathologic growth of Lactobacillus bacteria (in surface cultures or sterile body fluids).
Evidence From Case Studies
Most case studies reported the recovery of an organism that resembled the administered
probiotic strain (see Evidence Table C4, Results). The years of publication of the case studies
encompass almost 40 years, during which time methods of identification have evolved. In
several cases, there remained some doubt whether the recovered strain was identical to the
administered organism. In most publications, authors suspected that there was an association
rather than being able to show conclusively that the administered and the recovered organism
were identical.
Several case studies did not report on an identification method, used phenotypic
identification alone, or used other indicators such as the temporal closeness to the reaction
(Burkhardt, 2005; Cesaro, 2000; Cherifi, 2004; Force, 1995; Henry, 2004; Hwang, 2009; Jensen,
1976; Ku, 2006; Ledoux, 2006; Lestin, 2003; Lungarotti, 2003; Mackay, 1999; Munakata, 2010;
41
Niault, 1999; Oh, 1979; Piechno, 2007; Pletinex, 1995; Rijnders, 2000; Spinosa, 2000; Tommasi,
2008; Trautmann, 2008; Viggiano, 1995; Zein, 2008; Zunic, 1991)
Other studies, in particular more recent ones, described a genetic fingerprinting approach to
match species or strains.
Lactobacillus. Conen (2009) reported that Lactobacillus rhamnosus species recovered from an
abscess were identical to the intervention species according to not further specified genetic
sequencing pattern and resistance testing. De Groote (2005) used sequencing of the ribosomal
operon region and strain typing of the isolates with pulsed field gel electrophoresis to show
identity of the intervention organism and the Lactobacillus rhamnosus blood stream isolates.
Kunz (2004) used PFGE to identify Lactobacillus GG from blood culture isolate in a case of
sepsis and intervention isolates. Land (2005) used repetitive element sequence-based polymerase
chain reaction DNA fingerprinting to match Lactobacillus GG isolates from bacteremia and
sepsis cases and the intervention isolate. Rautio (1999) used pulsed-field gel electrophoresis
(PFGE) to identify Lactobacillus rhamnosus species.
Presterl (2001) used randomly amplified polymorphic DNA polymerase chain reaction
(RAPD)-PCR assays to distinguish pathogens and the probiotic strain and concluded that the
Lactobacillus rhamnosus isolate causing endocarditis and septic arthritis was not identical with
the probiotic yogurt Lactobacillus rhamnosus isolate as initially suspected.
Bifidobacterium. Ohishi (2010) used polymerase chain reaction analysis and strain-specific
identification by a randomly amplified polymorphic DNA analysis to confirm the identity of
sepsis isolates and the Bifidobacterium breve BBG-01 intervention.
Saccharomyces. Bassetti (1998) used pulsed field gel electrophoresis (PFGE) to match
Saccharomyces cerevisiae species seen in fungemia with the intervention species. Fredenucci
(1998) used electrophoretic patterns and variations in DNA-band patterns to establish the identity
of the administered Saccharomyces boulardii [cerevisiae] organisms and fungemia isolates.
Hennequin (2000) used mitochondrial DNA patterns to compare fungemia isolates and
intervention Saccharomyces boulardii [cerevisiae] organisms. Lherm (2002) used a comparison
of the polymorphism of nuclear and mitochondrial DNA with 13 restriction enzymes from the
Saccharomyces boulardii [cerevisiae]) isolated in patients and the intervention. Lolis (2008)
used sequencing analysis on the DNA of the fungemia strain isolated as Saccharomyces
cerevisiae and the isolate obtained from the intervention product and reported 98 percent
correspondence. Munoz (2005) reported that Saccharomyces cerevisiae isolates were compared
in PCR fingerprinting profiles. Perapoch (2000) used molecular identification based on
mitochondrial DNA restriction analysis and chromosomal DNA profiles to show that
Saccharomyces cerevisiae isolates were identical. Piarroux (1999) used DNA sequences to
compare Saccharomyces boulardii [cerevisiae] isolates. Riquelme (2003) used PFGE clonality
banding patterns to match Saccharomyces cerevisiae isolates.
Streptococcus. No case studies associated with Streptococcus strains used as probiotics were
identified.
Enterococcus. No case studies associated with Enterococcus strains used as probiotics were
identified.
42
Bacillus. Oggioni (1998) used randomly amplified polymorphic DNA technique for two Bacillus
subtilis strains.
Summary and Strength of Evidence Key Question 1
What is the evidence that the active (e.g., live or viable) and lyophilized forms of probiotics
(Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus) as
single ingredients or in combination with other probiotics or prebiotics in all delivery vehicles
(and formulations) when used to cure, treat, mitigate or prevent a disease or reduce disease risk
are safe in the short term? Long term?
Volume: 387 studies
Risk of bias: Medium
The evidence to answer this Key Question stems from a variety of study designs and quality.
Although a large number of RCTs have been identified, the majority was not designed to
systematically assess safety outcomes.
Consistency: Inconsistent
The RCTs, CCTs, and case series show very different results from case studies.
Directness: Direct
The evidence base includes a large number of RCTs directly comparing intervention and
control group participants.
Precision: Imprecise
The majority of included studies use a moderate sample size; very few large studies have
been identified. The studies are not powered to detect differences in adverse event incidences.
The identified evidence is insufficient to answer the Key Question with confidence.
The current literature is not sufficient to allow statements on the safety of probiotics in
research studies if the term “probiotics” comprises the genera Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus. The currently available literature
describes primarily Lactobacillus interventions, alone or in combination with other genera, most
often Bifidobacterium, and some interventions use Saccharomyces organisms. The available
literature includes only a few reports on the genera Streptococcus, Enterococcus, and Bacillus.
The absence of case reports of serious adverse events potentially caused by products containing
Streptococcus or Enterococcus strains cannot be used as an indicator that the risk of serious
adverse events is absent: the overall identified body of literature reporting on the presence and
absence of harms indicates absence of relevant literature. The microorganisms have not been
used in research studies, which may indicate less use in clinical practice.
Few studies indicated what adverse events were monitored. The clinical studies such as
controlled clinical trials, and parallel and crossover randomized controlled trials and
observational case series that reported on monitoring of adverse events listed gastrointestinal
adverse events such as diarrhea, vomiting, and constipation as explicitly monitored.
Individual outcomes that were often reported on were death, diarrhea, constipation, and
nausea, seemingly equally frequent across treatment arms. Individual outcomes such as mortality
43
and allergy sensitization should be assessed in a risk-benefit analysis including the outcome
regardless of whether it was investigated as a safety concern or efficacy measure according to
reports of failed effectiveness.
We have identified a number of case studies reporting cases of fungemia and some
bacteremia cases that are likely to have been caused by the administered probiotic strain. The
number of cases is small considering the volume of the literature searched; however, the studies
indicate that probiotic strains can be associated with serious adverse events and that they can be
linked to the use of probiotic products. To quantify the risk, study designs other than case studies
are needed (e.g., RCTs). Even though the risk potential has been documented in the literature,
studies do not routinely state that they assessed the risk of infections caused by the administered
strain. None of the identified case series, CCTs, or crossover and parallel RCTs reported an
infection caused by the administered probiotic strain.
In the absence of a control group and multiple alternative explanations for the adverse events
reported in case series, it is not possible to attribute the events to the probiotics intervention.
Across RCTs, there was no evidence for a statistically significantly increased relative risk of
the quantity of adverse events for intervention participants compared to control based on two
alternative measures: the number of participants with adverse events per treatment arm (RR 0.98;
95% CI: 0.93, 1.04; p=0.537) and the number of adverse event incidences per treatment group
(RR 1.00; 95% CI: 0.93, 107; p=0.999) in short and medium followup studies.
The review did not identify comparative population surveillance studies that systematically
assessed safety. Very few publications were identified that reported on long-term effects of
probiotics use.
Key Question 2. What are characteristics and associations of the reported
harms in Question 1?
All 387 studies meeting criteria for full data abstraction were considered to answer Key
Question 2.
The overview presented at the beginning of this chapter and Key Question 1 show the
literature is incomplete with regard to the assessment of adverse events potentially associated
with probiotics interventions. The evaluation of the characteristics and associations is limited to
adverse events as currently reported in research studies.
(2a) What interactions between probiotics and medications are reported?
None of the included studies reported a formal interaction analysis for safety data. A number
of studies commented on interaction effects for efficacy outcomes, but none of the studies
investigated statistically whether medication leads to differential safety results
For the purpose of this review, we recorded whether participants in included studies used
antibiotics, corticosteroids, immune suppressants, dietary therapies, or other pertinent
cotreatments (e.g., chemotherapy) that might possibly influence the adverse events experienced
by participants. We found a large number of parallel RCTs where participants systematically
used additional treatments apart from the probiotics preparation under review. To address the
question of an interaction between probiotics and medications, we differentiated RCTs broadly
into those that reported a pertinent cotreatment and those that did not and added this factor to a
meta-regression predicting effect size. This analysis compares the risk ratio between intervention
and control group participants for studies with cotreatments and for studies without cotreatments,
and determines whether this difference in risk is statistically significant.
44
Using the number of participants with adverse events, we found that the relative risk to
experience an adverse event for studies with cotreatments was slightly higher but not statistically
significantly different from studies without pertinent cotreatments (RR 1.12; 95% CI: 0.99, 1.26;
p=0.074). This interaction analysis is based on 106 RCTs for which data were available for
pooling. In total, 44 of these RCTs reported pertinent cotreatments. These numbers are based on
the number of participants experiencing an adverse event. Using the total number of events
across groups as a sensitivity analysis for the robustness of the result, we find a very similar
result: the relative risk for studies with cotreatments was 1.04 times higher than for studies
without cotreatments (95% CI: 0.90, 1.20; p=0.627), also indicating no evidence for a
statistically significant difference in the relative risk of probiotics for studies with and without
cotreatments. This interaction analysis is based on 195 studies; 86 included cotreatments.
Methodologically it is problematic trying to identify an interaction signal across studies rather
than having information that stems from within studies, so this result has to be interpreted with
caution.
It is noteworthy that the included case studies that reported harms such as fungemia and
bacteremia appear to be primarily in patients with multiple morbidities. Although the
concomitant medications were not explicitly listed in all studies, the underlying conditions make
it very likely that these patients were taking other medications (see Evidence Table C1, Study
and Participant Details in the appendix for a description of patients). Whether an interaction
between probiotics and medications contributed to the observed adverse events, and whether this
interaction exists independent of a possible interaction between the underlying condition and
probiotics cannot be determined in case studies.
Key Question 6 reports stratified analyses for the individual reported cotreatments.
(2b) What harms related to acquired antibiotic resistance and/or
transferability are reported?
We included reports of acquired antibiotic resistance as well as antifungal resistance, given
that the scope of the review included Saccharomyces strains. However, only studies reporting on
patient health outcomes were eligible for inclusion in the review; hence this Key Question
considered antibiotic or antifungal resistance and transferability incidences as a patient health
outcome with clinical significance. Reports of laboratory tests showing antibiotic or antifungal
resistance of microbial strains in isolation are outside the scope of the review.
None of the parallel or crossover RCTs, CCTs, or case series reported an incidence of
antibiotic resistance and/or transferability. With regard to monitoring antibiotic resistance or
transferability, one RCT (Reid, 1992) explicitly reported that none of the participants with
urinary tract infections in a Lactobacillus suppository intervention showed any evidence of
super-infection.
Antibiotic or antifungal resistance was addressed in six case reports. Conen (2009) report that
Lactobacillus rhamnosus strains recovered from an abscess were resistant to cephalosporin
classes I through IV and carbapenems but the patient improved with imipenem, clindamycin, and
fluconazole. Oggioni (1998) describe an immunocompromised patient with recurrent septicemia.
The patient’s condition deteriorated despite antibiotic therapy. Bacillus subtilis strains isolated
during fever episodes showed resistance to penicillin, erythromycin, rifampin, and novobiocin in
two samples. Ohishi (2010) describe a neonate with omphalocele who developed
Bifidobacterium septicemia. The isolated strain was susceptible in vitro to penicillin and
ampicillin sulbactam but not to meropenem or amikacin. Piechno (2007) described a case of
45
fungemia in a cancer patient; one of the blood cultures showed the presence of Saccharomyces
boulardii [cerevisiae] and indicated resistance to amphotericin B and possibly fluconazole. The
patient recovered after a course of voriconazole. Trautmann (2008) reported on an intensive care
patient who developed fungemia and presented with fever after initial clinical improvement
while on fluconazole. The patient was able to leave the intensive care unit after administration of
caspofungin. Zein (2008) reported on a diabetic patient who developed Lactobacillus rhamnosus
septicemia; an antibiogram indicated resistance to nalidixic acid, vancomycin, and teicoplanin.
The patient recovered after amoxicillin treatment.
(2c) What is the nature of harms, and do these include only standard harms
or also harms that might be uniquely applicable to the use of a probiotic?
Key Question 1 addressed primarily the quantity of adverse events and specific harms that
were monitored and / or reported. The adverse events reported in the included studies were found
within many organ systems. To explore the nature of the adverse events, we used the CTCAE
system to differentiate adverse events and added an additional category, ‘other,’ so that all harms
could be classified. The categorization system can be seen in Appendix B (data extraction form).
By far the most commonly reported incidence across all included studies was a
gastrointestinal symptom (category VII in the Evidence Table C4, Results), followed by the
category Infections and Infestations (category XI), and the “other” category (category XXVII).
The last category included deaths not further specified, unclear adverse events (e.g., “collapse,”
“general health problems”), and summary incidences (“ear, nose, throat symptoms”).
The graph shows the distribution of adverse events within the categories for all probiotic
intervention arms (up to three per study) across studies and study designs. For studies that
included a control group, frequencies are also shown. Figure 10 shows data from all included
studies, both controlled and uncontrolled.
46
Figure 10. Adverse events per CTCAE category for participants using probiotics and control
participants (up to 3 probiotics intervention groups, 1 control group
700
600
500
400
Tx
Con
300
200
100
0
The categories VII (Gastrointestinal disorders), XI (Infections and infestations); and also
XXVII (Other) are the most common categories describing the observed adverse events. Some
encountered adverse events were included in categories X (Investigations), XX (Renal and
urinary disorders); XXII (Respiratory, thoracic and mediastinal disorders), and XXIII (Skin and
subcutaneous tissue disorders). The other categories (Blood and lymphatic system disorders;
Cardiac disorders; Congenital, familial and genetic disorders; Ear and labyrinth disorders;
Endocrine disorders; Eye disorders; General disorders and administration site conditions;
Hepatobiliary disorders; Immune system disorders; Injury, poisoning and procedural
complications; Metabolism and nutrition disorders; Musculoskeletal and connective tissue
disorders; Neoplasms benign, malignant and unspecified (including cysts and polyps); Nervous
system disorders; Pregnancy, puerperium and perinatal conditions; Psychiatric disorders;
Reproductive system and breast disorders; Social circumstances; Surgical and medical
procedures; and Vascular disorders) rarely described the reported adverse events.
The following sections report the risk of adverse events separately for each of the three
established domains (gastrointestinal, infections, and ‘other’). The ‘other’ category was analyzed
together with all other observed incidences, excluding only categories VII and XI.
Gastrointestinal Adverse Events
To investigate the relative risk for a gastrointestinal adverse event to occur, we pooled the
parallel RCTs that reported on the presence or the absence of these adverse events. The risk for
participants in probiotics intervention groups, relative to non-probiotics control group
participants, was 1.03 (95% CI: 0.89, 1.18, p=0.693) indicating that the probiotic interventions
were not associated with a statistically significantly increased risk of gastrointestinal adverse
events. Overall, there was no evidence across the included RCTs for a statistically significantly
47
increased risk to experience a gastrointestinal symptom in the probiotic group compared to
another group from the same participant population with similar co-interventions and the
presence or absence of underlying diseases. The control groups either received a placebo, no
treatment, or the co-medication or infant formula without the probiotic supplement.
The analysis was based on 126 parallel RCTs. Studies comparing two probiotic or synbiotic
treatments were excluded from this analysis and only one probiotic group was selected per study
so that each study entered the meta-analysis only once (the main treatment group, most similar to
the control group apart from the probiotic addition). This analysis included 104 studies that use
Lactobacillus strains alone or in combination, indicating that Lactobacillus organisms were most
commonly used in the included RCTs. Figure 11 graphically represents individual and pooled
point estimates and 95% CIs obtained in included RCTs. Due to the large number of studies,
numerical estimates and study identifiers of individual RCTs could not be displayed.
48
Figure 11. Graphical representation of the RR of the number of gastrointestinal adverse events
across RCTs
49
The forest plot demonstrates that individual results differed across studies, sometimes
favoring the control group and sometimes the intervention group, with no clear trend in either
direction. Confidence intervals were wide in the large majority of studies, and very few
individual studies reported a statistically significant difference between intervention and control
group participants. The pooled risk difference between groups for gastrointestinal adverse events
was 0.006 (95% CI: -0.001 0.012, p=0.071). The small difference between intervention and
control group participant incidences was not statistically significant at the 5 percent level.
All individual study results are shown in the Evidence Table C4, Results. Stratified analyses
for individual genera, participant characteristics or other intervention characteristics are reported
in the following sections.
Infections and Infestations
We also pooled all incidences of infections and infestations (CTCAE category XI) across the
included 65 parallel RCTs that reported the presence or the absence of these adverse events. The
relative risk for individuals in probiotics groups, relative to a control, was 1.00 (95% CI: 0.87,
1.16, p=0.967). Across all included studies, genera, participant groups, and interventions, there
was no difference in the risk of experiencing infections and infestations.
Figure 12 graphically represents individual and pooled point estimates and 95% CIs obtained
in included studies. The numbering on the left hand side of the forest plot indicates the
investigated genus. The number 1 indicates that a Lactobacillus strain was part of the
intervention. In total, 39 percent of studies investigated blends and most often the blend included
a Lactobacillus strain. The number 2 indicates that Bifidobacterium was present without
Lactobacillus. Number 3 indicates that Saccharomyces organisms were present without
Lactobacillus and Bifidobacterium. The number 4 indicates that Streptococcus or Enterococcus
strains were present without Lactobacillus, Bifidobacterium, or Saccharomyces strains. The
number 6 indicates that the intervention included Bacillus strains, but no Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, or Enterococcus strains. Due to the large
number of studies, numerical estimates and study identifiers of individual RCTs could not be
displayed.
50
Figure 12. Graphical representation of the RR of the number of infection and infestation adverse
events across RCTs
51
The forest plot demonstrates that individual results differed across studies, sometimes
favoring the control group and sometimes the intervention group, with no clear trend in either
direction. Confidence intervals were wide in the large majority of studies, and no individual
study reported a statistically significant difference between intervention and control group
participants. Considering the absolute risk difference model, the risk difference across treatment
and control groups was not detectable (RD 0.000; 95% CI: -0.002, 0.002, p=0.918). There was
no indication that reported infections and infestations were more common in probiotics groups
compared to a comparable participant sample per group across all included parallel RCTs. All
individual study results are shown in the Evidence Table C4, Results. Stratified analyses for
individual genera, participant characteristics, or other intervention characteristics are reported in
the following sections.
Other Adverse Events
The relative risk for individuals in the intervention group compared to the controls was 1.01
(95% CI: 0.91 1.12, p=0.923). In total, 131 RCTs were included in this analysis. The category
‘other’ contains all other adverse event incidences that were not categorized as gastrointestinal in
nature or part of the infections and infestations adverse event domain. This category included the
number of deaths, when the cause of death was not specified and attributed to a specific organ
system.
Figure 13 graphically represents individual and pooled point estimates and 95% CIs obtained
in included RCTs. In this analysis, the majority of included trials contributing data on other
adverse events (107/131) used a Lactobacillus strain alone or in combination with other genera.
Due to the large number of included studies, numerical estimates and study identifiers of
individual RCTs could not be displayed.
52
Figure 13. Graphical representation of the RR of the number of other adverse events across RCTs
53
The forest plot demonstrates that individual results differed across studies, sometimes
favoring the control group and sometimes the intervention group, with no clear trend in either
direction. Confidence intervals were wide in the large majority of studies, and very few
individual studies reported a statistically significant difference between intervention and control
group participants. The risk difference to experience any of the other adverse events (not
gastrointestinal or infections) across treatment groups relative to control was 0.001 (95% CI:
0.003, 0.004; p=0.713). There was no indication that the adverse event incidences were more
frequent in a group using probiotic organisms.
All individual study results are shown in the Evidence Table C4, Results. Stratified analyses
for individual genera, participant characteristics or other intervention characteristics are reported
in the following sections. Evidence pertaining to serious adverse events is documented in Key
Question 5.
Unique Harms
Generally, the identified literature was not very specific with regard to the adverse events
that were monitored. The assessment and results evidence table shows, for example, that several
studies analyzed blood chemistry variables, but researchers rarely reported exactly what they
monitored, and none of the included studies highlighted incidences of unusual or unique results.
Harms unique to probiotics were primarily infections attributed to the administered organism.
Several case studies reported a DNA-based identification of strains (see section 1c). Of all other
included studies, only a few reported explicitly that infections, bacteremia, or sepsis incidences
could possibly be attributed to the administered probiotics strain (see response to Key Question
1h). In the studies that monitored the incidence of infection, none was observed to have been
caused by probiotic organisms. Some trials explicitly reported that no incidences of serious
infections occurred (see Evidence Table C4, Results). Other trials reported only the number of
incidences of sepsis as an adverse event, and it was not clear whether the administered probiotic
strain was considered as a possible cause of the infection.
The frequency of reported gastrointestinal symptoms in the existing literature is noteworthy;
however, neither the quantity nor the quality is unique to probiotics intake; similar symptoms in
a similar quantity were also encountered in control groups.
Summary and Strength of Evidence Key Question 2
What are characteristics and associations of the reported harms in Question 1?
Volume: 387 in total, but varied across subquestions and analyses
Risk of bias: Medium
The evidence to answer this Key Question stems from a variety of study designs and quality.
Consistency: Inconsistent
The RCTs, CCTs, and case series show different results from case studies.
Directness: Varies across subquestions
The evidence base includes a large number of RCTs.
Precision: Precise
54
The majority of included studies use a moderate sample sizes but studies were pooled in a
meta-analysis.
The identified evidence is moderate to low with regard to being able to answer the Key
Question with confidence.
As described, the interventions and adverse events are not well documented and studies were
not designed to assess adverse events systematically. The majority of studies investigated
Lactobacillus interventions, alone or in combination with other genera, most often
Bifidobacterium. Studies rarely reported efforts to monitor adverse events specific to probiotic
products. Hence, evaluations of the safety might change with future, more targeted, assessment
of adverse events.
Across all included studies, by far the most commonly reported adverse events were
gastrointestinal in nature, followed by reported infections and infestations. The third most
common category was the “other” category for symptoms that could not be assigned to one of
the organ systems outlined in the applied CTCAE system. While the case studies primarily
reported infections suspected or confirmed to be caused by an administered probiotics strain, the
majority of other studies reported gastrointestinal incidences.
Across identified RCTs, there was no indication that participants using probiotic organisms
experienced statistically significantly more gastrointestinal adverse events, infections and
infestations, or other adverse events compared to control group participants. Individual
comparisons were based on a large number of RCTs.
There is a lack of individual studies assessing interaction effects of medication affecting
adverse events. An indirect comparison of RCTs in participants with pertinent co-medications
compared to studies not describing these comedications indicated a slightly increased, but not
statistically significantly different, relative risk ratio of adverse events between treatment and
control group participants.
We identified only a very small number of studies addressing acquired antibiotic resistance
as a patient outcome with clinical relevance. Evidence for potential harms came from case
studies in patients with multiple morbidities. Resistance was reported only to selected antibiotics.
Adverse events other than infections potentially caused by the administered probiotics strain
and unique to probiotics were not addressed in the literature. Evidence for infections came from
case studies; included trials did not report on this outcome and/or did not find any cases and did
not highlight adverse events unique to probiotics use.
Key Question 3. What is the evidence that harms of Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus differ by product and delivery characteristics?
Very few studies were identified that explicitly investigated the effects of a commercially
available food product (see Evidence Table C2, Intervention). The majority of identified studies
appeared to provide a probiotic intervention prepared especially for the particular research study
to investigate a beneficial health effect in participants with moderate health impairments.
Most included studies investigated Lactobacillus and/or Bifidobacterium preparations. In
particular there were few reports on the genera Enterococcus, and Bacillus.
The reporting of the interventions was insufficient. A large number of studies did not report
the strain that was investigated. The lack of reporting is a safety concern.
55
(3a) What is the scientific evidence that harms differ by delivery vehicle
including excipients or novel delivery vehicles?
We extracted the investigated product name where reported in the publication. Different
products such as Actimel, Culturelle, Infloran, or Yakult were described. However, the majority
of studies did not state any product name and reported only the genus, such as Lactobacillus, that
was given to participants.
By far the most common delivery vehicle was a pill or capsule, used in 101 included studies
(see Evidence Table C2, Intervention). We also identified 29 studies of probiotic organisms in a
dairy drink (Arunachalam, 2000; Barrett, 2008; Beausoleil, 2007; Boge, 2009; Cobo Sanz, 2006;
Conen, 2009; Felley, 2001; Gotteland, 2003; Guillemard, 2010; Guyonnet, 2009; Hensgens,
1976; Ishikawa, 2003; Kajander, 2008; Merenstein, 2010; Newcomer, 1983; O'Mahony, 2005;
Rautio, 1999; Rio, 2002; Salminen, 2004; Seppo, 2003; Simren, 2010; Songisepp, 2005;
Spanhaak, 1998; Srinivasan, 2006; Sykora, 2005; Turchet, 2003; Wang, 2004; Yang, 2008).
Twenty-one studies used enriched yogurt (Anukam, 2008; Bajaj, 2008; Carlsson, 2009; de Roos,
1999; Fukuda, 2008; Higashikawa, 2010; Kajimoto, 2002; Kim, 2008; Manley, 2007; MartinezCanavate, 2009; Miyaji, 2006; Olivares, 2006; Parfenov, 2005; Parfenov, 2005; Presterl, 2001;
Sakamoto, 2001; Salminen, 1988; Sullivan, 2003; Tomoda, 1991; Wheeler, 1997; Xiao, 2003).
Among all identified studies, 29 added probiotic organisms to an infant formula (Bin-Nun, 2005;
Chouraqui, 2008; Chouraqui, 2004; Cooper, 2006; Correa, 2005; Dupont, 2010; Gibson, 2009;
Haschke-Becher, 2008; Kirjavainen, 2003; Langhendries, 1995; Lin, 2008; Maldonado, 2009;
Millar, 1993; Petschow, 2005; Puccio, 2007; Reuman, 1986; Ruiz-Palacios, 1996; Saavedra,
2004; Scalabrin, 2009; Stratiki, 2007; Urban, 2008; van der Aa, 2010; Vendt, 2006; Vlieger,
2009; Weizman, 2006; Weizman, 2005; Ziegler, 2003).
Other studies used less common delivery vehicles such as vaginal suppositories; powder,
often to be dissolved in water; chewing gum; drops; spray; or cultures on gauze pads as the
Evidence Table C2, Intervention shows. Where available, we extracted the information on the
delivery vehicle, such as whether the preparation was diluted with water or juice (Champagne,
2005) or mixed with breast milk (Lin, 2005). However, most studies did not describe exactly
how the preparation was taken and whether it varied across participants.
Only one study was identified that compared two different delivery vehicles directly
(Isolauri, 1991), that is, providing direct evidence on the effect of delivery vehicles. In this study,
a group of children given a Lactobacillus casei GG fermented milk product was compared to a
group of children using Lactobacillus GG as a lyophilized powder to promote recovery from
acute diarrhea. The study reported that on day one, 58 percent of children in the milk product
group vomited compared to 43 percent in the powder group; on day two, 21 percent versus 22
percent vomited; on day three, 0 versus 9 percent vomited, and after that, no more vomiting
occurred. One other study (Metts, 2003) randomized participants to vaginal suppositories of
Lactobacillus acidophilus, suppositories and oral capsules containing Lactobacillus and
Bifidobacterium strains, and placebo; one participant in the oral and vaginal suppository group
and one in the placebo group reported vaginal discharge. These individual study results do not
allow any conclusions regarding the effects of one delivery vehicle over the other.
Metaregression: Delivery Vehicle
In the absence of direct comparisons, we investigated the delivery vehicle further in a meta
regression. A metaregression adding the factor “delivery vehicle” to a meta-analysis model
indicated that adverse events results differ by delivery vehicle based on the number of
56
participants with adverse events (p=0.0157) as well as based on the number of adverse event
incidences (p=0.040). The risk ratio between probiotic group participants and control group
participants appeared to vary based on the chosen delivery vehicle. Hence, we investigated
individual delivery vehicle further in stratified analyses.
Pill/Capsule
First, we compared the relative risk seen in a probiotics group using a pill, capsule, or gelcap
compared to the risk of adverse events seen in a group across the included parallel RCTs. This
subgroup represents the majority of included studies, as this delivery vehicle was most
commonly used. We excluded all studies where the vehicle was described as a “tablet,” as it was
not clear from the original publication whether this was equivalent to a pill that was meant to be
swallowed or a chewable tablet or a tablet that dissolves in water, for example.
Compared to controls, participants in a probiotics group were not more likely to experience
adverse events, based on the number of participants with adverse events (RR 1.02; 95% CI: 0.92,
1.14; p=0.654; RD -0.001; 95% CI: -0.006, 0.004; p=0.746) or based on the number of adverse
event incidences (RR 0.94; 95% CI: 0.0.80, 1.1.10; p=0.439; RD -0.001; 95% CI: -0.009, 0.008;
p=0.888) in this subgroup of studies using pills, capsules, or gelcaps as the probiotics delivery
vehicle.
Exploring the nature of the reported adverse events across probiotics and control groups in
these studies, there was also no difference in gastrointestinal complaints (RR 1.02; 95% CI: 0.76,
1.36; p=0.898; RD 0.001; 95% CI: -0.007, 0.009; p=0.868), a trend but no statistically significant
effect for infections and infestations (RR 1.24; 95% CI: 0.92, 1.67; p=0.151; RD 0.001; 95% CI:
-0.004, 0.006; p=0.702), or for other adverse events (RR: 0.89; 95% CI: 0.72, 1.10; p=0.292; RD
-0.001; 95% CI: -0.013, 0.011; p=0.868).
Yogurt/Dairy
Secondly, we undertook a stratified analysis for studies that delivered the probiotic
organisms in a yogurt or dairy drink. It is conceivable that probiotic organisms react to the
delivery vehicle; hence participants in probiotics groups might have an increased risk of adverse
events in dairy or yogurt studies. Infant formulas were excluded from this analysis in order not to
add another confounder (all infant formula studies have infants as participants).
Compared to controls, participants in a probiotics group were not more likely to experience
adverse events, based on the number of participants with adverse events (RR 1.01; 95% CI: 0.90,
1.13; p=0.847; RD 0.001; 95% CI: -0.016, 0.017; p=0.921). However, based on the number of
adverse event incidences in the 24 studies that used this delivery vehicle and reported data, the
relative risk was 1.37 (95% CI: 1.05, 1.79; p=0.022), indicating that participants in the probiotics
groups experienced more adverse events than control group participants. The absolute risk
difference between studies was 0.023; it was not statistically significant (95% CI: -0.003, 0.049;
p=0.078).
Exploring the nature of the reported adverse events in this subgroup of studies across
probiotics and control groups, there was a trend for more gastrointestinal complaints (RR 1.30;
95% CI: 0.83, 2.04; p=0.245; RD 0.032; 95% CI: -0.006, 0.070; p=0.098), a trend for more
infections and infestations (RR 1.99; 95% CI: 0.51, 7.80; p=0.321; RD 0.004; 95% CI: -0.004,
0.011; p=0.307), and a trend for more “other” adverse events (RR: 1.81; 95% CI: 0.98, 2.32;
p=0.063; RD 0.003; 95% CI: -0.004, 0.011; p=0.388). However, none of the results showed a
57
statistically significantly increased relative risk or absolute risk difference for adverse events in
dairy or yogurt studies comparing treatment to control group participants.
There were too few studies to investigate systematic differences between yogurt and dairy
studies or to differentiate less common delivery vehicles further in a meta-analysis. Infant
formula study results are presented in the response to Key Question 4d in the section on children.
Results of all individual studies are shown in the Evidence Table C4, Results.
Overall, there was an indication that safety results may differ by delivery vehicle. However,
given the type of analysis (an indirect analysis across studies), this result has to be regarded with
caution and cannot replace evidence from direct, within study comparisons. In addition, chosen
delivery vehicles can in part be confounded with participant characteristics (e.g. infant formula).
(3b) What is the scientific evidence that harms differ by genus, species,
and strain (including intraspecies strain variations)?
The interventions in the included studies were not well documented. In many cases it was not
reported what strains of organisms were used; only the genera, and sometimes, but not always
the species, were stated. To meet inclusion criteria for the review, studies had to report a specific
genus contained in the tested intervention.
Genus
The available research volume differs for the six investigated probiotic agents. A
Lactobacillus strain was part of the intervention in 215 (68 percent) of the included studies,
thereby being the most commonly studied genus. This number includes Lactobacillus strains not
explicitly used as a probiotic agent but included in the product, for example as a starter culture
for yogurt. Bifidobacterium was included in 32 percent of studies. Saccharomyces organisms
were investigated in 13 percent of studies. Streptococcus strains were included in 15 percent of
studies; this number includes studies investigating Streptococcus strains explicitly as probiotic
agents as well as other uses such as part of a yogurt starter culture. Enterococcus strains were
investigated in 16 studies only (5 percent of included studies). Preparations containing Bacillus
strains were investigated in 10 studies (3 percent).
With regard to direct comparisons of genera across the included controlled studies, only very
few studies were identified that directly compared the effects of two different genera within the
study. Cui (2004) compared Bacillus coagulans and Bifidobacterium longum in the treatment of
acute and chronic diarrhea and reported that body weight, body temperature, respiratory rate,
heart rate, blood pressure, routine blood tests, and liver and renal function were within normal
limits after treatment, and no adverse reactions were found. Dekker (2009) compared the safety
of Lactobacillus rhamnosus HN001 and Bifidobacterium animalis lactis HN019 in a study of
infants with asthma, hay fever, or eczema and found a rate of 19.6 percent versus 18.5 percent of
hospitalizations in the two groups (17.6 percent for placebo) and found no statistically significant
differences in gastrointestinal adverse events (diarrhea, reflux, abdominal pain, or vomiting)
across groups. De Simone (2001) compared a commercial product containing Streptococcus
thermophilus, Bifidobacterium strains, Lactobacillus acidophilus, Lactobacillus plantarum,
Lactobacillus casei, Lactobacillus delbrueckii bulgaricus, and Streptococcus faecium to a
product containing Enterococcus faecium in the treatment of irritable bowel syndrome and found
no significant changes in blood counts and chemistry in the groups.
Margreiter (2006) compared a Lactobacillus gasseri and Bifidobacterium longum
intervention with Enterococcus faecium and reported no lab abnormalities in either group.
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O’Mahony (2005) found no changes in blood counts, serum chemistry, or serum
immunoglobulins across groups receiving Lactobacillus salivarius salivarius UCC4331,
Bifidobacterium infantis 35624, or placebo. There was one case each of epistaxis, unstable
angina, and chest pain due to anxiety, but the group was not specified. Weizman (2005) stated
that there was no difference between growth parameters, behavior, or stooling patterns, and there
was no difference in the incidence of bloody stools or hospitalization across a Bifidobacterium
lactis BB-12, Lactobacillus reuteri ATCC 55730, and placebo group.
Lactobacillus. Probiotic studies often used Lactobacillus strains in combination with other
genera, but we also identified a substantial number of studies using exclusively Lactobacillus
strains. The identified case studies describing harms potentially associated with this genus are
described in Key Question 1. To quantify risks, we compared participants in parallel RCTs
where one group received a Lactobacillus intervention and the other group received no or
nonprobiotic treatment. In parallel RCTs, the relative risk for intervention participants to
experience an adverse event was 0.98 (95% CI: 0.87, 1.11; p=0.785) compared to the
nonprobiotic control group, based on all studies that used exclusively Lactobacillus strains and
reported the number of participants with adverse events. Figure 14 shows the risk differences
observed in individual RCTs.
59
Figure 14. RR number of participants with adverse events Lactobacillus RCTs
Individual study results varied, and there was no indication that the number of participants
with adverse events differed systematically between groups on a Lactobacillus strain
intervention and an equivalent group of control participants. The risk difference was -0.003 (95%
CI: -0.014, 0.009; p=0.668). Using the alternative measure, the number of incidences per group,
the relative risk was 0.96 (95% CI: 0.88, 1.06; p=0.421) and the corresponding risk difference
was 0.002 (95% CI: -0.007, 0.011; p=0.746).
To explore the nature of adverse events experienced in Lactobacillus exclusive trials, we
differentiated gastrointestinal complaints, infections and infestations, and all other reported
adverse events. There was no statistically significant difference between intervention and control
group in their risk to experience any of the three different types of adverse events
(gastrointestinal events: RR 1.05; 95% CI: 0.83, 1.24; p=0.885; RD 0.007; 95% CI: -0.004,
0.018; p=0.206; infections and infestations: RR 1.09; 95% CI: 0.90, 1.31; p=0.374; RD -0.001
(95% CI: -0.004, 0.003; p=0.762; or other reported adverse events: RR 0.91; 95% CI: 0.80, 1.04;
p=0.182; RD -0.002; 95% CI: -0.008, 0.004; p=0.496).
We also investigated the genus Lactobacillus as a factor in a metaregression comparing
studies that used Lactobacillus strains (alone or in combination) with interventions that did not.
The relative risk ratio across studies did not indicate that the Lactobacillus genus was associated
60
with a statistically significantly increased risk of adverse events compared to other genera based
on the number of participants with adverse events (relative risk ratio 1.08; 95% CI 0.95, 1.22;
p=0.224). This result was confirmed by the alternative measure of adverse event incidences
(relative risk ratio 1.08; 95% CI: 0.89, 1.31; p=0.794).
Bifidobacterium. Probiotic studies often used Bifidobacterium strains in combination with other
genera, and we also identified a few studies using exclusively Bifidobacterium organisms. The
identified case study describing harms potentially associated with this genus is described in Key
Question 1. Selecting only parallel RCTs that used exclusively Bifidobacterium products, the
relative risk based on the number of participants with adverse events was 0.92 (95% CI: 0.82,
1.03; p=0.141) between groups. Figure 15 shows the estimated relative risk reported in each
included RCT.
Figure 15. RR number of participants with adverse events Bifidobacterium RCTs
Individual study results varied, and there was no indication that the number of participants
with adverse events differed systematically between a group taking a Bifidobacterium strain and
an equivalent control group not taking probiotics. The equivalent risk difference was -0.006
(95% CI: -0.017, 0.004; p=0.228) across all included trials. Using the alternative measure, the
number of adverse event incidences, the relative risk was 0.90 (95% CI: -0.74, 1.10; p=0.302) for
intervention participants compared to control, with a corresponding risk difference of -0.005
(95% CI:--0.0145, 0.004; p=0.289).
To explore the nature of adverse events experienced in exclusively Bifidobacterium trials, we
differentiated gastrointestinal complaints, infections and infestations, and all other reported
adverse events. There was no statistically significant difference between intervention and control
group in their risk to experience any of the three most common types of adverse events
(gastrointestinal events: RR 1.02; 95% CI: 0.55, 1.90; p=0.941; RD 0.003; 95% CI: -0.017,
0.024; p=0.752; infections and infestations: RR 0.75; 95% CI: 0.55, 1.02; p=0.067; RD -0.018;
61
95% CI: -0.057, 0.021; p=0.366; or other reported adverse events: RR 1.22; 95% CI: 0.71, 2.09;
p=0.468; RD -004; 95% CI: -0.013, 0.006; p=0.463).
We also investigated the genus Bifidobacterium as a factor in a metaregression comparing
studies that used Bifidobacterium strains (alone or in combination) with interventions that did
not. The relative risk ratio across studies did not indicate that the Bifidobacterium genus was
associated with an increased or reduced risk of adverse events compared to other genera, based
on the number of participants with adverse events (relative risk ratio 1.04; 95% CI 0.93, 1.17;
p=0.700). This result was confirmed by the alternative measure of adverse event incidences
(relative risk ratio 1.11; 95% CI: 0.96, 1.28; p=0.794).
Saccharomyces. We identified a number of case studies describing harms potentially associated
with this genus; details are reported in the response to Key Question 1. Selecting only parallel
RCTs investigating exclusively Saccharomyces interventions, the relative risk of adverse events
in the intervention group was 1.00 (95% CI: 0.46, 2.18; p=0.993) compared to control and based
on the number of participants with adverse events. The forest plot in Figure 16 shows the results
of RCTs that were included in the analysis.
Figure 16. RR number of participants with adverse events Saccharomyces RCTs
Individual study results varied: Some studies reported no adverse events in either group or an
equal number of events; there was no indication that the number of participants with adverse
events differed systematically between a group taking a Saccharomyces strain and an equivalent
control group not taking probiotics. The risk difference for intervention and control group
participants was not detectable (RD 0.000; 95% CI: -0.005, 0.005; p=0.890) in the
Saccharomyces trials. Using the alternative measure, the number of adverse event incidences per
treatment group, the relative risk was 1.15 (95% CI: 0.38, 3.52; p=0.802), also not statistically
significantly different from that of control group participants, and the corresponding risk
difference was -0.001 (95% CI: -0.025, 0.024; p=0.956).
To explore the nature of adverse events experienced in RCTs using exclusively
Saccharomyces organisms, we differentiated gastrointestinal complaints, infections and
infestations, and all other reported adverse events. There was no statistically significant
62
difference between intervention and control groups in their risk to experience gastrointestinal
adverse events (RR 1.05; 95% CI: 0.25, 4.49; p=0.947; RD -0.002; 95% CI: -0.031, 0.027;
p=0.892). There was a trend for more infections and infestations in intervention participants
compared to control, but it was not statistically significant across the three studies that reported
on infections and infestations (RR 1.69; 95% CI: 0.21, 13.53; p=0.622), and the risk difference
was not detectable (RD 0.000; 95% CI -0.006, 0.006; p=0.919). There was also no statistically
significant difference for all other adverse events (RR 1.19; 95% CI: 0.23, 6.05; p=0.832; RD
0.005; 95% CI: -0.047, 0.056; p=0.863)
We also investigated the genus Saccharomyces as a factor in a metaregression comparing
studies that used Saccharomyces strains (alone or in combination) with interventions that did not.
The relative risk ratio across studies did not indicate that the Saccharomyces genus was
associated with a statistically significantly increased risk of adverse events compared to other
genera, based on the number of participants with adverse events (relative risk ratio 1.08; 95% CI
0.51, 2.27; p=0.845). This result was confirmed by the alternative measure of adverse event
incidences (relative risk ratio 1.57; 95% CI: 0.77, 3.20; p=0.215).
Streptococcus. Very few studies were identified that studied exclusively Streptococcus strains.
Across the parallel RCTs using exclusively Streptococcus strains, the relative risk for adverse
events was 0.99 (95% CI: 0.78, 1.25; p=0.907) in the intervention group, compared to an
equivalent control group. The forest plot in Figure 17 shows results obtained in individual RCTs.
Figure 17. RR number of participants with adverse events Streptococcus RCTs
The analysis was based on only three RCTs, the individual study results varied, and there
was no indication that the number of participants with adverse events differed systematically
between groups taking Streptococcus and control group participants. The corresponding risk
difference in Streptococcus RCTs was -0.004 (95% CI: -0.084, 0.076; p=0.528). Using the
alternative measure, the number of adverse event incidences, there was also no statistically
significant difference between intervention and control groups (RR 0.90 (95% CI: 0.45, 1.79;
63
p=0.768; RD -0.014; 95% CI: -0.056, 0.029, p=0.532), this analysis is also based on only three
RCTs. The results of the individual studies are reported in the Evidence Table C4, Results.
We also investigated the genus Streptococcus as a factor in a metaregression comparing
studies that used Streptococcus strains (alone or in combination) with interventions that did not.
The relative risk ratio across studies did not indicate that the Streptococcus genus was associated
with an increased or reduced risk of adverse events compared to other genera, based on the
number of participants with adverse events (relative risk ratio 1.03; 95% CI 0.91, 1.17; p=0.624).
However, the result using the alternative measure of adverse event incidences indicated that
intervention participants were at a greater risk of adverse events compared to other genera
(relative risk ratio 1.43; 95% CI: 1.09, 1.87; p=0.009).
Enterococcus. Few Enterococcus studies were identified. The relative risk seen in the
Enterococcus arm compared to control was 0.85 (95% CI: 0.47, 1.54; p=0.588) across all studies
that reported data. The forest plot in Figure 18 shows the individual results obtained in the
included RCTs.
Figure 18. RR number of participants with adverse events Enterococcus RCTs
The analysis was based on only five RCTs, and most studies reported no adverse events or an
equal number of adverse events for participants using an Enterococcus product and control group
participants. The risk difference across Enterococcus treatment arms was -0.008 (95% CI:
0.051, 0.036, p=0.733) in Enterococcus trials. Using the alternative measure, the number of
adverse event incidences, there was also no difference between intervention and control group
(RR 1.33; 95% CI: 0.43, 4.16; p=0.624; RD 0.002; 95% CI: -0.019, 0.023, p=0.833); this
analysis is based on six RCTs. The results of the individual studies are reported in the Evidence
Table C4, Results.
We also investigated the genus Enterococcus as a factor in a metaregression comparing
studies that used Enterococcus strains (alone or in combination) with interventions that did not.
The relative risk ratio across studies did not indicate that the Enterococcus genus was associated
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with a statistically significantly increased or reduced risk of adverse events compared to other
genera, based on the number of participants with adverse events (relative risk ratio 0.88; 95% CI
0.52, 1.51; p=0.507). This finding was confirmed by the alternative measure of adverse event
incidences (relative risk ratio 0.79; 95% CI 0.39, 1.60; p=0.507).
Bacillus. Few Bacillus studies were identified, as indicated in Figure 19. We included the study
described by La Rosa (2003), although the study originally described the investigated organism
as Lactobacillus coagulans. The relative risk for intervention participants exposed to Bacillus
organisms to experience an adverse event was 0.99 (95% CI: 0.44, 2.22; p=0.973) compared to
control and based on the number of participants with adverse events.
Figure 19. RR number of participants with adverse events Bacillus RCTs
The analysis was based on only three RCTs with an exclusive Bacillus intervention, and
individual study results varied. The corresponding risk difference in Bacillus RCTs was -0.014
(95% CI: -0.057, 0.029, p=0.529). The pooled number of adverse incidences could not be
computed, as only two studies reported the number of individual adverse event incidences for
both treatment groups. The only other study that investigated a Bacillus intervention (Cui, 2004)
found no adverse reactions in either the Bacillus coagulans group or the control group receiving
Bifidobacterium longum.
We also investigated the genus Bacillus as a factor in a metaregression comparing studies
that used Bacillus strains (alone or in combination) with interventions that did not. The relative
risk ratio across studies did not indicate that the Bacillus genus was associated with a statistically
significantly different risk of adverse events compared to other genera, based on the number of
participants with adverse events (relative risk ratio 0.94; 95% CI 0.44, 2.01; p=0.883). This result
was confirmed by the alternative measure of adverse event incidences (relative risk ratio 0.88
95% CI 0.27, 2.92; p=0.841).
The indirect comparison of genera across studies did not indicate genera-specific safety
results, with the exception of Streptococcus interventions: a metaregression based on the number
of adverse incidences indicated a different risk ratio for participant and control group participants
compared to other genera. However, this result was not confirmed based on the alternative
measure, the number of participants with adverse events; the risk difference between intervention
65
and control groups was not statistically significantly different; and only few studies were
identified overall that used other genera than Lactobacillus and Bifidobacterium alone or in
combination. Finally, direct comparisons within studies are needed to answer this Key Question
with confidence. Figure 20 shows the relative risk ratio and confidence intervals for studies using
each genus, compared with all other RCTs using other genera in the probiotics interventions.
Figure 20. Comparison of adverse events across genera (RR log scale)
Relative Risk
10
1
0.1
The absence of case reports of serious adverse events potentially caused by Streptococcus or
Enterococcus (see Key Question 1c) can not be used as an indication that the risk of serious
adverse events is absent: The overall identified body of literature reporting on the presence and
absence of harms indicates absence of relevant literature. The strains have not been used in
research studies, which may indicate less use in clinical practice.
Species
We identified one study comparing different species within genera. Rosenfeldt (2003)
compared Lactobacillus rhamnosus plus Lactobacillus reuteri with another preparation
containing Lactobacillus casei alactus, Lactobacillus delbrueckii lactis, and Lactobacillus GG
ATCC 53103 and reported mild, transitory abdominal pain in two participants in the former
group (one participant in the placebo group reported abdominal pain and loose stools).
The case studies that used genetic fingerprinting methods to match administered and
recovered organisms identified species specified as Lactobacillus rhamnosus or LGG,
Bifidobacterium breve, Saccharomyces boulardii [cerevisiae], and Bacillus subtilis (see Key
Question 1).
Given the potentially unreliable identification of species actually used in the intervention
studies, the large number of blends, the differences in dosing, the absence of direct comparisons,
and the unsystematic assessment of adverse events across studies, it appears infeasible to draw
conclusions regarding species-specific safety in interventions studies.
Strains
We identified four studies comparing different probiotic strains. Chouraqui (2008) compared
Bifidobacterium longum BL999 plus Lactobacillus rhamnosus LPR with BL999 plus
Lactobacillus paracasei ST11 and found 7 incidences of noteworthy adverse events in the first
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group (1 diarrhea, 1 surgery, 3 bronchiolitis, 2 inguinal hernia; n=70) and 4 in the second group
(2 vomiting, 1 pyelonephritis, 1 bronchiolitis; n=74). Gracheva (1999) reported one incident of
abdominal pain in a group given Bifidobacterium bifidum forte to treat acute intestinal infections,
chronic diseases of the gastrointestinal tract, and viral hepatitis B (the participant withdrew) but
no incidence in another Bifidobacterium bifidum treatment group. The exact strains were not
reported. Higashikawa (2010) compared yogurt containing Lactobacillus plantarum SN35N with
yogurt containing Lactobacillus plantarum SN13T and reported no abnormal changes in
urinalysis or in serum biochemical parameters in either group. Krasse (2005) compared 2
Lactobacillus reuteri strains (both of human origin but not named) and reported that 1/20
participants in one of the groups experienced increased bowel movement.
Some included studies compared groups consuming a yogurt product enriched with probiotic
organisms to a control group consuming ordinary yogurt, and the results are documented in the
evidence tables, but other comparisons of probiotic species were not found.
No other studies made direct comparisons between probiotic products or compared mixtures
of genera, species, or strains that would allow insight into the differential adverse event rates of
individual species or individual strains. Based on the extremely limited number of studies that
directly compared adverse events between probiotic organisms of different species or strains, it is
not possible to draw any conclusions regarding the comparative safety of species or strains. Few
studies employed a single species or strain; few studies characterized or verified the exact strain
used; and given that microbial strains also mutate relatively quickly, the potential for attributing
a particular event to a particular strain, let alone comparing events attributed to particular strains,
is limited.
(3c) What is the scientific evidence that harms differ between active and
lyophilized forms of probiotics?
In many studies, the form of the probiotic organism was not described, as can be seen in the
Evidence Table C2, Intervention. We identified 10 studies that compared adverse events between
forms of organisms, but these were comparisons of viable and heat-killed strains rather than
comparisons between active and lyophilized forms.
The direct comparisons did not indicate that adverse events were restricted to or more
common in viable preparations.
Alberda (2007) compared viable probiotic strains (Lactobacillus, Bifidobacterium,
Streptococcus strains) with bacterial sonicates and reported one case of bowel obstruction and
one congestive heart failure death in the viable treatment group. There was one death due to
respiratory failure in the sonicates group and one myocardial infarction in the placebo groups.
No cases of Lactobacillus induced sepsis occurred in this group of critically ill patients. Awad
(2010) compared living and heat-killed LGG preparations to reduce sepsis and necrotizing
enterocolitis in neonates and reported 14 deaths in the heat-killed arm compared to 5 deaths in
the viable intervention arm. No cases of probiotic bacteria in blood samples were observed.
Horvat (2010) reported one mild wound infection with secretion in the heat-killed group of a
synbiotic intervention containing Lactobacillus, Pediococcus, and Leuconostoc strains. Isolauri
(1991) compared a Lactobacillus casei GG fermented milk product with Lactobacillus GG as a
freeze-dried powder (as described in section 3a, delivery vehicles) and reported no significant
difference in vomiting across groups of children recovering from diarrhea. Kirjavainen (2003)
randomized infants with atopic eczema and cow’s milk allergy to placebo, viable Lactobacillus
GG, or heat-killed Lactobacillus GG. The study was prematurely terminated due to complaints
67
of adverse gastrointestinal symptoms in the heat-killed group. In total, 5/13 children in the heatkilled LGG group reported diarrhea, while none in the viable group or the placebo group
reported any adverse events (p=0.05). Merenstein (2009) reported one incidence of emesis in the
active and one incidence of constipation in the heat-killed group. Rampengan (2010) compared a
live and a heat-killed Lactobacillus preparation and reported four versus three adverse events
(respiratory or bowel symptoms) in the respective groups. Rayes (2002) compared active and
heat-killed Lactobacillus plantarum 299 strains and found 6/31 abdominal side effects in the
active group, 11/31 in the heat-killed group and 8/32 in the not enriched enteral nutrition formula
group in liver transplant recipients. In a study on patients with major abdominal surgery, Rayes
(2002) reported three incidences of abdominal distention, four of abdominal cramps, and zero of
diarrhea in the active Lactobacillus plantarum 299 group compared to six, five, and zero events
in the heat-killed group; the corresponding control group incidences were four, six, and zero.
Tsuchiya (2004) compared a synbiotic with (presumably) active Lactobacillus and
Bifidobacterium strains with a similar heat-killed preparation and found no overt clinical or
biochemical adverse side effects, but “a few” of the irritable bowel syndrome participants
presented initially with transient diarrhea-like symptoms (group unclear). Xiao (2003) compared
lyophilized and heat-killed Lactobacillus acidophilus to an active strain and found three cases of
vomiting in the active group compared to one case in the heat-killed group. There was one case
of constipation and one case of insomnia in the heat-killed group.
The authors’ descriptions of the investigated organisms varied to such an extent in the
included studies that the data do not seem suitable for an analysis across trials using
metaregression or subgroup analyses. In particular, the description of “active” may have been
used interchangeably with “viable” rather than explicitly differentiating active and lyophilized
forms. Very few studies indicated that they independently tested the content of the preparation
given to participants, either for contaminants or for the viability of the included organisms at the
time of the intervention.
(3d) Does harm differ by products containing a single probiotic versus a
mixture of probiotics?
The Evidence Table C4, Results lists the organisms that constituted the intervention for easy
reference. Overall, 60 percent of the included studies investigated the effect of only one genus
believed to have probiotic properties, while 40 percent investigated the effect of a mixture of
organisms, for example using a product that contained Lactobacillus and Bifidobacterium strains.
Only two studies were identified that compared a single probiotic with a mixture of probiotic
organisms directly. As described previously, De Simone (2001) compared a commercial product
including several Streptococcus, Bifidobacterium, and Lactobacillus strains to treatment with
Enterococcus faecium and found no significant changes in blood counts and chemistry across
groups. Margreiter (2006) compared results of Lactobacillus gasseri plus Bifidobacterium
longum treatment with the results of a group receiving Enterococcus faecium and reported no
adverse events or clinically relevant abnormalities in laboratory characteristics. One other study
(Metts, 2003) randomized participants to vaginal suppositories of Lactobacillus acidophilus,
suppositories and oral capsules containing Lactobacillus and Bifidobacterium strains, and
placebo; one participant in the oral and vaginal suppository group and one in the placebo group
reported vaginal discharge. Kim (2006) compared interventions with 5, 6, and 12 probiotic
species and reported that one participant with pre-existing hypertension had elevated blood
pressure, loose stool, diarrhea, and dehydration in the 12-species treatment group, one participant
68
each in the 5- and the 6-species groups reported loose stool, diarrhea, and worsening of
gastrointestinal symptoms.
In the absence of further direct comparisons, we compared the included trials indirectly in
subgroup analyses and a metaregression.
Single Probiotic Strain Interventions
A stratified analysis for studies using only one probiotic strain indicated a somewhat reduced,
although not statistically significant, relative risk of adverse events compared to control (0.94;
95% CI: 0.86, 1.03; p=0.171) based on the number of participants with adverse events. The
corresponding risk difference between intervention and control group participants was -0.001
(95% CI: -0.006, 0.003; p=0.557). Using the alternative measure, the number of adverse event
incidences showed a similar result, a relative risk of 0.98 for probiotic intervention participants
(95% CI: 0.89, 1.07; p=0.600; RD -0.001; 95% CI: -0.005, 0.003; p=0.748).
We also explored the nature of the adverse events encountered in single-strain studies and
found no statistically significant differences in the relative or absolute risk for any of the adverse
event groups (gastrointestinal events: RR 1.00; 95% CI: 0.82, 1.22; p=0.988; RD 0.003; 95% CI:
-0.004, 0.009; p=0.434; infections and infestations: RR 1.07; 95% CI: 0.80, 1.44; p=0.828; RD
0.000; 95% CI: -0.003, 0.003; p=0.790; all other events: RR 1.03; 95% CI: 0.89, 1.18; p=0.708;
RD 0.002; 95% CI: -0.002, 0.006; p=0.335) when comparing intervention and control group
participants.
Multiple Probiotic Strains Interventions
Across studies with multiple probiotic strains, the relative risk for the number of participants
with adverse events was slightly higher compared to the result observed for single probiotic
strains but it was not different from the risk for control group participants (RR 1.01; 95% CI:
0.94, 1.09; p=0.729), the corresponding risk difference was -0.001 (95% CI: -0.010, 0.008;
p=0.79). Similar results were seen using the alternative measure, the number of adverse
incidences (RR 1.06; 95% CI: 0.94, 1.20; p=0.317; RD 0.006; 95% CI: -0.001, 0.013; p=0.106).
Both types of intervention showed no statistically significantly increased risk of adverse events
compared to control; however, results appeared to favor single-strain interventions compared to
interventions including multiple probiotic strains.
We also explored the nature of the adverse events encountered in multiple strain studies but
found no statistically significant differences in the relative or absolute risk for any of the adverse
event groups (gastrointestinal events: RR 1.06; 95% CI: 0.86, 1.30; p=0.571; RD 0.003; 95% CI:
-0.-003, 0.009; p=0.317; infections and infestations: RR 0.98; 95% CI: 0.84, 1.15; p=0.828; RD
0.001; 95% CI: -0.005, 0.004; p=0.790; all other events: RR 0.97; 95% CI: 0.82, 1.15; p=0.746;
RD -0.002 (95% CI: -0.007, 0.004; p=0.536) when comparing intervention and control group
participants.
Meta-Regression: Single Versus Multiple Probiotics
To find out whether the risk for adverse events was significantly different between these two
kinds of interventions, we conducted a meta-regression. The metaregression did not indicate a
statistically significant difference for the risk of adverse events between single and multiple
strain interventions (relative risk ratio 0.93; 95% CI: 0.82, 1.04; p=0.205).
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(3e) Does harm differ by products containing only probiotics and those
containing a mixture of probiotics and prebiotics?
A number of studies were identified that investigated a synbiotic product; that is containing a
probiotic as well as a prebiotic, or explicitly gave probiotic organisms together with prebiotics.
Some studies were identified that compared the effects of probiotics and synbiotics directly.
Satokari (2001) and also Alander (2001) reported one incident of gastrointestinal symptoms and
one participant not completing the study in the prebiotic treatment group (galacto
oligosaccharide), and no adverse events in the probiotic group or the group consuming probiotics
and prebiotics (as described in the response to Key Question 1f). Chouraqui (2008) reported 7/70
adverse event incidences in a group receiving Bifidobacterium longum, Lactobacillus
rhamnosus, and galacto-oligosaccharide; 4/74 incidences in a second group receiving
Bifidobacterium longum, Lactobacillus paracasei, and prebiotics; 11/70 incidences in the
probiotics group; and 7/70 in a control group (for event details see Evidence Table C4, Results).
De Preter (2006) compared Saccharomyces boulardii [cerevisiae], lactulose, and placebo in
various sequences and reported that “some” participants experienced flatulence in the lactulose
and placebo phases. Fujimori (2009) reported no adverse events related to blood counts, liver
enzymes, total protein, albumin, total cholesterol, triacylglycerol, serum urea nitrogen,
creatinine, and electrolytes across groups receiving probiotic organisms (Bifidobacterium
longum), prebiotics (psylium), or synbiotics (both preparations). Ishikawa (2005) reported the
deaths of two participants who died from colorectal cancer in a probiotic group during a 4-year
study on prevention of colorectal tumors compared to one death from colorectal cancer in the
group that consumed probiotics and wheat bran biscuits; in addition, one participant in this group
died from cerebral hemorrhage, and one reported peritonitis, but no lung cancer death occurred
in either group. Tomoda (1991) reported no changes in blood chemistry in treatment groups
receiving a Bifidobacterium intervention with or without lactulose. Underwood (2009) reported
four cases of necrotizing enterocolitis, six infections, and three cases of feeding intolerance in the
probiotics group compared to one, two, and zero incidences of the same outcome in the synbiotic
group. Worthley (2009) reported that 11/18 participants in the synbiotic group reported excessive
flatus compared to 5/19 in the probiotic group.
In the absence of further direct comparisons we investigated differences between probiotics
and synbiotics in subgroup analyses and a metaregression.
Probiotics Only
Probiotic studies showed a relative risk of 0.98 (95% CI: 0.92, 1.04; p=0.446) for the number
of participants with adverse events, comparing probiotics and control groups, and a risk
difference of -0.001 (95% CI: -0.05, 0.004; p=0.681). Using the number of incidences per group
as an alternative measure, no significant difference between probiotics and control groups are
shown either (RR 1.01; 95% CI: 0.93, 1.09; p=0.879; RD 0000; 95% CI: -0.003, 0.003;
p=0.916).
We also explored the nature of the adverse events encountered in all studies that used a
probiotic rather than a synbiotic and found no differences in the relative or absolute risk for any
of the adverse event groups, comparing intervention and control group participants
(gastrointestinal events: RR 1.04; 95% CI: 0.88, 1.22; p=0.678; RD 0.001; 95% CI: -0.003,
0.005; p=0.545; infections and infestations: RR 1.04; 95% CI: 0.89, 1.22; p=0.618; RD 0.000;
95% CI: -0.003, 0.003 p=0.810; all other events: RR 1.01; 95% CI: 0.89, 1.14; p=0.901; RD
0.001; 95% CI: -0.003, 0.004; p=0.774).
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Synbiotics Only
Selecting only synbiotic studies, that is, studies that explicitly gave a product that contained
prebiotics as well as probiotics, or studies that gave probiotics together with prebiotics, we found
a slightly higher risk of adverse events than seen in the probiotics-only studies (RR 1.08; 95%
CI: 0.83, 1.39; p=0.582; RD 0.001; 95% CI: -0.013, 0.015; p=0.880) but no statistical difference
between intervention and control group participants, based on the number of participants with
adverse events. This result was confirmed using the alternative measure, the number of adverse
event incidences (RR 1.05; 95% CI: 0.84, 1.32; p=0.670; RD 0.017; 95% CI: -0.004, 0.037;
p=0.108).
We also explored the nature of the adverse events encountered in studies using synbiotics and
found no statistically significant differences in the relative or absolute risk for any of the adverse
event groups (gastrointestinal events: RR 1.01; 95% CI: 0.76, 1.34; p=0.947; RD 0.008; 95% CI:
-0.004, 0.019; p=0.202; infections and infestations: RR 0.85; 95% CI: 0.61, 1.17; p=0.324; RD
0.001; 95% CI: -0.004, 0.005; p=0.748); all other events: RR 1.00; 95% CI: 0.82, 1.21; p=0.972;
RD 0.001; 95% CI: -0.005, 0.006; p=0.824) comparing intervention and control group
participants.
Meta-Regression: Probiotics Versus Synbiotics
To establish whether the results seen in probiotics only and synbiotics studies differ
statistically significantly, a metaregression was undertaken. This analysis indicated no
statistically significant difference in the number of adverse events (RR ratio 1.10; 95% CI: 0.84,
1.44; p=0.480 for number of participants with adverse events and 1.01; 95% CI: 0.93, 1.09;
p=0.879 for adverse event incidences).
Summary and Strength of Evidence Key Question 3
What is the evidence that harms of Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus differ by product and delivery characteristics?
Volume: Varied across questions
Risk of bias: Medium
The evidence to answer this Key Question stem from a variety of study designs and quality.
Consistency: Inconsistent
Very few studies overall were identified that directly compared delivery characteristics.
Indirect comparisons showed only trends in replications rather than confirming exact results.
Directness: Indirect
Very few direct comparisons were identified; the majority of comparisons were indirect,
across different RCTs.
Precision: Imprecise
The majority of included studies used small or moderate sample sizes and although some
large studies were included, these were not designed to monitor adverse events.
Overall, the identified evidence is insufficient to answer the Key Question with confidence.
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The lack of detail in the description of administered probiotic organisms in most studies
hindered evaluations of the safety. Many studies did not specify which probiotic strains were
investigated, nor was there indication that intervention preparations were tested for identity of
the included organisms, viability, or contaminants.
Stratified analyses by probiotic genus identified a large number of studies exclusively using
Lactobacillus strains; about a dozen studies on Bifidobacterium entered stratified analyses; and
there were a small number of exclusive Saccharomyces interventions. However, there were very
few studies using Streptococcus, Enterococcus, and Bacillus strains exclusively, and only some
studies using these genera in combination with other genera. Due to the absence of studies on the
latter group, there is an insufficient evidence base to answer product-specific safety questions.
However, even for Lactobacillus, Bifidobacterium, and Saccharomyces research, there is a lack
of direct comparisons between genera; information on the genera-specific safety of probiotics is
primarily based on indirect comparisons.
Stratified analyses indicated that adverse events were not statistically significantly increased
in treatment participants compared to control group participants for any of the reviewed genera.
In indirect comparisons, there was some indication that interventions including Streptococcus
strains showed more adverse events compared to the other genera, but as outlined before, the risk
for intervention participants relative to control group participants was also not increased in these
interventions.
There is a lack of studies directly comparing product characteristics. There was some
indication across studies that safety findings may differ by delivery vehicle. Intervention
participants in yogurt or dairy product studies were more likely to experience adverse event
incidences than control group participants in subgroup analyses (RR 1.37; 95% CI: 1.05, 1.79;
p=0.022). However, studies directly comparing delivery vehicles are missing.
The only included studies that compared the form of probiotic organisms directly compared
viable and heat-killed organisms. Heat-killed organisms are not included in prominent definitions
of probiotics; hence, this comparison is of minor interest. There was no indication that active
forms were associated with a higher number of adverse events. The reporting of the form of
organisms was too poor in included studies to allow a systematic investigation of the influence of
the form.
There was a trend of single probiotic studies to report fewer adverse events compared to
studies using a mixture of organisms; however, this finding was based on an indirect comparison
across studies, in the absence of direct comparisons, and the difference did not reach statistical
significance.
We did not identify evidence showing that synbiotics differ from probiotics with respect to
adverse events; however, there is a lack of direct comparisons.
Key Question 4. How do the harms of Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus vary based on
(a) dose (cfu); (b) timing; (c) mode of administration (e.g., catheter); (d) age
(all ages, including infants), gender, ethnicity, disease or immunologic
status of the patient; (e) relationship to efficacy?
Although a large number of probiotics studies are included in the review, the identified
studies rarely addressed more complex questions such as associations of participant or study
characteristics and adverse events, which should be investigated with appropriate multivariate
72
methods. The number of studies contributing to answer the Key Questions varied across
subquestions.
(4a) Is there a threshold or dose-response relationship between probiotics
and harm? Does the duration of intervention relate to harm?
Threshold/Dose Response
Few studies were identified that compared different doses of a probiotic product. We
considered the daily dose, rather than the length of exposure, for this question.
Lactobacillus. In the controlled trials, most studies investigated effects of Lactobacillus dosing.
Basu (2009) compared two doses of 1010 and 1012 cfu of LGG powder among children with acute
watery diarrhea and recorded that five children in the higher dose group dropped out due to
electrolyte imbalance (compared with three in the lower dose group); three developed septicemia
(compared with one in the low-dose group); one death occurred in the control group (compared
with none in the treatment groups). Gao (2010) compared doses using 1 or 2 capsules containing
50 billion cfu Lactobacillus acidophilus and Lactobacillus casei and reported 1 case of fever in
the higher dose group that was not study-related according to the authors, and 1 incidence of
hematochezia in the control group. Hemmerling (2009) randomized participants to 5 * 108, 109,
2 * 109 cfu of Lactobacillus crispatus CTV-05 organisms or placebo, and reported that all
participants experienced at least 1 of 45 adverse events without any apparent pattern associated
with treatment arms. Ishikawa (2003) compared a dose of 2 * 107 versus 108 cfu of Lactobacillus
salivarius, Lactobacillus acidophilus and Lactobacillus rhamnosus GG and reported that 2
participants withdrew due to soft stools and abdominal discomfort, but it was not reported to
which group these participants had been allocated. Karvonen (2001) compared Lactobacillus
reuteri in doses of 105, 107, and 109 cfu and concluded that abdominal symptoms (days with
discomfort, pain, or cramps) were similar across groups of neonates. Lu (2004) compared what
they characterized as a low (1.5 * 108 cfu), medium (2.7 * 108 cfu), and high (4 * 108 cfu) dose
of Lactobacillus rhamnosus given to participants and reported no episodes of vomiting, diarrhea,
constipation, abdominal pain, cough, or other allergic reaction. Nobuta (2009) randomized
participants to 3 * 109, 6 * 109, 1010, or 3 * 1010 cfu Lactobacillus brevis KB290 or placebo and
reported that 1 participant in the first group reported abdominal pain, 1 participant in the second
group reported a cold, and 1 participant in the group with the highest dose reported abdominal
pain and diarrhea. Petschow (2005) compared a low (106 cfu), medium (107 cfu) and high (108
cfu) dose of LGG and found that stool consistency, flatulence, and fussiness were similar among
groups. Tursi (2008) randomized participants to various doses of Lactobacillus casei casei DG
and reported 2 incidences of epigastric pain, 1 nausea, 1 diarrhea, but the group allocation was
unclear; 1 participant in the 1.6 * 107 group developed acute bronchial pneumonia.
Bifidobacterium (alone or in combination). Gill (2001) compared Bifidobacterium lactis HN019
given in a dose of 5 * 1010 or 5 * 109 cfu and 1 participant in the lower dose reported digestive
discomfort. Guyonnet (2009) compared a group eating 1 pot of a commercially available
probiotic yogurt versus 2 pots of yogurt (each containing 1.25 * 1010 cfu Bifidobacterium lactis
DN-173010 and yogurt cultures (1.2 * 109 Streptococcus thermophilus and Lactobacillus
bulgaricus) and reported no adverse effects on digestive comfort. Larsen (2006) compared doses
of 108, 109, 1010, and 1011 cfu of Bifidobacterium animalis lactis BB-12 and Lactobacillus
paracasei paracasei CRL-431 and reported 1 case of diarrhea in the 1010 group and that across
73
all groups, 68 percent of participants reported flatulence, 37 percent of abdominal bloating, and
22 percent of headache. Ruiz-Palacios (1996) compared a low (106 cfu), medium (108 cfu), and
high dose (1010 cfu) of a probiotic blend containing Lactobacillus reuteri, Lactobacillus
acidophilus, and Bifidobacterium infantis and reported that intake, incidence of vomiting,
abdominal discomfort, gas, and stool characteristics were not statistically significantly different
across groups. Saavedra (2004) compared a dose of 106 and 107 cfu of Bifidobacterium, lactis,
Bb 12 and Streptococcus thermophilus and reported that 3 infants in the higher dose treatment
group withdrew due to a viral rash, loose stools, or vomiting.
Saccharomyces. De Preter (2006) randomized participants to various groups and treatment
periods receiving 2 or 4 times 250mg of Saccharomyces boulardii [cerevisiae] and reported that
some participants reported flatulence during prebiotic intake (but not during probiotic intake).
A case series (Elmer, 1995) described a group of participants that used a Saccharomyces
boulardii [cerevisiae] product in increasing doses required to achieve a satisfactory response; the
study reported that 1/7 participants reported intestinal gas (dose unknown).
Streptococcus and Enterococcus. Borgia (1982) compared treatment groups received one, two, or
three capsules of Streptococcus [Enterococcus] faecium SF68 or control interventions in a trial
to prevent side effects of antibiotic treatment and reported two cardiovascular deaths, but it was
not clear to which treatment group these participants had been allocated. Other blends including
these genera are described in the Bifidobacterium section.
Bacillus (alone or in combination): No controlled trial was identified that compared different
doses of Bacillus.
In a case series, Garrido (2005) administered 100mL of a product containing 108 cfu/ml of
Lactobacillus and Bacillus strains daily for 1 week, increasing the dose to 200 mL during the
second week, and 500mL during the third week. They reported mild increases of borborygmi
during the last week.
Overall, no threshold effect or trend was identified indicating that a higher dose was
associated with a larger number of reported adverse events. However, comparing the exposure
across studies, it is apparent that there is no accepted standard of what is considered a low or
high dose of exposure. The high dose in one comparative study is the low dose in another.
Dosing depended in part on the publication year, with later publications using higher doses, and
the dose characteristics are also likely to be genera or species dependent, precluding systematic
analyses. In addition, many studies used a mixture of organisms, confounding potentially
existing effects of dose-response relationships for specific genera, species, or strains.
Intervention Duration
Many of the included studies used intervention periods of short duration, often only 1 week.
For analysis purposes, we characterized short-term use as 1 month or less and long-term use as 1
year or more. In total, 46 percent of studies reported intervention periods of 1 month or less.
Only 5 percent of all identified studies reported on long-term use of probiotic products. In the
remaining studies (49 percent), participants used probiotics for longer than 1 month but less than
1 year (medium-term use), or in rare cases, it could not be established how long the study
product was used. The exact reported intervention duration is shown for each study in Evidence
74
Table C2, Intervention. We undertook stratified analyses and metaregression to explore whether
the intervention duration is associated with encountered adverse events.
Short-term use. The relative risk of adverse events across all short-term studies was 1.02 (95%
CI: 0.89, 1.17; p=0.780), with no detectable risk differences between treatment and control
groups (RD 0.000; 95% CI: -0.005, 0.004; p=0.866) based on the number of participants with
adverse events. Using the alternative measure, the number of adverse event incidences, results
were very similar (RR 1.12; 95% CI: 0.96, 1.31; p=0.138; RD 0.008; 95% CI: -0.002, 0.017;
p=0.132).
Medium-term use. Medium-term studies showed a relative risk of 0.98 (95% CI: 0.92, 1.04;
p=0.470; RD -0.001; 95% CI -0.012, 0.010; p=0.889) based on the number of participants with
adverse events. The total number of adverse event incidences showed very similar results (RR
0.95; 95% CI: 0.87, 1.04; p=0.283; RD 0.000; 95% CI -0.003, 0.003; p=0.914), also indicating
no increased risk of adverse events for intervention participants compared to controls.
Long-term use. Adverse events associated with long-term use is of particular interest. The 18
identified studies that reported on long-term use (defined as one year or longer) included 1 case
study (Jensen, 1976) that described a patient who used Saccharomyces boulardii [cerevisiae] for
several years and was hospitalized for fever of unknown origin. We did not identify any other
observational studies, such as case series, on long-term use.
The other long-term studies were controlled trials; adverse events results varied, sometimes
favoring the intervention, sometimes the control group. To investigate whether the intervention
duration was associated with an increased risk of adverse events, we undertook a subgroup
analysis for long-term use in parallel RCTs. The individual RCTs investigated Lactobacillus
interventions (Aso, 1995; Aso, 1992; Bousvaros, 2005; Connolly, 2005; Dekker, 2009; Prantera,
2002; Reid, 1995), a Bifidobacterium intervention (Sazawal, In press), a blend of Lactobacillus
and Bifidobacterium strains (Gionchetti, 2003; Ishikawa, 2003), or a blend of Lactobacillus,
Bifidobacterium, and Streptococcus (Miele, 2009; Mimura, 2004). First, considering the number
of participants with adverse events, the relative risk was RR: 0.76; 95% CI: 0.41, 1.39; p=0.259)
for intervention participants compared to control group participants, with a trend favoring
intervention participants, although not statistically significantly. The forest plot in Figure 21
shows the individual studies that entered the analysis.
75
Figure 21. RR number of participants with adverse events in long-term use RCTs
Individual study results varied, sometimes favoring the probiotics group, sometimes the
control group. The risk difference between treatment and control group participants was very
small and not statistically significant (RD -0.006; 95% CI -0.016, 0.004; p=0.259). Using an
alternative measure, the total reported incidences per group, the results also do not indicate a
relative or absolute risk difference from control group participants (RR 0.86; 95% CI: 0.69, 1.08;
p=0.209; RD -0.005; 95% CI: -0.014, 0.005; p=0.311).
Each individual encountered adverse event in the intervention and control groups is
documented in the Evidence Table C4, Results. To explore the nature of the adverse events
associated with long-term use, we differentiated gastrointestinal complaints, infections and
infestations, and other adverse events and undertook separate analyses. None of the analyses
indicated an increased risk of adverse events in any of the three categories, compared to control
group participants (gastrointestinal events: RR 1.02; 95% CI: 0.57, 1.84; p=0.932; infections and
infestations: RR 1.84; 95% CI: 0.59, 5.74; p=0.293; all other adverse events: RR 0.78; 95% CI:
0.59, 5.02; p=0.075).
Metaregression. None of the stratified analyses indicated a statistically significantly increased
risk of adverse events for intervention participants compared to control group participants.
However, the subgroup analyses indicated that long-term use may be associated with fewer
adverse events compared to results found in short-term and medium-term use studies. In order to
investigate whether the results differ statistically significantly between studies, we undertook a
meta-regression. For this, two different analyses were available.
First, we used a categorical variable differentiating short-term, medium-term, and long-term
use. For the number of participants with adverse events, no statistically significant difference
was found (p=0.596); however, for the number of adverse event incidences, studies differed
76
significantly across short-, medium-, and long-term use (p=0.039). We then used the intervention
duration as a continuous variable, extracting the exact duration of the intervention in months.
This analysis did not confirm a statistically significant difference between studies associated with
the length of the intervention; neither an analysis based on the number of participants with
adverse events (p=0.115), nor one based on the number of adverse event incidences (p=0.162)
showed a statistically significant difference. It has to be kept in mind that the proportion of
identified long-term use studies was very small compared to the overwhelming proportion of
short- and medium-term studies reported in the literature.
(4b) Is there a relationship between time of onset of harm and time of
probiotic administration? How does time of exposure affect harm? Is harm
sustained after the intervention or exposure stops?
For the purpose of this review, we recorded the time of onset of the harm whenever possible.
The time of onset was then compared to the timing of the administration of the probiotic. We
also recorded any information regarding the clinical course of adverse events and the length of
time for which harms were sustained after the intervention was stopped and the participant was
no longer exposed to the probiotic product. Few studies provided information on the onset of
adverse events, but some of these studies, in particular the case studies, gave some insight into
the development of harms.
Timing descriptions included information on gastrointestinal side effects such as
constipation, which was reported in two studies. In one of these studies, constipation began 2
weeks after treatment while another did not pass stools beginning on the third day of the
intervention period (Hirata, 2002; Rosenfeldt, 2002) and 10 days after treatment in one case
(Loguercio, 1987). Loose stools and diarrhea were also reported on the first day of treatment, 3
days into treatment, on days 3 to 7 of treatment, and accompanied by abdominal discomfort after
1 week of taking probiotic (Black, 1991; Fukuda, 2008; Gotteland, 2003; Ishikawa, 2003); at 10
days (Mimura, 2004); in the third week of treatment after dose increase (Garrido, 2005); or after
1 month (Glintborg, 2007). Projectile vomiting after 2 hours was reported in one infant (Hwang,
2009). Vomiting occurred on the first day of treatment and incidences continued until the third
day (Isolauri, 1991) in another study. One study reported one participant leaving the study on the
second day due to nausea (Tasli, 2006); large amounts of gas on the third day (Beck, 1961);
increased appetite was reported for the first 5 days of treatment (Anukam, 2006), another
reported that four participants discontinued during the first week because of vomiting (Xiao,
2003); and bloating occurred primarily during the first week of treatment in three reports
(Gionchetti, 2007; Parfenov, 2005; Ranganathan, 2009). One study reported that one participant
dropped out on day 11, following 1 week of abdominal pain (Nobuta, 2009). General
gastrointestinal side effects were reported in anotherone study at week 1 (Lee, 2010).
With regard to infections, a submandibular abscess was noted 2 weeks after study entry in
one study (Vleggaar, 2008); one participant received antibiotics for bronchitis after 3 weeks
(Reid, 2001); one infant developed a viral rash after 30 days (Saavedra, 2004); an abscess
developed after 4 weeks (Conen, 2009); a coryza-like illness developed in the second month of
treatment (Ishikawa, 2003); one case of liver abscess was reported in one case after 4 months of
probiotic ingestion (Rautio, 1999); D-lactic acidosis was diagnosed after 3 months (Oh, 1979),
and 4 months (Ku, 2006).
Reports of more serious infections included incidences of fungemia and bacteremia. Cases of
fungemia began 4 days (Fredenucci, 1998; Lungarotti, 2003), 5 days (Lolis, 2008; Piechno,
77
2007; Richard, 1988; Viggiano, 1995; Zunic, 1991), 7 days in two cases (Cherifi, 2004; Munoz,
2005), 8 days (Hennequin, 2000; Munoz, 2005), 10 days (Ohishi, 2010), 13 days (Pletinex,
1995), 18 days (Bassetti, 1998), 20 days (Riquelme, 2003), 21 days (Niault, 1999), 32 days
(Hennequin, 2000), 7 weeks (Hennequin, 2000; Trautmann, 2008) and 2 months (Hennequin,
2000) after starting treatment. Bacteremia was seen after a median of 9 days in four patients
(Richard, 1988) and 1.5 weeks (De Groote, 2005), 20 days (Land, 2005), and 3 weeks (Ledoux,
2006) after starting probiotic treatment. Sepsis started after “several” days (Rijnders, 2000), 6
days (Lestin, 2003), 23 days (Kunz, 2004), and 179 days (Kunz, 2004) of treatment. These
adverse events developed while using probiotics. Only Niault (1999) and Land (2005) reported
on adverse events that developed after the treatment was stopped.
Other adverse events that occurred included local burning and irritation on the first 2 days of
product application (Di Pierro, 2009); colposcopy findings of erythema, petechiae, edema,
abrasion, and laceration on days 1, 7 and/or 14 (Hemmerling, 2009); anemia in 1 infant at 6
months and in 16 at 2 years (Kuitunen, 2009); one case of cervicobrachialgia that began 2 weeks
after stopping active treatment (Ligaarden, 2010); increased days with eye symptoms early in
treatment (Ouwehand, 2009); and a flare of rheumatoid arthritis at week 1 in one participant
(Lee, 2010).
Few studies provided information on the clinical course of experienced adverse events.
Gastrointestinal events appeared to resolve spontaneously, regardless of whether the intervention
was continued or discontinued. The described cases of bacteremia and sepsis resolved within 24
to 72 hours (Bassetti, 1998; Land, 2005) or 8 days (Ledoux, 2006) in the studies that provided
information on the clinical course. Blood cultures were negative after 10 days (Kunz, 2004) and
21 days (De Groote, 2005). Fungemia resolved within 58 hours (Hennequin, 2000), 6 days
(Viggiano, 1995), 8 days (Piechno, 2007), 10 days (Pletinex, 1995), 11 days (Riquelme, 2003),
13 days (Trautmann, 2008), 15 days (Niault, 1999), 18 days (Riquelme, 2003), 60 days
(Hennequin, 2000), 3 weeks (Hennequin, 2000), or 6 months (Conen, 2009). Sepsis cleared after
14 days (Zein, 2008). Burning and irritation lasted only a few hours (Di Pierro, 2009). Increased
eye symptoms resolved within a month (Ouwehand, 2009). One participant experienced
pseudomonas aeruginosa septicemia from leg cellulitis believed to be due to spending time in a
public hot tub (Bajaj, 2008) and died on day 67 of the study.
(4c) Does the route of administration (e.g., orally, jejunostomy tube, central
venous catheter) relate to harm?
We differentiated a number of routes of administration—oral, enteral feeding, intravenous
catheter, intravaginal, and topical routes of administration—to investigate whether the route of
administration of probiotics is linked to the risk of adverse events. As the route of administration
depends primarily on clinical necessity, no study was identified that directly compared two
routes of administration. To identify potentially different safety trends associated with the use of
a particular route of administration, we undertook stratified analyses and a metaregression to
compare across studies.
Oral Administration
In most of the included studies, the participants consumed the probiotic organisms orally
(272/387); participants swallowed pills or capsules or ate probiotics-enriched food. This number
included 17 case studies that reported the mode of administration.
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To investigate whether adverse events are more frequent in probiotic interventions compared
to control interventions, we undertook a stratified analysis. Across all parallel RCTs that reported
oral administration, the relative risk of adverse events for intervention participants compared to
controls was 0.98 (95% CI: 0.93, 1.04; p=0.581) based on the number of participants with
adverse events. The corresponding risk difference between groups was -0.001 (95% CI: -0.005,
0.003; p=0.207). Based on the alternative measure, the number of adverse event incidences, no
statistically significant difference between intervention and control group participants could be
found either (RR 1.01; 95% CI: 0.93, 1.08; p=0.960; RD 0.003; 95% CI: -0.002, 0.009;
p=0.207).
To explore the nature of encountered adverse events, we differentiated gastrointestinal
complaints, infections and infestations, and all other reported adverse events. In none of the
categories did the probiotic intervention group show an increased risk compared to control
(gastrointestinal: RR 1.06; 95% CI: 0.91, 1.25; p=0.453; RD 0.007; 95% CI: -0.001, 0.015;
p=0.072; infections and infestations: RR 0.98; 95% CI: 0.85, 1.14; p=0.831; RD 0.000; 95% CI:
-0.003, 0.003; p=0.886; other adverse events: RR 0.98; 95% CI: 0.88, 1.11; p=0.782; RD 0.000;
95% CI: -0.004, 0.003; p=0.867). Individual adverse events reported in each study are shown in
Evidence Table C4, Results.
Enteral Administration
A number of studies (43/387) reported on interventions where probiotics were administered
through enteral feeding tubes in hospitalized patients. We grouped all studies that described the
use of a nasal tube or gastric feeding tubes, or indicated a jejunostomy in this category. This
group included 11 of the 29 case studies that reported the mode of administration for described
patients.
To investigate whether this group of studies reported more adverse events in a probiotics
group than in a control group from the same patient population, we undertook a stratified
analysis. Even if adverse events are more likely in patients needing enteral feeding overall, and
events may have a greater clinical impact in these people (e.g., an infection), it is critical to
evaluate whether patients on probiotics experience more adverse events relative to a control
group with similar patient characteristics. A pooled analysis based on the number of participants
with adverse events indicated no statistically significantly different risk or trend of an increased
risk compared to control (RR 0.84; 95% CI: 0.55, 1.29; p=0.350; RD -0.002; 95% CI: -0.022,
0.017; p=0.828). Using the alternative measure, the number of adverse event incidences, no
statistically significantly increased risk was identified either (RR 1.15; 95% CI: 0.86, 1.55;
p=0.350; RD 0.001; 95% CI: -0.009, 0.011; p=0.777).
To explore the nature of encountered adverse events, we differentiated gastrointestinal
complaints, infections and infestations, and all other reported adverse events. In none of the
categories did the probiotic intervention group show an increased risk compared to controls
(gastrointestinal events: RR 0.85; 95% CI: 0.51, 1.42; p=0.527; RD 0.010; 95% CI: -0.019,
0.038; p=0.507; infections and infestations: RR 1.17; 95% CI: 0.69, 1.99; p=0.567; RD 0.000;
95% CI: -0.008, 0.008; p=0.969; other adverse events: RR 1.29; 95% CI: 0.82, 2.03; p=0.273;
RD 0.004; 95% CI: -0.013, 0.020; p=0.637). Individual adverse events reported in each study are
shown in Evidence Table C4, Results.
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Other Routes of Administration
Fifteen studies included in this review investigated the intravaginal administration of
probiotic organisms. Most of the adverse events related to the administration of probiotic
organisms or placebo were mild to moderate (such as vaginal discharge). None of the case
studies reported this mode of administration.
Based on the number of women with adverse events in each treatment group, the parallel
RCTs reported no statistically increased risk of adverse events compared to controls (RR 1.06;
95% CI: 0.72, 1.57; p=0.761; RD -0.004; 95% CI: -0.054, 0.046; p=0.870). No statistically
significant difference compared to control or even a trend for increased risk of events was
identified in the alternative measure, the number of adverse event incidences either (RR: 0.84;
95% CI: 0.57, 1.23; p=0.363; RD -0.013; 95% CI: -0.039, 0.012; p=0.313).
To explore the nature of encountered adverse events in studies with an intravaginal
administration of probiotics, we differentiated gastrointestinal complaints, infections and
infestations, and all other reported adverse events. In none of the adverse event categories did the
probiotic intervention group show an increased risk compared to control (gastrointestinal events:
RR 0.67; 95% CI: 0.16, 2.78; p=0.583; RD -0.005; 95% CI: -0.022, 0.013; p=0.612; infections
and infestations: RR 1.51; 95% CI: 0.57, 1.99; p=0.408; RD 0.035; 95% CI: -0.069, 0.14;
p=0.505; all other adverse events: RR 0.74; 95% CI: 0.43, 1.26; p=0.0.268; RD -0.016; 95% CI:
-0.052, 0.020; p=0.389). Individual adverse events reported in each study are shown in Evidence
Table C4, Results.
With regard to other routes of administration, four studies reported a topical application of
probiotic organisms. Details of the intervention and the adverse events results are shown in the
evidence tables. Across the three parallel RCTs, no statistically significant difference in adverse
events between intervention and control group could be detected (RR 1.06; 95% CI: 0.65, 1.72;
p=0.817; RD 0.048; 95% CI: -0.045, 0.0140; p=0.311).
The nature of the adverse events encountered with topical applications varied. Falck (1999)
used alpha-streptococci to treat recurrence of streptococcal pharyngotonsillitis and reported that
16 percent of participants reported respiratory complaints related to the common cold compared
to 13 percent in the control group. Klarin (2008) reported 5/23 deaths in the treatment group
(Lactobacillus plantarum 299) compared to 6/21 in the control group of intubated patients. Peral
(2009) reported that five patients with burns in the Lactobacillus plantarum group had (tolerable)
pain, there were no local or systemic allergic symptoms, and the administered organism was not
found in blood or wound samples. Roos (1996) reported 13 participants with throat pain,
headache, coughing, runny nose, common cold, and fever compared to 18 control group
participants reporting similar adverse events, among the 130 participants with streptococcal
pharyngotonsillitis.
The case of Saccharomyces boulardii [cerevisiae] sepsis reported by Piechno (2007)
described the use of an intravenous catheter for parenteral nutrition; no other study reported
explicitly on this route of administration
Metaregression: Routes of Administration
To investigate whether study results different significantly based on the route of
administration, we undertook a metaregression adding the route of administration as a moderator
in the meta-analysis. Based on both alternative measures of adverse event risks, no statistically
significant difference was found (number of participants with adverse events: p=0.840; number
of adverse event incidences: p=0.633). In addition, enteral feeding is a route of administration as
80
well as intrinsically related to the participant characteristics. Differences associated with
participant characteristics, such as the health status, are described in the next result section (4d).
(4d) How does harm relate to subpopulations, including different age
groups (specifically including neonates and infants under age 24 months),
men and women, ethnic/race subgroups, or health status (healthy to high
risk) individuals?
Age
The majority of the identified studies included adult participants. We distinguished, where
possible, studies in children (up to 18), adults, and elderly participants (using 65 as the age cut
off).
Children. We identified 123 studies that included children. Some of the studies in children
exposed them to probiotic organisms prenatally with the mother consuming probiotic organisms
as well as postnatally. Overall, studies in children tended to be better reported than studies in
adults. This pertained to the reporting of the intervention (e.g., reporting the strain of the
administered probiotics) and the reporting of the adverse events (e.g., reporting a list of adverse
events that was determined a priori and monitored and then reporting on the results).
Seventeen of the included 43 case studies described children (Barton, 2001; Cesaro, 2000;
De Groote, 2005; Hennequin, 2000; Hwang, 2009; Ku, 2006; Kunz, 2004; Land, 2005;
Lungarotti, 2003; Munakata, 2010; Ohishi, 2010; Perapoch, 2000; Pletinex, 1995; Trautmann,
2008; Viggiano, 1995).
In total, we identified 35 parallel RCTs that reported the total number of participating
children in a group receiving probiotics compared to a group of children not using probiotics,
and the total number of children with adverse events per treatment group. Most studies in
children investigated Lactobacillus interventions, alone or in combination with Bifidobacterium,
some studies used only Bifidobacterium strains (in infant formulae), and there were some
exceptions of studies using Saccharomyces (Kurugol, 2005), Streptococcus (Roos, 2001),
Enterococcus (Bellomo, 1979), or Bacillus (La Rosa, 2003 [Lactobacillus sporogenes]) strain
interventions. The relative risk of children in probiotics groups to experience an adverse event
was not statistically significantly different from children receiving the control intervention (RR
0.96; 95% CI: 0.88, 1.04; p=0.296). The forest plot in Figure 22 shows the individual study
results.
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Figure 22. RR number of children with adverse events
The risk difference across intervention and control group participants was -0.004 (95% CI:
0.012, 0.004; p=0.302) based on the number of children with adverse events in each group. The
alternative measure, the relative risk of adverse event incidences, was 0.95 (95% CI: 0.87, 1.04;
p=0.296) comparing intervention and control groups was similar and the corresponding risk
difference was -0.001 (95% CI: -0.004, 0.003; p=0.757); this analysis is based on a much larger
number of trials (75 RCTs), as the number of individual adverse event incidences was reported
more often than the number of children with adverse events per treatment group.
For very young children (under 24 months of age), the relative risk to experience an adverse
event was 0.96 (95% CI: 0.88, 1.05; p=0.332; 27 trials) compared to the control group, and the
risk difference was -0.005 (95% CI: -0.013, 0.004; p=0.289), indicating no trend for increased
adverse events associated with the probiotics intervention. The alternative measure, the relative
risk of adverse event incidences, was similar, with a relative risk of 0.94 (95% CI: 0.86, 1.03;
p=0.202; 65 RCTs) comparing intervention and control groups, and the corresponding risk
difference was -0.001 (CI: -0.005, 0.003; p=0.0505).
To explore the nature of encountered adverse events, we differentiated gastrointestinal
complaints, infections and infestations, and all other reported adverse events. In none of the
categories did the probiotic intervention group show an increased risk compared to control
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(gastrointestinal events: RR 0.99; 95% CI: 0.80, 1.22; p=0.895; RD 0.001; 95% CI: -0.005,
0.008; p=0.706; infections and infestations: RR 0.94; 95% CI: 0.77, 1.14; p=0.511; RD 0.000;
95% CI: -0.004, 0.004; p=0.999; all other adverse events: RR 0.98; 95% CI: 0.86, 1.12; p=0.748;
RD -0.001; 95% CI: -0.005, 0.004; p=0.683). Individual adverse events reported in each study
are shown in Evidence Table C4, Results.
Adults. The majority of identified studies included adult participants (233 studies). A separate
meta-analysis for parallel RCTs with only adult participants indicated a relative risk of adults in
probiotics group to experience an adverse event of 0.97 (95% CI: 0.79, 1.19; p=0.745) compared
to control. The individual results are shown in the forest plot in Figure 23, and the corresponding
risk difference was 0.001 (95% CI: -0.009, 0.011; p=0.865). Individual study results varied,
sometimes favoring the probiotic intervention group, sometimes the control group. The pooled
results indicated no trend that the intervention was associated with a higher risk of adverse
events compared to control.
Figure 23.RR number of adults with adverse events
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The alternative measure, the relative risk of adverse event incidences, was 1.02 (95% CI:
0.82, 1.27; p=0.851; 63 RCTs) comparing intervention and control groups and the corresponding
risk difference was 0.005 (95% CI: -0.005, 0.015; p=0.319), both also not indicating a
statistically significant risk of adverse events compared to control.
To explore the nature of encountered adverse events, we differentiated gastrointestinal
complaints, infections and infestations, and all other reported adverse events. In none of the
categories did the probiotic intervention group show an increased risk compared to controls
(gastrointestinal events: RR 1.17; 95% CI: 0.82, 1.67; p=0.392; RD 0.006; 95% CI: -0.004,
0.015; p=0.225; infections and infestations: RR 1.39; 95% CI: 0.66, 2.93; p=0.386; RD 0.006;
95% CI: -0.017, 0.030; p=0.597; all other adverse events: RR 0.98; 95% CI: 0.72, 1.32; p=0.884;
RD 0.004; 95% CI: -0.005, 0.012; p=0.430). Individual adverse events reported in each study are
shown in Evidence Table C4, Results.
Elderly. Although one-third of the identified studies included participants 65 years of age or
older, studies exclusively in the elderly account for only 5 percent of the review sample. In
addition, elderly participants were explicitly excluded from 5 percent of the included studies (of
those studies that were not in infants or other specified age samples). We identified 17 studies in
total that reported exclusively on participants 65 years of age or older. Among these were several
case studies of serious infections (Cherifi, 2004; Henry, 2004; Jensen, 1976; Mackay, 1999;
Munoz, 2005; Oggioni, 1998; Rautio, 1999; Rijnders, 2000; Tommasi, 2008).
One of the two identified case series with elderly participants reported no adverse events
(An, 2010); in the other one, two of the participants with dementia died during the followup, and
one experienced diarrhea (Carlsson, 2009).
Only a small number of controlled trials targeted exclusively elderly participants (Boge,
2009; De Simone, 1992; Gill, 2001; Guillemard, 2010; Stotzer, 1996). Based on four parallel
RCTs that reported on the number of participants with adverse events, as depicted in Figure 24,
the relative risk of elderly participants in the probiotics group experiencing an adverse event was
0.94 (95% CI: 0.82, 1.08; p=0.367) compared to controls, and the risk difference was -0.013
(95% CI: -0.069, 0.033; p=0.545) indicating that the intervention was not associated with an
increased relative risk of adverse events. The individual RCTs investigated Lactobacillus in
combination with Bifidobacterium or Streptococcus/Enterococcus strains.
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Figure 24. RR number of elderly participants with adverse events
The nature of the encountered adverse events varied across RCTs that studied participants 65
years of age and older.
The Boge (2009) trials reported common infectious diseases, and Guillemard (2010) reported
muscular-bone adverse events, gastrointestinal adverse events, and infections other than common
infectious diseases, but the exact number per treatment group was not reported. De Simone
(1992) reported 2 participants with incidences of intestinal rumbling and flatulence compared to
1 participant with variation in stool consistency and diarrhea among 15 elderly participants
taking Bifidobacterium bifidum and Lactobacillus acidophilus treatment and 10 elderly control
participants. Gill (2001) reported only one case of digestive discomfort in the control group in a
study using Bifidobacterium lactis HN019 to enhance immunity. Of the 17 elderly participants
with small intestinal bacterial overgrowth described by Stotzer (1996), 1 was excluded from a
crossover trial on Lactobacillus fermentum due to the deterioration of her general condition
(presumably associated with radiation enteritis after treatment for ovarian cancer); 1 other
participant was excluded due to side effects not further described.
Given the paucity of trials exclusively in the elderly, we also investigated the presence of
participants 65 years of age or older in the study samples and its effects on adverse events. A
metaregression showed no statistically significant effect based on the number of participants with
adverse events (p=0.438) and based on the number of adverse event incidences (p=0.991).
Metaregression. Age: In order to investigate whether different safety results are reported for
different age groups for treated participants relative to controls (relative risk ratio), we tested this
assumption in a meta-regression. Based on the number of participants with adverse events, there
was no indication that the risk of experiencing an adverse event in the treatment group relative to
controls differs by age (p=0.559, joint significance test). For the outcome adverse event
incidences, no analysis could be undertaken due to the small number of studies in the elderly.
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Gender
Almost all samples in the included studies were of mixed gender. We identified 38 studies
describing female participants only and 35 studies that included only male participants. The case
studies described more male than female patients, where gender was reported (see Evidence
Table C1, Study Details), and 24 of the exclusively male studies were case studies. Very few
parallel RCTs with exclusively male participant samples were identified. Studies in female
participants were primarily those using the vaginal route of administration, and the results have
been described under Key Question 4c.
To investigate whether there was any indication that adverse events depended on the sex of
the participants, we added gender as a moderator in a metaregression model. This question was
investigated using two different approaches. First, we investigated exclusively male and
exclusively female parallel RCTs (categorical variable analysis). Second, we used the number of
female participants in each RCT as a moderator for safety results (continuous variable analysis).
In both analyses, there was no indication that encountered adverse events due to probiotics
compared to control was more common in female or in male participant groups based on the
number of participants (categorical variable analysis: p=0.188; continuous variable analysis:
p=0.210) and the number of adverse event incidences (categorical variable analysis: p=0.123;
continuous variable analysis: p=0.447).
Ethnicity
With regard to race and ethnicity, almost none of the studies targeted a particular
demographic group, and many studies provided no information regarding these participants’
features, as recorded in the Evidence Table C1, Participant and Study Details.
Health Status
The clinical characteristics of participants included in the identified studies are reported in
Evidence Table C1, Participant and Study Details. The included studies report on participants
with widely varying health conditions. In addition to indicating the specific clinical condition
(where applicable), we also differentiated participants on a continuum ranging from generally
healthy to critically ill. A large number of included studies (229 studies) could not be classified
as enrolling either critically ill or generally healthy persons but fell into the middle of this
continuum. This group included the many studies in participants being treated for a health
concern such as IBS, ulcerative colitis, Crohn’s disease, diabetes, or other similar health
concerns. Of all included studies, 83 were in participants that could be classified as generally
healthy. In all, 76 studies described high-risk patients, that is, those hospitalized for serious
health concerns and critically ill patients.
Of note, 13 percent of included studies reported explicitly that immunocompromised
participants were excluded from identified studies.
Generally healthy. First, of all included case studies that reported cases of serious adverse events
such as fungemia and bacteremia, only one reported case (see Jensen, 1974) was considered
generally healthy before the onset of the observed adverse event.
To investigate whether healthy participants using probiotics were more likely to experience
adverse events compared to control group participants not using probiotics we undertook a
subgroup analysis for all studies enrolling generally healthy participants. There was no indication
that healthy participants using probiotics were statistically significantly more likely to suffer
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from adverse events than control group participants based on the number of participants with
adverse events (RR 0.95; 95% CI: 0.88, 1.03; p=0.207; RD -0.004; 95% CI: -0.016, 0.008;
p=0.491), and similar results were seen based on the number of adverse event incidences (RR
0.96; 95% CI: 0.83, 1.10; p=0.544; RD 0.008; 95% CI: -0.004, 0.020; p=0.213).
To explore the nature of encountered adverse events, we differentiated gastrointestinal
complaints, infections and infestations, and other adverse events. There was no indication of a
statistically significantly increased risk of gastrointestinal complaints (RR 1.10; 95% CI: 0.88,
1.39; p=0.401; RD 0.013; 95% CI: -0.003, 0.029; p=0.117) or infections and infestations (RR
0.86; 95% CI: 0.68, 1.08; p=0.198; RD 0.002; 95% CI: -0.005, 0.009; p=0.198). There was a
trend for more other adverse events compared to control (RR 1.30; 95% CI: 0.96, 1.75; p=0.094;
RD 0.002; 95% CI: -0.003, 0.007; p=0.476). However, this trend was not statistically significant
across studies.
Medium health status. For 17 case studies, the preceding health status of the presented patients
was categorized as medium on a scale ranging from generally healthy to critically ill, the
described patients varied, or the health status before the probiotic associated adverse event was
not reported.
To investigate whether the participants with medium health status studied in the included
trials were more likely to experience adverse events compared to control group participants not
using probiotics we undertook a subgroup analysis for all parallel RCTs studying this health
status group. There was no indication that participants with medium health status were
statistically significantly more likely to suffer from adverse events than control group
participants, based on the number of participants with adverse events (RR 1.03; 95% CI: 0.94,
1.13; p=0.491; RD -0.001; 95% CI: -0.005, 0.003; p=0.475), and similar results were seen based
on the number of adverse event incidences (RR 1.04; 95% CI: 0.95, 1.13; p=0.379; RD 0.002;
95% CI: -0.004, 0.008; p=0.560).
To explore the nature of encountered adverse events, we differentiated gastrointestinal
complaints, infections and infestations, and other adverse events. There was no indication of a
statistically significantly increased risk of gastrointestinal complaints (RR 1.00; 95% CI: 0.83,
1.22; p=0.975; RD 0.004; 95% CI: -0.003, 0.011; p=0.263.), infections and infestations (RR
1.09; 95% CI: 0.90, 1.32; p=0.384; RD -0.001; 95% CI: -0.005, 0.004; p=0.802), or other
adverse events (RR 1.01; 95% CI: 0.88, 1.16; p=0.856; RD 0.000; 95% CI: -0.005, 0.005;
p=0.925).
Critically ill. Twenty-five case studies reporting on 42 cases (Barton, 2001; Cesaro, 2000; De
Groote, 2005; Force, 1995; Hennequin, 2000; Henry, 2004; Kniehl, 2003; Ku, 2006; Kunz, 2004;
Land, 2005; Ledoux, 2006; Lestin, 2003; Lherm, 2002; Lolis, 2008; Oggioni, 1998; Ohishi,
2010; Perapoch, 2000; Piechno, 2007; Richard, 1988; Rijnders, 2000; Riquelme, 2003;
Trautmann, 2008; Viggiano, 1995; Zein, 2008; Zunic, 1991) explicitly described a high-risk
patient, an individual who was critically ill before consuming probiotic organisms and
experienced any subsequent associated harms. Described cases were patients who were already
hospitalized for other conditions, who suffered from multiple health concerns, or who had to be
considered high risk due to a serious health condition.
Adverse events are more likely and potentially more harmful in critically ill and high-risk
patients. To investigate whether any of the observed adverse events could be linked to probiotic
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intake, we undertook a stratified analysis for all parallel RCTs studying critically ill or high-risk
patients, such as patients currently being treated in an intensive care unit or babies with very low
birth weight. This analysis can show whether participants using probiotics were more likely to
experience adverse events compared to a control group with similar health status and similar co
interventions and risk factors apart from the probiotics intake.
Almost all interventions in critically ill patients included Lactobacillus strains. Some studies
used Bifidobacterium strains alone or in combination with Lactobacillus. Across studies, there
was no indication that critically ill and high risk participants taking probiotics were more likely
to experience adverse events than control participants with the same health status (RR 0.79; 95%
CI: 0.51, 1.22; p=0.286) when comparing the number of participants with adverse events per
treatment arm. The forest plot in Figure 25 shows results obtained in individual studies.
Figure 25. RR number of critically ill or high-risk participants with adverse events
Results differed in individual studies, sometimes favoring the probiotics, sometimes the
control group. The observed risk difference across treatment and control group participants was
0.001 (95% CI: -0.020, 0.019; p=0.955). Using the alternative measure, the number of incidences
per treatment arm, the relative risk for treatment group participants was 0.91 (95% CI: 0.76,
1.09; p=0.297). The risk difference between treatment and control group participants was too
small to be detected (RD 0.000; 95% CI: -0.005, 0.004; p=0.62).
To explore the nature of adverse events encountered in studies of critically ill or high risk
participants, we differentiated gastrointestinal symptoms, infections and infestations, and other
adverse events. No statistically significant differences between control and intervention
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participants could be observed for gastrointestinal adverse events (RR 0.91; 95% CI: 0.56, 1.50;
p=0.718; RD 0.000; 95% CI: -0.008, 0.008; p=0.956), for infections and infestations (RR 1.15;
95% CI: 0.70, 1.88; p=0.576; RD 0.000; 95% CI: -0.003, 0.003; p=0.997), or other adverse
events (RR 0.88; 95% CI: 0.72, 1.08; p=0.214; RD -0.001; 95% CI: -0.007, 0.006; p=0.787).
We explored in a sensitivity analysis whether the difference in adverse events is still non
significant when the deaths reported in the PROPATRIA trial (Besselink, 2008) are added. In our
categorization system, the patients and their baseline disease were not seen as critically ill, but
the patients were predicted to have a severe disease course; hence, it is possible to classify them
as critically ill/high risk. The sensitivity analysis showed similar results, also not indicating a
statistically significantly increased risk of adverse events (RR 0.98; 95% CI: 0.83, 1.17; p=0.871;
RD 0.000; 95% CI: -0.004, 0.005; p=0.856).
Metaregression. Health status: To investigate whether the reported adverse events differed
across the three types of studies, we undertook a metaregression. There was no indication that
adverse events differed statistically significantly depending on the health status of the
participants, based on the number of participants with adverse events (p=0.329) as well as the
number of adverse event incidences (p=0.352) observed in treatment and control groups.
(4e) Do randomized controlled studies that report harm show efficacy or no
efficacy?
In total, 59 percent of included studies that monitored the presence or absence of harms
described the intervention as effective; 23 percent described the intervention as not effective, and
for the remaining studies, it was not clearly stated or the authors reported mixed results. We used
the abstract of the publication as the author’s summary statement. The efficacy of the included
interventions was not the target of the review; hence, we did not extract data that would allow an
independent analysis of the efficacy or effectiveness of the intervention. Whether interventions
were considered effective by the authors is indicated for each study in the Evidence Table C4,
Results.
To investigate whether reported adverse events are associated with the efficacy of the
intervention, we differentiated studies where the intervention was described as effective and
studies where it was described as not effective and added this variable as a moderator to a meta
analysis. Unclear publications were excluded from this analysis. There was no statistically
significant indication that adverse event results differed across studies based on the efficacy of
the intervention using the number of participants with adverse events (relative risk ratio 0.99;
95% CI: 0.88, 1.12; p=0.909) or the number of adverse event incidences (relative risk ratio 0.93;
95% CI: 0.80, 1.08; p=0.352).
Summary and Strength of Evidence Key Question 4
How do the harms of Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus,
Enterococcus, and Bacillus vary based on (a) dose (cfu); (b) timing; (c) mode of administration
(e.g., catheter); (d) age (all ages, including infants), gender, ethnicity, disease or immunologic
status of the patient; (e) relationship to efficacy?
Volume: Varied across questions
Risk of bias: Medium
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The evidence to answer this Key Question stem from a variety of study designs and quality.
Consistency: Inconsistent
The high level of evidence studies show different results from case studies.
Directness: Indirect
Few direct comparisons; the majority of comparisons are indirect across different studies.
Precision: Imprecise
The majority of included studies use moderate sample sizes, but studies were pooled in a
meta-analysis.
The identified evidence is insufficient or has to be characterized as low with regard to being
able to answer the Key Question with confidence.
Only a few studies in the literature explore the effect of intervention and participant
characteristics on safety.
Very few studies explored the effect of different treatment doses on the experienced adverse
events. Definitions of high and low dose varied across the small number of studies that attempted
to conduct dose comparisons. This issue, together with other confounders, hindered systematic
evaluation of a dose-response relationship.
Very few published studies were identified that investigated the effects of long-term use of
probiotics; information on the safety of long-term consumption is lacking.
There were few descriptions of the time of onset of harms and the further clinical course of
adverse events. In the few studies that reported on the time of onset of gastrointestinal effects,
most effects were observed in the first three days of treatment. The onset of infections tended to
occur one or several weeks later, however this information is primarily based on case studies.
The described bacteremia cases cleared within 8 days; several fungemia cases took up to 3 weeks
to clear.
The route of administration is as much an intervention as it is a patient characteristic, and
direct comparisons across routes of administrations are unlikely. In indirect comparisons, we
found no evidence that the form of administration (oral, enteral, or other) of probiotic organisms
pointed to an increased risk of participants in the probiotics group to experience an adverse event
relative to a comparable control group from the same participant population.
Stratified analyses and metaregressions showed no increased risk for adverse events for
children, adults, or elderly participants who took probiotics compared to adverse events observed
in equivalent control groups; however it has to be noted that only very few studies were
identified that reported on elderly participants.
The identified case studies described more male than female patients. In indirect comparisons
across RCTs, we found no indication that encountered adverse events relative to control group
incidences depend on the sex of the participants.
The included studies did not provide enough information to investigate whether safety results
are associated with ethnic characteristics.
With regard to the health status of participants, there was some indication that health status is
associated with the experience of an adverse event when using probiotics. Case studies reporting
serious adverse events described health-compromised patients, not generally healthy participants,
contracting (most commonly) a serious infection potentially caused by probiotic organisms.
However, a subgroup analysis of RCTs in critically ill patients did not show a statistically
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significantly increased risk of experiencing adverse events for participants using probiotics
compared to control group participants with similar patient characteristics.
There was no indication that the efficacy of the intervention was associated with encountered
adverse events across all included parallel RCTs.
Key Question 5. How often does harm associated with Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus lead to hospital admission or lengthened hospitalization?
The following describes the evidence related to hospitalizations as well as serious adverse
events.
Hospitalizations
None of the case series, controlled trials, crossover RCTs, or parallel RCTs indicated that the
use of a product including Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus,
Enterococcus, or Bacillus led to a hospital admission. Evidence for hospital admissions due to
probiotics use came only from case studies. However, we also recorded all hospitalizations in
included studies, regardless of perceived associations with the study products in question.
Lactobacillus intervention. Conen (2009) described a patient with ulcerative colitis who was
hospitalized with a neck abscess that the authors associated with the intake of a product
containing Lactobacillus rhamnosus (DNA-based identification). LeDoux (2006) described a
patient with AIDS and Hodgkin’s disease who presented to the emergency department with
fever, intermittent chills, and left neck pain with swelling; the diagnosis of bacteremia due to
Lactobacillus acidophilus was associated with the intake of a probiotic medication. Mackay et al.
(1999) reported on a patient with Lactobacillus rhamnosus-associated endocarditis who was
admitted to the hospital; the patient was taking a probiotic preparation that included
Lactobacillus rhamnosus, Lactobacillus acidophilus, and Streptococcus faecalis. Munakata
(2010) described a child with short bowel syndrome admitted to a hospital for evaluation of
ataxia; the authors associated the diagnosis of D-lactic acidosis with a probiotic product
containing Lactobacillus acidophilus, Lactobacillus bulgaricus, Streptococcus faecalis, and
Streptococcus faecium. Oh (1979) described a patient brought to the emergency room because of
sudden disorientation, blurred vision, nausea, and vomiting. D-lactic acidosis was associated
with Lactobacillus acidophilus intake. Rautio (1999) described a diabetic patient who was
admitted to a hospital because of a 2-week history of mild abdominal discomfort and then fever.
The diagnosis of liver abscess was associated with a dairy drink containing Lactobacillus
rhamnosus GG (DNA-based identification). Tommasi (2008) described a patient admitted to a
hospital for persistent fever and night sweating who was later diagnosed with bacteremia,
associated with consumption of Lactobacillus casei- containing products. The case report by
Zein (2008) described a hospital admission due to fever, headaches, nausea, and vomiting. The
publication linked the Lactobacillus rhamnosus-associated septicemia to a probiotic product
containing Lactobacillus rhamnosus, Bifidobacterium bifidum, Lactobacillus acidophilus,
Lactobacillus bulgaricus, Lactobacillus casei, Bifidobacterium longum, and Streptococcus
thermophilus.
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Bifidobacterium intervention. No study was identified that reported a new hospitalization other
than the potentially Lactobacillus-associated case reported by Zein (2008), which involved use
of a probiotics blend that included Bifidobacterium organisms.
Saccharomyces intervention. Hwang (2009) reported on an infant who was treated for presumed
bacterial colitis and in addition was taking a Saccharomyces boulardii [cerevisiae] product and
who presented to the emergency department with repetitive vomiting and cyanosis, requiring
intravenous fluid resuscitation. The condition was assumed to be food protein-induced
enterocolitis syndrome caused by the probiotic intervention, according to the authors. Jensen
(1974) reported on a patient admitted to a hospital with fever, diaphoresis, and nausea, which the
authors associated with the patient’s use of a Saccharomyces cerevisiae product.
Streptococcus intervention. No study was identified that reported a new hospitalization other
than the potentially Lactobacillus-associated case studies described above that used blends.
Enterococcus intervention. No study was identified that reported a new hospitalization other than
the potentially Lactobacillus-associated case studies described above that used blends.
Bacillus intervention. Oggioni et al. (1998) reported on an immunocompromised patient
admitted to a hospital with high fever who subsequently developed septicemia that was
associated with previous treatment with Bacillus subtilis (DNA-based identification).
All other case reports were in patients who were already hospitalized, or an in-hospital
treatment was not reported.
All hospitalizations. Given that the specific diagnostic reason for hospitalization may be difficult
to determine and hospitalizations may not have been associated with probiotic product use at all
by other study investigators, we recorded all hospitalizations mentioned in included studies
during or after receiving the study intervention. The outcome, hospitalization, was not an
inclusion criterion per se for this review. Only hospitalizations recorded in publications
addressing adverse events were considered, and studies using the number of hospitalizations as
an efficacy or effectiveness measure were not sought. Only new hospitalizations were considered
for this question; participants already hospitalized when a probiotic intervention was initiated
were not counted. As shown in the Evidence Table C4, Results, a number of studies reported
SAEs of which several must have led to hospitalizations. However, the studies did not report this
outcome explicitly, and in order to provide a systematic evidence overview, only the exact
reported outcome was considered for all treatment groups.
A case series described by Huynh (2009) reported that one child with acute ulcerative colitis
taking a product containing various Lactobacillus, Bifidobacterium and Streptococcus strains
was hospitalized for vomiting and diarrhea, diagnosed as viral gastroenteritis. No virus or
bacterial pathogens were isolated from the stool.
In 12 parallel RCTs that reported the number of new hospitalizations, the relative risk was
1.14 (95% CI: 0.79, 1.65; p=0.470; 11 RCTs), and the risk difference was 0.007 (95% CI:
0.006, 0.020; p=0.276) indicating that the probiotics intervention was not associated with a
statistically significantly higher risk of hospitalization across all parallel RCTs. Study authors did
not report that the intervention caused the hospitalizations in the included trials, but Gibson
(2008) reported 18/72 serious adverse events that required hospitalizations in the treatment group
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compared to 11/70 in the control group. The authors reported further that three events in total
were judged to be possibly related to the formula intervention (one gastrointestinal problem in
each group and one respiratory problem in the control group).
None of the identified studies indicated that the evaluated intervention led to a lengthened
hospitalization. Only five studies (Kerac, 2009; Mackay, 1999; Munakata, 2010; Oggioni, 1998;
Tommasi, 2008) included in the review reported the number of newly hospitalized patients and
the length of hospitalization (this number excludes in-hospital samples, and studies that used the
length of hospitalization as an efficacy or effectiveness measure were also not sought). In the
included controlled studies, Kerac (2009) reported 27/399 readmissions to hospital in a group of
malnourished Malawian children receiving synbiotics compared to 16/396 children in the control
group. The other data on the length of hospitalization stem from case studies. The participant
described by Oggioni (1998) remained in the hospital 25 days; in the case described by Mackay
(1999), 14 days; the child with D-lactic acidosis described by Munakata (2010) was hospitalized
for 25 days; and the case described by Tommasi (2008) appears to have spent a total of about 90
days in the hospital but not necessarily without interruption when symptoms were under control.
Serious Adverse Events
We also investigated the quality of the adverse events, apart from exploring the quantity
(Key Question 1) and the nature of the adverse events (Key Question 2). For all recorded adverse
events reported in the individual studies, we assessed whether the experienced harm was a
serious adverse event such as a hospitalization or recorded incidences of death. For a
conservative analysis, we also included any sign of probiotics bacteria in blood samples as a
serious adverse event.
Several included studies reported on the presence or absence of serious adverse events, in
particular the case studies. The results of case studies have been summarized in Key Question 1c.
However, some controlled studies also reported on the presence or absence of serious adverse
events and these studies allow a comparison of the risk experienced in a probiotic group
compared to that of participants not using probiotics but from a similar population and with
comparable underlying diseases, cointerventions, and other factors that may contribute to serious
adverse events. Some of the included studies enrolled critically ill patients; the occurrence of
serious adverse events and health concerns regardless of any association with probiotics is more
likely in this clinical population than in other participant groups.
In total, 67 parallel RCTs reported on the presence or the absence of at least one serious
adverse event, recorded the number of serious adverse event incidences in the treatment and the
control group arms, and also reported the total number of participants in each treatment arm.
Only the main treatment group was compared with the control group most similar to the
treatment group minus the probiotics.
The relative risk of a serious adverse event was 1.06 (95% CI: 0.97, 1.16; p=0.201),
indicating that probiotics interventions were not associated with a statistically significantly
higher risk of serious adverse events. The forest plot for the relative risk is shown in Figure 26.
The graph is ordered by the included probiotic genera, starting with Lactobacillus, used alone or
in combination with other genera, followed by Bifidobacterium (#2) interventions that did not
include a Lactobacillus strain, and finally Saccharomyces (#3) interventions without
Lactobacillus or Bifidobacterium strains In total, 39 percent of studies investigated blends, and
most often the blend included a Lactobacillus strain. The lack of Streptococcus, Enterococcus,
and Bacillus interventions is highlighted in the following text.
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Figure 26. RR number of participants with serious adverse events
Results in most included trials were accompanied by wide confidence intervals, and the
obtained relative risks within the individual RCTs varied greatly, sometimes favoring the
probiotics group, sometimes the control group. A large effect indicating problems with probiotics
was seen only in the PROPATRIA trial (Besselink, 2008), a failed effectiveness study in patients
with acute pancreatitis. The pooled risk difference for a serious adverse event was not detectable
(RD 0.000; 95% CI: -0.003, 0.003; p=0.866) across the treatment groups. The risk of a serious
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adverse event was low in both groups, and the difference between the probiotic and control
groups was not detectable. The Evidence Table C4, Results shows all serious adverse events
reported in all included studies.
Lactobacillus intervention. As documented in the Key Question 1 section, the serious adverse
events associated with a Lactobacillus intervention where administered species or strains were
matched with genetic fingerprinting approaches included two cases of an abscess, two cases of
bacteremia, and one case of sepsis.
To quantify the risk of serious adverse events associated with Lactobacillus strains, we
stratified parallel RCTs by genus. Interventions exclusively using Lactobacillus strains indicated
no increased risk of serious adverse events compared to controls (RR 1.03; 95% CI: 0.93, 1.14;
p=0.614; RD 0.000; 95% CI: -0.006, 0.006; p=0.981). In order to explore further whether the
genus of the organism could be associated with reported serious adverse events, we undertook a
metaregression adding the genus as a moderator to a meta-analysis of serious adverse events.
This analysis compared studies that used Lactobacillus strains, alone or in combinations with
other microorganisms, with interventions that did not. The relative risk ratio across studies did
not indicate that the Lactobacillus genus was associated with a statistically significantly different
risk of serious adverse events compared to other genera (relative risk ratio 1.07; 95% CI: 0.78,
1.46; p=0.423).
Bifidobacterium intervention. As documented in the Key Question 1 section, the serious adverse
events associated with a Bifidobacterium interventions where administered species or strains
were matched with genetic fingerprinting approaches included one documented case of
septicemia. No stratified analysis of parallel RCTs to quantify the risk of serious adverse events
could be undertaken, as no study was identified that used exclusively Bifidobacterium strains and
reported on the presence or the absence of a serious adverse event. A metaregression adding the
presence of the genus Bifidobacterium in the intervention as a moderator to a meta-analysis of
serious adverse events did not indicate that the Bifidobacterium genus was associated with a
statistically significantly increased risk of serious adverse events (relative risk ratio 1.18; 95%
CI: 0.96, 1.47; p=0.814).
Saccharomyces intervention. As documented in the Key Question 1 section, the serious adverse
events associated with a Saccharomyces interventions where administered species were matched
with genetic fingerprinting approaches included 20 cases of fungemia. No stratified analysis
could be undertaken for parallel RCTs to quantify the risk, as no study was identified that used
exclusively Saccharomyces strains and reported on the presence or the absence of a serious
adverse event. A metaregression adding the presence of the genus Saccharomyces in the
intervention as a moderator to a meta-analysis of serious adverse events did not indicate that the
Saccharomyces genus was associated with a statistically significantly increased risk of serious
adverse events (relative risk ratio 0.68; 95% CI: 0.22, 2.07; p=0.494).
Streptococcus intervention. No Streptococcus intervention where administered species were
matched with genetic fingerprinting approaches was identified, and a stratified analysis for
parallel RCTs also could not be undertaken, as no study was identified that used exclusively
Streptococcus strains and reported on the presence or the absence of a serious adverse event. A
metaregression adding the presence of the genus Streptococcus in the intervention as a moderator
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to a meta-analysis of serious adverse events did not indicate that the Streptococcus genus was
associated with a statistically significantly increased risk of serious adverse events (relative risk
ratio 1.17; 95% CI: 0.54, 2.54; p=0.695).
Enterococcus intervention. No Enterococcus intervention where administered species were
matched with genetic fingerprinting approaches was identified and a stratified analysis for
parallel RCTs could also not be undertaken, as no study was identified that used exclusively
Enterococcus strains and reported on the presence or the absence of a serious adverse event. A
metaregression adding the presence of the genus Enterococcus in the intervention as a moderator
to a meta-analysis of serious adverse events did not indicate that the Enterococcus genus was
associated with a statistically significantly increased risk of serious adverse events (relative risk
ratio 0.59; 95% CI: 0.06, 6.05; p=0.656).
Bacillus intervention. As documented in the Key Question 1 section, the serious adverse events
associated with a Bacillus intervention where administered species were matched with genetic
fingerprinting approaches included 1 case of sepsis. No stratified analysis and metaregression
could be undertaken for parallel RCTs to quantify the risk of serious adverse events due to the
lack of Bacillus studies reporting on serious adverse events.
We also explored pertinent subgroups that were identified in the review with regard to
serious adverse events. The quality of adverse events can be very different, ranging from mild
complaints to critical events, and analyses in prior chapters have shown that some investigated
participants and some intervention characteristics warrant more exploration.
Serious adverse events by health status. We also explored whether critically ill participants
taking probiotics were more likely to experience serious adverse events compared to control
group participants. In these patients, serious adverse events are of critical importance. There was
no indication that critically ill patients were more likely to experience serious adverse events
when we stratified results for this subgroup. The relative risk in studies with participants of this
health status to experience a serious adverse event was 1.01 (95% CI: 0.89, 1.14; p=0.898; RD
0.002; 95% CI: -0.004, 0.004; p=0.973) relative to control group participants with similar
clinical symptomatology. In addition, we added health status as a variable to a meta-analysis in
order to see if health status moderates reported serious adverse events seen in participants
relative to control group participants, but there was also no empirical evidence for an increased
or reduced risk of serious adverse events that depended on the participants’ health status
(p=0.481).
Serious adverse events by participant age. Children in probiotics groups were not more likely to
experience serious adverse events than control group participants (RR 1.02; 95% CI: 0.92, 1.14,
p=0.685; RD 0.002; 95% CI: -0.006, 0.003, p=0.458). The few published studies in the elderly
did not report on the presence or absence of serious adverse events. Comparing the relative risk
ratio of children and adults for serious adverse events, there was a significant difference
(p=0.019) indicating that adults in probiotics groups were more likely to experience serious
adverse events; however this result was driven entirely by the PROPATRIA trial (Besselink,
2008) in acute pancreatitis, which reported statistically significantly more incidences of death in
the probiotics group compared to control. Excluding this study, there was no evidence of serious
adverse event results being moderated by participants’ ages (p=0.728).
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Serious adverse events by delivery vehicle. Stratified analyses indicated that yogurt and dairy
delivery vehicles may influence the ratio of risks for adverse events seen in intervention and
control groups. There was no evidence that intervention participants in yogurt and dairy studies
were statistically more likely to experience adverse events compared to control group
participants (RR 1.16; 95% CI: 0.38, 3.56, p=0.793); RD 0.001; 95% CI: -0.009, 0.012,
p=0.219). In addition, we added delivery vehicles as a variable to a meta-analysis in order to see
if this factor moderated reported serious adverse events seen in participants relative to control
group participants, but there was also no empirical evidence for an increased or reduced risk of
serious adverse events depending on the vehicle the probiotic organisms were delivered in
(p=0.998).
Serious adverse events by route of administration. There was a trend but no evidence for a
statistically significantly different risk for patients receiving probiotics through enteral feeding
tubes to experience a serious adverse event compared to control group participants (RR 1.21;
95% CI: 0.92, 1.58, p=0.168; RD 0.002; 95% CI: -0.008, 0.011, p=0.694), based on the existing
literature. We also added routes of administration as a variable to a meta-analysis in order to see
if these factors moderated the serious adverse events seen in participants relative to control group
participants, but there was no evidence for an increased or reduced risk of serious adverse events
that depended on the route of administration (p=0.714).
Summary and Strength of Evidence Key Question 5
How often does harm associated with Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus lead to hospital admission or lengthened
hospitalization?
Volume: 26 studies for hospitalization, 66 controlled trials for serious adverse events
Risk of bias: Medium
Evidence to answer this Key Question stems from RCTs and case studies, but the RCTs may
not have reported on the outcome of hospitalization consistently
Consistency: Inconsistent
Directness: Direct
Several comparative studies if the Key Question is widened to include serious adverse events
Precision: Precise
The identified evidence has to be characterized as medium to low with regard to being able to
answer the Key Question with confidence.
While several case studies reported a new hospitalization associated with the consumption of
a product, including Saccharomyces, Lactobacillus, or Bacillus strains, none of the case series,
CCTs, or parallel and crossover RCTs reported that a probiotics intervention led to a
hospitalization in the intervention participants.
A comparison of all reported hospitalizations regardless of the perceived association with the
intervention treatment indicated no statistically significantly increased risk in probiotics
interventions compared to the number of hospitalizations in control group participants. However,
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the number of hospitalizations due to adverse events was explicitly reported on in only a few of
the included studies, older publications may not have associated a hospitalization with probiotics
intake, and several studies reported on participants who were already hospitalized.
Only a few studies overall reported on the presence or absence of serious adverse events
following the FDA definition, as outlined in the method section. Results for serious adverse
events varied across RCTs, sometimes favoring the probiotics group and sometimes the control
group, and differences across probiotic and control groups were not statistically significant. The
same result was obtained for Lactobacillus and Saccharomyces interventions, but there were too
few studies (Bifidobacterium) or no studies (Streptococcus, Enterococcus, Bacillus) to analyze
serious adverse events as studies did not report on the presence or absence of serious adverse
events.
We also investigated pertinent subgroups that were highlighted in previous chapters of the
report. There was no evidence to document an increased risk of critically ill patients in probiotics
groups experiencing more serious adverse events than critically ill patients in a control group; the
health status of participants was not associated with an increased risk of serious adverse events
relative to control group participants. Children in intervention groups were not more likely to
experience serious adverse events compared to control group children, but a formal systematic
analysis of age as a moderator could not be undertaken due to the absence of reporting on the
presence or absence of serious adverse events in the few identified studies in the elderly. The
ratio of adverse events between intervention and control group participants also was not affected
by the delivery vehicle or the route of administration. However, this finding is again based on an
indirect comparison across studies; direct evidence is missing.
Key Question 6. How does harm associated with Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus relate to use of concomitant antibiotics, confounding diet therapies,
corticosteroid use, immune suppressants, or other potential confounders?
None of the studies included in this review reported a statistical interaction analysis
investigating whether confounders such as concomitant antibiotics, diet therapies, corticosteroid
use, use of other immune suppressants, or other variables affects adverse events associated with
probiotics. An interaction effect might indicate that participants on probiotics and antibiotics are
more likely to experience adverse events, beyond the adverse events that can be expected in a
control group of patients with similar characteristics.
A potential interaction effect between probiotics and medications has been explored in the
Key Question 2a and indicated a trend but no statistically significant indication that intervention
participants in studies with pertinent cointerventions report more adverse events than control
group participants with corresponding cotreatments.
Antibiotics
A substantial number of identified studies described concomitant antibiotic use (110/387). In
these studies, probiotics were often given to counterbalance adverse events caused by antibiotics,
for example, to prevent or treat antibiotic-associated diarrhea. We included only those studies
that did report on adverse events associated with probiotics, that is, studies addressing the safety
of probiotics in addition to efficacy or effectiveness outcomes. Studies reporting only on the
efficacy or effectiveness of probiotics in the prevention or reduction of antibiotics-associated
adverse events were outside the scope of this review.
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In order to answer the question of whether participants using probiotics and antibiotics
simultaneously makes them more at risk to experience adverse events associated with probiotics,
we undertook a stratified analysis for all RCTs with concomitant antibiotic treatment. There was
a trend but no statistically significant indication that participants in the probiotics group were
more likely to experience adverse events compared to control group participants also taking
antibiotics, based on the number of participants with adverse events (RR 1.07; 95% CI: 0.94,
1.23; p=0.271; RD 0.001; 95% CI: -0.005, 0.006; p=0.855) as well as according to the number of
adverse incidences across groups (RR 1.13; 95% CI: 0.91, 1.41; p=0.272; RD 0.005; 95% CI:
0.004, 0.014; p=0.259).
Exploring the nature of the adverse events further, there was also no indication that
participants experience statistically significantly more gastrointestinal adverse events compared
to control group participants (RR 1.10; 95% CI: 0.82, 1.48; p=0.530; RD 0.006; 95% CI: -0.004,
0.016; p=0.253), more infections and infestations (RR 1.07; 95% CI: 0.56, 2.06; p=0.835; RD
0.000; 95% CI: -0.003, 0.003; p=0.945), or more other adverse events (RR 1.13; 95% CI: 0.91,
1.41; p=0.270; RD 0.005; 95% CI: -0.005, 0.015; p=0.365).
Participants were also not more likely to experience serious adverse events compared to
control group participants also on antibiotic cotreatment (RR 1.04; 95% CI: 0.91, 1.19; p=0.534;
RD 0.000; 95% CI: -0.005, 0.005; p=0.972).
Diet Therapies
Seven studies (five parallel and one crossover RCT) were identified that described
participants on a particular diet regime (e.g., a diet based on the American Heart Association
guidelines) in addition to probiotics intake. The relative risk for the number of participants with
adverse events in this subgroup of studies was 1.08 (95% CI: 0.74, 1.58; p=0.683; RD 0.003;
95% CI: -0.043, 0.048; p=0.898), and the relative risk for the number of adverse event incidences
in the treatment arms was 0.97 (95% CI: 0.79, 1.18; p=0.724; RD -0.001; 95% CI: -0.020, 0.018;
p=0.948).
There was also no indication of differences in gastrointestinal complaints (1.10; 95% CI:
0.82, 1.48; p=0.530; RD 0.006; 95% CI: -0.004, 0.016; p=0.253), infections and infestations
(1.09; 95% CI: 0.53, 2.24; p=0.808; RD 0.000; 95% CI: -0.003, 0.003; p=0.945), other adverse
events (RR 0.94; 95% CI: 0.75, 1.16; p=0.538; RD 0.004; 95% CI: -0.023, 0.031; p=0.784) or
serious adverse events (RR 1.02; 95% CI: 0.89, 1.18; p=0.749; RD 0.010; 95% CI: -0.016,
0.036; p=0.449) compared to control group. However, it should be noted that the stratified
analyses were based on between three and seven RCTs only, due to the small number of studies
reporting concomitant diet therapies. Most individual trials reported either no adverse events or
similar incidences across groups.
Corticosteroid Use
There were 26 studies that reported using corticosteroids in conjunction with an intervention
of probiotic organisms. None of these studies reported an interaction analysis or related the
adverse events experienced to the use of confounding corticosteroids with probiotics.
In order to answer the question of whether participants using probiotics and corticosteroids
simultaneously makes them more at risk to experience adverse events associated with probiotics,
we undertook a stratified analysis for all RCTs with concomitant corticosteroid treatment. There
was no indication that participants in the probiotics group were more likely to experience adverse
events compared to control group participants also taking corticosteroids, based on the number of
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participants with adverse events (RR 1.04; 95% CI: 0.88, 1.22; p=0.650; RD 0.002; 95% CI:
0.032, 0.035; p=0.920) as well as according to the number of adverse incidences across groups
(RR 1.06; 95% CI: 0.77, 1.46; p=0.719; RD 0.000; 95% CI: -0.021, 0.021; p=0.986).
Exploring the nature of the adverse events further, there was a trend but no statistically
significant indication that participants experience statistically significantly more gastrointestinal
adverse events compared to control group participants (RR 1.11; 95% CI: 0.73, 1.68; p=0.615;
RD 0.000; 95% CI: -0.030, 0.030; p=0.992), more infections and infestations (1.15; 95% CI:
0.79, 4.68; p=0.466; RD 0.008; 95% CI: -0.039, 0.054; p=0.750), or more other adverse events
(RR 1.29; 95% CI: 0.83, 2.01; p=0.257; RD 0.007; 95% CI: -0.010, 0.232; p=0.448).
Participants were also not more likely to experience serious adverse events compared to
control group participants also on corticosteroid cotreatment (RR 1.01; 95% CI: 0.33, 3.10;
p=0.980; RD 0.012; 95% CI: -0.027, 0.051; p=0.545).
Immune Suppressants
Eight studies, including three case studies, were identified that reported on patients using
probiotics while taking immune suppressant medications several studies described patients with
ulcerative colitis.
Two case reports in patients using immune suppressants to control an underlying condition
described fungemia infections (Bassetti, 1998; Zunic, 1991), and one case report reported an
abscess potentially associated with Lactobacillus rhamnosus.
One of the case series in patients on immune suppressant medications noted a patient with an
erythema around the anus (Benchimol, 2004), and two other case series reported several
gastrointestinal incidences in patients with ulcerative colitis (Huynh, 2009; Karimi, 2005).
One RCT in patients with atopic dermatitis listed abdominal pain as an adverse event with
2/24 in the treatment group compared to 1/24 in the prebiotics control group (Passeron, 2006).
An RCT in transplant patients noted diarrhea, abdominal pain, and abdominal cramps similarly
distributed across treatment arms (Rayes, 2005). Tursi (2010) reported 8/65 adverse events such
as abdominal bloating with or without discomfort compared to 9/66 patients with adverse events
in the control group in an RCT in patients with ulcerative colitis
No other pertinent confounder was identified in this review that clearly warranted further
investigation.
Summary and Strength of Evidence Key Question 6
How does harm associated with Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus relate to use of concomitant antibiotics, confounding
diet therapies, corticosteroid use, immune suppressants, or other potential confounders?
Volume: Indirect comparisons are based on 387 studies, no evidence from individual interaction
studies
Risk of bias: Medium
Evidence to answer this Key Question stems from RCTs and case studies
Consistency: Inconsistent
Directness: Indirect
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Question can be analyzed only through cross-study comparisons or subgroup analyses
Precision: Precise
There is insufficient evidence to answer this Key Question with confidence.
We did not identify studies meeting the review inclusion criteria that reported statistical
interactions between concomitant antibiotics, diet therapies, corticosteroid use, or immune
suppressants.
Although the risk of adverse events in general might be higher in participants on multiple
medications, in subgroup analyses of studies in which the intervention participants as well as the
control group participants received antibiotics or corticosteroids, no statistically significantly
increased risk of adverse events was identified among intervention participants. Across RCTs,
there was no evidence for a statistically significant interaction between these medications and the
risk for adverse events being increased in the treatment group relative to the control group.
We identified only a few studies with concomitant diet therapies, and studies in participants
using immune suppressants were also largely absent in the existing literature. The few studies
identified did not indicate an increased risk of adverse events, but rare events are difficult to
assess, and the existing evidence base is not sufficient to draw conclusive conclusions.
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Discussion
Results Summary
The review demonstrates that there is a large volume of literature on probiotics. However, the
literature provided only limited evidence to address the questions the review set out to answer.
The search of 10 databases combined with reference screening of included studies and pertinent
reviews identified 11,201 publications, and 622 studies were included in the review. Of these
622 studies, 235 studies made only nonspecific safety statements (“well tolerated”), and the
remaining 387 studies reported the presence or absence of one or more specific adverse events.
The review includes a large number of randomized controlled trial (RCTs); however, the
majority of these were not designed to monitored adverse events but primarily tested the efficacy
of probiotics in managing, treating, or preventing clinical symptoms. The quality of included
studies varied within study design categories; only a minority of trials reported adequate
randomization methods, concealment of treatment group allocation, and blinding of outcome
assessors to the treatment group; and studies were not powered to assess adverse events. Adverse
events were poorly documented and publications seldom stated what parameters were monitored.
Further, in the majority of included studies, interventions were poorly documented, lacking
detail, for example, on the specific probiotic strain that was administered as well as the dose and
viability.
Identified case studies indicated that fungemia, bacteremia, and sepsis may be associated
with administered probiotic organisms. None of the identified case series, controlled clinical
trials (CCTs), parallel and crossover RCTs reported an infections caused by the administered
probiotic strains. However, these studies did not monitor routinely for such infections; reported
adverse events were primarily gastrointestinal in nature. In parallel RCTs, no statistically
increased risk for adverse events in the quantity of adverse events was observed, analyzing the
number of participants with adverse events and reported adverse event incidences per treatment
group. Exploring the nature of reported events in the literature, we found that adverse events
were gastrointestinal in nature, addressed infections and infestations, or addressed other adverse
events. In none of the different types of adverse events did parallel RCT show a statistically
significantly increased risk for adverse events in intervention participants compared to control.
Across studies, there was also no statistically significantly increased risk of serious adverse
events associated with probiotic product use. Long-term effects are largely unknown as very few
existing studies report on followup periods of one year or more.
Stratifying studies by probiotic genus, it was apparent that the existing literature covers
primarily the genus Lactobacillus, alone or in combination with other genera, most frequently
Bifidobacterium. There was some evidence from a metaregression that indicated Streptococcus
interventions may be associated with a larger number of adverse events compared to other
genera, but evidence from direct, head-to-head comparisons is lacking. Stratifying RCTs that
used each genus exclusively, no statistically significant difference between intervention and
control group participants was observed for any of the six genera. However, published reports on
the genera Enterococcus, Bacillus, Streptococcus are largely absent from the literature.
Saccharomyces interventions and Bifidobacterium interventions were also rare, and a substantial
proportion of studies used blends of probiotic organisms.
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The review aimed to address a large number of participant and intervention variables and
their effect on safety. Direct evidence comparing intervention factors is largely absent from the
existing literature. Few studies directly compared the safety of different product or participant
characteristics. Indirect comparisons indicated that effects of delivery vehicles should be
investigated further. Analyzing participant factors such as health status showed that case studies
described adverse events in patients with existing health concerns, often already hospitalized
when potentially probiotics associated infections occurred. However, RCTs did not indicate a
statistically significantly increased risk of adverse events in healthy, medium-risk, or critically ill
participant groups compared to control.
Scope and Limitations
This evidence report considers a large number of studies and addresses a large number of
research questions. Unlike the majority of existing reviews, this evidence report considers only
adverse events reported in studies of probiotics, and does not cover efficacy or effectiveness
questions for the management, prevention, or treatment of clinical symptoms or other indications
for using probiotic products. For a risk–benefit analysis, both aspects would need to be
considered.
A substantial number of reviews summarizing individual studies of effects of probiotics have
been published. However, existing reviews focus on selected interventions, selected probiotic
genera, selected patient groups, or selected outcomes (Abad, 2009; Alfaleh, 2008; Allen, 2003;
Barclay, 2007; Boyle, 2009; Boyle, 2008; Brenner, 2009; Butterworth, 2008; Chande, 2009;
Chande, 2008; Chmielewska, 2010; Chou, 2008; Dendukuri, 2005; Deshpande, 2007;
Deshpande, 2010; Doherty, 2009; Doron, 2008; Dugoua, 2009; Fuccio, 2009; Gawronska, 2005;
Gurusamy, 2008; Holubar, 2010; Hoveyda, 2009; Johnston, 2007; Kahn Ch, 2009; KalePradhan, 2010; Lirussi, 2007; Mallon, 2007; McFarland, 2005; McFarland, 2010; Miller, 2009;
Moayyedi, 2008; Osborn, 2007; Petrov, 2009; Pillai, 2008; Rolfe, 2006; Sachdeva, 2009;
Szajewska, 2010; Szajewska, 2005; Szajewska, 2001; Szajewska, 2004; Tung, 2009;
Vouloumanou, 2009; Wang, 2009; Watkinson, 2007; Whelan, 2010; Wu, 2008; Zigra, 2007).
This evidence report has a broader scope, and due to the large number of included studies, allows
unique statistical analyses. Adverse events reported in intervention studies of probiotic
organisms are largely rare events encountered by only a small number of participants. Thus,
large sample sizes are necessary to be able to detect any statistically significant incidence rates of
such adverse events.
Search
This review aimed to capture the safety of probiotics, in particular the safety of
Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus used
as probiotic agents. The search strategy was primarily designed to capture all explicitly identified
probiotic studies, and steps were taken to ensure the completeness of the body of evidence of
probiotic literature. We identified a large number of publications on probiotics and carefully
screened full paper copies of all publications that might contain information on the safety of
probiotics. Other studies that investigated the same genera in ways that resembled their use as
probiotic agents but did not label their interventions as probiotic studies were not excluded but
were also not sought systematically as outlined in the search strategy justification, and no claim
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of completeness is made. These studies were primarily identified through reference mining, that
is, scanning the bibliographies of included studies and pertinent review articles. This review was
not restricted to particular species, strains, patient group, clinical fields, settings, or study design,
and the sought interventions included genera such as Bacillus with known pathogenic properties,
hence the decision to restrict the search to probiotic studies rather than expanding it to the wider
literature on the individual bacteria and yeast strains. Judging from our experience, future
reviews targeted towards more specific research questions should use a combination of search
terms covering both the term “probiotic” and the genus to identify those studies that used a
particular strain as a probiotic agent.
This review adopted a thorough process of identifying information on the safety of probiotics
by screening full paper copies of empirical studies on probiotics, regardless of whether the safety
of probiotics was mentioned in the summary of the article, that is, the title or abstract of the
publication. Initial experiments with search filters have shown that screening studies at the title
or abstract level would have resulted in missing a large proportion of the pertinent literature. The
majority of included studies were not tagged by databases as including safety information, the
title and the abstract gave no indication that adverse events would be addressed in the
publication, and in the overwhelming majority of studies other than case reports, safety was not
the main aim of the publication.
The review focuses on published literature, and a substantial number of studies of probiotics
have been published in scientific journals. However, there may also be a substantial number of
unpublished studies, most likely from manufacturers of probiotics. This factor, combined with
the fact that we could not be certain studies that failed to mention adverse events indeed had no
adverse events, limits the utility of the review as a basis for true risk–benefit analysis of
probiotics.
Probiotics
This exploratory review on the safety of probiotics lists the reported presence and absence of
adverse events for interventions that used Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus organisms as probiotic agents. The imbalance of
genera in the included studies (favoring Lactobacillus alone and in combination with
Bifidobacterium) presumably reflects the research conducted to date.
We adopted a very inclusive definition of probiotics. However, there is an ongoing debate
about whether yogurt should be considered a probiotic product, since yogurt contains live
bacteria (e.g., Guarner, Perdigon, Corthier, et al., 2005) of genera that are associated with
probiotic properties, and the debate also extends to whether there is any reason to think adverse
events need to be monitored for yogurt and lactic acid bacteria products (e.g., MacGregor, Smith,
Thakker and Kinsella, 2002). For this review, yogurt studies that did not explicitly report the
addition of a probiotic agent, that is, a strain in addition to the yogurt starter culture, were
excluded.
A distinct limitation of this review is that most of the identified studies provided insufficient
information on the intervention, that is, a clear description of the microbes that were included in
the investigated probiotic product. The lack of identification or proper classification of the
administered probiotic organisms is a safety concern in itself. A large number of published
studies did not report the strain of the probiotic agent included in the preparation. Given that the
efficacy of probiotics is often considered strain specific, the informational value of these studies
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has to be questioned. Lack of documentation is hindering efficacy as well as safety evaluations
(EFSA, 2009; Shane, 2010) and limits overviews necessary for consumers and policymakers.
A further limitation is the uncertain reliability of the reported product details. For this
literature review, we rely on the information reported by the study authors. Very few studies
reported using accepted methods (or any methods) to test the content of preparations given to
participants. The exact organisms as well as any contaminants present in the preparations are
pertinent information. For example, included studies indicated that the species used was
Lactobacillus sporogenes however; the species designation Lactobacillus sporogenes is now
considered an invalid name for Bacillus coagulans (Becker, 1950; De Clerck, 2004; Jung, 2009).
Similarly, some studies reported on Streptococcus faecium and Streptococcus faecalis, which
have been transferred to the genus Enterococcus (Schleifer, 1984). A study published in 2006
conducted a survey of commercial probiotic strains and found that 28 percent of the strains
intended for use in humans as probiotics were misidentified at the genus or species level (Huys,
2006). Other reports show that products can contain more species than noted on the product
labels (Marcobal, 2008; Underwood, 2009).
Also, over the time span covered by our literature search, many of the employed organisms
may have undergone mutations (spontaneous or otherwise), identification techniques have
improved (e.g., revealing them to be less similar to a more familiar strain or to belong to a
different genus than previously thought), and taxonomic name changes were introduced (see,
e.g., Masco, 2004; Mattarelli, 2008; No Author, 2008; Li, 2006; Posteraro, 2005; Morita, 2009).
Finally, we identified a large number of studies that gave a blend of different probiotic
organisms to participants. These studies individually do not permit to attribute reported harms to
a particular genus, species, or strain. Metaregressions can to some extent trace effects across
studies, but this process cannot replace adequate study designs to investigate the safety of
probiotic strains.
Intervention Studies
This report was explicitly limited to assessing the outcomes of interventions (as opposed to
merely passive or accidental exposure). We identified a large number of intervention studies in
the international literature assessing the effects of Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus used as probiotic agents. A number
of publications exists that systematically collated example cases of fungemia associated with
Saccharomyces cerevisiae (e.g., Munoz, 2005), or infections associated with Lactobacillus (e.g.,
Aguirre, 1993; Husni, 1997), or Bifidobacterium (e.g., Bourne, 1978). However, we considered
only those case descriptions that reported a preceding intervention, that is, the purposeful use of
probiotics. This limitation also pertains to reports from hospitals describing outbreaks of
fungemia such as reports on an intensive care unit (ICU) where patients did not purposefully
consume probiotics, but the yeast was reported to linger in the ICU (Cassone, 2003). One of the
included case studies (Perapoch, 2000) also reported on an infant who appeared to have
contracted an infection from an infant treated with Saccharomyces cerevisiae who later
developed fungemia; hence, spread of infections should also be monitored in research studies.
The review considered studies without study design restrictions and it includes a large
number of different study designs such as parallel and crossover RCTs, CCTs, case series, and
case studies. However, the literature search did not identify any observational cohort studies
comparing two cohorts or retrospective case-control studies on the safety (or even the efficacy)
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of organisms used for their probiotic properties; all observational data came from case series
following only one intervention group and case studies. The reason for this lack of large-scale
observational studies of probiotic safety is unclear but may be the result of a general presumption
of probiotic safety on the part of epidemiologists (and the failure to implicate them as the cause
of any particular conditions). A 2002 epidemiological study addressing a similar question
assessed changes in the incidence of Lactobacillus-associated bacteremia in Finland after a rapid
increase in the use of Lactobacillus rhamnosus GG as a probiotic agent. The study found no
increase in the incidence of Lactobacillus-associated bacteremia in the population, although a
small proportion of isolates matched the strain of the probiotic agent, using the typing
technology available at that time (Salminen, 2002).
Safety
The review identified a large number of relevant publications addressing the safety of
probiotic products. For RCTs, we identified a similar volume of publications that addressed the
potential efficacy of probiotic preparations but not their safety. It is not possible to extrapolate
from the lack of mention of adverse events that no adverse events occurred in interventions (e.g.,
the adverse events associated with a particular trial might be reported in an accompanying or
subsequent, not-yet-published, article). Even fewer RCTs reported on the presence and the
absence of specific adverse events.
The review identified a large number of publications that made vague safety statements such
as “the intervention was well tolerated” and “there were no adverse events.” We compiled these
vague references to safety to allow a complete overview of the existing literature, but these
studies were analyzed separately from studies with more specific statements. This group of
studies reported no information on what was monitored or how “well tolerated” was defined. For
an evidence report such as this whose purpose is to synthesize the evidence, these studies are of
little informational value.
When publications reported that there were no adverse events, we did not make inferences
from this statement to specific outcomes. Although it may appear plausible to assume that this
means no death or hospitalizations occurred, this assumption is very problematic and should not
replace actual empirical evidence on the safety of probiotics. The safety of probiotics has only
recently been considered as an issue warranting further investigation (Liong, 2008). Older
publications may not have thought to associate such harms with an intervention considered
completely harmless. In order to advance the empirical evidence on the safety of probiotics,
studies should monitor and report the presence and also the absence of specific harms.
For this review we extracted all reported adverse events, regardless of whether the authors of
the publication considered these in their summary statement regarding the safety of probiotics.
We also included outcomes regardless of the author’s assurance that the event was unrelated to
the intervention. Such judgments are difficult to make and may change with increasing
knowledge of the safety of probiotics. Very few publications appear to have addressed the
assessment of the strength of association between adverse event and intervention systematically,
as reported for example in Gibson (2009).
Safety reviews on probiotics have focused on various aspects of safety such as toxicity, the
potential for translocation, and antibiotic resistance or other virulence factors (Ishibashi, 2001;
Sanders, 2010; Yazdankhah, 2009). This report operationalized safety as the presence or absence
of unintended adverse health events in probiotics interventions for human participants. We
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document the quantity, quality, and nature of adverse events reported in research studies using
probiotics to reduce risk of and prevent or treat disease in vivo.
Efficacy studies for which the efficacy outcome was the mitigation of an adverse event (e.g.,
efficacy of probiotics in preventing or treating antibiotic-induced diarrhea or other negative
health outcomes) were excluded unless (1) the outcome was actually exacerbated in the probiotic
treatment group compared to baseline or to a control group and this outcome was one of the main
safety findings of the paper (stated in the abstract of the publication, so-called treatment
failures); or (2) the safety of the probiotics, themselves, was also explicitly addressed in the
publication. This operationalization is not without problems but it is a pragmatic solution
adopted in other recent overviews of the safety literature (e.g., Pitrou, Boutron, Ahmad &
Ravand, 2009).
Particular outcomes addressed in this review warrant further investigation as a risk-benefit
analysis in a review that includes all studies reporting on a particular outcome such as all-cause
mortality. Such a review would need to include all studies addressing the outcome, regardless of
whether the outcome was considered a measure of efficacy or an unintended effect.
Key Questions
Key Question 1. What is the evidence that the active and lyophilized forms
of probiotics (Lactobacillus, Bifidobacterium, Saccharomyces,
Streptococcus, Enterococcus, and Bacillus) as single ingredients or in
combination with other probiotics or prebiotics in all delivery vehicles (and
formulations) when used to cure, treat, mitigate or prevent a disease or
reduce disease risk are safe in the short term? Long term?
The question of whether probiotic interventions are safe cannot be answered with sufficient
confidence based on the existing literature. The existing literature includes primarily the genera
Lactobacillus, alone and in combination with other genera, often Bifidobacterium; adverse
events associated with other genera are not well documented.
Case studies indicated that primarily fungemia, but also bacteremia, and incidences of sepsis
have been linked to administered probiotic organisms. Although the confidence of matching
strains has only recently been improved through DNA-based matching methods, the existing
reports indicate that an association between administered probiotic strains and observed
infections must be considered (Liong, 2008).
RCTs, CCTs, and case series did not report that they routinely monitor for the kinds of
infections identified in case reports. This is particularly distressing as the identified case studies
span a long period; the infectious potential of probiotic organisms is not a recent observation
(Jensen, 1976; Richard, 1988). Most controlled trials did not state what harms were monitored,
and the safety of the probiotic products was not addressed systematically. Poor reporting of
adverse events is not specific to studies on probiotic products but a general concern of
intervention studies (Ioannidis, 2004).
None of the identified case series, CCTs, or parallel and crossover RCTs reported an
infections caused by the administered probiotic strains. However, these studies did not monitor
routinely for such infections. The absence of reliable evidence on adverse events should not be
mistaken for evidence of the absence of adverse events. The adverse events reported in RCTs in
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the current literature do not suggest a widespread risk, but future studies that explicitly monitor
for the safety issues of concern are needed to quantify the actual risk of specific adverse events
in intervention studies.
Frequently reported individual adverse events were deaths that occurred during the study
followup period; many gastrointestinal incidences such as diarrhea, constipation, or nausea; and
respiratory infections. These types of outcomes were reported for both study arms, participants
using probiotics as well as participants in control groups. Across studies most incidences were
distributed evenly across treatment groups; nonetheless, there were individual studies such as the
PROPATRIA trial reported by Besselink et al. (2008), a study of failed effectiveness reported a
higher mortality rate in the probiotic treatment group than in the control group in patients with
acute pancreatitis, which indicates that individual outcomes such as mortality should be
monitored. In particular, as the mechanism of action must be investigated further, the study
reported no incidences of infections caused by the administered probiotics organisms
(Lactobacillus and Bifidobacterium strains). In a further publication, this mortality rate was
determined to be increased in those taking probiotics who had organ failure, as compared to
those who did not (Besselink, 2009). The analysis of individual outcomes also suggests that
treatment failures should be highlighted in current research. Although treatment failures were not
considered per se for this review, failed efficacy was sometimes considered a safety concern
(Besselink, 2008; Boyle, 2008) and a central outcome of the study. Individual outcomes such as
mortality should be assessed in a risk–benefit analysis that includes the outcome regardless of
whether it was investigated as a safety concern or efficacy measure (i.e., where probiotics were
given to reduce mortality).
To approach the question of safety of probiotics, we also systematically investigated the
quantity of adverse events reported in probiotics studies. This information is meaningful only in
comparison to a control group, a comparable group with similar patient characteristics, co
interventions, and other similar circumstances that permit investigation of whether adverse
events are increased with probiotics use. We investigated two alternative measures, the number
of patients with adverse events in each treatment group and the number of adverse-event
incidences per treatment group. Each measure has inherent advantages and disadvantages, and
the measures are not identical, as a single participant can experience multiple adverse events.
Across all individual studies and identified adverse events, parallel RCTs did not indicate a
statistically significantly increased risk of adverse events in either of the complementary
measures. However, it has to be considered, though, that the existing literature is dominated by
Lactobacillus-based interventions, both in combination with several other genera or alone.
Finally, the current literature also does not permit statements on the long-term safety of
probiotics. With few exceptions, the existing literature reports on short- and medium-term use of
probiotics assessed for a short or medium-term followup period. Research on probiotics has
increased dramatically in recent years and studies in the near future may report more information
on long-term effects of probiotics.
Key Question 2. What are characteristics and associations of the reported
harms in Question 1?
The reported adverse events were primarily gastrointestinal in nature, others concerned
infections and infestations, and a large group of studies did not fit any particular category in the
published system used to classify adverse events (DHHS, 2009). While the case studies primarily
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reported infections suspected or confirmed to be caused by an administered probiotic organism,
the majority of other studies reported gastrointestinal incidences. In the included RCTs, there
was no indication that participants using probiotic organisms have a higher risk of experiencing
gastrointestinal adverse events than those not using them and this was also the case for infections
and infestations and all other reported adverse events across studies. Studies rarely reported
efforts to monitor harms specific to probiotic product interventions, including infections due to
the administered strains. Hence, evaluations of the safety might change with future, more
targeted, assessment of adverse events (Liong, 2008).
There is a lack of studies investigating potential interactions between probiotics and other,
concomitantly administered, medications. The descriptions of cases experiencing serious adverse
events suggest that either multiple medications or the underlying condition may have contributed
to the severe adverse events reported but studies systematically addressing interaction effects are
lacking.
We identified only a very small number of studies addressing acquired antibiotic resistance
as a patient outcome with clinical relevance. Evidence for potential harms came from case
studies in patients with multiple morbidities. Reported resistance pertained only to selected
antibiotics. However, it has to be noted that we restricted the current review to patient outcomes,
only where antibiotic resistance and translocation were described as clinical adverse events were
these eligible for inclusion in the review. This excluded, for example, in vitro and animal
research on the potential, or lack of potential, for antibiotic resistance and translocation that has
been published for the investigated genera (Abe, 2010; Corthesy, 2007; Ishibashi, 2001).
Key Question 3. What is the evidence that harms of Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus differ by product and delivery characteristics?
We set out to answer a large number of research questions related to the interventions and
delivery characteristics. However, identified studies lacked detail in their description of
administered probiotic organisms. Many studies did not specify which probiotic strains were
investigated, nor was there indication that intervention preparations were tested for identity of
the included organisms, viability, or contaminants.
The question of genus-specific safety profiles is not easy to answer with the existing
literature. The review included probiotic organisms that were very different in nature (bacterial
as well as yeast strains) with different histories and research experiences of using the genera as
probiotic products (e.g., Lactobacillus versus Enterococcus). The number of identified fungemia
case reports associated with of Saccharomyces boulardii [cerevisiae] outnumbered case reports
of infections reported for the bacterial strains. However, RCTs, CCTs, and case series
investigated primarily Lactobacillus, alone or in combination with Bifidobacterium strain
interventions; the available evidence, including reports of the absence and the presence of
adverse events as well as effectiveness studies, is very unbalanced across genera.
The kind of postmarket reports of adverse events that participants might encounter when
using probiotic products had to be elicited from studies that often investigated products that
included different genera or gave different probiotic genera for very different purposes, to
different participant groups, in different doses and potencies. Very few studies provided head-to
head comparisons of different genera. For the included RCTs, we undertook stratified analyses
for each genus in studies that used organisms from one genus only, for example, all studies using
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exclusively Lactobacillus organisms. Stratified analyses by probiotic genus showed no increased
risk of adverse events for any of the genera in studies using the genus in question exclusively. In
addition, we undertook a metaregression and investigated each genus as a moderator in studies
that used a particular genus alone or in combination with other genera (e.g., all studies including
a Lactobacillus strain). There was some indication that interventions including Streptococcus
strains showed a higher risk of adverse events compared to the other genera. However, this result
was based on a small number of studies given the paucity of studies using genera other than
Lactobacillus and direct evidence is missing.
Included studies used unique interventions that comprised a large number of different species
and strains to investigate the efficacy, and in some cases the safety, for use as probiotic agents.
Typically, there were too few comparable studies to enable individual safety statements for
species or strains: many studies used interventions that included more than one probiotic
organism so that it was not possible to link encountered adverse events to specific species or
strains, and as outlined before, the documentation and validation of the interventions as well as
the monitored adverse events were lacking. Other factors, such as a history of safe use of species
in the food production, data on the prevalence of opportunistic infections, or reports of resistance
to antibiotic or antifungal medications, may be considered to determine the potential for safe use.
(see e.g., EFSA opinion, 2007; [Cote, 2006.]). However, these factors do not preclude the
occurrence of rare adverse events, and such known properties of genera or species are only
useful if there is evidence to suggest that all strains within the genus or within a species can be
expected to behave similarly. Assuming that because a genus or individual species has low
toxicity, no strain of the genus or species and no intervention including organisms of that genus
or species can cause adverse events in intervention studies appears to be an overgeneralization.
There is also a lack of studies directly comparing product characteristics such as the mode of
delivery. Indirect comparisons across the RCTs identified in this review indicated that the
potential effect of different delivery vehicles should be investigated further. Subgroups indicated
more adverse event incidences in the treatment group when probiotics were taken in a yogurt or
other dairy product than when taken in any other vehicle. It must be kept in mind that no study
actually compared adverse events between a yogurt/other dairy vehicle and any other vehicle
within the same study; nevertheless, there are alternative explanations for such an observation.
Probiotic organisms might maintain greater viability in dairy than nondairy vehicles, or the
adverse events are actually attributable to lactose intolerance. Given that many consumers
consume probiotics as part of dairy or yogurt products, this effect should be further investigated
in direct comparisons. The possibility that the use of a particular food as a vehicle for probiotic
organisms might alter their viability (and therefore the potential efficacy and toxicity) has been
explored in a number of studies (Champagne, 2005), and some have reported that Lactobacillus
rhamnosus GG isolated from 15 different manufactured food products (carriers) showed strain
differences that could affect both efficacy and safety (Grzeskowiak, 2010).
The only included studies that compared the form of probiotic organisms directly compared
viable and heat-killed organisms. Heat-killed organisms are not included in prominent definitions
of probiotics; hence, this comparison is of minor interest. There was no indication that active
forms were associated with a higher number of adverse events. The characterization of
organisms was too poor in included studies to allow a systematic investigation of the influence of
the form. Also seldom tested or reported was the viability of the administered organisms:
Considering that probiotics are live organisms and that they presumably need to remain live to be
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fully functional, it is concerning that few studies demonstrated that they were indeed able to
maintain the evaluated organisms in a live and robust state. Related to this concern, Bacillus
species are capable of forming spores, which would affect the count of viable organisms in a
preparation. Furthermore, because several of the genera of interest are primarily anaerobic,
exposure to oxygen during storage could easily affect viability. Another factor that might lower
the potency of probiotic products is the failure to consider the potential for cryogenic damage
during lyophilization and/or storage and to compensate by adding a cryoprotectant (see e.g.,
Savini, 2010).
We did not identify conclusive evidence in the existing literature showing that interventions
with a mixture of different organisms reported more adverse events than studies using one
probiotic strain only or that synbiotics (mixtures of prebiotics and probiotics) differ from
probiotics; however, there is a lack of direct comparisons. Although the risk of adverse events
(as well as the efficacy) is not necessarily comparable across species and strains, direct head-to
head comparisons are largely absent in the literature and in practice, probiotic interventions often
included several different probiotics genera, species, and strains.
Key Question 4. How do the harms of Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus vary based on
(a) dose (cfu); (b) timing; (c) mode of administration (e.g., catheter); (d) age
(all ages, including infants), gender, ethnicity, disease or immunologic
status of the patient; (e) relationship to efficacy?
Only a few primary studies explored the effect of intervention and participant characteristics
on safety. Both the variation in definitions of high and low dose across published studies and
other factors such as the inherent differences in the compared organisms as outlined previously
precluded a systematic evaluation of a dose-response relationship.
Very few published studies were identified that investigated the effects of long-term use of
probiotics, that is, intervention durations of 1 year or longer; information on the safety of longterm use is lacking. Given the current research interest (Shane, 2010) studies will hopefully
provide needed evidence on long-term interventions.
There were few descriptions of the time of onset of harms relative to treatment and the
further clinical course of adverse events. In the few studies that reported on the time of onset of
gastrointestinal effects, most effects were observed within in the first 3 days of treatment. The
onset of infections tended to occur 1 to several weeks after initiation of probiotics use; however,
this information is primarily based on case studies and was not systematically reported. A further
pertinent question may be the optimal time for administering probiotics, that is, early to prevent,
rather than aiming to treat or improve particular conditions, which may be associated with the
risk–benefit ratio of interventions (Arciero, 2010; Sanders, 2010).
In indirect comparisons across all identified RCTs in this review, we found no evidence that
a particular mechanism or route of administration of probiotic organisms (e.g., through enteral
feeding) was associated with an increased risk of an adverse event relative to a control group. In
the literature, serious adverse events associated with probiotic use have been linked to catheter
use (e.g., Sanders, 2010). However, the route of administration is closely linked to the health
status of participants.
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With regard to the health status of participants, there was some indication that health status is
associated with the risk for an adverse event when using probiotics. The majority of case studies
reporting serious adverse events described a critically ill patient or someone suffering from
multiple morbidities when they contracted a serious infection potentially caused by probiotic
organisms. There was some indication in the metaregressions that health status may predict an
increased risk of adverse events associated with probiotic organisms. However, a subgroup
analysis of all controlled trials enrolling critically ill participants did not show a statistically
significantly increased risk of experiencing adverse events for participants using probiotic
organisms compared to control group participants with similar patient characteristics. Critically
ill patients may be more prone to experience adverse events; however, these were not associated
with the use of probiotics; adverse events were equally distributed across treatment groups.
Further large controlled studies are needed to identify any increased risk for rare but pertinent
adverse events, and the risk–benefit ratio should be considered (also Whelan, 2010).
For studies enrolling patients with compromised health, it would appear appropriate to use a
data monitoring committee. A study by the Society for Clinical Trials’ DAMOCLES Study
Group found that only about 25 percent of articles presenting the main results of clinical trials
mentioned having used a data monitoring committee to ensure the appropriate collection of data
throughout the trial (Sydes, 2004). Such committees would also be helpful in standardizing the
collection of adverse event data in large, well-powered trials as well as in some smaller trials in
populations of interest; a data monitoring working group has provided a set of guidelines (STC,
2006).
To assess the role of the age in the safety of probiotics, we stratified studies according to the
age of participants and undertook separate analyses for studies in children, adults, or elderly
participants. The stratified analyses did not indicate an increased risk of adverse events in any of
the subgroups associated with the use of probiotics compared to corresponding control group
participants. However it has to be noted that very few studies were identified that reported on
elderly participants.
The identified case studies described more male than female patients. In the RCTs, we
investigated the results of subgroups in female only and male only studies as well as analyzing
the percent of female participants as a factor in a meta-analysis. In these indirect comparisons
across RCTs, we found no indication that encountered adverse events relative to control group
incidences depend on the gender of the participants.
The included studies did not provide enough information to investigate whether probiotic
safety is associated with racial/ethnic characteristics. It should be kept in mind that the majority
of included studies were conducted in European countries where ethnic characteristics are rarely
assessed in research studies. The research field needs to advance much further in order to be able
to answer such specific questions regarding the safety of probiotics; such evidence is not
available for other more established interventions (such as antibiotics use) either.
In total, 59 percent of included studies were explicitly described as effective by the study
authors for the various applications of probiotic use under investigation. We found no indication
that the efficacy of an intervention was related to the number of encountered adverse events
across all included RCTs.
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Key Question 5. How often does harm associated with Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus lead to hospital admission or lengthened hospitalization?
While several case studies reported a new hospitalization potentially associated with the
consumption of a product including Saccharomyces, Lactobacillus, or Bacillus strains, none of
the case series, CCTs, and parallel and crossover RCTs reported that a probiotics intervention led
to a hospitalization in the intervention participants. A comparison of all reported hospitalizations
regardless of the perceived association with the intervention treatment indicated no statistically
significant risk in probiotics interventions compared to the number of hospitalizations in control
group participants. However, the number of hospitalizations due to adverse events was only
explicitly reported on in a few of the included studies. Older publications may not have
associated a hospitalization with probiotics intake, and several studies were in participants
already hospitalized. As outlined previously, the safety of probiotic products has only recently
been considered as an issue warranting further investigation (Liong, 2008).
A proportion of included studies reported on the presence or absence of serious adverse
events following the Food and Drug Administration definition. Results for serious adverse event
varied across RCTs, sometimes favoring the probiotics group and sometimes the control group,
and differences across probiotic and control group were not statistically significant. The same
result was obtained for Lactobacillus and Saccharomyces interventions, but there were too few
studies (Bifidobacterium) or no studies (Streptococcus, Enterococcus, Bacillus) in order to
analyze serious adverse events for other genera, as studies did not report on the presence or
absence of serious adverse events. The reporting of adverse events appears to have improved in
recent years, presumably due to stricter guidelines and higher standards imposed by journals, for
example, making it mandatory to report on adverse events when reporting the results of RCTs
(e.g., Item 19 of the CONSORT statement, “All important harms or unintended effects in each
group”). Relevant to this review is that the reporting of the presence and absence of infections
has increased in particular, possibly a reaction in part to the PROPATRIA trial reported by
Besselink et al. (2008).
We also investigated pertinent subgroups that were of particular interest to this evidence
report. Most notably, we did not find evidence that health-compromised patients were at
increased risk of experiencing more serious adverse events than health-compromised control
group participants. However, it has to be taken into account that the monitoring and reporting of
adverse events is lacking, existing interventions were again primarily Lactobacillus
interventions, and future assessments may come to different conclusions as the evidence base
improves.
Key Question 6. How does harm associated with Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and
Bacillus relate to use of concomitant antibiotics, confounding diet therapies,
corticosteroid use, immune suppressants, or other potential confounders?
Multivariate analyses in primary research studies are suitable to systematically trace
interactions between cointerventions and probiotic use. In studies where some of the participants
use these cointerventions while others do not, this factor and its effect on the study outcome can
be investigated. We did not identify studies meeting the review inclusion criteria that reported
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statistical interactions between concomitant antibiotics, diet therapies, corticosteroid use, or
immune suppressants and probiotics.
Although the risk of adverse events in general might be higher in participants on multiple
medications, the crucial issue for this Key Question is whether participants in probiotics
interventions are more likely to experience adverse events compared to corresponding control
group participants. Interactions between comorbidities and cotreatments are complex research
questions (Fitzgerald, 2010). For example, we might assume an interaction between
corticosteroids and probiotics when studies in participant samples using corticosteroids report a
higher risk ratio of adverse events than other studies. In subgroup analyses of identified studies
in which the intervention participants as well as the control group participants received
corticosteroids, we found no statistically significantly increased risk of adverse events for
intervention participants compared to control.
Probiotic interventions have been the focus of much research interest for the prevention of
side effects associated with antibiotics (Abernethy, 2008; Cots, 2008; D'Souza, 2002; Doron,
2008; Elmer, 1998; Jack, 2010; Johnston, 2005; Johnston, 2006; Kale-Pradhan, 2010; Katz,
2006; Marshall, 2008; McFarland, 2005; McFarland, 2009; McFarland, 2006; Oldfield, 2008;
Rohde, 2009; Ruszczynski, 2008; Szajewska, 2005; Szajewska, 2006; Wilcox, 2009; Young,
1998; Zou, 2009). While efficacy studies for the prevention of side effects were not eligible for
inclusion in the review, we included those studies that addressed side effects of probiotics in
addition to side effects of antibiotics where feasible, through the design and the adverse event
monitoring of the study. Across RCTs, there was no evidence for a statistically significantly
increased risk of adverse events for intervention participants compared to controls or an
interaction between antibiotics and probiotics.
We identified only a few studies with concomitant diet therapies. Studies in participants
using immune suppressants were also largely absent in the existing literature and patients on
immune suppressants were systematically excluded from a number of RCTs. The existing
evidence base is not sufficient to draw any meaningful conclusions from adverse events observed
in the few studies that addressed these patients.
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Future Research
Our search of the published literature on probiotics failed to uncover answers to several of
the questions posed by the sponsors and identified little information on several of the organisms
of interest. Performing a formal gap analysis was beyond the scope of the review; however a
major aim of these recommendations for future research must be to fill in the research gaps we
identified.
Monitoring and reporting. Future studies should describe the intervention and the results of
interventions in more detail. This improved description would entail, first of all, documenting the
investigated product with regard to the genus, species, and strain. As technology and methods
develop, this should also entail a more reliable, DNA-based validation of the characteristics of
the included microorganisms, that is, the valid identification of the studied organism and the
purity or the identification of all included microorganism in the study product. There is a need
for more reliable information on the identity, potency, and viability of the included
microorganisms given to participants at the time of the intervention as this may depend on the
storage and delivery vehicles chosen for interventions.
Future studies should describe which adverse events were monitored to allow a clearer
overview of the presence and absence of adverse events in probiotics studies, in order to quantify
the risk of adverse events for future intervention participants. The reporting of adverse events
should follow reporting guidelines such as the extension of the CONSORT statement for harms
(Ioannidis, 2004). In addition, there are comprehensive systems for cataloging adverse events
such as the CTCAE system. The mention of adverse events almost in passing, as is typical for
the existing literature, is hindering knowledge accumulation.
Generally, it should be standard to monitor and report on adverse events in interventions;
general research into microbial behavior and early toxicity investigations cannot replace
empirical evidence for the presence and absence of adverse events in studies aiming to reduce
risk for, prevent, or treat diseases in human participants.
Study designs. Long-term effects of probiotics interventions are largely unknown and should be
considered in future studies; despite the large number of publications on probiotics, there is a
lack of long-term assessment studies. There is also a need to evaluate the long-term use of
probiotics, that is, intervention durations of more than a few weeks, as are currently typical. In
addition, the current literature is dominated by clinical research studies; large cohort studies
following populations who have self-selected to use probiotics as dietary supplements or food
components are needed to fully understand the effectiveness and safety of probiotics. Population
surveillance studies and case-control studies are largely absent from the literature.
Research questions. Studies are needed to explore potential adverse events associated with
interventions that include the genera Enterococcus and Bacillus, and possibly the use of some
Streptococcus species, as well as the use of Saccharomyces in some patient groups; the majority
of existing studies report on Lactobacillus, alone or in combination with other genera, most
commonly Bifidobacterium strains. In addition, it is possible that safety results differ not only by
genus but also by species or strains; hence, all probiotics research studies should report adverse
events and not rely on results obtained with other species or strains.
115
The current literature rarely reports assessment efforts to monitor harms specific to
probiotics, and more targeted assessments may change our understanding of the safety of
probiotics from what is presented in this evidence report. The harms assessment should consider
safety issues warranting further investigation as documented in this review. This process would
include systematically monitoring for infections associated with probiotic organisms. Critical
patient outcomes such as all-cause mortality or hospitalizations as well as treatment failures as
suggested by reports of failed efficacy and effectiveness studies (for example, allergy
sensitization) should be assessed in future primary research using controlled trials. Reviews
should consider all studies measuring the outcome regardless of whether that outcome was
utilized to evaluate the efficacy of the intervention or observed as an adverse event.
There is also a lack of studies addressing complex research questions such as interactions
with participant, product, or intervention factors associated with the use of probiotic products.
These effects should be addressed with appropriate multivariate analyses, or where possible, in
head-to-head comparisons. With regard to participant characteristics studies evaluating effects on
elderly participants are largely absent from the current literature. There is indication that
participants with compromised health should be monitored closely for potential adverse events
associated with probiotics, such as through the use of data monitoring boards. Controlled trials
are needed to determine whether these patients are more likely to experience adverse events
compared to control groups with similar participant characteristics, in order to address riskbenefit questions. Interactions with delivery vehicles, in particular yogurt and dairy products,
should be investigated further in direct, head-to-head comparisons in order to fully understand
the effect of these vehicles.
116
Conclusions
Despite a substantial number of publications on probiotics little evidence is available to
answer specific questions regarding their safety in research studies. RCTs and case studies
diverge in the outcomes they report, there is a lack of assessment and structured reporting of
adverse events, and interventions are poorly documented. The available evidence in RCTs does
not indicate an increased risk; however, rare adverse events are difficult to assess and the current
literature is not well equipped to answer specific questions on the safety of probiotics in
intervention studies with confidence. To quantify potential health risks the presence and absence
of adverse events should be reported, adverse events should be monitored (particularly in healthcompromised participants), infections due to the administered organisms and treatment failures
should be documented; and the effect of delivery vehicles should be assessed systematically. In
addition, few studies currently exist that report on effects in the elderly, the long-term effects of
probiotics use, or on interventions based on genera other than Lactobacillus. These limitations
hinder conclusions regarding the safety of probiotics used to reduce risk and prevent or treat
disease.
117
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181
Acronyms and Abbreviations
AHRQ – Agency for Healthcare Research and Quality
ATCC – American Type Culture Collection
CAERS – CFSAN Adverse Event Reporting System
CBER – Center for Biologics Evaluation and Research
CCTs – controlled clinical trials
CFSAN – Center for Food Safety and Applied Nutrition
cfu – colony forming units
CI – confidence interval
CTCAE – Common Terminology Criteria for Adverse Events classification system
DARE – Database of Abstracts of Reviews of Effects
EFSA – European Food Safety Authority
EPC – Evidence-based Practice Center
FAO/WHO – Food and Agriculture Organization of the United Nations and the World Health
Organization
FDA – Food and Drug Administration
GRAS – generally recognized as safe
IND – investigational new drug
ITT – intention-to-treat
MANTIS – Manual, Alternative and Natural Therapy Index System
NCCAM – National Center for Complementary and Alternative Medicine
NCI-CTC – National Cancer Institute Common Toxicity Criteria
NTIS – National Technical Information Service
ODS – National Institutes of Health Office of Dietary Supplements
RCT – randomized controlled trial
RD – risk difference
RR – risk ratio
SAE – serious adverse event
TEP – Technical Expert Panel
182
Appendix A. Exact Search Strings and List of
Manufacturers
Exact Search Strings
Probiotics—Search Methodologies
SEARCH #1:
DATABASE SEARCHED & TIME PERIOD COVERED:
PubMed – 1966-8/2010
SEARCH STRATEGY:
probiotic* OR prebiotic* OR pre-biotic* OR synbiotic*
NOT
animals NOT humans
NUMBER OF ITEMS RETRIEVED: 6491
===============================================================
SEARCH #2:
DATABASE SEARCHED & TIME PERIOD COVERED:
Cochrane Database of Systematic Reviews via OVID Online Service – All dates
SEARCH STRATEGY:
probiotic* OR prebiotic* OR synbiotic* {No Related Terms}
NUMBER OF ITEMS RETRIEVED: 27
===============================================================
SEARCH #3:
DATABASE SEARCHED & TIME PERIOD COVERED:
Cochrane Database of Abstracts of Reviews of Effects (DARE) – All dates
SEARCH STRATEGY:
probiotic* OR prebiotic* OR synbiotic* {No Related Terms}
NUMBER OF ITEMS RETRIEVED: 17
===============================================================
SEARCH #4:
DATABASE SEARCHED & TIME PERIOD COVERED:
Cochrane Central (Controlled Clinical Trials Register) – All dates
SEARCH STRATEGY:
probiotic* OR prebiotic* OR synbiotic* {No Related Terms}
A-1
NUMBER OF ITEMS RETRIEVED: 151
===============================================================
SEARCH #5:
DATABASE SEARCHED & TIME PERIOD COVERED:
CINAHL with Full Text – 1981-8/2010
SEARCH STRATEGY:
TI ( probiotic* OR prebiotic* OR synbiotic* ) OR AB ( probiotic* OR prebiotic* OR synbiotic*
) OR SU ( probiotic* OR prebiotic* OR synbiotic* )
Search modes - Boolean/Phrase
NUMBER OF ITEMS RETRIEVED: 1633
===============================================================
SEARCH #6:
DATABASE SEARCHED & TIME PERIOD COVERED:
NTRL – National Technical Reports Library (NTIS database) – ~1800-8/2010
SEARCH STRATEGY:
probiotic OR probiotics OR prebiotic OR prebiotics OR synbiotic OR synbiotics
NUMBER OF ITEMS RETRIEVED: 99
NUMBER OF RELEVANT ITEMS RETRIEVED AFTER INITIAL SCREENING: 12
===============================================================
SEARCH #7:
DATABASE SEARCHED & TIME PERIOD COVERED:
Toxline/Toxfile – 1964 – 8/2010
SEARCH STRATEGY:
probiotic* OR prebiotic* OR synbiotic*
NUMBER OF ITEMS RETRIEVED: 371
===============================================================
SEARCH #8:
DATABASE SEARCHED & TIME PERIOD COVERED:
Allied & Complementary Medicine via DIALOG Online Service File 164– 1984-8/2010
SEARCH STRATEGY:
probiotic? OR prebiotic? OR synbiotic?
NUMBER OF ITEMS RETRIEVED: 134
===============================================================
SEARCH #9:
DATABASE SEARCHED & TIME PERIOD COVERED:
MANTIS (Manual, Alternative, and Natural Therapy) via DIALOG Online Service File 91 –
1880-5/2009
A-2
SEARCH STRATEGY:
probiotic? OR prebiotic? OR synbiotic?
NUMBER OF ITEMS RETRIEVED: 238
===============================================================
SEARCH #10:
DATABASE SEARCHED & TIME PERIOD COVERED:
Academic Universe Company Profiles
SEARCH STRATEGY:
(probiotic! OR prebiotic! OR synbiotic!) AND (sic(mfg OR manufact! OR preparation) OR
naics(mfg OR manufact! OR preparation))
AND
U.S. OR intenational companies
NUMBER OF ITEMS RETRIEVED: 355
===============================================================
SEARCH #11:
DATABASE SEARCHED & TIME PERIOD COVERED:
Embase – 1974-8/2010
SEARCH STRATEGY:
probiotic? OR prebiotic? OR synbiotic?
AND
Human
NUMBER OF ITEMS RETRIEVED: 6536
===============================================================
SEARCH #12:
Agricola - 1970 – 8/2010
SEARCH STRATEGY:
probiotic? or prebiotic? or synbiotic?
AND
safe? or harm? or adverse or death or complication? or toxic?
NUMBER OF ITEMS RETRIEVED: 506
List of Manufacturers
The table lists manufacturers of probiotic, prebiotic or synbiotic products. The companies
were identified searching the web pages of the IPA and ISAPP, www.usprobiotics.org, the
database Nexis, the NLM Dietary Supplements Labels Database, a Google product search,
examples listed in published papers and guidelines (e.g., World Gastroenterology Organisation
Practice Guideline; Douglas & Sanders, 2008), and personal files (all searched May 2009).
A-3
Identified Manufacturers
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
Manufacturer
21st Century HealthCare, Inc.
4Life Research
Abbott Laboratories
ADM Alliance Nutrition, Inc.
Advanced Muscle Science
Agropur
Agtech Probiotic Fertilizers
Alacer Corporation
Albertsons
Alcon Laboratories, Inc
Allergy Research Group
ALVA-AMCO Pharmacal Cos, Inc.
American Health, Inc.
American Ingredients Inc.
American Nutrition
Amerifit Brands, Inc.
AmVac
Anthony Robbins Companies
Applied Nutriceuticals
Applied Nutrition
Ardeypharm
Aria Foods
Arthritis Research Corporation
Asahi Kasei Corporation
AST Sports Science
Atkins Nutritionals, Inc.
Attune Foods
Bally Total Fitness Corporation
Barlean's Organic Oil
Barry Callebaut AG
Bausch & Lomb
Bayer Corporation/Consumer Care Division
Bayer Health Care (Phillips’)
Belvedere Jay Brands
Beneo-Orafti
Berkeley Premium Nutraceuticals, Inc.
Bio Human Netics, Inc.
Biobank Co
Biocodex
BioGaia AB
BioImmersion
Bio-k Plus
BioNatures
Biotech Corporation
Biotech Research
Biotest Brands
Biotics Reaearch Corporation
Blairex Laboratories, Inc.
Block Drug
Bradley Pharmaceuticals
Bradley Pharmaceuticals Inc
Brewster Foods
Bristol-Meyers Squibb Company
Bronson Laboratories
BSN
California Academy of Health, Inc.
A-4
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
Calpis USA Inc.
Carb Wise
Cargill Texturizing Solutions
CCA Industries, Inc.
Cerbios-Pharma
Champion Nutrition, Inc.
Chattem, Inc.
China Meihua Biological Technology
China-Biotics
Choongang Biotech Co Ltd
Chr. Hansen
Clinicians Choice Inc.
ConAgra Foods
Contract Pharmacal Corp.
Coromega Corp.
Costco Wholesale Corporation (CWC), Inc.
(Distributor)
Country Life
CSA Nutraceuticals, LLC
Culturelle/Amerifit Brands
Custom Probiotics
CytoSport, Inc.
Danisco
Danone/Dannon
Desert Health Products Inc
Designs For Health
Doctor’s Best, Inc.
Douglas Laboratories
Dow
DrNatura
DSM Food Specialties France SAS
EAS (Experimental and Applied Sciences)
Eclectic Institute
Ecological Formulas/Cardiovascular Research
Ltd.
Emerald Laboratories
EnCoate
Encysive Pharmaceuticals Inc
Eniva Corporation
Enzymatic Therapy, Inc.
Epic Nutrition
Ergopharm
Essential Formulas Inc
Fenchem
Flora
Fonterra Co-operative Group Ltd.
Futurebiotics, LLC
Futureceuticals
Gaia Herbs
Ganeden Biotech
Garden of Life
Gatorade Company, The
General Mills
GeneThera, Inc.
GenMont Biotech
GlaxoSmithKline (GSK)
Global Health Trax Inc
GNC (General Nutrition Companies), Inc.
Great Ocean Ingredients
A-5
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
GTC Nutrition, LLC
GumRunners, LLC
Harmonium International
Health & Nutrition Systems International Inc
Health Asure, Inc.
Health Plus, Inc.
Healthy N Fit Nutritionals
Healthy Origins Products
Hello Imports, LLC
Hunan Taizinai Group Co Ltd
HVL, Inc./Douglas Laboratories
IDS Sports
Imagenetix, Inc.
Inkine Pharmaceuticals
Institut Rosell Lallemand Inc
Inverness Medical Innovations, Inc.
Iovate Health Sciences U.S.A. Inc.
IR Biosciences Holdings Inc
Irwin Naturals
iSatori Technologies
ISS Research
J.R. Carlson Laboratories
Jarrow Formulas
Jay Robb
Kellogg (Canada and USA)
Kendy USA
Kibow Biotech
Klaire Labs
Klein-Becker USA
Kmart
Koninklijke Friesland Foods
Kraft
Labrada Nutrition
LacPro
Larkspur Wren Industries
Leiner Health Products Inc. (LHP, Inc.) (Dist.)
Lichtwer Pharma
Life Enhancements Products, Inc.
Life Extension Foundation
Life Plus International
Lifeway Foods
LifeWise Naturals
Longs Drug Stores Corporation
Mayor Pharmaceuticals Laboratory, Inc.
McNeil Nutritionals
Mead Johnson & Company
Meiji Dairies Corporation
Merck
Merz Pharmaceuticals, LLC
Metabolife International, Inc.
MET-Rx Engineered Nutrition
MGI GP Inc
Michael's Naturopathic Programs
Mission Pharmacal Company
Molecular Nutrition, LLC
Montana Naturals, Inc.
Morinaga Milk Industry
MRM-USA
Muscle Marketing USA, Inc.
A-6
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
MuscleTech Research and Development Inc.
Naked Juice Company
Nancy’s Yogurt
Natrol, Inc.
Naturade
Natural Balance, Inc.
Natural Bridges Products, Inc.
Natural Factors
Natural Factors Nutritional Products Inc.
Natural Organics Inc.
Natural Products, Inc.
Naturally Vitamins
Nature Made Nutritional Products
Nature’s Sunshine Products Inc
Nature’s Way Holding Company
Natures Answer
Natures Benefit
Natures Best Inc
Natures Bounty, Inc.
Natures Resource Products
Natures Secret
Natures Sunshine
Natures Way Products, Inc.
Nebraska Cultures
Nestlé Nutrition USA
Nestlé Purina
New Chapter
New York Health Care, Inc.
NewMark
Newmark (NMK)
Newmark / New Chapte...
Next Foods
Next Proteins International
NFI Consumer Products
NIZO Food Research B.V.
Norrmejerier
North Star Nutritionals
Northwest Natural Products
Novartis Consumer Health, Inc.
Novato Swan Research
Novogen Ltd
Now
Now Foods
Nutracea
Nutraceutical Corporation
Nutraceutical Science Institute (NSI)
Nutraceutix
Nutramax Laboratories, Inc.
NutraSanus
NutriCology, Inc.
Nutri-Health
Nutrition Now, Inc.
Nuvim, Inc.
NxLabs
Olympian Labs Inc.
On The Rock Nutrition
Optimal Therapeutics, Inc.
Optimum Nutrition
A-7
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
Oragenics Inc
Organobalance GmbH
P.L. Thomas & Company
Passion 4 Life, LLC
PatentHealth, LLC
Performance Labs, Inc.
Pharmanex
Pharmaton
Pharmavite, LLC
Physician Formulas
PhysioLogics
Planetary Formulas
Premier Nutrition
Probi
Probi AB
Probiomics Ltd
Probiotical
Procter and Gamble
Prolab Nutrition
Pulmuone – Wildwood
Pure Encapsulations, Inc.
Pure Prescriptions, Inc.
Pure Research Products
PureTek Corporation
Puritans Pride
Qingdao Eastsea Pharmaceutical Co
Quantum Health
Questcor Pharmaceuticals Inc
Radiance Vitamins
Rainbow Light
Rainbow Light Nutritional Systems
Real Health Laboratories, Inc.
Remington Health Products
Renaissance Herbs, Inc.
Renew Life
ReNew Life Formulas, Inc.
Renutra/Pivotal Health Solutions
Rexall Sundown, Inc.
Richardson Labs, Inc.
RidgeCrest Herbals, Inc.
Rite Aid Company (Distributor)
Sanofi-Aventis
Sausalito Lark Systems
Schiff
Schiff Products, Inc. (Distributor)
Sedona Labs
Sensus
Shaklee Corporation
Sigma-Tau Pharmaceuticals, Inc.
Slimfast Foods Co.
Solgar
Solvay
Somaxon Pharmaceuticals
Spectrum Essentials
Spectrum Organic Pro...
Spectrum Organic Products, Inc.
Super Nutrition Inc.
Synbiotics
Synbiotics Corporati...
A-8
291.
292.
293.
294.
295.
296.
297.
298.
299.
300.
301.
302.
303.
304.
305.
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
331.
332.
333.
334.
335.
Ta'am-Teva Altman
Target Corporation (Distributor)
Tensall Bio-Tech Company, Limited
The WholeSoy Co.
Tiburon Cardinal Laboratories
Trace Minerals Research
Trader Joes (Distributor)
Transitions For Health, Inc.
TrimSpa
Tropical Oasis Inc.
Twinlab Corporation
Twinwealth Biotech
U.S. Nutrition
UAS Laboratories
Udos choice
Ultimate Nutrition
Unilever
Universal Nutrition
Upsher-Smith Laboratories, Inc.
Urex Biotech
Valio Worldwide
Vincent Foods, LLC
Vitabase
Vitamin Shoppe, The
Vitamin World, Inc.
Vitarich
VPX (Vital Pharmaceuticals)
VSL Pharmaceuticals
Wakunaga of America
Weider Nutrition Group
Weil Nutritional Supplements
Wellements
Western Research Laboratories
Whole Health Products, LLC
Winclove
Windmill Health Products
Wonder Laboratories
World Nutrition, Inc.
World Organics Corporation
WorldWide SportNutrition
Wyeth
Wyeth Consumer Healthcare
Yakult
Yerba Prima
Zoller Laboratories
A-9
Appendix B. Sample Data Extraction Forms
ID: _____________________
Reviewer:
First Author, Year:
____________
LAST NAME ONLY, PUBLICATION YEAR
Number of publications: _____ ENTER ‘1OF 1’ IF ONLY ONE
Description and IDs of related papers (if more than one
:
publication)
Study Details & Participant Information
Country _____________________________
Country category
CHECK ALL THAT APPLY
US .......................................................................
Europe.................................................................
Asia (Japan, China, Taiwan, Korea, Singapore) .
Other or n/a .........................................................
Study design
CIRCLE ONE
Case study [1c] ....................................................0
Case series (uncontrolled) [1a,b]..........................1
Case-Control (probiotics as risk factor) [1d,e] .....2
Cohort study (comparing 2 cohorts) [1d,e] ........... 3
Controlled clinical trial (controlled by investigator) [1a,b]
Parallel RCT [1a,b] ..............................................5
Other: _______________________________
n/a .....................................................................
4
Mechanistic study – could the study be described as a mechanistic study (e.g.
investigating how, why probiotics may work)? [1f]
CIRCLE ONE
No .....................................................................0
Unclear - Somewhat unclear ............................1
Yes ....................................................................2
Source:
CIRCLE ONE
Conference abstract, letter.................................0
Unclear - Somewhat unclear ............................1
Journal article....................................................2
B-1
Was the safety of probiotics the main aim of the paper?
No .....................................................................0
Unclear - Somewhat unclear ............................1
Yes ....................................................................2
Sample size category [4]
1-10 ....................................................................0
11-100 ................................................................1
100+ ...................................................................2
n/a - unclear.......................................................
Age at exposure to probiotics[4]
Young (prenatal to teens) ..................................0
Adult ................................................................1
Elderly (> 65 yrs) ..............................................2
n/a, multiple – no info or mix .........................
Age at data collection category (majority groups) [4]
CHECK ALL THAT APPLY
Prenatal .............................................................
Newborns (≤1 mos)...........................................
Infants (>1 - 12 mos).........................................
Toddlers (>12 - 24 mos)....................................
Children (> 2 to 11yrs)......................................
Teens (12 - 17yrs) .............................................
Adults (18 - 65 yrs) ...........................................
Elderly (> 65 yrs) ..............................................
Mix....................................................................
Other: ______________________________....
n/a – no info ......................................................
Gender [4d]: % Female: ____
Other info (if no % is given):
“Mostly female” “Mostly male”
n/a - no info, not reported
Race and ethnicity [4d]: Did the study target a particular demographic group or
reported subgroup analyses for particular groups?
n/a - no particular group; no
info
B-2
Disease or immunologic status [4d]: Does the study focus on patients with any of the
following health conditions?
CHECK ALL THAT APPLY . CONSIDER ONLY SUBSTANTIAL NUMBER OF PATIENTS, NOT 1 PATIENT WITH IBS WITHIN HEALTHY SAMPLE
Healthy participants
Cancer
Obesity
Exposure to toxins
Intestinal detox therapy
Short gut syndrome
Gastrointestinal (unspecified)
IBS
IBD
Diarrhea
Colitis
Crohn’s disease
Dermatologic (unspecified)
Eczema
Atopic dermatitis
Invasive devise
Immuno-compromised, HIV
Chronic infection
Immunologic (unspecified)
Vaginal yeast infection
H. pylori
Lactose intolerance
Allergies (not lactose)
Other health condition: SPECIFY
Other health condition: SPECIFY
Other health condition: SPECIFY
Other health condition: SPECIFY
n/a – not specified, none of the above
Overall, assuming a continuum ranging from healthy to clinically high risk what
describes the participants best [4d]
CIRCLE ONE
Generally healthy ..............................................0
n/a - medium, neither, unclear...........................1
High risk ...........................................................2
B-3
Exclusion criteria: does the study explicitly exclude
the following groups?
CHECK ALL THAT APPLY
Newborn or infants, under 2 years ....................
Older participants (>65) ...................................
Immune compromised, critically ill, high risk ..
Pregnant women................................................
Other (recurrent) group: SPECIFY
___________________________________ ...
n/a – not specified, none of the above...............
Probiotic function
CIRCLE ONE
None specifically / nutrition (e.g. contained in yoghurt) 1
Prevention ........................................................2
Treatment (e.g. to counterbalance adverse effects of antibiotics
Varies - Varies by participant ...........................4
n/a .....................................................................5
3
Does the study include any of the following co-treatments (confounders) [6]?
CHECK ALL THAT APPLY
Concomitant antibiotics ....................................
Diet therapies ....................................................
Corticosteroid use .............................................
Immune suppressants ........................................
Other, specify: ________________________ ..
n/a - none of the above ......................................
Did the authors file an Investigation of New Drug (IND) form prior to the
research? [1a]
CIRCLE ONE
No .....................................................................0
Unclear - Somewhat unclear ............................1
Yes ....................................................................2
B-4
Describe the Main Probiotics Intervention and Control Group, if any, here
Intervention Group ARM 1 IN CONTROLLED TRIALS WITH MULTIPLE ACTIVE ARMS
Control Group: DESCRIBE CONTROL GROUP HERE, NOT ANY ADDITIONAL ACTIVE ARMS FIRST
Control category (control group or other non-probiotic control)
None (uncontrolled study,
no pre-test)........................... 1
Pre-test (no other control group) . 2
Placebo ................................... 3
Non-probiotic Tx .................... 4
ADD MORE INTERVENTION PAGES AND STAPLE TO THE BACK OF THIS FORM IF THERE ARE MORE THAN
2 TREATMENT ARMS WHERE PROBIOTICS WERE GIVEN.
Other probiotic ................... 5
Synbiotics ........................... 6
Prebiotics ............................ 7
Other - specify:
_____________________ .. 8
N/A - unclear ...................... 9
If “Other probiotic”, extract the following:
Product name ____________________________________
Product name ____________________________________
Further product description (IF NECESSARY)
Product description (E.G. VSL CONTAINS…)
Delivery vehicle [3a]
CHECK ALL THAT APPLY
Infant formula..................................................
Yogurt .............................................................
Dairy drink (e.g.Yakult) ..................................
Pill, capsule, gelcap ........................................
Mixed in with food (e.g. drops in porridge) ...
_________________________________)
Other (SPECIFY, POTENTIALLY NEW CATEGORY?):
Varies by participants......................................
n/a, unclear .....................................................
Target of intervention
CHECK ALL THAT APPLY
Patient..............................................................
Mother, patient in utero ...................................
n/a, unclear ......................................................
Single - Single or probiotic mixture
CIRCLE ONE
Delivery vehicle [3a]
CHECK ALL THAT APPLY
Infant formula .................................................
Yogurt .............................................................
Dairy drink (e.g.Yakult)..................................
Pill, capsule, gelcap ........................................
Mixed in with food (e.g. drops in porridge) ...
_________________________________)
Other (SPECIFY, POTENTIALLY NEW CATEGORY?):
Varies by participants......................................
n/a, unclear .....................................................
Target of intervention
CHECK ALL THAT APPLY
Patient .............................................................
Mother, patient in utero...................................
n/a, unclear ......................................................
Single - Single or probiotic mixture
Mix of probiotics...............................................0
Varies by participant or unclear ........................1
1 probiotic strain only........................................2
CIRCLE ONE
Mix of probiotics (genus, species, strain) .........0
Varies by participant or unclear ........................1
1 probiotic strain only .......................................2
B-5
Intervention Group
Control Group
Synbiotic - Single or mixed probiotics and prebiotics? [3e] CIRCLE ONE
Synbiotic - Single or mixed probiotics and prebiotics? [3e] CIRCLE ONE
Probiotic only ....................................................0
Varies by participant, unclear............................1
Synbiotic (probiotic and prebiotics) ..................2
Genus investigated in the study [3b]
Probiotic only....................................................0
Varies by participant, unclear ...........................1
Synbiotic (probiotic and prebiotics)..................2
CHECK ALL THAT APPLY
Genus investigated in the study [3b]
Lactobacillus ...................................................
Bifidobacterium...............................................
Saccharomyces ...............................................
Streptococcus ..................................................
Enterococcus ...................................................
Bacillus............................................................
Varies by participant .......................................
n/a ...................................................................
Notes (E.G. STREPT. USED FOR FERMENTION)__________________________________
Details of all contained Probiotics STATE N/A WHERE NOT AVAILABLE
Genus
Species
Strain
Form (ACTIVE,
LYOPHILIZED, HEAT
KILLED /
TYNDALLIZED)
Potency
CHECK ALL THAT APPLY
Lactobacillus ...................................................
Bifidobacterium ..............................................
Saccharomyces ...............................................
Streptococcus ..................................................
Enterococcus ...................................................
Bacillus ...........................................................
Varies by participant .......................................
n/a ...................................................................
Notes (E.G. STREPT. USED FOR FERMENTION)____________________________________
Details of all contained Probiotics STATE N/A WHERE NOT AVAILABLE
Genus
Species
Strain
Form (ACTIVE,
(DOSE OF ACTIVE
LYOPHILIZED, HEAT
KILLED /
TYNDALLIZED)
MICROORGANISM
ACCORDING TO
PRODUCT LABEL)
A
A
B
B
C
C
D
D
E
E
F
F
G
G
H
H
B-6
Potency
(DOSE OF ACTIVE
MICROORGANISM
ACCORDING TO
PRODUCT LABEL)
Intervention Group
Characterize the consumption of above probiotics
CHECK ALL THAT APPLY
Mix - Each participant consumes a mixture of the above
probiotic genera / only 1 strain..........................................
Varies – Genera/strain/species and mixture/single genera
varies by participants.........................................................
n/a .........................................................................................
Dose and frequency of above probiotics [4a]:
Dose
Number
_________
Frequency
Unit
_________
Varies by participant..............
Varies over time ....................
n/a .........................................
Route of administration [4c]
Number
_________
Per
_________
Varies by participant............
Varies over time...................
n/a .......................................
CHECK ALL THAT APPLY
Oral .................................................................
Enteral, feeding / nasal /G tube, jenunostomy.
Intravenous catheter ........................................
Intravaginal .....................................................
Topical ............................................................
Other, specify:________________________ .
Varies by participant and or genus..................
n/a ...................................................................
Duration of probiotic use during study in months [4a]
Varies – Duration varies by participant...........
n/a – no exact information on duration of use.
Long term use – which category does the group fall into [4a]
Short term (≤ 1 month)......................................0
Medium, varies, or unclear................................1
Long term (≥1 year) ..........................................2
B-7
Control Group
Characterize the consumption of probiotics
CHECK ALL THAT APPLY
Mix - Each participant consumes a mixture of the above
probiotic genera / only 1 strain .........................................
Varies – Genera/strain/species and mixture/single genera
varies by participants ........................................................
n/a ........................................................................................
Dose and frequency of above probiotics [4a]:
Dose
Number
_________
Frequency
Unit
_________
Varies by participant ..............
Varies over time .....................
n/a .........................................
Route of administration [4c]
Number
_________
Per
_________
Varies by participant ............
Varies over time ...................
n/a ........................................
CHECK ALL THAT APPLY
Oral..................................................................
Enteral, feeding / nasal /G tube, jenunostomy.
Intravenous catheter ........................................
Intravaginal .....................................................
Topical.............................................................
Other, specify:________________________ .
Varies by participant and or genus ..................
n/a ...................................................................
Duration of probiotic use during study in months [4a]
Varies – Duration varies by participant...........
n/a – no exact information on duration of use .
Long term use – which category does the study fall into [4a]
Short term (≤4 weeks) .......................................0
Medium, varies, or unclear................................1
Long term (≥1 year) ..........................................2
B-8
Verification
Was the dose of active microorganism verified?
No, not described, none of the below apply ...................... 0
Somewhat unclear ............................................................. 1
Yes, verified ....................................................................... 2
n/a, varied by participant, e.g. in observational
study ..............................................................................
Treatment Group (arm 1)
Potency (dose of active
microorganism) according
to study test
Test used to check the
Culture (patent or
amount of organisms
repository / culture
collection designation)
Number of viable bacteria per dose
Arm 2 if applicable
Potency (dose of active
microorganism) according
to study test
Number of viable bacteria per dose
A
A
B
B
C
C
D
D
E
E
F
F
G
G
H
H
Contaminants mentioned?
Test used to check the
amount of organisms
CIRCLE ONE
Contaminants mentioned?
No .....................................................................0
Somewhat unclear ............................................1
Yes (specify __________________________) 2
n/a – no test .....................................................
CIRCLE ONE
No .....................................................................0
Somewhat unclear ............................................1
Yes (specify __________________________) 2
n/a – no test .....................................................
B-9
Culture (patent or
repository / culture
collection designation)
Assessment
Was a published tool used to assess harms? [1a, d]CHECK ALL THAT APPLY
No, unlikely.......................................................0
Possible .............................................................1
Yes SPECIFY____________________________...2
Assessed safety parameters - what did the study monitor (explicit
description of what they looked out for) [1a, 1d]
CHECK ALL EXAMPLES THAT APPLY IF EXACT WORDING WAS USED, OTHERWISE WRITE OUT OR MARK
CLEARLY IN TEXT COPY WHAT SHOULD BE ENTERED IN ACCESS
Death ...............................................................
Stroke ..............................................................
MI....................................................................
Infections (not restricted to sepsis)..................
Sepsis...............................................................
Fungemia.........................................................
Endocarditis.....................................................
Deleterious physiologic/metabolic activity .....
Allergy.............................................................
Hematocytometric values ................................
Liver and renal function ..................................
Diarrhea...........................................................
Bloating ...........................................................
Abdominal pain ...............................................
Adverse / unexpected events, side effects (not
further specified but named outcome in
method section) ...........................................
Data collection - What method was used to record harms?
CHECK ALL THAT APPLY
Participant diary ..............................................
Participant questionnaire.................................
Telephone interview........................................
Healthcare provider assessment, face to face ..
Other SPECIFY__________________________ ..
n/a – no info provided .....................................
Duration of follow-up category
Follow-up after consumption stopped
CIRCLE ONE
No, consumption ongoing ................................0
Consumption has stopped (recently); unclear ..1
Consumption has stopped long ago (≥ 1 year) ..2
ENTER EXACT TEXT OR INDICATE WHICH TEXT SECTION SHOULD BE ENTERED
n/a (unclear, not specified) .......................
Hospital admission or lengthened hospitalization explicitly assessed?
[5]
CIRCLE ONE
Short-term (<6 months) ....................................0
Unclear - Somewhat unclear ............................1
Long-term (≥ 1 year).........................................2
CIRCLE ONE
No....................................................... 0
Possible – somewhat unclear ............. 1
Yes...................................................... 2
B-10
n/a – none of the above [4d]............................
Results
Does the study describe an analysis to accomplish any of the
CHECK ALL THAT APPLY
following?
Differentiate probiotics and medication effects
Differentiate effects of probiotics and
confounders ...................................................
Trace interactions between harms .....................
Trace interactions between probiotics and
medications (statistical interaction effect or
subgroup analysis [2a] ...................................
Unclear ..............................................................
No, none of the above .......................................
Effectiveness – according to the abstract (check conclusion) of the
publication is the probiotic intervention described as effective
(with regard to health outcomes other than harms) [4e] CIRCLE ONE
No .....................................................................0
Partially, unclear ...............................................1
Yes ....................................................................2
Does the study provide a direct comparison (= within study
comparison, e.g. there are 2 groups in the study or the study
reports subgroup analyses) of any of the following: [4e]
Genera [3b] .....................................................
Species [3b] .....................................................
Strains [3b] ......................................................
Forms (e.g. active vs lyophilized) [3c] ............
Delivery vehicles (e.g. milk drink) [3a] ..........
Genera mix – single vs mixture of prob.genera [3d]
Genera mix – single vs mixture of prob.genera [3d]
Synbiotic mix – probiotics only vs probiotics and prebiotics mix [3e]
Dose [4a] .........................................................
Timing [4b] .....................................................
Mode of administration (e.g. catheter) ............
n/a – none of the above....................................
Does the study provide subgroup analysis for any of the
following:
Gender [4d] ....................................................
Age [4d] ..........................................................
Ethnicity [4d]...................................................
Disease or immunologic status (healthy vs high risk) [4d]
B-11
Assessed and Reported Harms for the Probiotics (Intervention) and Control Group
1.
2.
3.
4.
5.
6.
7.
8.
Blood and lymphatic system
Cardiac
Congenital, familial and genetic
Ear and labyrinth
Endocrine
Eye
Gastrointestinal
General and administration site
conditions
9. Hepatobiliary
10.Immune system
11.Infections and infestations
12.Injury, poisoning and procedural
complications
13.Investigations
14.Metabolism and nutrition
15.Musculoskeletal/connective tissue
16.Neoplasms benign, malignant and
unspecified (incl. cysts, polyps)
17.Nervous system
18.
Pregnancy, puerperium
and perinatal conditions
19.
Psychiatric
20.
Renal and urinary
21.
Reproductive system,
breast
22.
Respiratory, thoracic,
mediastinal
23.
Skin and subcutaneous
tissue
24.
Social circumstances
25.
Surgical and medical
procedures
26.
Vascular
27.
Other/Unclear, does
not apply
If paper doesn’t distinguish between intervention and control group,
check here
Probiotics Intervention Group ARM 1 IN CONTROLLED TRIALS WITH MULTIPLE ACTIVE ARMS
ENTER CODE, WRITE IN CATEGORY, AND COLLECT HARMS DATA
Code Harm
S
A
E
# of patients
n/a if
unknown
Control Group ONLY DESCRIBE CONTROL GROUP HERE, NOT ANY ADDITIONAL ACTIVE ARMS
Notes
ENTER CODE, WRITE IN CATEGORY, AND COLLECT HARMS DATA
Code Harm
Patients with AEs (if clearly stated) [1]:
______
NUMBER
or
S
A
E
# of patients
n/a if
unknown
Notes
_______
PERCENT
Patients with AEs (if clearly stated) [1]:
Other information, above system does not apply
B-12
______
or
_______
Safety of probiotics used to reduce risk and prevent or treat disease: State of the research
NUMBER
PERCENT
Other information, above system does not apply
Was acquired antibiotic resistance and/or transferability reported?
[2b]
CIRCLE ONE
No....................................................... 0
Unclear – somewhat unclear .............. 1
Yes...................................................... 2
Probiotics treatment Group
Timing and Duration: Is there information 1. on the time of onset of harm
and probiotic use (e.g., when did symptoms start in relation to probiotics
use) and 2. how long the harm was sustained after the intervention or
exposure stopped? [4b]
n/a - unknown, not mentioned
Yes (describe)....................................................................
DESCRIBE TIMING AND DURATION FOR EACH HARM SEPARATELY IF STATED
Hospitalizations: Number of (new) hospital admissions [5]
ONLY STATE 0 IF IT WAS EXPLICITLY ASSESSED
n/a - unknown, not mentioned ...........
Length of hospitalization [5]
days
n/a - unknown, not mentioned ...........
Did the study describe an antibiotic therapy designed to treat
unintended pathology caused by the probiotics? [1g]
CIRCLE ONE
No....................................................... 0
Unclear – somewhat unclear .............. 1
Yes...................................................... 2
B-13
Safety of probiotics used to reduce risk and prevent or treat disease: State of the research
Yes...................................................... 2
n/a - no probiotics..............................
Control Group
Timing and Duration: Is there information 1. on the time of onset of harm
and probiotic use (e.g., when did symptoms start in relation to probiotics
use) and 2. how long the harm was sustained after the intervention or
exposure stopped? [4b]
n/a - unknown, not mentioned
Yes (describe)....................................................................
DESCRIBE TIMING AND DURATION FOR EACH HARM SEPARATELY IF STATED
Hospitalizations: Number of (new) hospital admissions [5]
ONLY STATE 0 IF IT WAS EXPLICITLY ASSESSED
n/a, unknown, not mentioned ............
Length of hospitalization [5]
days
n/a - unknown, not mentioned ...........
Did the study describe an antibiotic therapy designed to treat
unintended pathology caused by the probiotics? [1g]
CIRCLE ONE
No....................................................... 0
Unclear – somewhat unclear .............. 1
Yes...................................................... 2
n/a - no probiotics..............................
Was acquired antibiotic resistance and/or transferability reported?
[2b]
CIRCLE ONE
No....................................................... 0
Unclear – somewhat unclear .............. 1
B-14
Probiotics treatment Group
Safety of probiotics used to reduce risk and prevent or treat disease: State of the research
Control Group
Was any other treatment (not antibiotics) for administered
organism reported?
CIRCLE ONE
Was any other treatment (not antibiotics) for administered
organism reported?
CIRCLE ONE
No....................................................... 0
Unclear – somewhat unclear .............. 1
Yes,2_____________________________
n/a - no probiotics..............................
No....................................................... 0
Unclear – somewhat unclear .............. 1
Yes, _____________________________
Did the study describe methods for recovery of the administered
organism from the gastrointestinal tract, serum, mouth, vagina?
[1h]
Did the study describe methods for recovery of the administered
organism from the gastrointestinal tract, serum, mouth, vagina?
CIRCLE ONE
No....................................................... 0
Unclear – somewhat unclear .............. 1
Yes...................................................... 2
[1h]
CIRCLE ONE
No....................................................... 0
Unclear – somewhat unclear .............. 1
Yes...................................................... 2
n/a, no probiotics ...............................
Add additional result pages and staple to the back of this form
if there is more than one treatment group using probiotics
B-15
Safety of probiotics used to reduce risk and prevent or treat disease: State of the research
Quality Assessment
Susceptibility to bias
Level of evidence
Level of evidence
Sample selection: Does the study design protect against selection bias?
CIRCLE ONE
CIRCLE ONE
I (RCT, CCT)
1
II (Cohort, case-control)
2
III (case series, case studies, mechanistic studies)
Unclear
No (e.g. case study, opportunity sample)
0
To some extent (e.g. all patients in unit)
1
3
Yes (e.g. consecutive patients; explicitly
representative)....................................................2
Reporting
Comparability of groups: Were the compared groups similar with regard to
prognostic factors for AEs, were they sampled from the same population;
or were there other differences apart from the intervention? CIRCLE ONE
Product reporting: Was the consumed genus, species and strain clearly
reported or could be ascertained from the authors? CIRCLE ONE
No, not fully comparable
0
Probably but somewhat unclear
1
Yes (e.g. baseline values reported and comparable) 2
No.......................................................................0
No, but info received from author
1
Yes
2
n/a (e.g. varies by participant)
n/a (no control, not even pre in pre-post).........
Assessment reporting: Were the assessed harms clearly reported? CIRCLE ONE
No (not clear what was monitored)
Somewhat unclear
Yes
Power: Was there a power calculation reported that considered an adverse
event?
CIRCLE ONE
0
1
2
No
0
Very large sample or significant AE differences
reported
1
Yes
2
Harms reporting: Were the observed (or the absence of) harms clearly
reported?
CIRCLE ONE
No
Somewhat unclear
Yes (n for all groups, for all AE)
Exposure / compliance: Can we be certain that the participants consumed
CIRCLE ONE
probiotics as described and intended?
0
1
2
No, information on compliance missing and exposure
unclear
0
Probably
1
Yes, e.g. via catheter in hospital; assessed; ~80%
Surveillance: Was there a standardized and prompted assessment of harms?
CIRCLE ONE
B-16
Safety of probiotics used to reduce risk and prevent or treat disease: State of the research
No, passive surveillance only, spontaneously reported
AE were recorded
0
Possible
1
Yes, active surveillance, structured assessment, part of
protocol
2
Randomization: Was the study described as randomized and was the
sequence generation for the randomization appropriate?
CIRCLE ONE
No, not described as randomized
0
Randomized but sequence unclear or not adequate
(allocated alternately, or according to date of birth,
hospital number)
1
Yes, randomized and adequate (table of random
numbers, computer generated)
2
Allocation concealment: If study was randomized, was the treatment
allocation concealed?
CIRCLE ONE
No (study personnel can predict group).............0
Unclear (possible, not enough information) ......1
Yes (cannot be predicted)
2
n/a (not randomized) ........................................
Participant blinding:
CIRCLE ONE
No, unlikely
0
Possible, but unclear ..........................................1
Yes
2
Outcome assessor blinding:
CIRCLE ONE
No, unlikely
0
Possible, but unclear ..........................................1
Yes
2
Dropouts: Are withdrawals and dropouts reported, including their original
group assignment, were the reason described and is the drop-out rate
acceptable, e.g. 20% short term, 30% long term?
CIRCLE ONE
No.......................................................................0
Partially (e.g. n reported, some reasons described) 1
Yes – reported, reason described, acceptable, no dr.o.
B-17
Safety of probiotics used to reduce risk and prevent or treat disease: State of the research
Problematic study (e.g. doubts if AE is associated
with probiotics, e.g. case study, infection strain and
probiotics could not be shown as being identical)
Unclear (cocktail of meds, a number of alternative
explanations for AE or different AE rates; cross-over
studies)
1
Yes (specific probiotic only difference between
groups)
2
Rate adjustment: When calculating rates of adverse events, were dropouts
and withdrawals analyzed as if they remained in the study for the
CHECK DIRECTION OF ANSWER MODE AND CIRCLE ONE
whole duration (unfair)?
Yes .....................................................................0
Possible ..............................................................1
No, adjusted or no drop-outs
2
n/a (case study) ................................................
ITT: Was an intention to treat (ITT) analysis described for the effectiveness
data? (Were all participants' data included in the analysis,
according to the treatment group to which they were
originally assigned, regardless of whether they completed
CIRCLE ONE
the treatment/study?
No, unlikely........................................................0
Possible ..............................................................1
Yes
2
n/a (no controls, no effectiveness analysis)
Confounding – confounding factors were considered in the design or analysis
CIRCLE ONE
No, unlikely
0
Possible, but unclear ..........................................1
Yes (e.g. multivariate analysis, RCT with explicit
similar co-interventions etc.)
2
Conflict: Is there potentially a conflict of interest
CIRCLE ONE
Yes (funded by manufacturer) ...........................0
Unclear (university aff. but no info on funding; meds donated)
............................................................................1
No (‘no conflict’ clearly stated)
2
General Applicability
Relevance: Is the study directly relevant to answering the review questions?
CIRCLE ONE
B-18
Appendix C. Evidence Tables
Evidence Table C1. Participant and study detail
Author, Year
Abrahamsson,
2007
Country
Sweden
Gen
era
L
Agerbaek, 1995 Denmark
St E
Aihara, 2005
Japan
L
Alberda, 2007
Canada
Allen, 2010
UK
Study
Source
Design
Sample
Size
Category
RCT
Journal
100+
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Prenatal
Newborn
Infant
Adults
48
0
Adults
30
Adults
Elderly
Newborn
Infant
57
RCT
11-100
RCT
11-100
Journal
LB
St
LB
RCT
11-100
RCT
100+
Journal
Anderson, 2003 n/a
LB
St
RCT
100+
Journal
Adults
Elderly
42
Andriulli, 2008
Italy
L
Journal
Nigeria
L
Anukam, 2008
Nigeria
L St
RCT
11-100
Journal
Adults
Elderly
Adults
Black
African
Adults
69
Anukam, 2006
RCT
100+
RCT
100+
Anukam, 2009
Nigeria
L
Journal
Adults
100
Arunachalam,
2000
Aso, 1992
New Zealand B
Journal
L
Aso, 1995
Japan
L
Awad, 2010
Egypt
L
RCT
100+
Journal
Adults
Elderly
Adults
Elderly
Teens
Adults
Elderly
Newborn
64
Japan
RCT
11-100
RCT
11-100
RCT
11-100
RCT
100+
L
RCT
11-100
Adults
100
Baerheim, 1994 Norway
Journal
Journal
Yes
Yes
Journal
Journal
Journal
Yes
Disease/
Immunologic
Status
Subgroups
General
Health
Infants
with n/a
family history of
allergic disease
Healthy
Healthy
participants
High-normal
n/a
blood pressure;
Mild hypertension
Exclusion
Criteria
Prevention
Milk protein
allergy;
Lactose
intolerance
Critically ill;
Risk of
infants
Probiotic
Function
atopy n/a
Prevention
Elective
abdominal
surgery
IBS
n/a
Prevention
n/a
Treatment
100
Bacterial
vaginosis
n/a
100
13
Diarrhea;
Immuno
compromised
Vaginal
yeast n/a
infection
Healthy
Healthy
participants
Cancer
n/a
16
Cancer
n/a
Prevention
50
Neonate
admitted to the
NICU
Urinary
tract n/a
infection
Prevention
C-1
Antibiotics
Steroids
None
nutrition
Treatment
Prevention
Elderly
High risk
Cotreatments
Treatment
Antibiotics
Antibiotics
Antibiotics
Treatment
Pregnancy
Treatment
Elderly
Treatment
Antibiotics
Prevention
Pregnancy
Treatment
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
11-100
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Bajaj, 2008
USA
LB
St
Banaszkiewicz,
2005
Poland
L
RCT
11-100
Journal
Barraud, 2010
France
LB
RCT
100+
Journal
Barreto-Zuniga, n/a
2001
LB
RCT
11-100
Journal
Adults
Elderly
21
Basu, 2007
India
L
RCT
100+
Journal
Infant
Toddler
47
Acute
diarrhea
Basu, 2007
India
L
Journal
Children
74
Basu, 2009
India
L
RCT
100+
RCT
100+
Journal
51
Beausoleil,
2007
Canada
L
RCT
11-100
Journal
Infant
Toddler
Children
Adults
Elderly
Bellomo, 1979
#13195
Switzerland
E
RCT
11-100
Journal
Newborn
Infant
Toddler
Children
36
Bertolami, 1999 Brazil
St E
C-RCT
11-100
Journal
Adults
66
Besselink, 2008 The
Netherlands
Bin-Nun, 2005 Israel
LB
Journal
41
Journal
Adults
Elderly
Infant
Black, 1997
n/a
LB
Journal
Adults
50
Boge, 2009
pilot
France
L St
RCT
100+
RCT
100+
CCT
11-100
RCT
11-100
Journal
Elderly
65
B St
Adults
22 White,
3 Black
Disease/
Immunologic
Status
Subgroups
Toddler
Children
Teens
Adults
Elderly
Yes
General
Health
Exclusion
Criteria
Nonalcoholic
n/a
minimal hepatic
encephalopathy
cirrhotics
Constipation
n/a
59
52
44
Patients
under
mechanical
ventilation
Alcohol-related
n/a
liver cirrhosis
Probiotic
Function
Treatment
High risk
Pregnancy
Treatment
Lactulose
Treatment
Antibiotics
Treatment
watery n/a
Treatment
Persistent
diarrhea
Diarrhea
n/a
Treatment
n/a
Treatment
Hospitalized
patients
on
antibiotics
Diarrhea;
Gastroenteritis/
enteritis;
toxic
dyspepsia;
Diarrhea
following
respiratory
infection
Mild to moderate
primary
hypercholesterol
emia
Acute
pancreatitis
Very low birth
weight
Healthy
participants
Healthy
participants
n/a
C-2
Cotreatments
High risk
Prevention
Antibiotics
Healthy
Treatment
Antibiotics
n/a
Treatment
Diet
n/a
Prevention
Antibiotics
Prevention
Healthy
Healthy
None
nutrition
5
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
100+
RCT
Journal
100+
Boge, 2009
France
L St
Borgia, 1982
Italy
St
Bousvaros,
2005
USA
L
RCT
11-100
Journal
Bravo, 2008
Chile
S
RCT
11-100
Journal
Brophy, 2008
UK
LB
Bruno, 1981
Italy
E
RCT
100+
RCT
11-100
C-RCT
11-100
% Female
Disease/
Immunologic
Status
Subgroups
Adults
Elderly
50
Children
Teens
White
85%,
Hispanic
4%, Black
8%
Adults
Elderly
37
77
Acute infectious n/a
disease
Journal
Adults
30
Journal
Adults
41
Spondylarthropat n/a
hy
Enteritis
n/a
Journal
Children
Teens
Adults
58
RCT
11-100
RCT
100+
Journal
Toddler
Children
Adults
Elderly
49
Children
Teens
43
Newborn
Infant
Toddler
Children
Infant
Bu, 2007
Taiwan
L
Chen, 2005
Taiwan
L
Chen, 2010
Taiwan
L
RCT
100+
Journal
Chou, 2010
Taiwan
LB
RCT
100+
Journal
Chouraqui,
2004
Chouraqui,
2008
Chui, 2009
France
LB
St
LB
Coccorullo,
2010
Italy
Connolly, 2005
Sweden
Journal
RCT
11-100
RCT
100+
L B E RCT
11-100
L
RCT
11-100
Journal
L
Journal
RCT
11-100
Yes
Journal
Unclear
Yes
Unclear
Journal
Yes
Newborn
Infant
Adults
Elderly
Infant
Infant
Healthy
participants
Chronic
pulmonary
tuberculosis
Crohn's disease
General
Health
63
L
China
Age
Ethnicity
Elderly
Bruzzese, 2007 n/a
France
Safety
Assess
-ment
Main
Aim
Probiotic
Function
5
n/a
Treatment
Antibiotics
n/a
Treatment
Steroids
High risk
Pregnancy
Treatment
Antibiotics
High risk
Treatment
Treatment
Treatment
n/a
Treatment
n/a
Prevention
n/a
Treatment
56
Preterm very low n/a
birth weight infant
Prevention
50
Healthy
participants
Healthy
participants
Severe
acute
pancreatitis
Functional
chronic
constipation
Family history of
allergy
Healthy
Prevention
Healthy
n/a
None
nutrition
Treatment
n/a
Treatment
Healthy
None
nutrition
51
27
45
C-3
Cotreatments
Healthy
n/a
45
Cystic
fibrosis;
Chronically
infected
with
pseudomonas
Chronic
constipation
Partial adhesive
small-bowel
obstruction
Asthma
and
allergic rhinitis
Exclusion
Criteria
Antibiotics
Steroids
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
100+
Cooper, 2006
n/a
B
Correa, 2005
Brazil
B St
RCT
100+
Journal
Cui, 2004
China
Ba
Journal
CunninghamRundles, 2000
USA
L
RCT
100+
CCT
11-100
Czaja, 2007
USA
L
RCT
11-100
Journal
Czech
Republic
De Preter, 2006 Belgium
L
de Roos, 1999
L St
RCT
11-100
C-RCT
11-100
RCT
11-100
RCT
11-100
Dadak, 2006
De Simone,
1992
The
Netherlands
Italy
S
LB
De Simone,
2001
Dekker, 2009
Italy
LB
St
New Zealand L
CCT
100+
RCT
100+
Delia, 2002
Italy
Delia, 2007
Italy
RCT
100+
RCT
100+
LB
St
LB
St
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Newborn
Infant
Yes
Journal
Infant
Toddler
Children
Adults
General
Health
42
30
Inpatients
receiving
antibiotics
Diarrhea
n/a
n/a
Recurrent urinary n/a
tract infection
Journal
17
Journal
Adults
51
Journal
Adults
72
Journal
Elderly
48
Long-term
patients
Healthy
participants
Healthy
participants
Healthy
participants
Journal
Prevention
High risk
Pregnancy
Lactating
ICU
Prevention
Treatment
Healthy
None
nutrition
Treatment
Healthy
None
nutrition
n/a
Treatment
Parent
with n/a
allergic disease
Prevention
Cancer;
Radiotherapy
Cancer
Prevention
C-4
Antibiotics
Treatment
Healthy
IBS
Cotreatments
Treatment
100
Yes
Breast
feeding
Immuno
compromised
Adults
50
Elderly
Prenatal
49
Newborn
Infant
Toddler
10%
Maori,
79%
European,
11% Other
Probiotic
Function
None
nutrition
Adults
83%
White,
13%
Asian, 3%
Native
American,
3%
Hispanic
Adults
Journal
Exclusion
Criteria
Infant of HIV
positive mother
Other
Yes
Disease/
Immunologic
Status
Subgroups
n/a
Elderly
Treatment
Radiation therapy
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
11-100
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Dewan, 2007
India
L St
Toddler
Children
Dolin, 2009
USA
Ba
RCT
11-100
Journal
Yes
Dubey, 2008
India
Yes
Turkey
RCT
100+
RCT
100+
Journal
Duman, 2005
LB
St
S
Journal
Yes
Dupont, 2010
France
LB
Journal
Yes
Dylewski, 2010
Canada
L
RCT
11-100
RCT
100+
Ehrstrom, 2010
Sweden
L
RCT
11-100
Journal
Adults
Eriksson, 2005
L
RCT
100+
Journal
Falck, 1999
Finland,
Norway,
Sweden
Sweden
St
RCT
100+
Journal
Felley, 2001
Switzerland
L
Journal
Feng, 1999
China
Folster-Holst,
2006
Germany
LB
St
L
RCT
11-100
RCT
11-100
RCT
11-100
Adults
100
Caucasian
95%
Children
Teens
Adults
Adults
34
Forestier, 2008
France
L
RCT
100+
Journal
French, 2009
Australia
L
Frohmader,
2010
Australia
LB
St
RCT
11-100
RCT
11-100
Journal
Journal
Yes
Newborn
Infant
Adults
Elderly
General
Health
Moderately
to n/a
severely
malnourished
IBS
n/a
Exclusion
Criteria
High risk
Treatment
High risk
Pregnancy
Lactating
Treatment
Rotavirus
n/a
diarrhea
H. pylori; Non- n/a
ulcer dyspepsia;
Peptic
ulcer
disease
Colic
n/a
49
Taking antibiotics n/a
100
Bacterial
vaginosis
Vulvovaginal
candidiasis
Bacterial
vaginosis
n/a
Tonsillitis
n/a
H. pylori
n/a
n/a
Probiotic
Function
Cotreatments
Antibiotics
Diet
Treatment
Treatment
Antibiotics
Treatment
High risk
Pregnancy
Breast
feeding
Pregnancy
Breast
feeding
Treatment
Antibiotics
Pregnancy
Breast
feeding
High risk
Treatment
Antibiotics
Treatment
Antibiotics
Elderly
Pregnancy
Treatment
Antibiotics
Treatment
Teens
Adults
Infant
Toddler
Children
Adults
Elderly
60
Diarrhea
n/a
Treatment
36
Atopic Dermatitis
n/a
Treatment
Steroids
30
High risk
Prevention
Antibiotics
Journal
Adults
58
Pregnancy
Adults
Elderly
33
None
nutrition
Treatment
Flu vaccination
Journal
ICU patients with
nasogastric
feeding tube
Healthy
Healthy
participants
ICU
patients
requiring enteral
nutrition through
feeding tube
Journal
Yes
Adults
76
Elderly
82%
Caucasian
Infant
Toddler
Adults
51
Disease/
Immunologic
Status
Subgroups
C-5
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Design
Sample
Size
Category
RCT
100+
RCT
11-100
RCT
100+
RCT
100+
Source
Fujimori, 2009
Japan
B
Gade, 1989
Denmark
St
Galpin, 2005
Malawi
L
Gao, 2010
China
L
Garcia Vilela,
2008
Brazil
S
RCT
11-100
Journal
Gerasimou,
2010
Ukraine
LB
RCT
11-100
Journal
Gibson, 2008
Australia
B
Journal
Gill, 2001
New Zealand B
Gionchetti,
2000
Italy
LB
St
RCT
100+
RCT
11-100
RCT
11-100
Gionchetti,
2003
Goossens,
2003
Italy
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Journal
Adults
58
Journal
Adults
78
Journal
Children
54
Journal
Adults
49
Elderly
10% Asian
Adults
Disease/
Immunologic
Status
Subgroups
General
Health
Colitis; Ulcerative n/a
colitis
IBS
n/a
Healthy
participants
Diarrhea
Exclusion
Criteria
Treatment
Healthy
Elderly
Prevention
n/a
High risk
Prevention
Antibiotics
None
nutrition
Antibiotics
Steroids
Treatment
Diet
Steroids
None
nutrition
None
nutrition
Treatment
38
Atopic Dermatitis
n/a
77
Elderly
Journal
Adults
43
L B S RCT
St
11-100
L
RCT
11-100
Journal
Adults
42
Healthy
participants
Healthy
participants
Ulcerative colitis;
Relapsing
pouchitis
Ulcerative colitis
Healthy
Journal
Infant
Toddler
Elderly
Journal
Adults
55
Healthy
participants
Healthy
Gracheva, 1999 Russia
B
CCT
100+
Journal
Gruber, 2007
L
RCT
100+
RCT
100+
RCT
100+
Journal
Infant
32
Journal
Elderly
63
Journal
Adults
23
RCT
100+
Journal
Adults
Elderly
50
The
Netherlands
Germany
Guillemard,
France
2010
Guyonnet, 2009 UK
L St
Habermann,
2001
E
Germany
LB
St
Yes
Crohn's disease n/a
in remission
Healthy
n/a
Infants
Elderly
n/a
Elderly
Pregnancy
GI
unspecific;
Hepatitis
B;
Acute intestinal
infections;
Chronic intestinal
and
digestive
tract conditions
Atopic Dermatitis Healthy
Healthy
participants
Healthy
participants
Treatment
None
nutrition
Treatment
Vitamins;
Symptomatic
treatment
High risk
Treatment
Steroids
Healthy
High risk
Prevention
Healthy
Elderly
Pregnancy
Breast
feeding
Pregnancy
None
nutrition
Chronic infection; n/a
Chronic recurrent
bronchitis
C-6
Steroids
Treatment
Toddler
Children
60
Cotreatments
Pregnancy
Elderly
Pregnancy
Breast
feeding
High risk
Yes
Probiotic
Function
Treatment
Evidence Table C1. Participant and study detail (continued)
Author, Year
Habermann,
2002
HaschkeBecher, 2008
Hatakka, 2008
Country
Gen
era
Study
Design
Sample
Size
Category
RCT
100+
RCT
11-100
C-RCT
11-100
RCT
11-100
RCT
11-100
Source
Germany
E
Chile
L
Finland
L
Heimburger,
1994
Hemmerling,
2009
USA
L
USA
L
Higashikawa,
2009
Japan
L
RCT
11-100
Journal
Hilton, 1997
USA
L
RCT
100+
Journal
Hirata, 2002
Japan
LS
Hochter,1990
Germany
S
Honeycutt,
2007
n/a
L
CCT
11-100
RCT
11-100
RCT
11-100
Hong, 2010
Korea
LB
RCT
11-100
Journal
Horvat, 2010
Slovenia
L
RCT
11-100
Ishikawa, 2002
Japan
Ishikawa, 2003
Japan
Ishikawa, 2005
Japan
Isolauri, 1991
Isolauri,1995
Safety
Assess
-ment
Main
Aim
Journal
Age
Ethnicity
General
Health
Exclusion
Criteria
Adults
100
83% white
Healthy
participants
Healthy
High risk
Pregnancy
None
nutrition
Diarrhea;
Constipation
n/a
Pregnancy
Treatment
Healthy
participants
Healthy
Infants
Elderly
High risk
Treatment
Journal
Adults
72
97%
Japanese,
3%
Chinese
Teens
48
Adults
Elderly
Adults
53
Hypertension
n/a
Journal
45
Diarrhea
n/a
Newborn
Infant
Toddler
Children
Adults
Elderly
34
ICU patients
33
IBS
n/a
Journal
Adults
Elderly
56
Adenocarcinoma
of the colon
n/a
L B S RCT
11-100
L
RCT
11-100
L
RCT
100+
Journal
Adults
48
Ulcerative colitis
n/a
Treatment
Journal
Adults
26
n/a
n/a
Prevention
Journal
Adults
Elderly
18
History
of n/a
colorectal tumors
Finland
L
RCT
11-100
Journal
Finland
L
RCT
11-100
Infant
Toddler
Children
Infant
Journal
Infant
Adults
Journal
Journal
Journal
0
20
Yes
Pregnancy
Probiotic
Function
Healthy
Yes
71
Disease/
Immunologic
Status
Subgroups
Recurrent
sinusitis
Healthy
participants
Hypercholesterol
emia
Tube-fed patients
Journal
Adults
% Female
Healthy
Treatment
n/a
None
nutrition
Treatment
n/a
Prevention
Antibiotics
Treatment
Elderly
Treatment
Prevention
Pregnancy
Breast
feeding
Infants
High risk
Antibiotics
Steroids
Treatment
Treatment
Prevention
Diarrhea
n/a
Treatment
Healthy
participants
Healthy
Treatment
C-7
Cotreatments
Steroids
Diet
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
11-100
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
Jirapinyo, 2002
Thailand
LB
Johansson,
1998
Kadooka, 2010
Sweden
L
Japan
L St
Kajander, 2005
Finland
LB
Kajander, 2008
Finland
LB
Kajimoto, 2002
Japan
Karvonen, 2001 n/a
LS
St
L
Kerac, 2009
Malawi
L
Kianifar, 2009
Iran
LB
RCT
11-100
Journal
Kim, 2006
additional
groups
described in
#3610
USA
L B S RCT
Ba
11-100
Journal
Yes
Kim, 2006
USA
LB
Ba
RCT
11-100
Journal
Yes
Kim, 2008
South Korea
LB
St
RCT
100+
Journal
Kirjavainen,
2003
Klarin, 2008
Finland
L
Journal
Infant
Sweden
L
RCT
11-100
RCT
11-100
Journal
Adults
Elderly
RCT
11-100
RCT
11-100
RCT
100+
RCT
11-100
RCT
11-100
RCT
11-100
RCT
100+
% Female
Disease/
Immunologic
Status
Subgroups
General
Health
Exclusion
Criteria
33
Sepsis;
Meningitis
Journal
Infant
Toddler
Children
Adults
77
Healthy
Journal
Adults
33
Healthy
participants
Over weight
Journal
Adults
76
IBS
n/a
93
IBS
n/a
49
Mild hypertension n/a
Treatment
Healthy
Healthy
participants
Severe
acute
malnutrition
Treatment
Journal
Journal
Adults
Yes
Journal
Newborn
Infant
Toddler
Children
Teens
Infant
Toddler
Children
Adults
Elderly
White
93%,
Black 6%,
Hispanic
1%
Adults
Elderly
White
93%,
Black 6%,
Hispanic
1%
Adults
Elderly
46
Moderate
dehydration
High risk
Probiotic
Function
Treatment
Pregnancy
Lactating
Pregnancy
Lactating
Treatment
Treatment
n/a
Treatment
Functional
disorder
GI n/a
Treatment
71
Functional
disorder
GI n/a
Treatment
53
H. pylori
50
Cow’s
allergy
Intubated,
ventilated,
critically ill
Pregnancy
Lactating
milk n/a
Treatment
Treatment
High risk
IBS meds, other
regular medications
Treatment
71
C-8
Antibiotics
None
nutrition
Treatment
n/a
n/a
Cotreatments
Prevention
Antibiotics
Diet
Antibiotics
Proton pump
inhibition
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Klarin,2005
Sweden
L
Knight, 2007
UK
L
Koning, 2008
The
Netherlands
Germany
Kotzampassi,
2006
Study
Source
Design
Sample
Size
Category
RCT
Journal
1-10
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Disease/
Immunologic
Status
Subgroups
General
Health
Exclusion
Criteria
47
Enterally
critically ill
Journal
Adults
Elderly
38
Journal
Adults
63
Infants High
risk
Pregnancy
Pregnancy
Lactating
Prevention
L B E RCT
11-100
L
RCT
100+
Prenatal
Newborn
Infant
55
None
nutrition
Prevention
Antibiotics
Journal
Ventilator
associated
pneumonia
Healthy
Healthy
participants
Family history of n/a
atopic disease
Greece
L
RCT
11-100
Journal
Adults
Elderly
18
Severe multiple
trauma victims
High risk
Pregnancy
Prevention
Antibiotics
Krasse, 2005
Sweden
L
Journal
Gingivitis
Finland
LB
44
High
risk
allergy
Kurugol, 2005
Turkey
S
RCT
100+
Journal
38
La Rosa, 2003
Italy
Ba
RCT
100+
Journal
Laitinen, 2008
Finland
LB
Journal
Langhendries,
1995
Larsen, 2006
Belgium
Denmark
LB
St
LB
Larsson, 2008
Norway
L
RCT
100+
RCT
11-100
RCT
11-100
RCT
11-100
Adults
Elderly
Prenatal
Newborn
Infant
Toddler
Infant
Toddler
Children
Infant
Toddler
Children
Teens
Adults
50
Kuitunen, 2009
RCT
11-100
RCT
100+
Lata, 2009
n/a
LB
Lawrence, 2005 USA
Li, 2004
Kopp, 2008
Japan
Journal
Journal
Yes
Yes
None
nutrition
Cotreatments
Adults
Elderly
RCT
100+
fed,
Probiotic
Function
Antibiotics
Prokinetic agents
Healthy
Treatment
for Healthy
Prevention
Diarrhea
n/a
Treatment
44
Infection
requiring
antibiotics
n/a
Treatment
Antibiotics
100
Pregnant
Healthy
Treatment
Dietary counseling
Healthy
participants
Healthy
participants
Bacterial
vaginosis
Healthy
None
nutrition
None
nutrition
Treatment
Antibiotics
Prevention
Antibiotics
Treatment
Antibiotics
None
nutrition
Antibiotics
Journal
Newborn
Infant
Adults
65
Journal
Adults
100
RCT
11-100
Journal
Adults
Elderly
0
Acute
Pancreatitis
n/a
Elderly
Pregnancy
Pregnancy
Breast
feeding
High risk
L
RCT
11-100
Journal
Adults
Elderly
87
Diarrhea
n/a
High risk
B
RCT
11-100
Journal
Newborn
Infant
Low birth weight
C-9
Healthy
n/a
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
C-RCT
Journal
11-100
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Ligaarden,
2010
Norway
L
Lighthouse,
2004
n/a
LB
RCT
11-100
Journal
Lin, 1989
USA
L
Journal
Lin, 2005
Taiwan
LB
Lin, 2008
Taiwan
LB
C-RCT
100+
RCT
100+
RCT
100+
Ljungberg,
2006
Sweden
LB
RCT
100+
Journal
69
IBS
Adults
Elderly
43
HCV-related
n/a
Child
B
liver
cirrhosis
n/a
n/a
Loguercio,
1987
Italy
E
RCT
11-100
Journal
Adults
Elderly
35
Lonnermark,
2010
Sweden
L
RCT
100+
Journal
Adults
58
Lu, 2004
Taiwan
L
Luoto, 2010
Finland
LB
CCT
11-100
RCT
100+
Mäkeläinen,
2003
Malaguarnera,
2007
Malaguarnera,
2010
Finland
B
Italy
B
Italy
B
Maldonado,
2009
Mandel, 2010
Spain
L
n/a
Ba
Manley, 2007
Australia
L
50
Newborn
Infant
Yes
45
Infant
Toddler
Yes
Journal
Yes
RCT
11-100
RCT
11-100
RCT
100+
Journal
Yes
RCT
11-100
RCT
11-100
Journal
C-RCT
11-100
Journal
General
Health
Adults
Journal
Journal
Disease/
Immunologic
Status
Subgroups
Prenatal
100
Newborn
Infant
Toddler
Adults
Caucasian
Adults
59
n/a
Exclusion
Criteria
Pregnancy
Breast
feeding
Probiotic
Function
Treatment
Treatment
Very low birth
weight
Very low birth
weight, preterm
Prevention
Children
with n/a
HLA
risk
genotype
Hepatic
encephalopathy
Treatment
Infections
requiring
antibiotics
Healthy
participants
Healthy
participants
n/a
High risk
Healthy
participants
Cirrhosis
Healthy
n/a
None
nutrition
Treatment
Healthy
Treatment
Healthy
Journal
Adults
50
Hepatic
encephalopathy
n/a
Treatment
Infant
51
Healthy
participants
Rheumatoid
arthritis
Healthy
None
nutrition
Treatment
Vancomycin
resistant
Enterococcus
n/a
C-10
n/a
Antibiotics
None
nutrition
None
nutrition
45
Adults
82
Elderly
100%
Caucasian
Adults
33
Elderly
Antibiotics
Prevention
Adults
Journal
Antibiotics
None
nutrition
Treatment
Journal
Yes
Cotreatments
Pregnancy
Treatment
Diuretics, Betablockers
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
11-100
Manzoni, 2006
Italy
L
Margreiter,
2006
Austria
LB
RCT
100+
Journal
Marotta, 2003
n/a
LB
C-RCT
11-100
RCT
100+
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
100+
Journal
Marrazzo, 2006 USA
L
Marseglia, 2007 Italy
B Ba
Marteau, 2004
France
L
Martiney, 2009
Brazil
L St
Martinez, 2008
Brazil
L
Martinez, 2009
Brazil
L
Mayanagi, 2009 Japan
L
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Very low
weight
Journal
Newborn
49
Infant
85% White
Adults
52
Elderly
99%
Caucasian
, 0.6%
Black
Adults
Journal
Adults
100
Children
Journal
Journal
Journal
Yes
Journal
Journal
n/a
Treatment
n/a
Pregnancy
51
Bacterial
vaginosis
Recurrent
respiratory
infections
n/a
Adults
52
Crohn's disease
n/a
Children
Teens
Teens
Adults
43
Respiratory
n/a
allergy
Vaginal
yeast n/a
Infection
High risk
Prevention
Hypersensitiv
ity to study
treatment
Elderly
Prevention
Pregnancy
Treatment
Teens
Adults
Adults
100
100
14
Journal
Yes
L
Adults
Elderly
Adults
Elderly
35
UK
RCT
100+
RCT
100+
Merenstein,
2009
USA
L B S RCT
100+
Journal
Toddler
Children
49
Merenstein,
2010
USA
L St
Journal
Children
49
USA
S
RCT
100+
Journal
42
Bacterial
vaginosis
Healthy
participants
Clostridium
difficile
associated
disease
Patients on beta
lactam antibiotics
Undergoing
major
elective
abdominal
surgery
Treated
with
antibiotics
for
upper respiratory
tract infection
Healthy
participants
C-11
Cotreatments
Prevention
Ulcerative colitis
77
McFarland,
1995
McNaught,
2002
birth
Probiotic
Function
Treatment
Adults
Elderly
S
Exclusion
Criteria
n/a
Yes
USA
General
Health
Diarrhea
Journal
McFarland,
1994
Disease/
Immunologic
Status
Subgroups
Treatment
Antibiotics
Antibiotics
Steroids
High risk
Pregnancy
Treatment
Antibiotics
High risk
Treatment
Antibiotics
None
nutrition
Treatment
Antibiotics
n/a
Treatment
Antibiotics
n/a
Treatment
Antibiotics
n/a
Treatment
Antibiotics
Healthy
Prevention
Antibiotics
n/a
Healthy
n/a
High risk
Pregnancy
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
11-100
Safety
Assess
-ment
Main
Aim
Yes
Metts, 2003
USA
L
Miele, 2009
Italy
LB
St
RCT
11-100
Journal
Millar, 1993
UK
L
Journal
Mimura, 2004
Italy, UK
Miyaji, 2006
Japan
LB
St
L
RCT
11-100
RCT
11-100
RCT
11-100
Morrow, 2010
USA
L
RCT
100+
Journal
Mukerji, 2009
USA
L
RCT
11-100
Journal
Naito, 2008
Japan
L
Journal
Newcomer,
1983
Niers, 2009
USA
L
The
Netherlands
LB
RCT
100+
RCT
11-100
RCT
100+
Niv, 2005
Israel
L
RCT
11-100
RCT
11-100
Journal
Nobuta, 2009
Japan
RCT (effect on
bowel
movement), 5
groups, group 3
not extracted
(AE not
mentioned)
O'Mahony,
Ireland
2005
L
L
RCT
11-100
Age
Ethnicity
% Female
Adults
100
Toddler
Children
Teens
45
Disease/
Immunologic
Status
Subgroups
Recurrent
Candida
vulvovaginitis
Ulcerative colitis
General
Health
n/a
Exclusion
Criteria
High risk
Pregnancy
n/a
Probiotic
Function
Prevention
Treatment
Preterm infant
Adults
44
Pouchitis
n/a
Prevention
Journal
Adults
Elderly
59
H. pylori; Upper n/a
gastrointestinal
symptoms
Mechanical
ventilation
Treatment
Journal
Journal
Journal
Journal
Yes
Adults
41
Elderly
Caucasian
79%,
Black
13%,
Hispanic
8%
Adults
57
93% White
Adults
Elderly
Adults
Elderly
Prenatal
Newborn
Infant
Toddler
Teens
Adults
Adults
Elderly
Adults
Elderly
White
19
60
Chronic
inflammatory
rhinosinusitis
Cancer
n/a
Prevention
Antibiotics
High risk
Pregnancy
Treatment
Steroids
Prevention
Lactase
n/a
deficiency
Family history of n/a
allergic disease
None
nutrition
Prevention
IBS
73
Tendency
constipation
64
IBS
C-12
n/a
Pregnancy
to Healthy
n/a
Antibiotics
High risk
Pregnancy
n/a
67
Steroids
Prevention
Journal
Yes
Cotreatments
Treatment
None
nutrition
High risk
Pregnancy
Treatment
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Ojetti, 2010
Italy
L
Olah, 2005
Hungary
L
Olivares, 2006
Spain
L St
Osterlund, 2007 Finland
L
Ouwehand,
2009
Ozkinay, 2005
Finland
LB
Turkey
L
Panigrahi, 2008 India
L
Parent, 1996
Belgium
L
Parfenov, 2005
Russia
Parfenov, 2005
Russia
LB
St
L St
Parra, 2004
Spain
L
Study
Design
Sample
Size
Category
RCT
11-100
RCT
11-100
RCT
11-100
RCT
100+
RCT
11-100
RCT
100+
RCT
11-100
RCT
11-100
CCT
11-100
CCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
Source
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Journal
Adults
85
Journal
Adults
Elderly
Adults
84
Adults
Elderly
Children
Teens
Adults
Elderly
Newborn
49
Journal
Adults
100
Journal
Adults
Journal
Journal
Journal
Journal
Journal
Journal
Yes
50
60
100
61
Disease/
Immunologic
Status
Subgroups
General
Health
Lactose
intolerant
Pancreatitis
n/a
Healthy
participants
Cancer
Healthy
n/a
Birch
pollen n/a
allergy
Vaginal infection n/a
Healthy
75
Adults
60
Journal
Adults
53
Journal
Journal
Treatment
Hemorrhoids
n/a
Treatment
Healthy
5
Children
Healthy
participants
Atopic Dermatitis
Adults
Burn patients
Adults
Elderly
Newborn
Infant
Cirrhosis
n/a
Treatment
49
Healthy
participants
Healthy
None
nutrition
36
Crohn's disease
n/a
Pregnancy
Treatment
Pregnancy
Breast
feeding
Pregnancy
Breast
feeding
Prevention
Argentina
L
Pereg, 2010
Israel
Petschow, 2005 USA
LB
St
L
RCT
11-100
RCT
11-100
Prantera, 2002
L
RCT
11-100
RCT
100+
Journal
Journal
Healthy
participants
Healthy
RCT
100+
Journal
Healthy
participants
Healthy
LB
High risk
Pregnancy
Treatment
Adults
Elderly
C-13
n/a
Antibiotics
Diet
Chemotherapy
Treatment
n/a
Peral, 2009
LB
None
nutrition
Treatment
n/a
L
Pregliasco,
Italy
2008
#5328 stage 1
Pregliasco,
Italy
2008
#5328, 3
studies, same
with multiple
arms reported
in 1 publication;
stage 3
Pregnancy
Lactating
Cotreatments
Treatment
None
nutrition
Treatment
Passeron, 2005 France
n/a
Infants
Elderly
Probiotic
Function
Treatment
Healthy
participants
Bacterial
vaginosis
Hemorrhoids
Journal
Exclusion
Criteria
High risk
Treatment
Pregnancy
Breast
feeding
Treatment
Prevention
Antibiotics
Antiacids and
vitamins if needed
Vitamins (both
groups)
Steroids
Immune suppressant
Antidiarrhoeals;
Colestyramine
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
100+
Safety
Assess
-ment
Main
Aim
RCT
100+
RCT
11-100
Journal
Yes
Age
Ethnicity
% Female
Pregliasco,
2008
stage 1
Puccio, 2007
Italy
LB
Italy
B
Rampengan,
2010
Indonesia
L
Ranganathan
Canada
LB
St
C-RCT
11-100
Journal
Rautava, 2008
Finland
LB
Journal
Rayes, 2002
n/a
L
RCT
11-100
RCT
11-100
Journal
Adults
Elderly
47
Rayes, 2002
Germany
L
RCT
11-100
Journal
Adults
Elderly
48
Rayes, 2005
n/a
L
RCT
11-100
Journal
Adults
42
Liver transplant
Rayes, 2007
n/a
L
RCT
11-100
Journal
Adults
Elderly
44
Reid, 1992
Canada
L
RCT
11-100
Journal
Adults
100
Reid, 1995
Canada
L
Journal
Adults
100
Ren, 2010
China
B
Journal
Prenatal
44
Reuman, 1986
USA
L
Journal
Newborn
Richelsen,
1996
Denmark
St E
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
Journal
Adults
Elderly
Undergoing
pylorus
preserving
pancreticoduode
nectomy
Acute
lower
urinary
tract
infection
Recurrent urinary
tract infections
Premature
infants
Premature
infants
Healthy
participants
Journal
Teens
Adults
Disease/
Immunologic
Status
Subgroups
General
Health
Healthy
participants
Healthy
Healthy
participants
Lactose
malabsorption
Healthy
Newborn
Infant
Children
Teens
54
Adults
Elderly
White 4,
Hispanic
1; Asian
10, Black
1
Infant
25
Chronic
kidney n/a
disease stage 3
and 4
51
Healthy
Healthy
participants
Undergoing
n/a
major abdominal
surgery;
Liver transplant;
Stomach,
pancreas or liver
surgery
48
48
C-14
Exclusion
Criteria
Pregnancy
Breast
feeding
Probiotic
Function
Cotreatments
Prevention
None
nutrition
Treatment
n/a
Pregnancy
Treatment
Prevention
Prevention
Antibiotics
Diet
Antibiotics
n/a
Sever renal
Treatment
insufficiency;
Cerebral
disorders;
Emergency
operation
Decompensa Prevention
ted renal
insufficiencie
s
Prevention
n/a
Pregnancy
Antibiotics
n/a
Healthy
Prevention
Antibiotics
Immune suppressant
Antibiotics
Prevention
Prevention
Antibiotics
None
nutrition
None
nutrition
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
11-100
RCT
Journal
100+
Safety
Assess
-ment
Main
Aim
Rio, 2002
Argentina
L
Roos, 1996
Sweden
St
Roos, 2001
Sweden
St
RCT
100+
Journal
Rose, 2010
Germany
L
RCT
100+
Journal
Rosenfeldt,
2002
Denmark
L
RCT
11-100
Journal
Rosenfeldt,
2003
2 studies in 1
paper #13297
Rouge, 2009
Denmark
L
C-RCT
11-100
Journal
France
LB
RCT
11-100
Journal
Ruiz-Palacios,
1996
n/a
LB
RCT
11-100
Saavedra, 2004 USA
B St
RCT
100+
Journal
Yes
Safdar, 2008
L
RCT
11-100
Journal
Yes
RCT
11-100
RCT
11-100
RCT
11-100
C-RCT
11-100
USA
Sahagun-flores, Mexico
2007
Saint-Marc,
France
1995
L
Salminen, 1988 Finland
L
Salminen, 2004 Finland
L
S
Age
Ethnicity
Infant
Toddler
Children
Teens
Adults
Infant
Toddler
Children
Infant
Toddler
% Female
Disease/
Immunologic
Status
Subgroups
Undernourished
65
0
General
Health
Exclusion
Criteria
n/a
Recurrent
n/a
streptococcal
pharyngotonsilliti
s
Recurrent otitis n/a
media
Wheezing
n/a
episodes; Family
history of atopic
disease
Diarrhea
n/a
Probiotic
Function
Cotreatments
Prevention
High risk
Prevention
High risk
Prevention
Antibiotics
Prevention
Antibiotics
Steroids
Infant
Toddler
Children
Teens
Adults
60
0
Healthy
participants
Newborn
43
Very low birth
weight
preterm
infants
Healthy
Healthy
participants
Treatment
51
Healthy
participants
Healthy
None
nutrition
Adults
Elderly
2
n/a
Prevention
Antibiotics
Journal
Adults
48
Inpatients
receiving
expected
receive
antibiotics
H. pylori
Pregnancy
Treatment
Antibiotics
Journal
Adults
6
Infants
Treatment
Necessary
medications
Journal
Adults
Elderly
Adults
100
Prevention
Radiation
Treatment
Antibiotics
HAART
Yes
Yes
Journal
Yes
Infant
Toddler
Children
Infant
Toddler
18
Immuno
compromised;
AIDS-related
diarrhea
Gynecologic
malignancies
Diarrhea;
Immuno
compromised
C-15
Elderly
Healthy
Treatment
None
nutrition
Prevention
or
to
n/a
n/a
n/a
Pregnancy
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Samanta, 2008
India
LB
Satokari, 2001
13281
Savino, 2006
Finland
B
Italy
L
Sazawal, 2010
India
B
Scalabrin, 2009 USA
L
Schrezenmeir,
2004
Germany
LB
Schultz, 2004
n/a
L
Seppo, 2003
Finland
L
Sierra, 2010
Spain
L
Simons, 2006
Australia
L
Simren, 2010
Sweden
Song, 2010
Korea
LB
St
S
Songisepp,
2005
Songisepp,
2005
Sood, 2009
Estonia
L
Estonia
L
India
Spanhaak,
1998
The
Netherlands
LB
St
L
Stockert, 2007
n/a
E
Stotzer, 1996
n/a
L
Stratiki, 2007
Greece
B
Sullivan, 2003
Sweden
LB
Study
Source
Design
Sample
Size
Category
RCT
Journal
100+
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Newborn
RCT
11-100
RCT
11-100
RCT
100+
RCT
100+
RCT
100+
Journal
Adults
Journal
Newborn
47
Infant
Toddler
Children
Newborn
50
Infant
Toddler
44
Children
Caucasian
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
100+
Journal
Journal
Journal
Yes
Journal
Journal
90
Disease/
Immunologic
Status
Subgroups
General
Health
Exclusion
Criteria
Preterm
infant;
very low birth
weight
Healthy
Healthy
participants
Colic
n/a
n/a
n/a
Healthy
Healthy
participants
Acute
bacterial n/a
infection
Probiotic
Function
Prevention
5
Treatment
High risk
Prevention
High risk
None
nutrition
Treatment
Crohn's disease
n/a
Treatment
Adults
51
Hypertension
n/a
Treatment
Adults
50
Healthy
Journal
Adults
64
Journal
Adults
70
Healthy
participants
Healthy
participants
IBS
n/a
Pregnancy
None
nutrition
None
nutrition
Treatment
Journal
Teens
Adults
Elderly
40
H. pylori
n/a
High risk
Pregnancy
Lactating
RCT
11-100
CCT
11-100
RCT
100+
RCT
11-100
Journal
Adults
38
Healthy
Journal
Adults
56
Adults
19
Healthy
participants
Healthy
participants
Ulcerative colitis
Journal
Adults
0
Healthy
participants
Healthy
RCT
11-100
C-RCT
11-100
Journal
Asthma
n/a
Journal
Children
Teens
Elderly
RCT
11-100
RCT
11-100
Journal
Newborn
Journal
Adults
Journal
Journal
Yes
Yes
Healthy
Healthy
n/a
Pregnancy
Healthy
participants
C-16
Healthy
Treatment
Antibiotics
Antibiotics
Steroids
Antibiotics
None
nutrition
None
nutrition
Treatment
None
nutrition
High risk
Small intestinal n/a
bacterial
overgrowth
Preterm infant
91
Cotreatments
Pregnancy
Treatment
Steroids
Treatment
Antibiotics
None
nutrition
None
nutrition
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Sykora, 2005
Czech
Republic
L
Tamura, 2007
Japan
L
Taylor, 2007
Australia
L
Tempe, 1985
France
S
Teran, 2008
Study
Source
Design
Sample
Size
Category
RCT
Journal
11-100
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Disease/
Immunologic
Status
Subgroups
General
Health
Exclusion
Criteria
Probiotic
Function
Children
Teens
60
H. pylori
n/a
Treatment
61
Allergic rhinitis
n/a
Prevention
Prevention
RCT
100+
RCT
100+
Journal
Adults
Journal
Newborn
Infant
Risk for atopic n/a
dermatitis
RCT
11-100
Journal
Adults
Elderly
ICU patients on
enteral feeding
Bolivia
L B S RCT
11-100
Journal
47
Acute rotavirus n/a
diarrhea
Thomas, 2001
USA
L
Journal
46
Hospitalized
n/a
Tomoda, 1991
Japan
Journal
50
n/a
Journal
Adults
80
Healthy
participants
IBS
Healthy
Tsuchiya, 2004
LB
St
LB
n/a
Elderly
None
nutrition
Treatment
Turchet, 2003
Italy
L
Journal
High risk
Prevention
n/a
Pregnancy
Treatment
Tursi, 2008
Italy
LB
St
L
Healthy
participants
Ulcerative colitis
Healthy
Italy
Adults
Elderly
Adults
Elderly
Adults
Elderly
67
Tursi, 2004
RCT
100+
CCT
1-10
CCT
11-100
RCT
100+
RCT
11-100
CCT
11-100
Newborn
Infant
Toddler
Adults
Elderly
Adults
Tursi, 2010
Italy
Adults
35
USA
Journal
Newborn
34
South Africa
B
RCT
100+
RCT
11-100
RCT
100+
RCT
100+
Journal
Underwood,
2009
Urban, 2008
LB
St
L
Journal
Newborn
Infant
Adults
Elderly
48
RCT
11-100
RCT
11-100
RCT
100+
RCT
100+
Journal
Infant
Journal
Urbansek, 2001 Hungary
L
Van der Aa,
2010
Van Gossum,
2007
Velaphi, 2008
The
Netherlands
n/a
B
South Africa
B
Vendt, 2006
Estonia
L
L
Journal
Yes
Journal
36
Antibiotics
Proton pump
inhibition
Prevention
Treatment
InfantsHigh
risk
Treatment
Antibiotics
Flu vaccine
Diverticular
n/a
disease of the
colon
Ulcerative colitis n/a
Prevention
Treatment
Immune suppressant
None
nutrition
None
nutrition
Treatment
Antibiotics
Radiation
34
Premature
infants
Infant of HIV n/a
infected mother;
Cancer;
Diarrhea;
Radiation
induced diarrhea
Atopic Dermatitis n/a
Treatment
Steroids
Adults
47
Crohn's disease
Prevention
Journal
Infant
50
Journal
Infant
50
Infant of
mother
Healthy
participants
Antibiotics
Steroids
Nevirapine
Journal
Yes
56
Illnesses of
digestive
tract
Cotreatments
74
C-17
n/a
HIV n/a
Healthy
High risk
None
nutrition
None
nutrition
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
C-RCT
Journal
11-100
Safety
Assess
-ment
Main
Aim
RCT
100+
RCT
11-100
Journal
Yes
Vleggaar, 2008
The
Netherlands
LB
Vlieger, 2009
LB
Wada, 2010
The
Netherlands
Japan
Wang, 2004
China
L St
RCT
11-100
Wang, 2007
Japan
B
Weizman, 2005 Israel
B
Weizman, 2006 Israel
B
Weston, 2005
Australia
L
Wewalka, 2002
Austria
L
Wheeler, 1997
USA
L St
Wildt, 2006
Denmark
LB
Williams, 2008
UK
LB
Wind, 2010
L
Wolf, 1994
The
Netherlands
USA
Wolf, 1998
USA
L
Worthley, 2009
Australia
B
Xia, 2010
China
L
Xiang, 2006
China
E Ba
Xiao, 2003
Japan
Xiao, 2003
China
LB
St
L
B
L
Age
Ethnicity
% Female
Disease/
Immunologic
Status
Subgroups
Adults
Elderly
7
Newborn
Infant
Toddler
Children
Teens
53
Journal
Children
Teens
48
Perennial allergic n/a
rhinitis
RCT
11-100
RCT
100+
RCT
11-100
RCT
11-100
Journal
Newborn
49
Journal
Infant
52
Newborn
Infant
Infant
Toddler
32
Low birth weight
infant
Healthy
Healthy
participants
Healthy
Healthy
participants
Atopic Dermatitis n/a
RCT
11-100
C-RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
C-RCT
11-100
RCT
11-100
RCT
11-100
RCT
11-100
RCT
100+
Journal
Adults
100
Teens
Adults
Adults
Elderly
Adults
67
Journal
Journal
Yes
Journal
Yes
Journal
Journal
Journal
60
46
Primary
sclerosing
cholangitis
Healthy
participants
Malignancy,
receiving
chemotherapy
General
Health
n/a
Exclusion
Criteria
Probiotic
Function
Pregnancy
Treatment
Pregnancy
None
nutrition
Prevention
Healthy
High risk
Pregnancy
None
nutrition
Treatment
Bacterial
vaginosis
Asthma
n/a
Collagenous
colitis
IBS
n/a
Healthy
42
Healthy
participants
Healthy
participants
Immuno
compromised
Healthy
participants
Cancer
n/a
None
nutrition
Treatment
7
86
Pregnancy
n/a
n/a
Elderly
Pregnancy
Pregnancy
Lactating
Pregnancy
Anti-inflammatories
Treatment
Anti-diarrheal drugs
Treatment
Adults
59
Journal
Yes
0
Journal
Yes
Adults
Elderly
Adults
35
Journal
Adults
Elderly
Adults
Elderly
Adults
54
Ulcerative colitis
n/a
Treatment
Journal
Adults
0
Healthy
Journal
Teens
Adults
Elderly
39
Healthy
participants
Chronic diarrhea
None
nutrition
Treatment
Journal
Journal
C-18
Healthy
n/a
Steroids
Treatment
Yes
InfantsElderl
y
Antibiotics
Treatment
Journal
Healthy
Chemo-therapy
Treatment
None
nutrition
Prevention
Elderly
Cotreatments
None
nutrition
None
nutrition
Treatment
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source
Design
Sample
Size
Category
RCT
Journal
100+
RCT
Journal
100+
Yang, 2008
China
Yao-Zong,
2004
China
LB
St
LE
Yonekura
Japan
L
Zhang, 2010
China
B
Ziegler, 2003
USA
B
Zocco, 2003
#3960
Italy
L
RCT
11-100
An, 2010
Korea
LB
Barrett, 2008
Australia
L
Beck, 1961
USA
L
Case
Series
11-100
Case
Series
11-100
Case
Series
11-100
Bekkali, 2007
The
Netherlands
LB
Journal
Bellomo, 1979
Switzerland
E
Case
Series
11-100
Case
Series
100+
Journal
Benchimol,
2004
Canada
LB
Berman, 2006
USA
LB
Bibiloni, 2005
Canada,
Italy, US
LB
St
Case
Series
1-10
Case
Series
1-10
Case
Series
11-100
RCT
100+
RCT
11-100
RCT
100+
Safety
Assess
-ment
Main
Aim
Age
Ethnicity
% Female
Disease/
Immunologic
Status
Subgroups
General
Health
Exclusion
Criteria
Probiotic
Function
Adults
100
Constipation
n/a
Adults
Elderly
Chinese/A
sian
Adults
Asian
Adults
Elderly
Newborn
Infant
Caucasian
Adults
37
Diarrhea
n/a
Pregnancy
Lactating
Treatment
69
Cedar pollinosis
n/a
Pregnancy
Treatment
50
Cancer
n/a
Prevention
Healthy
participants
Healthy
None
nutrition
44
Ulcerative colitis
n/a
Journal
Elderly
58
Chronic
constipation
n/a
Treatment
Journal
Adults
Elderly
72
IBS
n/a
Treatment
Journal
Children
Teens
Adults
Elderly
Children
Teens
54
Various
abdominal
symptoms
n/a
Treatment
50
Constipation
n/a
Treatment
Mixed
44
Journal
Children
50
Gastroenteritis;
Healthy
Enteritis;
Toxic
dyspepsia;
Enteritis following
respiratory
infection
Cancer;
Diarrhea; Colitis
Journal
Adults
0
Healthy
participants
Healthy
Adults
53
Ulcerative colitis
n/a
Journal
Journal
Yes
Journal
Journal
Yes
C-19
Cotreatments
Treatment
High risk
Pregnancy
Antibiotic
treatment
High risk
Pregnancy
Lactating
Antibiotics
Treatment
Treatment
Antibiotics
Treatment
Antibiotics
Immune suppressant
Treatment
Treatment
Steroids
Azathioprine or 6
mercaptopurine
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Bruce, 1988
Canada
L
Bruni, 2008
Italy
L
Carlsson, 2009
Sweden
L
Cobo Sanz,
2006
Spain
L St
Colecchia,
2006
Italy
B
Di Pierro, 2009
Italy
L
Dughera, 2007
Italy
B
Elmer, 1995
USA
S
Fukuda, 2008
Japan
B
Gabrielli, 2009
Italy
Ba
Garrido, 2005
n/a
L Ba
Gionchetti,
2007
Italy
LB
St
Glintborg, 2006
Denmark
L
Gniwotta, 1977
Germany
S
Gotteland, 2003 Chile
L
Study
Source Safety
Design
Assess
Sample
-ment
Size
Main
Category
Aim
Case
Journal
Series
1-10
Case
Journal Yes
Series
11-100
Case
Series
11-100
Case
Series
100+
Case
Series
100+
Case
Series
100+
Case
Series
100+
Case
Series
1-10
Case
Series
100+
Case
Series
11-100
Case
Series
1-10
Case
Series
11-100
Case
Series
11-100
Case
Series
100+
Case
Series
11-100
Age
Ethnicity
Teens
Adults
Journal
Infant
Toddler
Children
Teens
Elderly
Journal
Children
Journal
Yes
% Female
100
87
Disease/
Immunologic
Status
Subgroups
General
Health
Treatment
Atopic Dermatitis; n/a
Cow's
milk
allergy
None
nutrition
Dementia;
Constipation
n/a
Healthy
participants
Healthy
None
nutrition
Treatment
61
IBS
n/a
Journal
Adults
100
n/a
Journal
Adults
71
Acute
vulvovaginal
affection
IBS
Yes
Adults
0
Journal
Yes
Adults
Elderly
84
Yes
Adults
65
Adults
50
Unclear
Journal
Journal
44
Adults
Ulcerative colitis; n/a
Mild pouchitis
n/a
Diarrhea
Adults
83
H. pylori
C-20
High risk
High risk
Pregnancy
n/a
Diarrhea;
Immuno
compromised
Constipation and n/a
abdominal
disorder
Small intestinal n/a
bacterial
over
growth
Healthy
Healthy
participants
H. pylori
Journal
Probiotic
Function
Recurrent urinary n/a
tract infections
Adults
Elderly
Journal
Exclusion
Criteria
Treatment
Antibiotics
Treatment
Treatment
Treatment
Pregnancy
Treatment
Treatment
None
nutrition
High risk
Pregnancy
Treatment
Treatment
Treatment
n/a
Cotreatments
Treatment
Antifungal
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Gruenwald,
2002
Germany
LB
Hensgens,
1976
Belgium
L
Huynh, 2009
Canada
LB
St
Karimi, 2005
The
Netherlands
LB
St
Kawamura,198
1
Japan
L
Kirchhelle,
1996
Germany
S
Kitajima, 1997
Lamiki, 2010
Lee, 2010
Lombardo,
2009
Luoto, 2010
Malin, 1996
Study 2
Malkov, 2006
Mego, 2005
Study
Source Safety
Design
Assess
Sample
-ment
Size
Main
Category
Aim
Case
Journal
Series
11-100
Case
Journal
Series
1-10
Case
Journal Yes
Series
11-100
Yes
Age
Ethnicity
% Female
81
Stress
exhaustion
Adults
Elderly
17
Granulopenia
Children
Teens
61
Ulcerative colitis
Adults
59
Crohn's disease; n/a
Ulcerative colitis
Irregular
bowel n/a
movement
and
abdominal
discomfort
Persistent
Healthy
traveler's
diarrhea
Preterm infant
Journal
Journal
Adults
Elderly
53
Case
Series
11-100
Japan
B
Case
Series
11-100
Italy
LB
Case
Series
11-100
New Zealand L B S Case
St
Series
11-100
Italy
L
Case
Series
11-100
Finland
L
Case
Series
100+
Finland
L
Case
Series
11-100
Russia
Ba
Case
Series
1-10
Slovak
E
Case
Republic
Series
11-100
Journal
Adults
Elderly
52
Journal
Yes
Newborn
Journal
Yes
Adults
Elderly
1
Adults
Elderly
0
Yes
Adults
Elderly
62
Yes
Newborn
Journal
General
Health
Adults
Case
Series
11-100
Case
Series
11-100
Journal
Disease/
Immunologic
Status
Subgroups
Diverticular
disease of
colon
Rheumatoid
arthritis
and Healthy
Elderly
High risk
Pregnancy
Severe
disease;
Lactating
Pregnancy
Probiotic
Function
Treatment
Vitamins
Prevention
Antibiotics
Treatment
Steroids
Immune suppressant
Treatment
Immune suppressant
Treatment
Treatment
n/a
Prevention
n/a
n/a
birth
Pregnancy
None
nutrition
Treatment
Prevention
Children
Teens
50
Juvenile chronic n/a
arthritis
Treatment
Journal
Adults
Elderly
70
Cancer
Treatment
Yes
Adults
Cancer;
Relapsed
leukemia
C-21
Antibiotics
None
nutrition
Journal
Journal
Cotreatments
the
IBS
Very low
weight
n/a
Exclusion
Criteria
n/a
acute
Treatment
Antibiotics
Chemotherapy;
immunomodulants
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Mego, 2006
Slovak
Republic
E
Michetti, 1999
Switzerland
L
Muting, 1968
Germany
B
Nobuta, 2009
#13315
Japan
L
Reid, 2001
Canada
L
Study
Source
Design
Sample
Size
Category
Case
Journal
Series
11-100
Case
Journal
Series
11-100
Case
Journal
Series
11-100
Safety
Assess
-ment
Main
Aim
Case
Series
11-100
Case
Series
1-10
Case
Series
11-100
Journal
Yes
Case
Series
11-100
Case
Series
11-100
Journal
Adults
6
Journal
Adults
28
Adults
42
Infant
Toddler
Children
Teens
Adults
43
56
Behcet's
syndrome
n/a
Treatment
Adults
83
Treatment
Teens
Adults
30
IBD
related n/a
spondyloarthropa
thy
Cystic fibrosis
n/a
L
Journal
Schneider,
2005
n/a
S
Shen, 2005
USA
LB
St
Case
Series
11-100
Journal
Srinivasan,
2006
UK
L
Case
Series
11-100
Journal
Tasli, 2006
Turkey
L
Journal
van
Bodegraven
2004
Weiss, 2010
n/a
LB
St
Israel
LB
St
Case
Series
11-100
Case
Series
11-100
Case
Series
1-10
Journal
% Female
Adults
Elderly
Adults
Yes
General
Health
Exclusion
Criteria
Cancer
40
Probiotic
Function
Children
Teens
Adults
Chronic
disease
liver n/a
Adults
Cancer
Healthy
None
nutrition
Bacterial
vaginosis
n/a
Treatment
Adults
Elderly
Pregnancy
Breast
feeding
Treatment
Treatment
Previous benign n/a
polyps or family
history
of
polyposis
H. pylori
n/a
None
nutrition
Healthy
n/a
participants;
Patient on long
term total enteral
nutrition
Ulcerative colitis n/a
Antibiotic
dependent
pouchitis
Critically
ill
children in ICU
None
nutrition
C-22
Cotreatments
Prevention
n/a
100
Yes
Disease/
Immunologic
Status
Subgroups
H. pylori
Journal
Rosenfeldt,
Denmark
2003
#6738 2 studies
in 1 paper
Sakamoto,
n/a
2001
L
Age
Ethnicity
Treatment
Treatment
High risk
Antibiotics
Treatment
Treatment
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Yim, 2006
Korea
LB
Zahradnik,
2009
USA
St
Zahradnik,
2009
USA
St
Barton, 2001
n/a
LE
Bassetti, 1998
Switzerland
S
Burkhardt, 2005 n/a
S
Cesaro, 2000
Italy
S
Cherifi, 2004
Belgium
S
Conen, 2009
Switzerland
L
De Groote,
2005
USA
L
Force, 1995
France
S
Fredenucci,
1998
France
S
Hennequin,
2000
France
S
Study
Source Safety
Age
Design
Assess Ethnicity
Sample
-ment
Size
Main
Category
Aim
Journal Yes
Case
Children
Series
Teens
11-100
Adults
% Female
Disease/
Immunologic
Status
Subgroups
General
Health
Exclusion
Criteria
Probiotic
Function
Atopic Dermatitis
n/a
Treatment
Cotreatments
Case
Series
11-100
Case
Series
11-100
Journal
Yes
Adults
Healthy
participants
Healthy
None
nutrition
Journal
Yes
Adults
Healthy
participants
Healthy
None
nutrition
Case
Study
1-10
Case
Study
1-10
Journal
Yes
Infant
100
Gastroschisis;
Preterm infant
Treatment
Antibiotics
Journal
Yes
Adults
100
Treatment
Antibiotics
Immune suppressant
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
11-100
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Journal
Yes
Adults
White
0
Arthritis,
n/a
polyarteritis
nodosa; Livedo
reticularis;
Raynaud's
phenomenon;
Renal failure
Spastic
tetra n/a
paresis
Journal
Yes
Infant
0
Acute
myeloid
leukemia
Prevention
Antibiotics
Chemotherapy
Elderly
100
Colitis
n/a
Treatment
Antibiotics
Yes
Adults
100
Diarrhea;
Ulcerative colitis
n/a
Treatment
Steroids
Immune suppressant
Journal
Yes
Infant
0
Short
syndrome
gut
Treatment
Antibiotics
Journal
Yes
Adults
100
AIDS;
Chronic
diarrhea
Treatment
Journal
Yes
Adults
0
Diarrhea
Journal
Yes
Toddler
Adults
Elderly
25
Cancer;
Ileal
atresia; COPD
Journal
C-23
n/a
Prevention
Treatment
Treatment
Antibiotics
Steroids
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Henry, 2004
Belgium
S
Hwang, 2009
Korea
S
Jensen, 1974
USA
S
Kniehl, 2003
Germany
Ba
Ku, 2006
China
LB
Kunz, 2004
USA
L
Land, 2005
n/a
L
LeDoux, 2006
USA
L
Lestin, 2003
Germany
S
Lherm, 2002
France
Lolis, 2008
Greece
Study
Source Safety
Age
Design
Assess Ethnicity
Sample
-ment
Size
Main
Category
Aim
Case
Journal Yes
Elderly
Study
1-10
Case
Unclear Yes
Infant
Study
1-10
% Female
General
Health
Exclusion
Criteria
Probiotic
Function
0
Cancer; Diarrhea
Treatment
0
Soy-induced food n/a
protein-induced
enterocolitis
syndrome
Healthy
Healthy
participants
Treatment
Myocardial
infarction
and
upper
GI
bleeding;
Coronary bypass
surgery, caecal
perforation;
Tachyarrhythmia,
fever,
and
diarrhea
Cancer;
Short
bowel syndrome
Treatment
Case
Study
1-10
Case
Study
1-10
Journal
Yes
Elderly
0
Journal
Yes
Adults
Elderly
0
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Journal
Yes
Children
Chinese
0
Journal
Yes
Newborn
Infant
0
Journal
Yes
50
Case
Study
1-10
Case
Study
1-10
Journal
Yes
Infant
Children
100%
White
Adults
Journal
Yes
Adults
S
Case
Study
1-10
Journal
Yes
S
Case
Study
1-10
Journal
Yes
Adults
Disease/
Immunologic
Status
Subgroups
Cotreatments
Antibiotics
Chemotherapy;
Radiation
Antibiotics
None
nutrition
Antibiotics
Treatment
Short
gut
syndrome;
Gastroschisis
Diarrhea
Treatment
Antibiotics
Varies
Antibiotics
0
AIDS; Hodgkin's
disease
5
Antibiotics
0
Diabetes;
Peripheral
arterial disease;
Bypass (after PB
admin)
Diarrhea;
Hospitalized
in
medical
and
surgical ICU
Acute pulmonary
edema
Treatment
Antibiotics
0
C-24
Treatment
Treatment
Antibiotics
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Lungarotti,
2003
Italy
S
Mackay, 1999
n/a
L St
Munakata,
2010
Japan
L St
Muñoz, 2005
Spain
S
Niault, 1999
France
S
Oggioni, 1998
Italy
Ba
Oh, 1979
USA
L
Ohishi, 2010
Japan
B
Perapoch, 2000 Spain
S
Piarroux, 1999
France
S
Piechno, 2007
France
S
Pletinex, 1995
Belgium
S
Presterl, 2001
n/a
L
Rautio, 1999
Finland
L
Study
Source Safety
Age
Design
Assess Ethnicity
Sample
-ment
Size
Main
Category
Aim
Case
Yes
Newborn
Study
1-10
Case
Journal Yes
Elderly
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
% Female
Disease/
Immunologic
Status
Subgroups
General
Health
n/a
Exclusion
Criteria
Probiotic
Function
Cotreatments
0
Preterm infant
Prevention
0
Mitral
valve n/a
prolapse;
Mild
mitral
value
regurgitation
Short
bowel n/a
syndrome
None
nutrition
Heart n/a
Treatment
Antibiotics
n/a
Treatment
Antibiotics
Journal
Yes
Children
100
Journal
Yes
Elderly
100
Diarrhea;
surgery
Unclear
Yes
100
COPD
Journal
Yes
Elderly
0
5
Journal
Yes
Adults
0
Cancer; Chronic
lymphocytic
leukemia
Diarrhea; Short n/a
bowel syndrome
Journal
Yes
Newborn
100
Omphalocele
None
nutrition
Journal
Yes
Infant
0
Congenital
cardiopathy
Treatment
Yes
n/a
n/a
Yes
Adults
0
Cancer;
Diarrhea; Colitis
Journal
Yes
Toddler
100
Diarrhea
Journal
Yes
Adults
White
0
Yes
Elderly
100
Diabetes
n/a
insipidus;
Biscuspid aortic
valve
Hypertension;
n/a
Diabetes
C-25
n/a
Antibiotics
Treatment
Treatment
5
Treatment
Antibiotics
Treatment
Antibiotics
None
nutrition
Intranasal octreotide
Treatment
Evidence Table C1. Participant and study detail (continued)
Author, Year
Country
Gen
era
Study
Source Safety
Age
Design
Assess Ethnicity
Sample
-ment
Size
Main
Category
Aim
Journal Yes
Adults
Case
Elderly
Study
1-10
% Female
50
Richard, 1988
Belgium
Ba
Rijnders, 2000
n/a
S
Case
Study
1-10
Journal
Yes
Elderly
0
Riquelme, 2003 n/a
S
Journal
Yes
Adults
50
Tommasi, 2008 Italy
L
Case
Study
1-10
Case
Study
1-10
Journal
Yes
Elderly
0
Trautmann,
2008
Germany
S
Journal
Yes
Teens
100
Viggiano, 1995
France
S
Journal
Yes
Teens
0
Zein, 2008
Lebanon
LB
St
Journal
Yes
Adults
Zunic, 1991
France
S
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Case
Study
1-10
Yes
Adults
Disease/
Immunologic
Status
Subgroups
General
Health
Head
trauma;
Endometrial
carcinoma;
Stroke
Diarrhea;
Subarachnoid
hematoma;
Hemiplegia
Immuno
compromised
Hypertension;
Diverticulosis;
Hemorrhoidal
bleeding; COPD
Subarachnoid
bleed
Exclusion
Criteria
Probiotic
Function
Cotreatments
Treatment
Treatment
Treatment
n/a
Antibiotics
Treatment
Treatment
Antibiotics
Severe burns
Treatment
Antibiotics
100
Diabetes;
Hypertension
Treatment
0
H. pylori;
Colectomy /
colostomy; Septic
shock
Treatment
*Abbreviations
Ba=Bacillus
B=Bifidobacterium
CCT=Controlled Clinical Trials
C-RCT=Cross-over Randomized Controlled Trial
E=Enterococcus
GI=Gastrointestinal
IBS=Irritable Bowel Syndrome
L=Lactobacillus
n/a=not available or not applicable
RCT=Randomized Controlled Trial
S=Saccharomyces
St=Streptococcus
C-26
Antibiotics
Steroids
Immune suppressant
Daktarin (antifungal)
Evidence Table C2. Intervention
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Abrahamsson,
2007
RCT
1
Agerbaek, 1995
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
5 days
Oral
1 per day
Duration Control
LongCategory
Term
Use
n/a
Oil droplets
Patient
Mother
Lactobacillus, reuteri, ATCC
55730, Lyophilized, 10^8 cfu
1
Gaio
Fermented milk
Patient
Enterococcus, faecium, n/a, n/a,
2*10^8 cfu/ml
Streptococcus, thermophilus, n/a,
n/a, 7*10^8 cfu/ml
Streptococcus, thermophilus, n/a,
n/a, 7*10^8 cfu/ml
200 ml
1 per day
Oral
1.5
months
Medium
term
Placebo
Aihara, 2005
RCT
1
Lactobacillus, helveticus, CM4,
n/a, n/a
6 tablets
1 per day
Oral
1
Lactobacillus, casei, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Lactobacillus, Plantarum, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Lactobacillus, Acidophilus, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
viable, 9*10^11 cfu/sachet
Bifidobacterium, longum, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Bifidobacterium, breve, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Bifidobacterium, Infantis, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
viable, 9*10^11 cfu/sachet
2 sachets
2 per day
Enteral
1 month
Short
term
0.25
months
Short
term
Placebo
Alberda, 2007
RCT
n/a
Pill
Patient
n/a
Sachet
Patient
Alberda, 2007
RCT
3
Lactobacillus, casei, n/a,
Sonicated, n/a
Lactobacillus, plantarum, n/a,
Sonicated, n/a
Lactobacillus, acidophilus, n/a,
Sonicated, n/a
Lactobacillus, delbrueckii
acidophilus, n/a, Sonicated, n/a
Bifidobacterium, longum, n/a,
Sonicated, n/a
Bifidobacterium, infantis, n/a,
Sonicated, n/a
Bifidobacterium, breve, n/a,
Sonicated, n/a
Streptococcus, salivarius
thermophilus, n/a, Sonicated, n/a
1 sachet 2
per day
Enteral
VSL#3
Sachets
Patient
C-27
Placebo
Long
term
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Allen, 2010
RCT
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
n/a
Pill
Patient
Mother
Lactobacillus, salivarius, CUL 61,
n/a, 6.25*10^9 cfu
Lactobacillus, paracasei, CUL 08,
n/a, 1.25*10^9 cfu
Bifidobacterium, animalis lactis,
CUL 34, n/a, 1.25*10^9 cfu
Bifidobacterium, bifidum, CUL 20,
n/a, 1.25*10^9 cfu
Trevis
Pill
Patient
1 capsule
Lactobacillus, acidophilus, LA-5,
3 per day
n/a, 4*10^9 cfu
Lactobacillus, bulgaricus, n/a, n/a,
4*10^9 cfu
Bifidobacterium, lactis, BB-12, n/a,
4*10^9 cfu
Streptococcus, thermophilus, n/a,
n/a, 4*10^9 cfu
Oral
Duration Control
LongCategory
Term
Use
Placebo
Medium
term
n/a
Anderson, 2003
RCT
1
Andriulli, 2008
RCT
1
Flontec
Powder, sachet
Patient
Lactobacillus, paracasei, B21060, 7 g
Lyophilized, 5*10^9 cfu/7g sachet 2 per day
Oral
Anukam, 2006
RCT
1
n/a
Mix
Patient
Lactobacillus, rhamnosus, GR-1,
Viable, 10^9 cfu
Lactobacillus, reuteri, RC-14,
Viable, 10^9 cfu
Oral
Anukam, 2008
RCT
1
n/a
Yogurt
Patient
Lactobacillus, delbrueckii
bulgaricus, n/a, n/a, n/a
Streptococcus, thermophilus, n/a,
n/a, n/a
Lactobacillus, rhamnosus, 6R-1,
n/a, 2.5*10^9 cfu/ml
Lactobacillus, reuteri, RC-14, n/a,
2.5*10^9 cfu/ml
100 ml
1 per day
Anukam, 2009
RCT
1
n/a
Mix
Patient
Arunachalam,
2000
RCT
1
DR10
Drink
Patient
Aso, 1992
RCT
1
Aso, 1995
RCT
Awad, 2010
RCT
Placebo
Medium
term
3
months
Medium
term
1 month
Short
term
Placebo
Oral
0.5
months
Short
term
Yogurt only
Lactobacillus, rhamnosus, GR-1, 1 capsule
Live, 5*10^9 cfu/dose
1 per day
Lactobacillus, reuteri, RC-14, Live,
5*10^9 cfu/dose
Oral
3
months
Medium
term
Placebo
Bifidobacterium, lactis, HN019,
Lyophilized, 1.5*10^11 cfu
180 ml
2 per day
Oral
Placebo
BiolActis Powder Lactobacillus, casei, n/a, Viable,
Powder
1*10^10 cfu/g
Patient
1g
3 per day
Oral
1
BLP
Patient
Lactobacillus, casei, n/a, Viable,
10^10
1g
3 per day
Oral
1
Lacteol fort
Eppendorf tube
Patient
Lactobacillus, acidophilus, GG,
Living, 6*10^9 cfu/g
1.5
months
Medium
term
12
months
Long
term
12
months
Long
term
Medium
term
C-28
2 per day
n/a
Enteral
2 per day
n/a
Placebo
No medication
or placebo
Placebo
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 tube 2
Enteral
per day
Duration Control
LongCategory
Term
Use
Awad, 2010
RCT
3
n/a
Eppendorf tube
Patient
Lactobacillus, rhamnosus, GG,
Heat-killed, 6*10^9 cfu
Baerheim, 1994
RCT
1
Gynophilus
Vaginal
suppository
Patient
Lactobacillus, casei rhamnosus,
n/a, live, 7.5*10^8 cfu
1
Vaginal
suppository
2 per week
6.5
months
Medium
term
Placebo
Bajaj, 2008
RCT
1
CC
Crème
Yogurt
Patient
Oral
2
months
Medium
term
No treatment
Banaszkiewicz,
2005
RCT
1
n/a
Pill
Patient
Lactobacillus, rhamnosus, ATCC
GG 53103, n/a, 10^9 cfu
10^9 cfu
2 per day
Varies by
participant
Oral
3
months
Medium
term
Placebo
Barraud, 2010
RCT
1
Ergyphilus
Pill
Patient
Lactobacillus, rhamnosus, GG,
Revivable, 2*10^10 cfu/capsule
Lactobacillus, casei, n/a,
Revivable, 2*10^10 cfu/capsule
Lactobacillus, acidophilus, n/a,
Revivable, 2*10^10 cfu/capsule
Bifidobacterium, bifidum, n/a,
Revivable, 2*10^10 cfu/capsule
5 capsule
1 per day
Enteral
Barreto-Zuniga,
2001
RCT
1
Microflorana-F
Oral mix
Patient
10 ml
Lactobacillus, acidophilus, n/a,
3 per day
n/a, n/a
Lactobacillus, helveticus, n/a, n/a,
n/a
Bifidobacterium, n/a, n/a, n/a, n/a
Oral
Basu, 2007
RCT
1
n/a
Powder in ORS
Patient
Lactobacillus, rhamnosus, GG,
n/a, 6*10^7 cfu
6*10^7
cells
2 per day
Oral
Basu, 2007
RCT
1
n/a
Powder packet
Patient
Lactobacillus, rhamnosus, GG,
n/a, 6*10^7 cfu/100ml
100 ml
2 per day
Oral
Basu, 2009
RCT
1
n/a
Powder
Patient
Lactobacillus, rhamnosus, GG,
n/a, 10^10 cfu
100 ml
2 per day
Oral
Basu, 2009
RCT
3
n/a
Powder
Patient
Lactobacillus, rhamnosus, GG,
n/a, 10^12 cfu
100 ml 2
per day
Oral
Beausoleil, 2007 1
RCT
n/a
Drink
Patient
Lactobacillus, acidophilus,
CL1285, n/a, 5*10^10 cfu
Lactobacillus, casei, n/a, n/a,
5*10^10 cfu
Jersey Streptococcus, thermophilus, n/a, 12 oz
n/a, n/a
1 per day
Lactobacillus, bulgaricus, n/a, n/a,
n/a
Lactobacillus, acidophilus, n/a,
n/a, n/a
Lactobacillus, casei, n/a, n/a, n/a
Bifidobacterium, n/a, n/a, n/a, n/a
C-29
Placebo
Short
term
0.75
months
Short
term
Placebo
Medium
term
ORS only
Short
term
Medium
term
Oral
Varies
over time
Non-probiotic
Glucoseelectrolyte
rehydration
solution only
Placebo
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Bellomo, 1979
RCT
1
Bertolami, 1999
C-RCT
Bioflorin
Mix
Powder
Patient
Enterococcus, faecium, SF-68,
Lyophilized, 3*10^7 cfu/dose
1
Gaio
Fermented milk
Patient
Streptococcus, thermophilus, n/a,
n/a, 5-20*10^8 cfu/ml
Streptococcus, thermophilus, n/a,
n/a, 5-20*10^8 cfu/ml
Enterococcus, faecium, n/a, n/a,
10^5-10^9 cfu/ml
Besselink, 2008
RCT
1
Ecologic 641
Sachet dissolved
in water
Patient
Lactobacillus, acidophilus, n/a,
Lyophilized, viable, 10^10
cfu/daily dose
Lactobacillus, casei, n/a,
Lyophilized, viable, 10^10
cfu/daily dose
Lactobacillus, salivarius, n/a,
Lyophilized, viable, 10^10
cfu/daily dose
Bifidobacterium, bifidum, n/a,
Lyophilized, viable, 10^10
cfu/daily dose
Bifidobacterium, lactis, n/a,
Lyophilized, viable, 10^10
cfu/daily dose
Bin-Nun, 2005
RCT
1
ABC Dophilus
Formula
Powder in breast
milk or formula
Patient
Bifidobacterium, infantis, n/a, n/a,
0.35*10^9 cfu
Bifidobacterium, bifidum, n/a, n/a,
0.35*10^9 cfu
Streptococcus, thermophilus, n/a,
n/a, 0.35*10^9 cfu
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1-3 dose
Oral
2-3 per day
Varies by
participant
Duration Control
LongCategory
Term
Use
200 g
1 per day
Oral
2
months
Medium
term
Placebo
Enteral
1 month
Short
term
Placebo
2 per day
n/a
Placebo
Short
term
Enteral
Medium
term
Varies by
participant
Feeding
supplement
only
Black, 1997
CCT
1
BioTura
Pill
Patient
Lactobacillus, acidophilus, n/a,
Lyophilized, 4*10^9 cfu/capsule
Bifidobacterium, bifidum, n/a,
Lyophilized, 4*10^9 cfu/capsule
1 capsule
3 per day
Oral
0.75
months
Short
term
Placebo
Boge, 2009
RCT
1
Actimel
Drink
Patient
Lactobacillus, casei, DN-114 001 100 g
(CNCMI-1518), n/a, n/a
2 per day
Streptococcus, thermophilus, n/a,
n/a, n/a
Lactobacillus, bulgaricus, n/a, n/a,
n/a
Oral
1.75
months
Medium
term
Placebo
Boge, 2009
RCT
1
Actimel
Drink
Patient
Lactobacillus, casei, DN
100 g
114001(CNCM1-1518), n/a, n/a
2 per day
Streptococcus, thermophilus, n/a,
n/a, n/a
Lactobacillus, bulgaricus, n/a, n/a,
n/a
Oral
3.25
months
Short
term
Placebo
Borgia, 1982
RCT
1
n/a
Pill
Patient
Streptococcus, faecium, SF-68,
Lyophilized, >7.5*10^7
cfu/capsule
Oral
2
months
Medium
term
Antibiotics
only
C-30
1 capsules
1 per day
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Streptococcus, faecium, SF68,
2 capsule 1 Oral
Lyophilized, >=75ml 1 cfu/capsule per day
Borgia, 1982
RCT
3
n/a
Pill
Patient
Borgia, 1982
RCT
4
n/a
Pill
Patient
Streptococcus, faecium, SF68,
Lyophilized, >=75ml 1
bacteria/capsule
3 capsules
1 per day
Oral
Bousvaros,
2005
RCT
1
LGG
Pill
Patient
Lactobacillus, rhamnosus, GG,
n/a, >=10^10
1 capsule
2 per day
Oral
Bravo, 2008
RCT
1
n/a
Pill
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, 5.1*10^9 cells/
capsule
1 capsule
2 per day
Oral
Brophy, 2008
RCT
1
n/a
Pill
Patient
Lactobacillus, salivarius, CUL 61,
Lyophilized, 6.25*10^9 cfu
Lactobacillus, paracasei, CUL 08,
Lyophilized, 6.25*10^9 cfu
Bifidobacterium, infantis, CUL 34,
Lyophilized, 6.25*10^9 cfu
Bifidobacterium, bifidum, CUL 20,
Lyophilized, 6.25*10^9 cfu
1 capsule
1 per day
Oral
Bruno, 1981
RCT
1
n/a
Pill
Patient
Enterococcus, faecalis, SF-68,
Lyophilized, 7.5*10^7 cfu/capsule
Bruzzese, 2007
C-RCT
1
n/a
Lactobacillus, rhamnosus, GG,
LGG dissolved in n/a, 6*10^9 cfu/d
ORS
Patient
Bu, 2007
RCT
1
Antibiophilus
Pill
Patient
Chen, 2005
RCT
1
Chen, 2010
RCT
Chou, 2010
RCT
Duration Control
LongCategory
Term
Use
24
months
Long
term
0.5
months
Short
term
3
months
Medium
term
Placebo
7.5*10^7
Oral
cfu capsule
3 per day
n/a
6*10^9 cfu Oral
1 per day
0.33
months
Short
term
6
months
Medium
term
Placebo
Lactobacillus, casei rhamnosus,
LCR 35, n/a, 8*10^8 cfu/day
2 capsules
2 per day
Oral
1 month
Short
term
Placebo
n/a
Tablet
Patient
Lactobacillus, acidophilus, n/a,
n/a, n/a
1 tablet
3 per day
Oral
1
n/a
Pill
Patient
Lactobacillus, gasseri, PM-A
0005, Lyophilized, 2*10^9
cfu/capsule
1 capsule
2 per day
Oral
1
Infloran
Breast milk
Patient
Lactobacillus, acidophilus, n/a,
n/a, 10^9 cfu/dose
Bifidobacterium, infantis, n/a, n/a,
10^9 cfu/dose
n/a
Formula
Patient
Bifidobacterium, lactis, BB-12,
Dried, viable, 1.5*10^8 cfu
Streptococcus, thermophilus, n/a,
Dried, viable, n/a
Lactobacillus, helveticus, n/a,
Dried, viable, n/a
Chouraqui, 2004 1
RCT
C-31
Placebo
Non-probiotic
Non-probiotic
Medium
term
2
months
Medium
term
Oral
2 per day
Varies by
participant
Placebo
Placebo
Medium
term
Oral
Varies by
participant
Placebo
Placebo
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Chouraqui, 2008 1
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
n/a
Formula
Patient
Bifidobacterium, longum, BL-999,
n/a, 1.29*10^8 cfu/100ml
Lactobacillus, rhamnosus, LPR,
n/a, 1.29*10^8 cfu/100ml
Chouraqui, 2008 3
RCT
n/a
Formulal
Bifidobacterium, longum, BL999,
n/a, 1.29 * 10^8 cfu/100ml
Lactobacillus, rhamnosus, LPR,
n/a, 6.45 * 10^8 cfu/100ml
Varies by
participant
Chouraqui, 2008 4
RCT
n/a
Formulal
Patient
Bifidobacterium, longum, BL999,
n/a, 1.29 * 10^8 cfu/100ml
Lactobacillus, paracasei, ST11,
n/a, 2.58 * 10^8 cfu/100ml
Varies by
participant
Chui, 2009
RCT
1
Bifid Triple
Pill
Patient
4 capsules
Lactobacillus, n/a, n/a, Live, n/a
Bifidobacterium, n/a, n/a, Live, n/a 2 per day
Enterococcus, n/a, n/a, Live, n/a
n/a, n/a, n/a, Live, n/a
Coccorullo,
2010
RCT
1
Reuterin
Oil suspension
Patient
Lactobacillus, reuteri, DSM 17938, 5 drops
n/a, 10^8 cfu/5 drops
1 per day
Connolly, 2005
RCT
1
n/a
Lactobacillus, reuteri, ATCC
Mixed in peanut 55730, n/a, 1*10^8 cfu/dose
oil
Patient
Cooper, 2006
RCT
1
n/a
Formula
Patient
Bifidobacterium, lactis, n/a, n/a,
2*10^7 cfu/g
4
months
Medium
term
Placebo
Enteral
0.5
months
Short
term
Placebo
n/a
2
months
Medium
term
12
months
Long
term
Placebo
Varies by
participant
Oral
Oral
5 drops
1 per day
n/a
Oral
Placebo
Formula only
Medium
term
n/a
Correa, 2005
RCT
1
Nan Probiotico
Formula
Patient
Bifidobacterium, lactis, n/a, n/a,
10^7 cfu/g
Streptococcus, thermophilus, n/a,
n/a, 10^7 cfu/g
>500 ml
1 per day
Oral
Cui, 2004
RCT
1
n/a
Tablet
Patient
Bacillus, coagulans, n/a, n/a, 10^8 10^8 cfu
cfu
3 per day
Oral
Cui, 2004
RCT
2
n/a
Pill
Patient
Bifidobacterium, longum, n/a, n/a,
10^8 cfu
10^8 cfu 3
per day
Oral
CunninghamRundles, 2000
CCT
1
n/a
Mix
Patient
Lactobacillus, plantarum, 299v,
Lyophilized, n/a
1 packet
1 per day
Oral
Enteral
Czaja, 2007
RCT
1
n/a
Vaginal
suppository
Patient
Lactobacillus, crispatus, CTV-05,
n/a, 5*10^8 cfu/suppository
1
Vaginal
suppository
1 per day
C-32
Duration Control
LongCategory
Term
Use
0.5
months
Short
term
Placebo
Other probiotic
Short
term
Placebo
Medium
term
0.25
months
Short
term
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dadak, 2006
RCT
1
Synbiotic
Forte
Patient
2000 Lactobacillus, Plantarum, 2362,
n/a, 10^10 cfu
Lactobacillus, paracasei
paracasei, 19, N/A, 10^10 cfu
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
n/a
De Preter, 2006
C-RCT
1
Perenterol
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, viable, 1-2.5*10^9
cells/250mg
250 mg
4 per day
Oral
De Preter, 2006
C-RCT
3
Perenterol
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, viable, 1-2.5*10^9
cells/250 mg
250 mg 2
per day
Oral
de Roos, 1999
RCT
1
n/a
Yogurt
Patient
Streptococcus, thermophilus, n/a,
n/a, n/a
2 per day
Lactobacillus, acidophilus, L-1,
Varies
n/a, 4.8*10^9-2.7*10^10 cfu/500ml over time
De Simone,
1992
RCT
1
Infloran
Pill
Patient
Lactobacillus, acidophilus, n/a,
n/a, 10^9 cfu
Bifidobacterium, bifidum, n/a, n/a,
10^9 cfu
De Simone,
2001
CCT
1
VSL#3-Yoris
Patient
Streptococcus, thermophilus, n/a, 3 g
Live, 10^11 cfu/g
1 per day
Bifidobacterium, n/a, n/a, Living,
10^11 cfu/g
Lactobacillus, acidophilus, n/a,
Live, 10^11 cfu/g
Lactobacillus, plantarum, n/a,
Live, 10^11 cfu/g
Lactobacillus, casei, n/a, Live,
10^11 cfu/g
Lactobacillus, delbrueckii
bulgaricus, n/a, Live, 10^11 cfu/g
Streptococcus, faecium, n/a, Live,
10^11 cfu/g
De Simone,
2001
CCT
2
Bioflorin
Pill
Patient
Enterococcus, faecium, n/a, Live,
2.5*10^7 cfu/capsule
Dekker, 2009
RCT
1
Fonterra NZ
Pill
Patient
Mother
Lactobacillus, rhamnosus, HN001, 1 capsule
n/a, 6*10^9 cfu
1 per day
Dekker, 2009
RCT
3
n/a
Drink
Patient
Mother
Bifidobacterium, animalis lactis,
HN019, n/a, 9*10^9 cfu
C-33
Placebo
Medium
term
n/a
2 capsules
4 per day
Duration Control
LongCategory
Term
Use
1 month
Short
term
Placebo
Oral
2
months
Medium
term
Yogurt only
Oral
1 month
Short
term
Placebo
Oral
0.33
months
Short
term
Other probiotic
3 capsules
1 per day
Oral
1 capsule 1 Oral
per day
Placebo
Long
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Delia, 2002
RCT
1
Delia, 2007
RCT
1
Dewan, 2007
RCT
Dolin, 2009
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 sachet
Oral
3 per day
Duration Control
LongCategory
Term
Use
VSL#3
Sachet
Patient
Lactobacillus, casei, n/a,
Lyophilized, 4.5*10^8 cfu/g
Lactobacillus, plantarum, n/a,
Lyophilized, 4.5*10^8 cfu/g
Lactobacillus, acidophilus, n/a,
Lyophilized, 4.5*10^8 cfu/g
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
4.5*10^8 cfu/g
Bifidobacterium, longum, n/a,
Lyophilized, 4.5*10^8 cfu/g
Bifidobacterium, breve, n/a,
Lyophilized, 4.5*10^8 cfu/g
Bifidobacterium, infantis, n/a,
Lyophilized, 4.5*10^8 cfu/g
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
4.5*10^8 cfu/g
VSL#3
Sachet
Patient
Lactobacillus, casei, n/a,
1 sachet
Lyophilized, viable, 4.5*10^8 cfu/g 3 per day
Lactobacillus, plantarum, n/a,
Lyophilized, viable, 4.5*10^8 cfu/g
Lactobacillus, acidophilus, n/a,
Lyophilized, viable, 4.5*10^8 cfu/g
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
viable, 4.5*10^8 cfu/g
Bifidobacterium, longum, n/a,
Lyophilized, viable, 4.5*10^8 cfu/g
Bifidobacterium, breve, n/a,
Lyophilized, viable, 4.5*10^8 cfu/g
Bifidobacterium, infantis, n/a,
Lyophilized, viable, 4.5*10^8 cfu/g
Streptococcus, saliva, n/a,
Lyophilized, viable, 4.5*10^8 cfu/g
n/a
1
n/a
Curd
Patient
Lactobacillus, bulgaricus, n/a, n/a, 100 g
10^8
2 per day
Streptococcus, thermophilus, n/a,
n/a, 10^8 cfu
Oral
0.5
months
Short
term
Non-probiotic
1
GanedenBC
Pill
Patient
Bacillus, coagulans, GB1-30
6086, n/a, 2*10^9 cfu/capsule
Oral
2
months
Medium
term
Placebo
C-34
1 capsule
1 per day
Placebo
Medium
term
Placebo
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dubey, 2008
RCT
1
Duman, 2005
RCT
Dupont, 2010
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
VSL#3
Sachet
Patient
Lactobacillus, acidophilus, n/a,
n/a, 9*10^10 cfu/sachet
Lactobacillus, paracasei, n/a, n/a, Varies by
9*10^10 cfu/sachet
participant
Lactobacillus, bulgaricus, n/a, n/a,
9*10^10 cfu/sachet
Lactobacillus, plantarum, n/a, n/a,
9*10^10 cfu/sachet
Bifidobacterium, breve, n/a, n/a,
9*10^10 cfu/sachet
Bifidobacterium, infantis, n/a, n/a,
9*10^10 cfu/sachet
Bifidobacterium, longum, n/a, n/a,
9*10^10 cfu/sachet
Streptococcus, thermophilus, n/a,
n/a, 9*10^10 cfu/sachet
1
Reflor
Pill
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
1
Modilac Digest 1 Lactobacillus, rhamnosus, n/a,
Formula
n/a, n/a
Patient
Bifidobacterium, infantis, n/a, n/a,
n/a
Dylewski, 2010
RCT
1
Ehrstrom, 2010
RCT
Eriksson, 2005
RCT
500 mg
2 per day
Duration Control
LongCategory
Term
Use
Placebo
Medium
term
n/a
Oral
n/a
0.5
months
Short
term
1 month
Short
term
Triple therapy
only
Formula only
BIO K+ CL1285
Fermented milk
Patient
Lactobacillus, acidophilus,
CL1285, n/a, 5*10^10 cfu/g
Lactobacillus, casei, n/a, n/a,
5*10^10 cfu/g
49-98 g
1 per day
Varies
over time
Oral
1
n/a
Pill
Patient
Lactobacillus, gasseri, LN40,
Lyophilized, viable, 10^8-10^10
cfu/capsule
Lactobacillus, fermentum, LN-99,
Lyophilized viable, 10^8-10^10
cfu/capsule
Lactobacillus, casei rhamnosus,
LN113, Lyophilized, viable, 10^8
10^10 cfu/capsule
Pediococcus, acidilactici, LN 23,
Lyophilized, viable, 10^8-10^10
cfu/capsule
1 capsule
2 per day
Vaginal
0.2
months
Short
term
Placebo
1
n/a
Tampon
Patient
Lactobacillus, gasseri, n/a,
Lyophilized, live, 10^8 cfu/tampon
Varies by
Lactobacillus, casei rhamnosus,
participant
n/a, Lyophilized, live, 10^8
cfu/tampon
Lactobacillus, fermentum, n/a,
Lyophilized, live, 10^8 cfu/tampon
Vaginal
1 month
Short
term
Placebo
C-35
Placebo
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Falck, 1999
RCT
1
Bactonormal
Suspension
spray
Patient
Streptococcus, mitis, n/a, n/a,
7*10^6 cfu/ml
Streptococcus, sanguis II, n/a,
n/a, 7*10^6 cfu/ml
Streptococcus, sanguis II, n/a,
n/a, 7*10^6 cfu/ml
Streptococcus, sanguis II, n/a,
n/a, 7*10^6 cfu/ml
Felley, 2001
RCT
1
LC-1
Drink
Patient
Lactobacillus, johnsonii, LA-1, n/a, 180 ml
1*10^7 cfu/ml
2 per day
Oral
Feng, 1999
RCT
1
Golden Bifido
Pill
Patient
Lactobacillus, n/a, n/a, Live,
1*10^9 cfu/g
Bifidobacterium, longum, n/a,
Live, 1*10^9 cfu/g
Streptococcus, thermophilus, n/a,
Live, 1*10^9 cfu/g
4 capsules
2 per day
Oral
Folster-Holst,
2006
RCT
1
LGG
Lactobacillus, rhamnosus, GG,
Mixed with mile n/a, 5*10^9 cfu/dose
on water
Patient
5*10^9 cfu
2 per day
Oral
Forestier, 2008
RCT
1
n/a
Varies
Patient
Lactobacillus, casei rhamnosus,
n/a, n/a, 10^9 cfu
10^9 cfu
2 per day
Oral
Enteral
French, 2009
RCT
1
PCC
Pill
Patient
Lactobacillus, fermentum, VRI
1 capsule
003, Lyophilized, 10^9 cfu/capsule 1 per day
Oral
Frohmader,
2010
RCT
1
VSL#3
Sachet
Patient
Lactobacillus, acidophilus, n/a,
Lyophilized, live, n/a
Lactobacillus, casei, n/a, Live
lyophilized, n/a
Lactobacillus, bulgaricus, n/a,
Lyophilized, live, n/a
Lactobacillus, plantarum, n/a,
Lyophilized, live, n/a
Bifidobacterium, longum, n/a,
Lyophilized, live, >10^10 cfu/g
Bifidobacterium, infantis, n/a,
Lyophilized, live, >10^10 cfu/g
Bifidobacterium, breve, n/a,
Lyophilized, live, >10^10 cfu/g
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
live, >10^11 cfu/g
4.5*10^11
cfu
2 per day
Enteral
Fujimori, 2009
RCT
1
Bificolon
Pill
Patient
Bifidobacterium, longum, n/a, n/a,
2*10^9 cfu
1 capsule
1 per day
Oral
Fujimori, 2009
RCT
3
n/a
Water
Patient
Bifidobacterium, longum, n/a, n/a,
2*10^9 cfu
1 capsule 1 Oral
per day
C-36
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
150 ml
Topical
2 per day
Duration Control
LongCategory
Term
Use
0.33
months
Short
term
Placebo
0.75
months
Short
term
Placebo
Other probiotic
Short
term
2
months
Medium
term
Placebo
Placebo
Medium
term
1.5
months
Medium
term
Placebo
Placebo
Short
term
1 month
Short
term
Prebiotic
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Duration Control
LongCategory
Term
Use
Streptococcus, faecium, n/a,
Lyophilized, n/a
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
4 tablets
n/a
2 per day
Gade, 1989
RCT
1
n/a
Pill
Patient
1 month
Short
term
Placebo
Galpin, 2005
RCT
1
LGG
Pill
Mix
Patient
Lactobacillus, rhamnosus, GG,
n/a, 5^10 cfu
2 capsules
1 per day
Oral
1 month
Short
term
Placebo
Gao, 2010
RCT
1
n/a
Pill
Patient
Lactobacillus, acidophilus,
CL1285, Live, 5*10^10
cfu/capsule
Lactobacillus, casei, LBC80R,
Live, 5*10^10 cfu/capsule
1 capsule
1 per day
Oral
Gao, 2010
RCT
3
n/a
Pill
Patient
Lactobacillus, acidophilus,
CL1285, Live, 5*10^10
cfu/capsule
Lactobacillus, casei, LBC80R,
Live, 5*10^10 cfu/capsule
2 capsule 1 Oral
per day
Garcia Vilela,
2008
RCT
1
Floratil
Pill
Patient
Saccharomyces, boulardii, 17,
Lyophilized, 4*10^8 cells/capsule
1 capsule
3 per day
Oral
Gerasimou,
2010
RCT
1
DDS(R) Junior
Mix
Powder
Patient
Bifidobacterium, lactis, UABLA-12, 1 gram
n/a, 5*10^9 cfu/g
2 per day
Lactobacillus, acidophilus, DDS-1,
n/a, 5*10^9 cfu/g
Oral
Gibson, 2008
RCT
1
n/a
Formula
Patient
Bifidobacterium, lactis, CNCM I
3446, n/a, 3.85*10^8 cfu
3
months
Medium
term
2
months
Medium
term
Placebo
Oral
7
months
Medium
term
Formula only
0.75
months
Short
term
Other probiotic
Varies by
participant
Gill, 2001
RCT
1
n/a
Sachet
Patient
Bifidobacterium, lactis, HN019,
Lyophilized, 1*10^9 cfu
5*10^10
organisms
1 per day
Oral
Gill, 2001
RCT
2
n/a
Patient
Bifidobacterium, lactis, HN019,
Lyophilized, 1*10^8 cfu/g
1*10^8
organisms
1 per day
Oral
C-37
Placebo
Short
term
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Gionchetti, 2000 1
RCT
Gionchetti, 2003 1
RCT
Goossens, 2003 1
RCT
n/a
Bag
Patient
Lactobacillus, casei, n/a,
Lyophilized, viable, 3*10^11 cfu/g
Lactobacillus, plantarum, n/a,
Lyophilized, viable, 3*10^11 cfu/g
Lactobacillus, acidophilus, n/a,
Lyophilized, viable, 3*10^11 cfu/g
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
viable, 3*10^11 cfu/g
Bifidobacterium, longum, n/a,
Lyophilized, viable, 3*10^11 cfu/g
Bifidobacterium, breve, n/a,
Lyophilized, viable, 3*10^11 cfu/g
Bifidobacterium, infantis, n/a,
Lyophilized, viable, 3*10^11 cfu/g
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
viable, 3*10^11 cfu/g
VSL#3
Lactobacillus, casei, n/a,
Packet
Lyophilized, 9*10^11 cfu
Patient
Lactobacillus, plantarum, n/a,
Lyophilized, 9*10^11 cfu
Lactobacillus, acidophilus, n/a,
Lyophilized, 9*10^11 cfu
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
9*10^11 cfu
Bifidobacterium, longum, n/a,
Lyophilized, 9*10^11 cfu
Bifidobacterium, breve, n/a,
Lyophilized, 9*10^11 cfu
Bifidobacterium, infantis, n/a,
Lyophilized, 9*10^11 cfu
Saccharomyces, salivarius
thermophilus, n/a, Lyophilized,
9*10^11
n/a
Lactobacillus, Plantarum, 299v,
In
fermented n/a, 1*10^9 cfu/ml
oatmeal drink
Patient
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
3 g bags
Oral
2x per day
Duration Control
LongCategory
Term
Use
9
months
Medium
term
Placebo
1 packet
1 per day
n/a
12
months
Long
term
Placebo
100 ml
2 per day
Oral
1 month
Short
term
Placebo
Gracheva, 1999 1
CCT
Bifidumbacterin
forte
Patient
Bifidobacterium, bifidum, n/a, n/a,
n/a
45 doses
Oral
2-3 per day
Gracheva, 1999 2
CCT
n/a
Patient
Bifidobacterium, bifidum, n/a,
Active, n/a
5 doses 2
per day
n/a
Gruber, 2007
RCT
Valio
Pill
Patient
Lactobacillus, rhamnosus, GG,
n/a, 5*10^9 cfu
1 capsule
2 per day
Oral
1
C-38
Other probiotic
Short
term
3
months
Medium
term
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
100 g
Oral
2 per day
Guillemard,
2010
RCT
1
Actimel
Drink
Patient
Lactobacillus, casei paracasei,
DN-114001, n/a, >=10^10
cfu/100g
Streptococcus, thermophilus, n/a,
n/a, >=10^9 cfu/100g
Lactobacillus, delbrueckii,
bulgaricus, n/a, >=10^9 cfu/100g
Guyonnet, 2009 1
RCT
Activia
Drink
Patient
Bifidobacterium, lactis, DN
1 pot
173010, n/a, 1.25*10^10 cfu/pot
1 per day
Streptococcus, thermophilus, n/a,
n/a, 1.2*10^9 cfu/pot
Lactobacillus, bulgaricus, n/a, n/a,
1.2*10^9 cfu/pot
Guyonnet, 2009 3
RCT
Activia
Drink
Patient
Bifidobacterium, lactis, DN-173
2 pots 1 per Oral
010, n/a, 1.25*10^10 cfu/pot
day
Streptococcus, thermophilus, n/a,
n/a, 1.2*10^9 cfu/pot
Lactobacillus, bulgaricus, n/a, n/a,
1.2*10^9 cfu/pot
Habermann,
2001
RCT
1
Symbioflor
Enterococcus, faecalis, n/a, Active 30 drops
Taken
orally, cells + autolysis, 1.5-4.5*10^7
3 per day
gargled,
cfu/ml
swallowed
Patient
Habermann,
2002
RCT
1
Symbioflor
Salt solution
Patient
Enterococcus, faecalis, Group D,
Active, 1.5-4.5*10^7 cfu/ml
HaschkeBecher, 2008
RCT
1
Nan 2
Formula
Patient
Lactobacillus, johnsonii, LA-1,
Live, 1*10^8 cfu/g
Hatakka, 2008
C-RCT
1
n/a
Pill
Patient
Lactobacillus, rhamnosus, LC705
DSM 7061, Lyophilized, 2*10^10
cfu/2 capsules
Propionibacterium, freudenreichii
shermanii, JS, Lyophilized,
2*10^10 cfu
Heimburger,
1994
RCT
1
Laxtinex
Granules
Patient
Lactobacillus, acidophilus, n/a,
Viable, n/a
Lactobacillus, bulgaricus, n/a,
Viable, n/a
Hemmerling,
2009
RCT
1
3
months
Medium
term
Placebo
0.5
months
Short
term
No
intervention
6
months
Medium
term
Placebo
6
months
Medium
term
Placebo
Oral
1 month
Short
term
Placebo
2 capsules
1 per day
Oral
1 month
Short
term
Placebo
1g
3 per day
Enteral
1 dose
1 per day
Vaginal
Oral
Oral
Enteral
3.75
11.25*10^7
cfu
3 per day
Varies by
participant
LACTIN-V
Lactobacillus, crispatus, CTV-05,
Single
use n/a, 5*10^8 cfu/dose
vaginal
applications
Patient
C-39
Duration Control
LongCategory
Term
Use
Placebo
Short
term
0.13
months
Short
term
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Hemmerling,
2009
RCT
3
n/a
Lactobacillus, crispatus, CTV-05,
Single
use n/a, 10^9 cfu/dose
vaginal
applications
Patient
Hemmerling,
2009
RCT
Higashikawa,
2009
RCT
4
n/a
Patient
Lactobacillus, crispatus, CTV-05,
n/a, 2*10^9 cfu/dose
1 dose 1
per day
Vaginal
1
n/a
Yogurt
Patient
Lactobacillus, plantarum, SN35N,
Viable, 1.9*10^8 cfu/g
Lactobacillus, plantarum, SN13T,
Viable, 0.2*10^8 cfu/g
100 g
1 per day
Oral
Higashikawa,
2009
RCT
2
n/a
Yogurt
Patient
Lactobacillus, plantarum, SN35N,
Viable, 1.96*10^8 cfu/g
Lactobacillus, plantarum, SN13T,
Viable, 0.04*10^8 cfu/g
100 g 1 per Oral
day
Higashikawa,
2009
RCT
3
n/a
Yogurt
Patient
Lactobacillus, lactis, A6, Viable,
1.722*10^8 cfu/g
Bifidobacterium, thermophilus,
510, Viable, 0.276*10^8 cfu/g
Lactobacillus, bulgaricus, C6,
Viable, 0.002*10^8 cfu/g
100 g 1 per Oral
day
Hilton, 1997
RCT
1
LGG
Mix
Patient
Lactobacillus, GG, n/a, n/a,
2*10^9 cfu
2*10^9 cfu
1 per day
Hirata, 2002
CCT
1
n/a
Sour milk
Patient
Lactobacillus, helveticus, n/a, n/a, 120 g
n/a
1 per day
Saccharomyces, cerevisiae, n/a,
n/a, n/a
Lactobacillus, helveticus, CM4,
n/a, n/a
Hochter,1990
RCT
1
Perenterol
Pill
Patient
Honeycutt, 2007 1
RCT
Culturelle
Pill
Patient
Hong, 2010
RCT
n/a
Packet
powder
water
Patient
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 dose 1
Vaginal
per day
Duration Control
LongCategory
Term
Use
1.5
months
Medium
term
Oral
Other probiotic
Placebo
Medium
term
Oral
2
months
Medium
term
Placebo
Saccharomyces, boulardii, n/a,
n/a, 50ml
3 capsules Oral
2-4 per day
0.25
months
Short
term
Placebo
Lactobacillus, rhamnosus, GG,
n/a, 10^9 cfu/capsule
1 capsule
1 per day
Bifidobacterium, bifidum, BGN4,
1 packet
of Lyophilized, 5*10^9 cfu/packet
2 per day
with Bifidobacterium, lactis, AD011,
Lyophilized, 5*10^9 cfu/packet
Lactobacillus, acidophilus, AD031,
Lyophilized, 5*10^9 cfu/packet
Lactobacillus, casei, IBS041,
Lyophilized, 5*10^9 cfu/packet
C-40
Varies
Placebo
Medium
term
Oral
2
months
Medium
term
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 sachet
Oral
2 per day
Horvat, 2010
RCT
1
Synbiotic 2000
Sachet
Patient
Lactobacillus, paracasei,
paracasei 19, Active, 10^10
cfu/sachet
Lactobacillus, plantarum, 2362,
Active, 10^10 cfu/sachet
Pediococcus, pentosaceus, 5
33:3, Active, 10^10 cfu/sachet
Leuconostoc, mesenteroides, 32
77:1, Active, 10^10 cfu/sachet
Horvat, 2010
RCT
2
n/a
Patient
Lactobacillus, paracasei
paracasei, 19, Heat-inactivated,
n/a
Lactobacillus, plantarum, 2362,
Heat-inactivated, n/a
Pediococcus, pentosaceus, 5
33:3, Heat-inactivated, n/a
Leuconostoc, mesenteroides, 32
77:1, Heat-inactivated, n/a
Ishikawa, 2002
RCT
1
BFM
Drink
Patient
Lactobacillus, acidophilus, YIT
100 ml
0168, Live, >10^9 cfu/100ml
1 per day
Bifidobacterium, breve, n/a, Live,
>10^9 cfu/100ml
Bifidobacterium, bifidum, n/a, Live,
>10^9 cfu/100ml
Ishikawa, 2003
RCT
1
n/a
Tablet
Patient
Lactobacillus, salivarius, TI 2711,
Lyophilized, 1*10^8 cfu
Ishikawa, 2003
RCT
3
n/a
Pill
Patient
Ishikawa, 2005
RCT
1
Ishikawa, 2005
RCT
Duration Control
LongCategory
Term
Use
0.1
month
Short
term
Other probiotic
Oral
12
months
Long
term
No treatment
5 tablets
5 per day
Oral
2
months
Medium
term
No treatment
Lactobacillus, salivarius, TI 2711,
Lyophilized, 2*10^7 cfu
5 tablets 5
per day
Oral
n/a
Powder
Patient
Lactobacillus, casei, Shirota, n/a,
10^10 cfu/g
1g
n/a
48
months
Long
term
Dietary
instructions
only
3
n/a
Powder
Patient
Lactobacillus, casei, Shirota, n/a,
10^10 cfu/g
1 g 3 per
day
n/a
Isolauri, 1991
RCT
1
LGG
Fermented milk
Patient
Lactobacillus, casei, GG, n/a,
10^10-11 cfu
125 g
2 per day
Oral
0.25
months
Short
term
Non-probiotic
Isolauri, 1991
RCT
3
LGG
Powder
Patient
Lactobacillus, casei, GG,
Lyophilized, 10^10-11 cfu
1 dose 2
per day
n/a
Isolauri,1995
RCT
1
LGG
Lactobacillus, casei, ATCC 53103, 0.1 g
Dry
powder Lyophilized, 5*10^9 cfu
2 per day
mixed with water
Patient
0.25
months
Short
term
Placebo
C-41
1 sachet 2
per day
Oral
Oral
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 capsule
Oral
3 per day
Duration Control
LongCategory
Term
Use
Jirapinyo, 2002
RCT
1
Infloran
Pill
Patient
0.25
months
Short
term
Placebo
Johansson,
1998
RCT
1
ProViva
Lactobacillus, plantarum, DSM
Rose-hip
drink 9843, 299v, n/a, 5*10^7 cfu/ml
fermented oats
Patient
400 ml
1 per day
Oral
0.75
months
Short
term
Placebo
Kadooka, 2010
RCT
1
n/a
Fermented milk
Patient
Streptococcus, thermophilus, n/a,
n/a, n/a
Lactobacillus, delbrueckii
bulgaricus, n/a, n/a, n/a
Lactobacillus, gasseri, SBT
2055(LG2055), Viable, 5*10^10
cfu/100g
100 g
2 per day
Oral
3
months
Medium
term
Fermented
milk only
Kajander, 2005
RCT
1
n/a
Pill
Patient
Lactobacillus, rhamnosus, LC
705, n/a, 8-9*10^9 cfu/capsule
Bifidobacterium, breve, BB 99,
n/a, 8-9*10^9 cfu/capsule
Lactobacillus, rhamnosus, GG,
n/a, 8-9*10^9 cfu/capsule
1 capsule
1 per day
n/a
6
months
Medium
term
Placebo
Kajander, 2008
RCT
1
LGG
Drink
Patient
1.2 daily
Lactobacillus, rhamnosus, GG
1 per day
ATCC 53103, n/a, 10^7 cfu
Lactobacillus, rhamnosus, LC 705
DSM 7061, n/a, 10^7 cfu
Bifidobacterium, animalis lactis,
BB-12 DSM 15954, n/a, 10^9 cfu
Oral
5
months
Medium
term
Placebo
Kajimoto, 2002
RCT
1
n/a
Yogurt
Patient
Lactobacillus, helveticus, n/a, n/a, 150 g
2 per day
n/a
Saccharomyces, cerevisiae, n/a,
n/a, n/a
Lactobacillus, helveticus, CM4,
n/a, n/a
Lactobacillus, delbrueckii
bulgaricus, n/a, n/a, n/a
Streptococcus, thermophilus, n/a,
n/a, n/a
Oral
2
months
Medium
term
Yogurt only
Karvonen, 2001
RCT
1
n/a
Varies
Patient
Lactobacillus, reuteri, n/a,
Lyophilized, 10^5 cfu
20 ml
1 per day
Oral
1 month
Short
term
Placebo
Karvonen, 2001
RCT
3
n/a
Varies
Patient
Lactobacillus, reuteri, n/a,
Lyophilized, 10^7 cfu
20 ml 1 per Oral
day
Karvonen, 2001
RCT
4
n/a
Varies
Patient
Lactobacillus, reuteri, n/a,
Lyophilized, 10^9 cfu
20 ml 1 per Oral
day
Lactobacillus, acidophilus, n/a,
Lyophilized, n/a
Bifidobacterium, infantis, n/a,
Lyophilized, n/a
C-42
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Kerac, 2009
RCT
1
Kianifar, 2009
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
>10^10 cfu Oral
1 per day
Varies by
participant
Duration Control
LongCategory
Term
Use
Synbiotic 2000
Forte
Ready-to-use
food
Patient
Lactobacillus, paracasei
paracasei, F-19 LM6 P-17806,
Lyophilized, 2.5*10^10 cfu
Lactobacillus, plantarum, 2362
LM6 P-20606, Lyophilized,
2.5*10^10 cfu/dose
Leuconostoc, mesenteroides, 23
77:1LMGP-20607, Lyophilized,
2.5*10^10 cfu/dose
Pediococcus, pentosaceus, 16:1
LMG P-20608, Lyophilized,
2.5*10^10 cfu/dose
1
Infloran
Powder
Patient
Lactobacillus, acidophilus, n/a,
n/a, 1*10^9 cfu/dose
Bifidobacterium, bifidum, n/a, n/a,
1*10^9 cfu/dose
1 dose
3 per day
Oral
0.2
months
Short
term
Placebo
Kim, 2006
RCT
1
n/a
Pill
Patient
Lactobacillus, acidophilus, n/a,
n/a, 5*10^7 cfu/dose
Bifidobacterium, bifidum, n/a, n/a, Varies
5*10^7 cfu/dose
over time
Lactobacillus, bulgaricus, n/a, n/a,
5*10^7 cfu/dose
Lactobacillus, lactis + leichmannii,
n/a, n/a, 5*10^7 cfu/dose
Lactobacillus, brevis + caseii, n/a,
n/a, 5*10^7 cfu/dose
Lactobacillus, caucasicus +
plantarum, n/a, n/a, 5*10^7
cfu/dose
Lactobacillus, fermenti +
helveticus, n/a, n/a, 5*10^7
cfu/dose
Saccharomyces, boulardii, n/a,
n/a, 5*10^7 cfu/dose
Oral
2
months
Medium
term
Other probiotic
Kim, 2006
RCT
2
n/a
Pill
Patient
Lactobacillus, acidophilus, n/a,
n/a, 5*10^7 cfu/dose
Varies
Bifidobacterium, bifidum, n/a, n/a, over time
5*10^7 cfu/dose
Bacillus, subtilis, n/a, n/a, 5*10^7
cfu/dose
Lactobacillus, bulgaricus, n/a, n/a,
5x10^7 cfu/dose
Lactobacillus, lactis, n/a, n/a,
5*10^7 cfu/dose
Bacillus, lichenformis, n/a, n/a,
5*10^7 cfu/dose
Oral
C-43
Placebo
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Kim, 2006
RCT
1
n/a
Pill
Patient
Lactobacillus, acidophilus, n/a,
n/a, 1*10^7 cfu/dose
Bifidobacterium, bifidum, n/a, n/a, Varies
1*10^7 cfu/dose
over time
Bacillus, subtilis, n/a, n/a, 1*10^7
cfu/dose
Lactobacillus, bulgaricus, n/a, n/a,
1*10^7 cfu/dose
Lactobacillus, lactis, n/a, n/a,
1*10^7 cfu/dose
Bacillus, licheniformis, n/a, n/a,
1*10^7 cfu/dose
Kim, 2006
RCT
3
n/a
Caplet
Patient
Bacillus, coagulans, n/a, n/a,
5*10^7 cfu/dose
Varies
Saccharomyces, boulardii, n/a,
over time
n/a, 5*10^7 cfu/dose
Bacillus, subtilis, n/a, n/a, 5*10^7
cfu/dose
Lactobacillus, salivarius, n/a, n/a,
5*10^7 cfu/dose
Lactobacillus, plantarum, n/a, n/a,
5*10^7 cfu/dose
Oral
Kim, 2008
RCT
1
Will Yogurt
Yogurt
Patient
Lactobacillus, acidophilus, HY
150 ml
2177, n/a, >10^5 cfu/ml
1 per day
Lactobacillus, casei, HY 2177,
n/a, >10^5 cfu/ml
Bifidobacterium, longum, HY
8001, n/a, >10^5 cfu/ml
Streptococcus, thermophilus, B-1,
n/a, >10^5 cfu/ml
Oral
Kirjavainen,2003 1
RCT
n/a
Formula
Patient
Lactobacillus, rhamnosus, GG,
Lyophilized, viable, 1*10^9 cfu/g
3*10^10
cfu/kg
Oral
Kirjavainen,2003 3
RCT
n/a
Formulal
Patient
Lactobacillus, rhamnosus, GG,
Heat-killed, 10^9 cfu/g
3*10^10
cfu/g
Oral
Klarin, 2008
RCT
1
n/a
Gauze swabs
Patient
Lactobacillus, plantarum, 299, n/a, 2 swabs
10^10 cfu/10 ml
2 per day
Topical
Klarin,2005
RCT
1
Probi AB
Fermented
oatmeal formula
Patient
Lactobacillus, plantarum, 299v,
n/a, 10^9 cfu/ml
Enteral
Synbiotic 2000
Sachet
Patient
Lactobacillus, paracasei
paracasei, n/a, n/a, 10^10
2 per day
cfu/sachet
n/a
Lactobacillus, plantarum, n/a, n/a,
10^10 cfu/sachet
Knight, 2007
RCT
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
2
months
Medium
term
Placebo
0.75
months
Short
term
Triple therapy
only
Placebo
Medium
term
Non-probiotic
Medium
term
Placebo
Medium
term
Varies by
participant
C-44
Duration Control
LongCategory
Term
Use
Enteral
Placebo
Short
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Koning, 2008
RCT
1
Ecologic AAD
Sachet
Patient
Bifidobacterium, bifidum, W 23,
n/a, 10^9 cfu/g
Bifidobacterium, lactis, W 18, n/a,
10^9 cfu/g
Bifidobacterium, longum, W 51,
n/a, 10^9 cfu/g
Enterococcus, faecium, W54, n/a,
10^9 cfu/g
Lactobacillus, acidophilus, W37,
n/a, 10^9 cfu/g
Lactobacillus, acidophilus, W55,
n/a, 10^9 cfu/g
Lactobacillus, paracasei, W72,
n/a, 10^9 cfu/g
Lactobacillus, plantarum, W62,
n/a, 10^9 cfu/g
Kopp, 2008
RCT
1
n/a
Pill
Patient
Mother
Lactobacillus, rhamnosus GG,
ATCC 53103, n/a, 5*10^9 cfu
Kotzampassi,
2006
RCT
1
Synbiotic
Forte
Sachet
Patient
Krasse, 2005
RCT
1
n/a
Chewing gum
Patient
Krasse, 2005
RCT
3
Kuitunen, 2009
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
5g
Oral
2 per day
Duration Control
LongCategory
Term
Use
0.5
months
Short
term
Placebo
2 capsules
1 per day
Oral
12 g
1 per day
Enteral
0.5
months
Short
term
Placebo
Lactobacillus, reuteri, n/a, Live,
1*10^8 cfu
1g
2 per day
Oral
0.5
months
Short
term
Placebo
n/a
Chewing gum
Patient
Lactobacillus, reuteri, n/a, Live,
1*10^8 cfu
1 gum 2
per day
Oral
1
n/a
Patient
Mother
Lactobacillus, rhamnosus, GG
(ATCC 53103), n/a, 5*10^9 cfu
Lactobacillus, rhamnosus, LC 705
(DSM 7061), n/a, 5*10^9 cfu
Bifidobacterium, breve, Bb 99
(DSM 13692), n/a, 2*10^8 cfu
Propionibacterium, freudenreichii,
shermanii JS (DSM 7076), n/a,
2*10^9 cfu
1 dose
1-2 per day
Varies by
participant
n/a
6
months
Medium
term
Placebo
Kurugol, 2005
RCT
1
n/a
Saccharomyces, boulardii, n/a,
Diluted
with n/a, n/a
water or juice
Patient
250 mg
1 per day
Oral
0.17
months
Short
term
Placebo
La Rosa, 2003
RCT
1
n/a
Pill
Patient
Lactobacillus, sporogenes, n/a,
n/a, 5.5*10^8 cfu
1 capsule
1 per day
Oral
0.3
months
Short
term
Placebo
Laitinen, 2008
RCT
1
n/a
Pill
Patient
Lactobacillus, rhamnosus, GG
ATCC-55 103, n/a, 10^10 cfu/day
Bifidobacterium, lactis, BB-12, n/a, n/a
10^10 cfu/day
2000 Lactobacillus, paracasei
paracasei, 19, n/a, 10^11 cfu
Lactobacillus, plantarum, 2362,
n/a, 10^11 cfu
C-45
Placebo
Medium
term
Oral
Placebo
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Langhendries,
1995
RCT
1
Larsen, 2006
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
n/a
Formula
Patient
Streptococcus, thermophilus, n/a,
n/a, n/a
Lactobacillus, helveticus, n/a, n/a,
n/a
Bifidobacterium, bifidum, n/a,
Viable, 10^6 cfu/g
1
n/a
Pill
Patient
Lactobacillus, paracasei
paracasei, CRL-431, n/a, 10^8
cfu/day
Bifidobacterium, animals lactis,
BB-12, n/a, 10^8 cfu/day
2 capsules
1 per day
Oral
Larsen, 2006
RCT
3
n/a
Pill
Patient
Lactobacillus, paracasei
paracasei, CRL-431, n/a, 1*10^9
cfu
Bifidobacterium, animalis lactis,
n/a, n/a, 1*10^9 cfu
2 capsules
1 per day
Oral
Larsen, 2006
RCT
4
10^10
Pill
Patient
Lactobacillus paracasei paracasei, 2 capsules
CRL-431, n/a, n/a, 1*10^10
1 per day
Bifidobacterium, animalis lactis,
n/a, n/a, 1*10^10
Oral
Larsson, 2008
RCT
1
EcoVag
Pill
Patient
Lactobacillus, gasseri, Lba EB01
DSM 14869, Lyophilized, >=10^8
9 cfu
Lactobacillus, rhamnosus, Lba
EBD1-DSM 14870, Lyophilized,
>=10^8-9 cfu
Vaginal
n/a
Patient
Bifidobacterium, infantis, n/a, n/a,
n/a
Bifidobacterium, bifidum, n/a, n/a,
n/a
Lactobacillus, acidophilus, n/a,
n/a, n/a
Lactobacillus, casei, n/a, n/a, n/a
Lactobacillus, salivarius, n/a, n/a,
n/a
Lactobacillus, lactis, n/a, n/a, n/a
Lata, 2009
RCT
1
Lawrence, 2005 1
RCT
LGG
Pill
Patient
Li, 2004
RCT
n/a
Dissolved
water
Patient
1
Ligaarden, 2010 1
C-RCT
n/a
Pill
Patient
Varies by
participant
n/a
2
months
Medium
term
Formula only
0.75
months
Short
term
Placebo
3
months
Medium
term
Placebo
Enteral
Placebo
Medium
term
n/a
Lactobacillus, rhamnosus, GG,
Lyophilized, 2.8*10^11-4*10^10
cfu
40 mg
2 per day
Oral
Bifidobacterium, breve, n/a, n/a,
in 1.6*10^8 cells/0.5ml
0.5 ml
2 per day
Enteral
Lactobacillus, plantarum, MF
1298, Lyophilized, live, 10^10
cfu/capsule
1 capsule
1 per day
Oral
C-46
Duration Control
LongCategory
Term
Use
Placebo
Medium
term
Medium
term
0.75
months
Short
term
No
supplement
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Lighthouse,
2004
RCT
1
SCM-III
Patient
Lactobacillus, acidophilus, n/a,
n/a, n/a
Lactobacillus, helveticus, n/a, n/a,
n/a
Bifidobacterium, n/a, n/a, n/a, n/a
Lin, 1989
C-RCT
1
Lactinex
Tablet
Patient
Lactobacillus, acidophilus, ATCC
4962, Viable, 2*10^6 cfu/tablet
Lactobacillus, bulgaricus, ATCC
33409, Viable, 2*10^6 cfu/tablet
Lin, 2005
RCT
1
Infloran
Mixed
breast milk
Patient
Lin, 2008
RCT
1
Lactobacillus, acidophilus, n/a,
with n/a, >=1,004,356
Bifidobacterium, infantis, n/a, n/a,
>=1,004,356
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
10 ml
n/a
3 per day
Duration Control
LongCategory
Term
Use
0.5
months
Short
term
Non-probiotic
1 tablet
4 per day
Oral
1.5
months
Medium
term
Placebo
125 mg/kg
2 per day
Oral
125 mg/kg
2 per day
Oral
Medium
term
Infloran; Bifidum
Formula
Added to breast
milk or formula
Patient
Lactobacillus, acidophilus, NCDD
1748, n/a, 10^9 cfu
Bifidobacterium, bifidum, NCDD
1453, n/a, 10^9 cfu
Ljungberg, 2006 1
RCT
n/a
Pill
Patient
Lactobacillus, rhamnosus, GG,
1 per day
n/a, 5*10^9 cfu
Lactobacillus, rhamnosus, LC705, n/a
n/a, 5*10^9 cfu
Bifidobacterium, breve, Bbi99, n/a,
2*10^8 cfu
Oral
Loguercio, 1987 1
RCT
Bioflorin
Pill
Patient
Enterococcus, faecium, SF-68,
n/a, 7.5*10^7 cfu/capsule
2 capsule
3 per day
Oral
Lonnermark,
2010
RCT
1
n/a
Lactobacillus, plantarum, 299v,
Drink
with n/a, 5*10^7 cfu/ml
Blueberries
+
oats gruel
Patient
200 ml
1 per day
Oral
Lu, 2004
CCT
1
n/a
Patient
Lactobacillus, rhamnosus, n/a,
n/a, 1.5*10^8 cfu/day
1.5*10^8
cfu
1 per day
n/a
Lu, 2004
CCT
3
n/a
Patient
Lactobacillus, rhamnosus, n/a,
n/a, 2.7*10^8 cfu
4*10^8 cfu
1 per day
n/a
Lu, 2004
CCT
4
n/a
Patient
Lactobacillus, rhamnosus, n/a,
n/a, 4*10^8 cfu
4*10^8 cfu
1 per day
n/a
Luoto, 2010
RCT
1
n/a
Pill
Patient
Mother
Lactobacillus, rhamnosus, GG
1 capsule
(ATCC 53103), n/a, 10^10
1 per day
cfu/capsule
Bifidobacterium, lactis, BB-12, n/a,
10^10 cfu/capsule
C-47
1.5
months
Medium
term
Breast
only
milk
Placebo
Placebo
Medium
term
0.33
months
Short
term
Non-probiotic
Placebo
Short
term
1 month
Medium
term
Oral
Short
term
Placebo
Dietary
counseling
only
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Mäkeläinen,
2003
RCT
1
n/a
Pill
Patient
Bifidobacterium, longum, 2C, n/a,
10^9 cfu
Bifidobacterium, longum, 46, n/a,
10^9 cfu
Malaguarnera,
2007
RCT
1
n/a
Patient
Bifidobacterium, longum, W11,
n/a, n/a
Malaguarnera,
2010
RCT
1
Maldonado,
2009
RCT
1
Mandel, 2010
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
2 capsules n/a
1 per day
n/a
n/a
n/a
Patient
Bifidobacterium, n/a, n/a, n/a, n/a
n/a
n/a
n/a
Formula
Patient
Lactobacillus, salivarius,
CECT5713, n/a, >=2*10^6 cfu/g
Oral
1
n/a
Caplet
Patient
Bacillus, coagulans, GBI-30,
6086, n/a, 2*10^9 cfu/caplet
1 caplet
1 per day
Oral
Manley, 2007
C-RCT
1
Vaalia yoghurt
Yogurt
Patient
Lactobacillus, rhamnosus, GG,
n/a, n/a
100 g
yogurt
1 per day
Oral
Manzoni, 2006
RCT
1
Dicoflor 60
Lactobacillus, rhamnosus, GG,
Packet
mixed n/a, 6*10^9 cfu/ml
with milk
Patient
n/a
Duration Control
LongCategory
Term
Use
0.75
months
Short
term
Placebo
3
months
Medium
term
2
months
Medium
term
6
months
Medium
term
2
months
Medium
term
1 month
Short
term
Placebo
Enteral
Non-probiotic
Placebo
Placebo
Yogurt only
Milk only
Medium
term
n/a
Margreiter, 2006 1
RCT
Omniflora
Pill
Patient
Lactobacillus, gasseri, n/a,
Lyophilized, 2*10^7-2*10^8
cfu/capsule
Bifidobacterium, longum, n/a,
Lyophilized, 2*10^7-2*10^8
cfu/capsule
50 mg
3 per day
Oral
Margreiter, 2006 2
RCT
Bioflorin
Pill
Patient
Enterococcus, faecium, Cernelle
68, n/a, 7.5*10^7 cfu/capsule
3 per day
n/a
Oral
Marotta, 2003
C-RCT
1
SCM-III
Patient
3 ml
Lactobacillus, acidophilus, n/a,
3 per day
n/a, n/a
Lactobacillus, helveticus, n/a, n/a,
n/a
Bifidobacterium, brevis, n/a, n/a,
n/a
Oral
0.5
months
Short
term
Non-probiotic
Marrazzo, 2006
RCT
1
n/a
Pill
Patient
Lactobacillus, crispatus, n/a, n/a,
10^8
1 capsule
2 per day
Vaginal
Placebo
n/a
Suspension
Patient
Bifidobacterium, clausii, n/a, n/a,
2*10^9 cfu/5 ml
1 vial
2 per day
Oral
3
months
Medium
term
3
months
Medium
term
Marseglia, 2007 1
RCT
C-48
Other probiotic
Short
term
No treatment
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Marteau, 2004
RCT
1
n/a
Packet
Patient
Lactobacillus, johnsonii, LA-1,
Lyophilized, 2*10^9 cfu/packet
Martiney, 2009
RCT
1
n/a
Yogurt
Patient
Lactobacillus, gasseri,
CECT5714, n/a, >=10^6 cfu/g
Lactobacillus, coryniformis,
CECT5711, n/a, >=10^6 cfu/g
Streptococcus, thermophilus, n/a,
n/a, 10^7 cfu/g
200 ml
1 per day
Oral
Martinez, 2008
RCT
1
n/a
Pill
Patient
Lactobacillus, rhamnosus, GR-1,
Viable, 1*10^9 cfu
Lactobacillus, reuteri, RC-14,
Viable, 1*10^9
2 capsule
1 per day
Martinez, 2009
RCT
1
n/a
Pill
Patient
Lactobacillus, rhamnosus, 6R-1,
Dried, 1*10^7 cfu/capsule
Lactobacillus, reuteri, RC-14,
Dried, 1*10^9 cfu/capsule
Mayanagi, 2009 1
RCT
n/a
Tablet
Patient
McFarland,
1994
RCT
1
McFarland,
1995
RCT
1
Duration Control
LongCategory
Term
Use
6
months
Medium
term
3
months
Medium
term
Placebo
Oral
1 month
Short
term
Placebo
2 capsules
1 per day
Oral
1 month
Short
term
Placebo
Lactobacillus, salivarius, WB21,
n/a, 6.7*10^8 cfu/tablet
1 tablet
3 per day
Oral
Placebo
n/a
Pill
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, 3*10^10 cfu
2 capsules
2 per day
Oral
2
months
Medium
term
1 month
Short
term
n/a
Pill
Patient
Saccharomyces, Boulardii, n/a,
n/a, 3*10^10 cfu/g
2 capsules
2 per day
Oral
500 ml
1 per day
Oral
McNaught, 2002 1
RCT
ProViva
Oatmeal
drink
Patient
Merenstein,
2009
RCT
Probugs
Fermented
drink
Patient
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
2 packets
Oral
1 per day
Lactobacillus, plantarum, 299v,
based n/a, 5*10^9 cfu/ml
Bifidobacterium, longum, n/a,
milk Active, live, n/a
Bifidobacterium, breve, n/a,
Active, live, n/a
Lactobacillus, acidophilus, n/a,
Active, live, n/a
Saccharomyces, florentinus, n/a,
Active, live, n/a
Lactococcus, lactis diacetylactis,
n/a, Active, live, n/a
Lactococcus, plantarum, n/a,
Active, live, n/a
Lactococcus, rhamnosus, n/a,
Active, live, n/a
Lactococcus, casei, n/a, Active,
live, n/a
C-49
Placebo
Placebo
Short
term
No treatment
Short
term
Oral
1 per day
Varies by
participant
Yogurt only
0.3
months
Short
term
Other probiotic
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Merenstein,
2009
RCT
2
Merenstein,
2010
RCT
1
Metts, 2003
RCT
1
Metts, 2003
RCT
3
Miele, 2009
RCT
1
Millar, 1993
RCT
1
Probugs
Patient
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 per day Oral
Varies by
participant
Bifidobacterium, longum, n/a,
Heat-killed, n/a
Bifidobacterium, breve, n/a, Heatkilled, n/a
Lactobacillus, acidophilus, n/a,
Heat-killed, n/a
Saccharomyces, florentinus, n/a,
Heat-killed, n/a
Lactococcus, lactis diacetylactis,
n/a, Heat-killed, n/a
Lactococcus, plantarum, n/a,
Heat-killed, n/a
Lactococcus, rhamnosus, n/a,
Heat-killed, n/a
Lactococcus, casei, n/a, Heatkilled, n/a
Dan
Active Lactobacillus, paracasei
1 bottle
(Actimel)
paracasei, DN-114 001/CNCM
1 per day
Drink
578, n/a, 10^8 cfu/g
Streptococcus, thermophilus, n/a,
Patient
n/a, >10^7 cfu/g
Lactobacillus, bulgaricus, n/a, n/a,
>10^7 cfu/g
n/a
Lactobacillus, acidophilus, S, n/a,
Vaginal
2*10^9 cfu/capsule
3 per week
Suppository
n/a
Patient
n/a
Lactobacillus, acidophilus, S, n/a,
Pill
n/a
2*10^9 cfu/capsule
Vaginal
Lactobacillus, acidophilus, S, n/a,
suppository
5*10^9 cfu/capsule
Patient
Bifidobacterium, bifidum, Malyoth,
n/a, 2*10^10 cfu/capsule
Lactobacillus, bulgaricus, LB-51,
n/a, 5*10^9 cfu
VSL#3
Lactobacillus, paracasei, n/a,
Packet
mixed Lyophilized, 9*10^8 cfu
1 per day
with beverage
Lactobacillus, plantarum, n/a,
Varies by
Patient
Lyophilized, 9*10^8 cfu
participant
Lactobacillus, acidophilus, n/a,
Lyophilized, 9*10^8 cfu
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
9*10^8 cfu
Bifidobacterium, longum, n/a,
Lyophilized, 9*10^8 cfu
Bifidobacterium, breve, n/a,
Lyophilized, 9*10^8 cfu
Bifidobacterium, infantis, n/a,
Lyophilized, 9*10^8 cfu
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
9*10^8 cfu
LGG
Lactobacillus, rhamnosus, GG,
10^8 cfu
Formula
n/a, 10^8 cfu
2 per day
Patient
C-50
Duration Control
LongCategory
Term
Use
Oral
3
months
Medium
term
Placebo
Vaginal
3.3
months
Medium
term
Placebo
Oral
12
months
Long
term
Placebo
Oral
0.5
months
Short
term
Milk only
Oral
Vaginal
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Mimura, 2004
RCT
1
VSL#3
Sachet
Patient
Miyaji, 2006
RCT
1
n/a
Yogurt
Patient
Morrow, 2010
RCT
1
Mukerji, 2009
RCT
1
Naito, 2008
RCT
1
n/a
Pill
Patient
n/a
Chewable tablet
Patient
n/a
Powder
Patient
Newcomer,
1983
RCT
1
Acidophilus milk
Drink
Patient
Lactobacillus, acidophilus, n/a,
n/a, 4*10^6 cfu/ml
Niers, 2009
RCT
1
Ecologic Panda
Powder
Patient
Mother
Bifidobacterium, bifidum, W23,
Lyophilized, 1*10^9 cfu
Bifidobacterium, lactis, W52,
Lyophilized, 1*10^9 cfu
Lactobacillus, lactis, W58,
Lyophilized, 1*10^9 cfu
Lactobacillus, reuteri, ATCC
55730, n/a, 10^8 cfu
Niv, 2005
RCT
1
Nobuta, 2009
RCT
1
Nobuta, 2009
RCT
3
Nobuta, 2009
RCT
4
BioGaia AB
Pill
Patient
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
6g
n/a
1 per day
Lactobacillus, acidophilus, n/a,
n/a, n/a
Lactobacillus, delbrueckii
bulgaricus, n/a, n/a, n/a
Lactobacillus, casei, n/a, n/a, n/a
Lactobacillus, plantarum, n/a, n/a,
n/a
Bifidobacterium, breve, n/a, n/a,
n/a
Bifidobacterium, longum, n/a, n/a,
n/a
Bifidobacterium, infantis, n/a, n/a,
n/a
Streptococcus, salivarius
thermophilus, n/a, n/a, n/a
Lactobacillus, gasseri, OLL2716
90 g
LG21, n/a, 1*10^9 cfu/g
2 per day
Lactobacillus, rhamnosus, GG,
n/a, 10^9 cfu/capsule
2 capsule
2 per day
Lactobacillus, rhamnosus, Roo11,
Active, 5*10^8 cfu
2 per day
n/a
Lactobacillus, casei, Shirota, n/a, 3 g
1*10^10 cfu/g
1 per day
6 oz
3 per day
Oral
Oral
Enteral
Oral
Oral
Oral
Oral
Varies by
participant
Oral
n/a
Pill
Patient
n/a
Pill
Patient
Lactobacillus, brevis, KB290,
Viable, 3*10^9 cfu/capsule
Varies
over time
3 capsule
1 per day
Lactobacillus, brevis, KB290,
Viable, 6*10^9 cfu/capsule
3 capsules
1 per day
Oral
n/a
Pill
Patient
Lactobacillus, brevis, KB290,
Viable, 3*10^10 cfu/capsule
3 capsules
1 per day
Oral
C-51
Oral
Duration Control
LongCategory
Term
Use
12
months
Long
term
Placebo
3
months
Medium
term
Placebo
Placebo
Medium
term
1 month
Short
term
12
months
Long
term
0.5
months
Short
term
13.5
months
Short
term
5.75
months
Medium
term
1 month
Short
term
Placebo
Chemotherapy
only
Placebo
Placebo
Placebo
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
10^10
n/a
bacterial
cells
1 per day
O'Mahony, 2005 1
RCT
Lactobacillus
Drink
Patient
Lactobacillus, salivarius, VCC
4331, Live, 10^10 cfu
O'Mahony, 2005 3
RCT
n/a
Drink
Patient
Bifidobacterium, infantis, 35624,
Live, 10^10 cfu
10^10 cfu 1 n/a
per day
Ojetti, 2010
RCT
1
Reuterin
Pill
Patient
Lactobacillus, reuteri, n/a, n/a,
2*10^8 cfu/pill
2 pills
2 per day
Olah, 2005
RCT
1
Synbiotic 2000
Enteral feed
Patient
Lactobacillus, n/a, 4 strains, n/a,
10^10 cfu
1
n/a
Yogurt
Patient
Streptococcus, thermophilus, n/a,
n/a, 10^8 cfu
Lactobacillus, coryniformis,
CECT5711, n/a, 2*10^9 cfu
Lactobacillus, gasseri,
CECT5714, n/a, 2*10^9 cfu
Osterlund, 2007 1
RCT
Gefilus
Pill
Patient
Lactobacillus, rhamnosus, 66
ATCC 53103, n/a, 1-2*10^10 cfu
Ouwehand,
2009
RCT
1
n/a
Pill
Patient
Ozkinay, 2005
RCT
1
Gynoflor
Vaginal tablet
Patient
Lactobacillus, acidophilus, NCFM
ATCC 700396, Viable, 1.25*10^9
cfu/capsule
Bifidobacterium, lactis, BI-04
(ATCC SD5219), Viable,
3.75*10^9 cfu/capsule
Lactobacillus, acidophilus, n/a,
Live, >10^7 cfu/tub
Panigrahi, 2008
RCT
1
GastroPlan
Lactobacillus, plantarum, ATCC
Synbiotics
in 20195, n/a, 10^9 cfu/2ml
dextrose saline
Patient
Parent, 1996
RCT
1
Gynoflor
Vaginal tablet
Patient
Lactobacillus, acidophilus, n/a,
Lyophilized, viable, 10^7 cfu/tablet
Activia
Yogurt
Patient
Lactobacillus, bulgaricus, n/a, n/a, 2 200ml
n/a
2 per day
Streptococcus, thermophilus, n/a,
n/a, n/a
Olivares, 2006
RCT
Parfenov, 2005
CCT
1
Oral
2
months
Medium
term
Placebo
0.3
months
Short
term
Placebo
Enteral
200 ml
1 per day
Prebiotic
Short
term
Varies by
participant
Oral
1 month
Short
term
Yogurt only
Oral
6
months
Medium
term
4
months
Medium
term
Chemotherapy
only
2 per day
n/a
1 capsule
1 per day
Oral
1 tablet
1 per day
Vaginal
Placebo
2 ml
1 per day
Oral
0.25
months
Short
term
Placebo
Vaginal
0.25
months
Short
term
Placebo
Oral
0.75
months
Short
term
No treatment
Placebo
Short
term
Varies by
participant
C-52
Duration Control
LongCategory
Term
Use
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 100
Oral
grams
2 per day
Duration Control
LongCategory
Term
Use
Parfenov, 2005
CCT
1
Actimel
Yogurt
Patient
Lactobacillus, bulgaricus, n/a,
Active, 10^7 cfu/100 g
Lactobacillus, casei, Defensis,
Active, 10^7 cfu/100g
Streptococcus, thermophilus, n/a,
Active, 10^8 cfu/100 g
Parra, 2004
RCT
1
n/a
Patient
Lactobacillus, casei, DN-114001,
n/a, 10^8-10^10 cfu/g
95 g
3 per day
Oral
Milk only
Lactobacillus, rhamnosus, Lcr35,
n/a, 1.2*10^9 cfu/dose
1.5 q
3 per day
Oral
n/a
Lactobacillus, plantarum, ATCC
Culture on gauze 10 241, n/a, 10^5 cfu/ml
pad
Patient
1 pad
1 per day
Topical
2
months
Medium
term
3
months
Medium
term
0.33
months
Short
term
Passeron, 2005
RCT
1
n/a
Alu-bag
Patient
Peral, 2009
RCT
1
Pereg, 2010
RCT
1
Bio-plus
Pill
Patient
Lactobacillus, acidophilus, n/a,
Lyophilized, 2*10^10 cfu/dose
Lactobacillus, bulgaricus, n/a,
Lyophilized, 2*10^10 cfu/dose
Bifidobacterium, bifidum, n/a,
Lyophilized, 2*10^10 cfu/dose
Streptococcus, thermophilus, n/a,
Lyophilized, 2*10^10 cfu/dose
1 dose
1 per day
Oral
6
months
Medium
term
Placebo
Petschow, 2005 1
RCT
n/a
Formula
Patient
Lactobacillus, rhamnosus, GG,
Active, live, 1*10^4 cfu/g
Oral
0.5
months
Short
term
Formula only
Petschow, 2005 3
RCT
Nutramigen
Formulal
Patient
Lactobacillus, rhamnosus, GG,
Active, live, 10^7 cfu/g
Petschow, 2005 4
RCT
Nutramigen
Formulal
Patient
Lactobacillus, rhamnosus, GG,
Active, live, 10^8 cfu/g
Prantera, 2002
RCT
Dicoflor 60
Lactobacillus, casei rhamnosus,
Bags - dissolved n/a, n/a, 6*10^9 cfu
in water
Patient
2.46 g
2 per day
Oral
12
months
Long
term
Placebo
n/a
Sachet
Patient
1 sachet
1 per day
Oral
3
months
Medium
term
Placebo
1
Pregliasco, 2008 1
RCT
Varies by
participant
Lactobacillus, plantarum, LP 02
LMG P-21020, Live, 10^10
cfu/0.1g
Lactobacillus, rhamnosus, LR 04
DSM 16605, Live, 10^10 cfu/0.1g
Bifidobacterium, lactis, BS-01
LMG P-21384, Live, 10^10
cfu/0.1g
C-53
0.75
months
Short
term
Prebiotic
Non-probiotic
Oral
Varies by
participant
Oral
Varies by
participant
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 sachet 1 Oral
per day
Pregliasco, 2008 3
RCT
n/a
Sachets
Patient
Lactobacillus, plantarum, LP 02
LMG P-21020, Live, 10^10
cfu/0.1g
Lactobacillus, rhamnosus, LR 04
DSM 16605, Live, 10^10 cfu/0.1g
Bifidobacterium, lactis, BS 01
LMG P-21384, Live, 10^10
cfu/0.1g
Pregliasco, 2008 1
RCT
n/a
Sachet
Patient
1 sachet
Lactobacillus, plantarum, LP 01
1 per day
LMG P-21021, n/a, 5*10^9 cfu
Lactobacillus, plantarum, LP 01
LMG P-21020, n/a, 5*10^9 cfu
Lactobacillus, rhamnosus, LR 04
DSM 16605, n/a, 5*10^9 cfu
Lactobacillus, rhamnosus, LR 05
DSM 19739, n/a, 5*10^9 cfu
Bifidobacterium, lactis, BS 01
LMG P-21384, n/a, 5*10^9 cfu
Oral
Pregliasco, 2008 3
RCT
n/a
Sachets
Patient
Lactobacillus, plantarum, LP 02
LMG P-21020, Live, 10^10
cfu/0.1g
Lactobacillus, rhamnosus, LR 04
DSM 16605, Live, 10^10 cfu/0.1g
Bifidobacterium, lactis, BS 01
LMG P-21384, Live, 10^10
cfu/0.1g
Lactobacillus, plantarum, LP 01
LMG P-21021, Live, 10^10
cfu/0.1g
Oral
Pregliasco, 2008 1
RCT
n/a
Sachet
Patient
1 sachet
Lactobacillus, plantarum, LP 02
1 per day
LMG P-21020, Live, 10^10
cfu/0.1g
Lactobacillus, rhamnosus, LR 04
DSM 16605, Live, 10^10 cfu/0.1g
Bifidobacterium, lactis, BS 01-LM6
P-21384, Live, 10^10 cfu/0.1g
Puccio, 2007
RCT
Nan
Formula
Patient
Bifidobacterium, longum, BL-999,
Live, 2*10^7 cfu
1
1 sachet 1
per day
3
months
Medium
term
Placebo
Oral
3
months
Medium
term
Placebo
Oral
3.7
months
Medium
term
Placebo
Oral
0.5
months
Short
term
Other probiotic
3
months
Medium
term
Placebo
Varies by
participant
Rampengan,
2010
RCT
1
Lacidofil
Pill
Patient
Lactobacillus, n/a, n/a, Live, n/a
Rampengan,
2010
RCT
Ranganathan
C-RCT
2
Dialac
Patient
Lactobacillus, n/a, n/a, Heat-killed, 2 sachets 1 Oral
n/a
per day
1
Kibow Biotics
Pill
Patient
Lactobacillus, acidophilus, KB31,
n/a, 5*10^9 cfu/capsule
Bifidobacterium, longum, KB35,
n/a, 5*10^9 cfu/capsule
Streptococcus, thermophilus,
KB27, n/a, 5*10^9 cfu/capsule
C-54
1 capsule
1 per day
2 capsule
3 per day
Duration Control
LongCategory
Term
Use
Oral
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Rautava, 2008
RCT
1
Rayes, 2002
RCT
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1*10^10 cfu Oral
1 per day
Duration Control
LongCategory
Term
Use
0.25
months
Short
term
Standard
crystalloid
solution only
0.3
months
Short
term
Parenteral or
enteral
nutrition only
Varies
0.5
months
Short
term
Placebo
n/a
Pill
Patient
Lactobacillus, rhamnosus, GG
ATCC 53103, n/a, 10^10 cfu
Bifidobacterium, lactis, BB-12, n/a,
10^10 cfu
1
n/a
Enteral formula
Patient
Lactobacillus, plantarum, 299,
Live, 1*10^9 cfu
10^9 cfu
2 per day
Enteral
Rayes, 2002
RCT
3
n/a
Enteral formula
Patient
Lactobacillus, plantarum, 299,
Heat-killed, 1*10^9 cfu
10^9 cfu 2
per day
Enteral
Rayes, 2002
RCT
1
n/a
Enteral formula
Patient
Lactobacillus, plantarum, 299,
Live, 10^9 cfu
10^9 cfu
2 per day
Enteral
Rayes, 2002
RCT
3
n/a
Enteral formula
Patient
Lactobacillus, plantarum, 299,
Heat-killed, n/a
10^9 cfu 2
per day
Enteral
Rayes, 2005
RCT
1
Synbiotic 2000
Sachet
Patient
Lactobacillus, paracasei
paracasei, F-19, n/a, n/a
Lactobacillus, plantarum, 2362,
n/a, n/a
2 per day
n/a
Rayes, 2007
RCT
1
n/a
Sachet
Patient
Lactobacillus, paracasei
paracasei, F-19, n/a, n/a
Lactobacillus, plantarum, 2362,
n/a, n/a
1 sachet
2 per day
Varies
0.3
months
Short
term
Placebo
Reid, 1992
RCT
1
n/a
Pill
Patient
Lactobacillus, casei rhamnosus,
GR-1, Lyophilized, 1.6*10^9
cfu/vial
Lactobacillus, fermentum, B-54,
Lyophilized, 1.6*10^9 cfu/vial
1 capsule
Vaginal
2
months
Medium
term
Placebo
Reid, 1995
RCT
1
n/a
Suppository
Patient
Lactobacillus, casei, GR-1,
Lyophilized, 1*10^9 cfu
Lactobacillus, fermentum, B-54,
Lyophilized, 1*10^9
1
Vaginal
suppository
1 per week
12
months
Long
term
Prebiotic
Ren, 2010
RCT
1
Charge Le Kang
Powder
Patient
Bifidobacterium, n/a, n/a, Live,
?1.0*10^6 cfu/g
Clostridium, butyricum, n/a, n/a,
n/a
250 mg
2 per day
Oral
Reuman, 1986
RCT
1
n/a
Formula
Patient
Lactobacillus, acidophilus, n/a,
n/a, 5*10^10 cfu/ml
1 ml
2 per day
Enteral
Gaio
Fermented milk
Patient
Enterococcus, faecium, n/a, n/a,
10^5-10^9 cfu/ml
Streptococcus, thermophilus, n/a,
n/a, 5-20*10^8 cfu/ml
Streptococcus, thermophilus, n/a,
n/a, 5-20*10^8 cfu/ml
200 ml
1 per day
Oral
Richelsen, 1996 1
RCT
C-55
Placebo
Medium
term
Non-probiotic
Short
term
Placebo
Medium
term
6
months
Medium
term
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Rio, 2002
RCT
1
n/a
Drink
Patient
Lactobacillus, acidophilus, n/a,
Viable, 10^7-10^8 cfu/ml
Lactobacillus, casei, n/a, Viable,
10^8 cfu/ml
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
3
months
Medium
term
Placebo
Topical
0.33
months
Short
term
Placebo
Varies by
participant
3 puffs
2 per day
Duration Control
LongCategory
Term
Use
Roos, 1996
RCT
1
n/a
Suspension
spray
Patient
Streptococcus, sanguis, n/a,
Lyophilized, 10^6 cfu/50ml
Streptococcus, mitis, n/a,
Lyophilized, 10^6 cfu/50ml
Streptococcus, sanguis, n/a,
Lyophilized, 10^6 cfu/50ml
Streptococcus, sanguis, n/a,
Lyophilized, 10^6 cfu/50ml
Roos, 2001
RCT
1
n/a
Spray
Patient
Streptococcus, sanguis, 2 strains, 6 puffs
2 per day
Lyophilized, 5*10^6 cfu/ml
Streptococcus, mitis, 2 strains,
Lyophilized, 5*10^6 5*10^6
5*10^6 cfu/ml
Streptococcus, oralis, n/a,
Lyophilized, 5*10^6 cfu/ml
Other
2
months
Medium
term
Placebo
Rose, 2010
RCT
1
LGG
Pill
Capsule
contents
reconstituted
water
Patient
Lactobacillus, rhamnosus, ATCC 1 capsule
53103 GG, n/a, 10^10 cfu/capsule 2 per day
Oral
6
months
Medium
term
Placebo
Lactobacillus, rhamnosus, 19070 10^10 cfu
Z, Lyophilized, 10^10 cfu
2 per day
Lactobacillus, reuteri, DSM 12246,
Lyophilized, 10^10 cfu
n/a
0.17
months
Short
term
Placebo
Oral
0.6
months
Short
term
Placebo
in
Rosenfeldt,
2002
RCT
1
n/a
Patient
Rosenfeldt,
2003
C-RCT
1
Lactobacillus, casei alactus,
n/a
Powder mixed in CHCC 3137, Lyophilized, 10^10
water on milk
cfu
Patient
Lactobacillus, delbrueckii lactis,
CHCC 2329, Lyophilized, 10^10
cfu
Lactobacillus, rhamnosus, 66
ATCC 53103, Lyophilized, 10^10
cfu
Rosenfeldt,
2003
C-RCT
3
n/a
Powder
mixed
with water or
milk
Patient
Lactobacillus, rhamnosus, 19070 10^10 cfu 2 Oral
2, Lyophilized, 10^10 cfu
per day
Lactobacillus, reuteri, DSM 12246,
Lyophilized, 10^10 cfu
Rouge, 2009
RCT
1
Valio
Pill
Patient
Lactobacillus, rhamnosus, GG,
Lyophilized, 10^8 cells/unit
Bifidobacterium, longum, BB 536,
Lyophilized, 10^8 cfu/unit
C-56
10^10 cfu
2 per day
4 capsule
1 per day
Enteral
Placebo
Short
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Ruiz-Palacios,
1996
RCT
1
Ruiz-Palacios,
1996
RCT
3
Ruiz-Palacios,
1996
RCT
4
Saavedra, 2004
RCT
1
Saavedra, 2004
RCT
n/a
Formula
Added
Pediasure
Patient
Lactobacillus, reuteri, n/a, n/a,
10^6 cfu
to Lactobacillus, acidophilus, n/a,
n/a, 10^6 cfu
Bifidobacterium, infantis, n/a, n/a,
10^6 cfu
n/a
Added
PediaSure
Patient
Lactobacillus, reuteri, n/a, n/a,
to 10^10 cfu
Lactobacillus, acidophilus, n/a,
n/a, 10^10 cfu
Bifidobacterium, infantis, n/a, n/a,
10^10 cfu
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
n/a
0.75
months
Short
term
Placebo
Oral
n/a
n/a
Patient
Lactobacillus, reuteri, n/a, n/a,
10^8 cfu
Lactobacillus, acidophilus, n/a,
n/a, 10^8 cfu
Bifidobacterium, infantis, n/a, n/a,
10^8 cfu
n/a
Formula
Patient
Bifidobacterium, lactis, BB-12, n/a,
10^6 cfu/g
Streptococcus, thermophilus, n/a, Varies by
participant
n/a, 10^6 cfu/g
Oral
3
n/a
Formulal
Patient
Bifidobacterium, lactis, BB-12, n/a,
10^7 cfu/g
Varies by
Streptococcus, thermophilus, n/a, participant
n/a, 10^7 cfu/g
Oral
Safdar, 2008
RCT
1
Florajen
Mix
Patient
Lactobacillus, acidophilus, n/a,
n/a, 2*10^7 cfu/capsule
1 capsule
3 per day
Oral
Sahagun-flores,
2007
RCT
1
n/a
Patient
Lactobacillus, casei, Shirota, n/a,
8*10^9 cfu/dose
1 dose
3 per day
Oral
Saint-Marc,
1995
RCT
1
n/a
Patient
Saccharomyces, boulardii, n/a,
n/a, 500mg/sachet
1 sachet
2 per day
n/a
Oral
Enteral
Salminen, 1988
RCT
1
n/a
Yogurt
Patient
Lactobacillus, acidophilus, NCDO
1748, Live, 2*10^9 cfu
150 ml
1 per day
Oral
Salminen, 2004
C-RCT
1
Valio
Drink
Patient
Lactobacillus, rhamnosus, GG,
n/a, 1-5*10^10 cfu/dose
C-57
Duration Control
LongCategory
Term
Use
Oral
n/a
0.5
months
Short
term
0.25
months
Short
term
0.25
months
Short
term
Medium
term
Oral
2 per day
n/a
Placebo
Medium
term
0.5
months
Short
term
Placebo
Antibiotics
only
Placebo
Dietary
counseling
only
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 dose
Oral
2 per day
Duration Control
LongCategory
Term
Use
Samanta, 2008
RCT
1
Satokari, 2001
RCT
1
n/a
Bifidobacterium, lactis, BB-12,
Powder added to Lyophilized, 3*10^10 cfu
yogurt
Patient
125 ml
2 per day
Oral
0.5
months
Short
term
Prebiotic
Satokari, 2001
RCT
3
n/a
Bifidobacterium, lactis, BB-12,
Combo of syrup Lyophilized, 3*10^10 cfu
+
powder
in
yogurt
Patient
125 ml 2
per day
Oral
Savino, 2006
RCT
1
n/a
Oil suspension
Patient
5 drops
1 per day
Oral
1 month
Short
term
Non-probiotic
Sazawal, 2010
RCT
1
n/a
Bifidobacterium, lactis, HN019,
Sachets of milk n/a, 3.3*10^6 cfu/sachet
powder
Patient
1 Sachet
3 per Day
Oral
12
months
Long
term
Placebo
Scalabrin, 2009
RCT
1
LGG
Formula
Patient
Lactobacillus, rhamnosus, GG,
n/a, 10^8 cfu/g
n/a
Formulal
Patient
Lactobacillus, rhamnosus, GG,
Lyophilized, 10^8 cfu/g formula
Pediasure
Protect
with
SmartChoice
Nutritional
supplementpowder mixed to
milk drink
Patient
Lactobacillus, acidophilus, n/a,
n/a, 10^9 cfu/g
Bifidobacterium, n/a, n/a, n/a,
10^9 cfu/g
120 ml
n/a
Mix
Breast milk
Patient
Bifidobacterium, infantis, n/a, n/a,
2.5*10^9 cfu/dose
Bifidobacterium, bifidum, n/a, n/a,
2.5*10^9 cfu/dose
Bifidobacterium, longum, n/a, n/a,
2.5*10^9 cfu/dose
Lactobacillus, acidophilus, n/a,
n/a, 2.5*10^9 cfu/dose
Lactobacillus, reuteri, ATCC
55730, n/a, 10^8 cfu/5 drops
Oral
Formula only
Medium
term
n/a
Scalabrin, 2009
RCT
3
Schrezenmeir,
2004
RCT
1
Schultz, 2004
RCT
1
LGG
Patient
Lactobacillus, rhamnosus, GG,
n/a, 2*10^9 cfu
2*10^9 cfu
1 per day
n/a
Seppo, 2003
RCT
1
Evolus
Drink
Patient
Lactobacillus, helveticus, LBK
16H, n/a, n/a
150 ml
1 per day
Oral
Sierra, 2010
RCT
1
n/a
Pill
Patient
Lactobacillus, salivarius,
CECT5713, n/a, 10^8 cfu/capsule
2 capsule
1 per day
Oral
C-58
Placebo
Medium
term
Oral
n/a
Oral
Medium
term
6
months
Medium
term
5.25
months
Medium
term
1 month
Short
term
Pediasure
only
Placebo
Milk only
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Lactobacillus, fermentum, n/a, n/a, 2 capsule
Oral
2*10^9 cfu
2 per day
Duration Control
LongCategory
Term
Use
Simons, 2006
RCT
1
PCC
Pill
Patient
Placebo
Simren, 2010
RCT
1
Cultura
Drink
Patient
200 ml
Lactobacillus, paracasei
2 per day
paracasei, F-19, n/a, >5*10^7
cfu/ml
Lactobacillus, acidophilus, La 5,
n/a, >5*10^7 cfu/ml
Bifidobacterium, lactis, BB-12, n/a,
>5*10^7 cfu/ml
Lactobacillus, bulgaricus, n/a, n/a,
n/a
Streptococcus, thermophilus, n/a,
n/a, n/a
Oral
2.5
months
Medium
term
2
months
Medium
term
Song, 2010
RCT
1
Bioflor250
Pill
Patient
Saccharomyces, boulardii, n/a,
n/a, 3*10^10 cfu/g
1 capsule
3 per day
Oral
1 month
Short
term
Triple therapy
only
Song, 2010
RCT
3
Bioflor 250
Pill
Patient
Saccharomyces, boulardii,
DA9601, n/a, 3*10^10 cfu/g
1 capsule 3 Oral
per day
Songisepp,
2005
RCT
1
n/a
Pill
Patient
Lactobacillus, fermentum, EE-3,
lyophilized, 9.2 log cfu
3 capsules
2 per day
Placebo
Songisepp,
2005
CCT
1
n/a
Drink
Patient
Lactobacillus, plantarum, LB-4,
150 ml
n/a, n/a
1 per day
Lactobacillus, buchneri, S-15, n/a,
n/a
Lactobacillus, fermentum, ME-3,
Lyophilized, 11.2-11.8 cfu
Oral
0.75
months
Short
term
0.75
months
Short
term
Sood, 2009
RCT
1
VSL#3
Sachet
Patient
Lactobacillus, paracasei, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Lactobacillus, plantarum, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Lactobacillus, acidophilus, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Lactobacillus, delbrueckii,
bulgaricus, Lyophilized, viable,
9*10^11 cfu/sachet
Bifidobacterium, longum, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Bifidobacterium, breve, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Bifidobacterium, infantis, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Streptococcus, thermophilus, n/a,
Lyophilized, viable, 9*10^11
cfu/sachet
Oral
3
months
Medium
term
Placebo
C-59
1 Sachet
4 per Day
Oral
Placebo
Goat's
only
milk
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Spanhaak, 1998 1
RCT
Yakult
Drink
Patient
Lactobacillus, casei, Shirota, n/a,
10^9 cfu/ml
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
100 ml
Oral
3 per day
Stockert, 2007
RCT
1
Symbioflor
Drops
Patient
Enterococcus, faecalis, n/a, n/a,
6*10^7 cfu
20 drops
3 per day
n/a
Stotzer, 1996
C-RCT
1
n/a
Pill
Patient
Lactobacillus, fermentum, KLO,
Lyophilized, 1-3*10^11
cfu/capsule
1 capsule
2 per day
Oral
Stratiki, 2007
RCT
1
PreN
Formula
Patient
Bifidobacterium, lactis, n/a, n/a,
2*10^7 cfu/g
1 month
Short
term
Placebo
2
months
Medium
term
1 month
Short
term
Placebo
Lactobacillus, acidophilus, NCFB
1748, n/a, 10^8 cfu/ml
Bifidobacterium, lactis, BB-12, n/a,
10^8 cfu/ml
Lactobacillus, paracasei
paracasei, F19, n/a, 10^8 cfu/ml
Lactobacillus, casei, DN-114 001, 100 ml
Live, 10^10 cfu/100ml
1 per day
Oral
0.5
months
Short
term
Placebo
Oral
0.5
months
Short
term
2
months
Medium
term
6
months
Medium
term
Placebo
Oral
Varies
over time
250 ml
2 per day
Placebo
Placebo
Medium
term
Sullivan, 2003
RCT
1
n/a
Yogurt
Patient
Sykora, 2005
RCT
1
Actimel
Drink
Patient
Tamura, 2007
RCT
1
n/a
Fermented milk
Patient
Lactobacillus, casei, Shirota, n/a,
4*10^10 cfu/80ml
80 ml
1 per day
Oral
Taylor, 2007
RCT
1
n/a
Powder
Patient
Lactobacillus, acidophilus, LAVRI 1 packet
A1, Lyophilized, 3*10^9 cfu/packet 1 per day
Oral
Tempe, 1985
RCT
1
Perenterol
Saccharomyces, cerevisiae,
Dissolved
in Hansen CBS5926, Active, 5*10^9
enteral nutrition cfu/capsule
solution
Patient
2 capsules
l per day
Enteral
Teran, 2008
RCT
1
n/a
Patient
Lactobacillus, acidophilus, n/a,
n/a, 1.25*10^6 cfu
Lactobacillus, rhamnosus, n/a,
n/a, n/a
Bifidobacterium, longum, n/a, n/a,
n/a
Saccharomyces, boulardii, n/a,
n/a, n/a
1g
2 per day
n/a
Thomas, 2001
RCT
1
n/a
Pill
Patient
Lactobacillus, rhamnosus, GG,
Live, 10^10 cfu
1 capsule
2 per day
Oral
C-60
Duration Control
LongCategory
Term
Use
Placebo
Placebo
Placebo
Short
term
Short
term
0.5
months
Short
term
Rehydration
solution only
Placebo
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Tomoda, 1991
CCT
1
Tomoda, 1991
CCT
3
n/a
Yogurt
Patient
Tsuchiya, 2004
CCT
1
SCM III
In a vitamin and
phyto-extracts
enriched medium
Patient
Tsuchiya, 2004
CCT
2
Turchet, 2003
RCT
1
Tursi, 2004
RCT
n/a
Yogurt
Patient
Bifidobacterium, longum, n/a, n/a,
10^8 cfu
Streptococcus, salivarius
thermophilus, n/a, n/a, n/a
Lactobacillus, delbrueckii
bulgaricus, n/a, n/a, n/a
Bifidobacterium, longum, n/a, n/a,
10^8 cfu/g
Saccharomyces, salivarius
thermophilus, n/a, n/a, n/a
Lactobacillus, delbrueckii
bulgaricus, n/a, n/a, n/a
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
130 g
Oral
1 per day
10 ml
3 per day
100 ml
2 per day
1
VSL#3
Bag
Patient
3g
1 per day
Tursi, 2008
CCT
1
Enterolactis
Pill
Patient
Tursi, 2008
CCT
3
Enterolactis
Patient
Lactobacillus, casei casei, DG,
n/a, 1.6*10^7 cfu/day
C-61
Yogurt only
Medium
term
130 g 1 per Oral
day
Lactobacillus, acidophilus, n/a,
n/a, 1.25*10^6 cfu/100ml
Lactobacillus, helveticus, n/a, n/a,
1.3*10^9 cfu/100ml
Bifidobacterium, n/a, n/a, n/a,
4.95*10^9 cfu/100ml
SCM III heat Lactobacillus, acidophilus, n/a,
inactivated
Heat-killed, 1.25*10^6 /100ml
symbiotic
Lactobacillus, helveticus, n/a,
Patient
Heat-killed, 1.3*10^6 /100ml
Bifidobacterium, n/a, n/a, Heatkilled, 4.95*10^9 /100ml
Actimel
Lactobacillus, casei, DN-114 001,
Drink
n/a, 10^8 cfu/ml
Patient
Lactobacillus, casei, n/a,
Lyophilized, 3*10^8 cfu/g
Lactobacillus, plantarum, n/a,
Lyophilized, 3*10^8 cfu/g
Lactobacillus, acidophilus, n/a,
Lyophilized, 3*10^8 cfu/g
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
3*10^8 cfu/g
Bifidobacterium, longum, n/a,
Lyophilized, 3*10^8 cfu/g
Bifidobacterium, infantis, n/a,
Lyophilized, 3*10^8 cfu/g
Bifidobacterium, breve, n/a,
Lyophilized, 3*10^8 cfu/g
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
3*10^8 cfu/g
Lactobacillus, casei casei, DG,
n/a, 8*10^6 cfu
Duration Control
LongCategory
Term
Use
n/a
3
months
Medium
term
Synbiotic
Oral
1 month
Short
term
No
study
product
Oral
2
months
Medium
term
Balsalazide
only
1.6*10^7
n/a
daily
10 per
day/month
1.6*10^7
n/a
daily 10 per
days/month
24
months
Long
term
Mesalazine
only
10 ml 3 per n/a
day
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Tursi, 2010
RCT
1
VSL#3
Sachet
Patient
Underwood,
2009
RCT
1
Culturelle
Pill
Patient
Underwood,
2009
RCT
3
Urban, 2008
RCT
1
Lactobacillus, paracasei, n/a,
Lyophilized, viable, 900*10^9
cfu/sachet
Lactobacillus, plantarum, n/a,
Lyophilized, viable, 900*10^9
cfu/sachet
Lactobacillus, acidophilus, n/a,
Lyophilized, viable, 900*10^9
cfu/sachet
Lactobacillus, delbrueckii,
bulgaricus, Lyophilized, viable,
900*10^9 cfu/sachet
Bifidobacterium, longum, n/a,
Lyophilized, viable, 900*10^9
cfu/sachet
Bifidobacterium, infantis, n/a,
Lyophilized, viable, 900*10^9
cfu/sachet
Bifidobacterium, breve, n/a,
Lyophilized, viable, 900*10^9
cfu/sachet
Streptococcus, thermophilus, n/a,
Lyophilized, viable, 900*10^9
cfu/sachet
Lactobacillus, rhamnosus, GG,
Viable, 5*10^8 cfu/dose
Lactobacillus, casei, n/a, n/a, n/a
ProBioPlus DDS Lactobacillus, acidophilus, n/a,
Mix
Viable, 5*10^8 cfu/dose
Patient
Bifidobacterium, longum, n/a,
Viable, 5*10^8 cfu/dose
Bifidobacterium, bifidum, n/a,
Viable, 5*10^8 cfu/dose
Bifidobacterium, infantis, n/a,
Viable, 5*10^8 cfu/dose
n/a
Bifidobacterium, lactis, n/a, n/a,
Formula
n/a
Patient
Urbansek, 2001
RCT
1
Antibiophilus
Sachet
Patient
Lactobacillus, rhamnosus, n/a,
n/a, 1.5*10^9 cfu
Van der Aa,
2010
RCT
1
n/a
Formula
Patient
Bifidobacterium, breve, M-16V,
n/a, 1.3*10^9 cfu/100ml
Van Gossum,
2007
RCT
1
LA1
Powder/Sachets
Patient
Lactobacillus, johnsonii, LA-1,
Lyophilized, 10^10 cfu/sachet
Velaphi, 2008
RCT
1
n/a
Formula
Patient
Bifidobacterium, Lactis, CNCM I
3446, n/a, n/a
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
2 sachet
Oral
2 per day
1 ml
2 per day
Varies
1 ml 2 per
day
Varies
Oral
Oral
Varies by
participant
Enteral
n/a
Oral
Varies by
participant
C-62
2
months
Medium
term
Placebo
Placebo
Short
term
Oral
Varies by
participant
1.5 g
3 per day
Duration Control
LongCategory
Term
Use
4
months
Medium
term
0.25
months
Short
term
3
months
Medium
term
Formula only
3
months
Medium
term
6
months
Medium
term
Maltodextrin
only
Placebo
Placebo
Formula only
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Vendt, 2006
RCT
1
Tutteli
Formula
Patient
Lactobacillus, rhamnosus, GG,
n/a, 10^7 cfu
Lactobacillus, acidophilus, n/a,
Lyophilized, 10^6 cfu/daily dose
Lactobacillus, casei, n/a,
Lyophilized, 10^6 cfu/daily dose
Lactobacillus, salivarius, n/a,
Lyophilized, 10^6 cfu/daily dose
Lactobacillus, lactis, n/a,
Lyophilized, 10^6 cfu/daily dose
Bifidobacterium, bifidum, n/a,
Lyophilized, 10^6 cfu/daily dose
Bifidobacterium, lactis, n/a,
Lyophilized, 10^6 cfu/daily dose
Bifidobacterium, animalis lactis,
BB-12 ATCC 27536, n/a, 1*10^7
cfu/g
Lactobacillus, paracasei
paracasei/g, CRL-431 (ATCC 55
544), n/a, 1*10^7 cfu/g
1 sachet
2 per day
Bifidobacterium, breve, BBG-01,
Lyophilized, live, 10^9 cfu/sachet
1 sachet
3 per day
Vleggaar, 2008
C-RCT
1
Ecologic 641
Sachet
Patient
Vlieger, 2009
RCT
1
Frisol
Formula
Patient
Wada, 2010
RCT
1
Wang, 2004
RCT
1
Wang, 2007
RCT
1
Weizman, 2005
RCT
1
Weizman, 2006
RCT
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
n/a
Sachet
Patient
n/a
Drink
Patient
n/a
Suspended
water
Patient
n/a
Formula
Patient
Bifidobacterium, lactis, BB-12, n/a,
10^7 cfu/g
n/a
Formula
Patient
Bifidobacterium, lactis, BB-12, n/a,
1*10^7 cfu/g
Oral
3
months
Medium
term
Oral
Varies by
participant
Prebiotic
Enteral
Oral
Varies by
participant
0.5 ml
2 per day
Placebo
Medium
term
Placebo
Medium
term
1 month
Short
term
Enteral
Medium
term
Oral
n/a
Oral
Varies by
participant
Weston, 2005
RCT
1
n/a
Sachet
Patient
Lactobacillus, fermentum, VRI
003 PCC, Lyophilized, 1*10^6 cfu
1*10^9 cfu
2 per day
n/a
Oral
Wewalka, 2002
RCT
1
Döderlein Med®
Pill
Patient
Lactobacillus, gasseri, n/a,
Lyophilized, 2*10^8-2*10^9
cfu/capsule
1 capsule
1 per day
Vaginal
C-63
Placebo
Medium
term
Varies by
participant
Streptococcus, thermophilus, n/a,
n/a, n/a
Lactobacillus, bulgaricus, n/a, n/a,
n/a
Lactobacillus, paracasei, LP-33,
Viable, 1*10^7 cfu/ml
Bifidobacterium, breve, M-16v,
in n/a, 1.6*10^8 cfu/0.5ml
Duration Control
LongCategory
Term
Use
Fermented
milk only
No
supplement
3
months
Medium
term
1 month
Medium
term
Placebo
2
months
Medium
term
0.2
months
Short
term
Placebo
Placebo
Non-probiotic
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
8 oz
Oral
2 per day
Duration Control
LongCategory
Term
Use
Wheeler, 1997
C-RCT
1
n/a
Yogurt
Patient
Lactobacillus, bulgaricus, n/a,
Live, 3.4*10^8 cfu/g
Streptococcus, thermophilus, n/a,
Live, 3.4*10^8 cfu/g
Lactobacillus, acidophilus, n/a,
Live, 3.4*10^8 cfu/g
1 month
Short
term
Yogurt only
Wildt, 2006
RCT
1
AB-Cap-10
Pill
Patient
Lactobacillus, acidophilus, LA-5,
n/a, 0.5*10^10 cfu
Bifidobacterium, animalis lactis,
BB-12, n/a, 0.5*10^10 cfu
2 capsules
2 per day
Oral
3
months
Medium
term
Placebo
Williams, 2008
RCT
1
LAB4
Pill
Patient
Lactobacillus, acidophilus, CUL 60 1 capsule
NCIMB 30152, n/a, 2.5*10^10
1 per day
cfu/capsule
Lactobacillus, acidophilus, CUL 21
NCIMB 30156, n/a, .5*10^10
cfu/capsule
Bifidobacterium, lactis, CUL 34
NCIMB 30172, n/a, .5*10^10
cfu/capsule
Bifidobacterium, bifidum, CUL 20
NCIMB 30153, n/a, .5*10^10
cfu/capsule
Oral
2
months
Medium
term
Placebo
Wind, 2010
RCT
1
n/a
Sachet
Patient
Lactobacillus, rhamnosus, PRSF
L477, Lyophilized, 5*10^10
cfu/sachet
2 sachet
1 per day
Oral
Placebo
1
n/a
Pill
Patient
Lactobacillus, reuteri,
MM53ATTCC SD 2112,
Lyophilized, 5*10^10 cfu/capsule
1 capsule
2 per day
Oral
Wolf, 1998
RCT
1
n/a
Packets to
added
beverages
Patient
1 packet
2 per day
Oral
0.75
months
Short
term
0.75
months
Short
term
0.75
months
Short
term
Wolf, 1994
RCT
Worthley, 2009
C-RCT
1
n/a
Pill
Patient
Bifidobacterium, lactis, LAFTI
B94, n/a, 5*10^9 cfu/capsule
1 capsule
1 per day
Oral
1 month
Short
term
Prebiotic
Worthley, 2009
C-RCT
3
n/a
Pill
Patient
Bifidobacterium, lactis, LAFTI
B94, n/a, 10^9 cfu/g
1 capsule 1 Oral
per day
Xia, 2010
RCT
1
n/a
Sachet
Patient
Lactobacillus, acidophilus, LA-11,
Live, 6-10 *10^8 cfu
1 Sachet
1 per day
Oral
Xiang, 2006
RCT
1
Medilac-S
Varies
Patient
Bacillus, subtilis, n/a, n/a, n/a
Enterococcus, faecium, n/a, n/a,
n/a
2 capsule
3 per day
Oral
Lactobacillus, reuteri, SD 2112,
be Lyophilized, 5*10^9 cfu/packet
to
C-64
Placebo
Placebo
Placebo
Short
term
1 month
Short
term
Sulfasalazine
only
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Bifidobacterium, longum, BL1, n/a, 100 ml
Oral
3.7*+-1.1*10^8 cfu
3 per day
Streptococcus, thermophilus, n/a,
n/a, 3.4+-0.7*10^8 cfu
Lactobacillus, delbrueckii
bulgaricus, n/a, n/a, 3.7+-1.7*10^7
cfu
Duration Control
LongCategory
Term
Use
Xiao, 2003
RCT
1
n/a
Yogurt
Patient
1 month
Short
term
Yogurt only
Xiao, 2003
RCT
1
Lacidophilin
Lactobacillus, acidophilus, LB,
Pill
Live, n/a
Chewable tablets
Patient
1 month
Short
term
Other probiotic
Xiao, 2003
RCT
2
Lacteol
Pill
Patient
Lactobacillus, acidophilus, n/a,
2 capsules
Heat killed, lyophilized, 5*10^9 cfu 2 per day
Oral
Yang, 2008
RCT
1
B10
Drink
Patient
Bifidobacterium, lactis, DN
100 g
173010, n/a, 1.25*10^10 cfu/pot
1 per day
Streptococcus, thermophilus, n/a,
n/a, 1.2*10^9 cfu/pot
Lactobacillus, bulgaricus, n/a, n/a,
1.2*10^9 cfu/pot
Oral
0.5
months
Short
term
Placebo
Yao-Zong, 2004 1
RCT
Bifico
Pill
Patient
Lactobacillus, bifidum, n/a, Live,
>=10^7 cfu
Lactobacillus, acidophilus, n/a,
Living, >=10^7 cfu
Enterococcus, n/a, n/a, Live,
>=10^7 cfu
420 mg
2 per day
n/a
1 month
Short
term
Dioctahedral
smectite
Yonekura
RCT
1
n/a
Powder
Patient
Lactobacillus, paracasei,
KW3110, n/a, 1*10^12 - 3*10^12
cfu/gm
1g
1 per day
Oral
3
months
Medium
term
Placebo
Zhang, 2010
RCT
1
Bifico
Pill
Patient
Bifidobacterium, n/a, n/a, Viable,
n/a
3 capsule
3 per day
Oral
Ziegler, 2003
RCT
1
n/a
Formula
Patient
Bifidobacterium, lactis, n/a, n/a,
3.6*10^7 cfu/g
5 tablets
3 per day
Oral
Oral
n/a
Zocco, 2003
RCT
1
Giflorex
Patient
Lactobacillus, rhamnosus, n/a,
Viable, 18*10^9 cfu/day
18*10^9
bacteria
1 per day
n/a
Zocco, 2003
RCT
3
Giflorex
Patient
Lactobacillus, rhamnosus, GG,
Viable, 18*10^9 cfu/day
18*10^9
bacteria 1
per day
n/a
C-65
Non-probiotic
Medium
term
4
months
Medium
term
12
months
Long
term
Formula only
Mesalazine
only
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
An, 2010
Case Series
1
n/a
Patient
Lactobacillus, acidophilus, LH
CBT, n/a, 3*10^11 cfu/g
Bifidobacterium, longum, SPM
1205, n/a, 3*10^11 cfu/g
Pediococcus, pentosaceus, PP
CBT, n/a, 3*10^11 cfu/g
Barrett, 2008
Case Series
1
Yakult
Drink
Patient
Lactobacillus, casei, Shirota, n/a,
6.5*10^6 cfu/65ml bottle
Beck, 1961
Case Series
1
Bacid
Pill
Patient
Lactobacillus, acidophilus, n/a,
Dried, viable, n/a
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
2 per day
n/a
Duration Control
LongCategory
Term
Use
0.5
months
Short
term
None
65 ml
1 per day
1.5
months
Medium
term
None
Oral
n/a
None
Medium
term
Varies by
participant
Bekkali, 2007
Case Series
1
Ecologic Relief
Patient
Bifidobacterium, bifidum, n/a, n/a,
4*10^9 cfu
Bifidobacterium, infantis, n/a, n/a,
4*10^9 cfu
Bifidobacterium, longum, n/a, n/a,
4*10^9 cfu
Lactobacillus, casei, n/a, n/a,
4*10^9 cfu
Lactobacillus, plantarum, n/a, n/a,
4*10^9 cfu
Lactobacillus, rhamnosus, n/a,
n/a, 4*10^9 cfu
4*10^9 cfu
1 per day
Bellomo, 1979
Case Series
1
Bioflorin
Mix
Powder
Patient
Enterococcus, faecium, SF-68,
Lyophilized, 3*10^7 cfu/g
1-3 doses
Oral
2-3 per day
Benchimol, 2004 1
Case Series
Probi
Patient
Lactobacillus, plantarum, 299v,
10^10 cfu
n/a, 10^10 cfu
1 per day
Lactobacillus, acidophilus, R0052,
Lyophilized, 10^10 cfu
Lactobacillus, rhamnosus, R0011,
Lyophilized, 10^10 cfu
Bifidobacterium, breve, R0070,
Lyophilized, 10^10 cfu
n/a
7
months
Medium
term
None
Berman, 2006
Case Series
n/a
Tablet
Patient
Lactobacillus, rhamnosus, n/a,
3 tablets
n/a, 2*10^9 cfu
1 per day
Lactobacillus, plantarum, n/a, n/a,
2*10^9 cfu
Lactobacillus, salivarius, n/a, n/a,
2*10^9 cfu
Bifidobacterium, bifidum, n/a, n/a,
2*10^9 cfu
Oral
2
months
Medium
term
None
1
C-66
n/a
1 month
Short
term
None
Placebo
Short
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Bibiloni, 2005
Case Series
1
VSL#3
Sachet
Patient
Bruce, 1988
Case Series
1
n/a
Lactobacillus, casei rhamnosus,
Topical solution 6R-1, Active, viable, 10^11 cfu/ml
(intravaginal)
Patient
Bruni, 2008
Case Series
1
Carlsson, 2009
Case Series
Cobo Sanz,
2006
Case Series
Lactobacillus, casei, n/a,
Lyophilized, 9*10^11 cfu/sachet
Lactobacillus, acidophilus, n/a,
Lyophilized, 9*10^11 cfu/sachet
Lactobacillus, bulgaricus, n/a,
Lyophilized, 9*10^11 cfu/sachet
Lactobacillus, plantarum, n/a,
Lyophilized, 9*10^11 cfu/sachet
Bifidobacterium, longum, n/a,
Lyophilized, 9*10^11 cfu/sachet
Bifidobacterium, infantis, n/a,
Lyophilized, 9*10^11 cfu/sachet
Bifidobacterium, breve, n/a,
Lyophilized, 9*10^11 cfu/sachet
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
9*10^11 cfu/sachet
Fiorilac, Dicoflor,
Reuterin
Sachet, diluted in
water
Patient
Lactobacillus, paracasei, I 1688,
n/a, 0.1*10^9-10*10^9 cfu
Lactobacillus, salivarius, I 1794,
n/a, 0.1*10^9-10*10^9 cfu
Lactobacillus, rhamnosus, GG,
n/a, 3*10^9 cfu
Lactobacillus, reuteri, n/a, n/a,
10^8 cfu/5 drops
1
Verum
Drickyoghurt
Yogurt
Patient
Lactobacillus, rhamnosus, LB-21,
n/a, n/a
Lactococcus, lactis, L1A, n/a,
>5*10^7 cfu/ml
1
Actimel
Drink
Patient
Colecchia, 2006 1
Case Series
Di Pierro, 2009
Case Series
Dughera, 2007
Case Series
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
2 sachets
Oral
2 per day
1 ml
2 per week
Duration Control
LongCategory
Term
Use
2
months
Medium
term
Vaginal
None
None
Medium
term
Other
0.03
months
Short
term
None
Oral
6
months
Medium
term
None
Lactobacillus, casei, BN-114 001,
1 per day
n/a, n/a
Lactobacillus, bulgaricus, n/a, n/a, Varies by
participant
n/a
Streptococcus, thermophilus, n/a,
n/a, n/a
Oral
2
months
Medium
term
None
Zir fos
Bag
Patient
Bifidobacterium, longum, W11,
n/a, n/a
3g
1 per day
n/a
None
1
Kramegin
Vaginal tablet
Patient
Lactobacillus, acidophilus, n/a,
n/a, 10^9 cfu/tablet
1 tablet
1 per day
Vaginal
1
Zir fos
Bag
Patient
Bifidobacterium, longum, W11,
n/a, 5*10^9 cfu/3g bag
3g
1 per day
Oral
1.25
months
Medium
term
0.33
months
Short
term
3
months
Medium
term
C-67
1 per day
n/a
200 ml
1 per day
None
None
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Elmer, 1995
Case Series
1
n/a
Pill
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
Fukuda, 2008
Case Series
1
n/a
Yogurt
Patient
Bifidobacterium, lactis, DN
17B010, n/a, 10^8 cfu
Varies
over time
85 g
1 per day
Gabrielli, 2009
Case Series
1
Enterogermina
Vial
Patient
Bacillus, clausii, n/a, n/a, 2*10^9
spores/vial
1 vial
3 per day
Garrido, 2005
Case Series
1
Chamyto
Liquid
Patient
Lactobacillus, johnsonii, LA-1, n/a,
1*10^8 cfu/ml
Lactobacillus (nonprobiotic strain),
helveticus, n/a, n/a, 2*10^7 cfu/ml
Bacillus, stearothermophilus
spores, n/a, n/a, 7*10^7 cfu/ml
Lactobacillus, casei, n/a,
Lyophilized, viable, 9*10^11
cfu/packet
Lactobacillus, plantarum, n/a,
Lyophilized, viable, 9*10^11
cfu/packet
Lactobacillus, acidophilus, n/a,
Lyophilized, viable, 9*10^11
cfu/packet
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
viable, 9*10^11 cfu/packet
Bifidobacterium, longum, n/a,
Lyophilized, viable, 9*10^11
cfu/packet
Bifidobacterium, breve, n/a,
Lyophilized, viable, 9*10^11
cfu/packet
Bifidobacterium, infantis, n/a,
Lyophilized, viable, 9*10^11
cfu/packet
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
viable, 9*10^11 cfu/packet
Lactobacillus, reuteri, ATCC
55730, n/a, 4*10^8 cfu/tablet
None
Oral
0.75
months
Short
term
None
Oral
2 packets
2 per day
n/a
1 month
Short
term
None
2 tablets
2 per day
Oral
6
months
Medium
term
None
9-12
capsules
per day
Varies by
participant
Oral
n/a
Varies
over time
VSL#3
Packet
Patient
Glintborg, 2006
Case Series
1
n/a
Pill
Patient
Gniwotta, 1977
Case Series
1
Perenterol
Pill
Patient
Saccharomyces, cerevisiae, n/a,
n/a, 50 mg/capsule
Chamyto
Drink
Patient
Lactobacillus, johnsonii, LA-1, n/a, 80 ml
>10^7 cfu/ml
8 per day
C-68
None
Medium
term
0.5
months
Short
term
1 month
Short
term
Gionchetti, 2007 1
Case Series
Gotteland, 2003 1
Case Series
Duration Control
LongCategory
Term
Use
None
None
Short
term
Oral
0.5
months
Short
term
None
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Gruenwald,
2002
Case Series
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1g
Oral
1 per day
Duration Control
LongCategory
Term
Use
Advanced
Formula
Multibionta
Pill
Patient
Lactobacillus, acidophilus, n/a,
n/a, 10^6 cfu/1g capsule
Bifidobacterium, bifidum, n/a, n/a,
10^6 cfu/1g capsule
Bifidobacterium, longum, n/a, n/a,
10^6 cfu/1g capsule
Hensgens, 1976 1
Case Series
n/a
Drink
Patient
Lactobacillus, acidophilus, n/a,
Viable, 10^8-10^11 cfu/ml
Lactobacillus, plantarum, n/a,
Viable, 10^8-10^11 cfu/ml
500 ml
1 per day
Oral
Huynh, 2009
Case Series
1
VSL#3
Sachet
Patient
Lactobacillus, casei, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, plantarum, n/a,
Lyophilized, 4.5*10^11 cfu/sachet
Lactobacillus, acidophilus, n/a,
Lyophilized, 4.5*10^11 cfu/sachet
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
4.5*10^11 cfu/sachet
Bifidobacterium, longum, n/a,
Lyophilized, 4.5*10^11 cfu/sachet
Bifidobacterium, breve, n/a,
Lyophilized, 4.5*10^11 cfu/sachet
Bifidobacterium, infantis, n/a,
Lyophilized, 4.5*10^11 cfu/sachet
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
4.5*10^11 cfu/sachet
0.5-2.5
sachets
2 per day
Varies by
participant
Oral
2
months
Medium
term
None
Karimi, 2005
Case Series
1
VSL#3
Sachet
Patient
Lactobacillus, acidophilus, n/a,
Lyophilized, 4*10^11 cfu
Lactobacillus, plantarum, n/a,
Lyophilized, 4*10^11 cfu
Lactobacillus, casei, n/a,
Lyophilized, 4*10^11 cfu
Lactobacillus, bulgaricus, n/a,
Lyophilized, 4*10^11 cfu
Bifidobacterium, longum, n/a,
Lyophilized, 4*10^11 cfu
Bifidobacterium, breve, n/a,
Lyophilized, 4*10^11 cfu
Bifidobacterium, infantis, n/a,
Lyophilized, 4*10^11 cfu
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
4*10^11 cfu
2 sachets
2 per day
n/a
3
months
Medium
term
None
Kawamura,1981 1
Case Series
n/a
Patient
Lactobacillus, casei, n/a, n/a, n/a
1g
3 per day
Oral
Kirchhelle, 1996 1
Case Series
n/a
Pill
Patient
Saccharomyces, boulardii, n/a,
n/a, 50 mg/capsule
1-3
capsules
3x per day
Varies by
participant
n/a
C-69
6
months
Medium
term
None
None
Short
term
None
Medium
term
Pre-test
Short
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Kitajima, 1997
Case Series
1
Yakult
Powder
Patient
Bifidobacterium, breve, YIT 4010,
n/a, 10^9 cfu/g
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
n/a
Duration Control
LongCategory
Term
Use
None
Short
term
Varies by
participant
Lamiki, 2010
Case Series
1
SCM-III
Microflorana-F
Patient
Lactobacillus, acidophilus, 145,
n/a, 1.25*10^6 cfu/100ml
Bifidobacterium, n/a, 420, n/a,
4.95*10^9 cfu/100ml
Lactobacillus, helveticus, ATC
15009, n/a, 1.3*10^9 cfu/100ml
10 ml
3 per day
Oral
6
months
Medium
term
None
Lee, 2010
Case Series
1
BLIS BioRestor
Powder
Patient
Lactobacillus, acidophilus, L10,
Viable, 4*10^8 cfu/g
Bifidobacterium, lactis, B94,
Viable, 4*10^8 cfu/g
Streptococcus, salivarius, K12,
Viable, 1*10^8 cfu/g
1g
2 per day
Oral
0.25
months
Short
term
Pre-test
0.5
months
Short
term
None
Lombardo, 2009 1
Case Series
Genefilus F19
Lactobacillus, paracasei
Sachet dissolved paracasei, F19, n/a, 12*10^9
in water
cfu/sachet
Patient
1 sachet
2 per day
Oral
Luoto, 2010
Case Series
1
n/a
Patient
Lactobacillus, rhamnosus, GG
ATCC 53103, n/a, 6*10^9
cfu/dose
6*10^9 cfu
1 per day
Enteral
Malin, 1996
Case Series
1
n/a
Powder
Patient
Lactobacillus, rhamnosus, GG
ATCC 53103, Lyophilized, 10^10
cfu
10^10 cfu
2 per day
Oral
Malkov, 2006
Case Series
1
n/a
Patient
Bacillus, oligonitrophilus, KU-1,
Active, stationary phase, 0.5
1*10^9 cells/ml
Mego, 2005
Case Series
1
Varies by
participant
n/a
Pill
Patient
Enterococcus, faecium, M-74,
Lyophilized, 6*10^9 cfu/capsule
6 capsules
3 per day
Lactobacillus, acidophilus, LA-1,
n/a, supernatant
50 ml
n/a
supernatant
Michetti, 1999
Case Series
1
n/a
Whey based
Patient
Muting, 1968
Case Series
1
n/a
Bifidobacterium, bifidum, n/a, n/a,
Milk powder in n/a
warm
water
solution
with
meals
Patient
C-70
Oral
Varies by
participant
None
1.5
months
Medium
term
Oral
None
None
Medium
term
0.5
months
Short
term
Oral
Varies by
participant
Pre-test
Medium
term
Enterococcus, faecium, M-74,
Lyophilized, 6*10^9-18*10^9
cfu/capsule
1
0.33
months
Short
term
Oral
n/a
Pill
Patient
Mego, 2006
Case Series
None
Medium
term
None
None
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Nobuta, 2009
Case Series
1
n/a
Beverage
Patient
Lactobacillus, brevis, KB290, n/a,
1*10^10 cfu/130 ml
Reid, 2001
Case Series
1
n/a
Probiotic
suspension-in
milk
Patient
Lactobacillus, rhamnosus, GR-1,
Viable, >10*9 cfu/3ml
Lactobacillus, fermentum, RC-14,
Viable, >10*9 cfu/3ml
3 ml
2 per day
Enteral
Rosenfeldt,
2003
Case Series
1
n/a
Powder
Patient
10^10 cfu
2 per day
Oral
Sakamoto, 2001 1
Case Series
n/a
Yogurt
Patient
Lactobacillus, rhamnosus, 19070
2, Lyophilized, 10^10 cfu
Lactobacillus, reuteri, DSM 12246,
Lyophilized, 10^10 cfu
Lactobacillus, gasseri, OLL 2716
(LG21), n/a, 1-1.4 *10^7 cfu/g
90 g
2 per day
Oral
Schneider, 2005 1
Case Series
n/a
Powder
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, n/a
500 mg
2 per day
Oral
Enteral
Shen, 2005
Case Series
1
VSL#3 Yovis
Patient
6g
1 per day
Oral
Srinivasan, 2006 1
Case Series
Yanult-yakult
Drink
Patient
Lactobacillus, acidophilus, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, plantarum, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, paracasei, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, bulgaricus, n/a,
Lyophilized, 4.5*10^8 cfu
Bifidobacterium, breve, n/a,
Lyophilized, 4.5*10^8 cfu
Bifidobacterium, infantis, n/a,
Lyophilized, 4.5*10^8 cfu
Bifidobacterium, longum, n/a,
Lyophilized, 4.5*10^8 cfu
Streptococcus, thermophilus, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, casei, Shirota, Live,
6.5*10^6 cfu/65ml
10^7 cfu
1 per day
Enteral
Tasli, 2006
Case Series
INERSAN VSL
Lozenge
Patient
Lactobacillus, brevis, CD2, n/a,
n/a
1 lozenges
6 per day
Oral
1
C-71
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
130 ml
Oral
3 per day
Duration Control
LongCategory
Term
Use
0.5
months
Short
term
0.5
months
Short
term
None
0.33
months
Short
term
2
months
Medium
term
0.25
months
Short
term
8
months
Medium
term
None
None
None
None
None
None
Short
term
0.25
months
Short
term
None
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
van
Bodegraven,
2004
Case Series
1
VSL#3
Patient
Weiss, 2010
Case Series
1
Bio-plus
Tablet
Patient
Yim, 2006
Case Series
1
n/a
Patient
Lactobacillus, casei, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, plantarum, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, acidophilus, n/a,
Lyophilized, 4.5*10^8 cfu
Lactobacillus, delbrueckii
bulgaricus, n/a, Lyophilized,
4.5*10^8 cfu
Bifidobacterium, longum, n/a,
Lyophilized, 4.5*10^8
Bifidobacterium, infantis, n/a,
Lyophilized, 4.5*10^8 cfu
Bifidobacterium, breve, n/a,
Lyophilized, 4.5*10^8 cfu
Streptococcus, salivarius
thermophilus, n/a, Lyophilized,
4.5*10^8 cfu
2 tablets
Lactobacillus, acidophilus, n/a,
1 per day
n/a, 7.5*10^8 cfu/tablet
Lactobacillus, bulgaricus, n/a, n/a,
7.5*10^8 cfu/tablet
Bifidobacterium, bifidum, n/a, n/a,
7.5*10^8 cfu/tablet
Streptococcus, thermophilus, n/a,
n/a, 7.5*10^8 cfu/tablet
ProBiora
Powder,
wash
Patient
Zahradnik, 2009 1
Case Series
ProBiora
Mouth wash
Patient
Barton, 2001
Case Study
Bacid
Lactobacillus, acidophilus, n/a,
Capsule added n/a, n/a
to formula
Enterococcus, faecium, n/a, n/a,
Patient
n/a
Bassetti, 1998
Case Study
1
Perenterol
Patient
Streptococcus, oralis, KJ3sm,
mouth Lyophilized, 10^6-10^8 cfu/bottle
Streptococcus, uberis, KJ2sm,
Lyophilized, 10^6-10^8 cfu/bottle
Streptococcus, rattus, JH145,
Lyophilized, 10^6-10^8 cfu/bottle
Streptococcus, oralis, KJ3sm,
Lyophilized, 10^8 cfu/bottle
Streptococcus, uberis, KJ2sm,
Lyophilized, 10^8 cfu/bottle
Streptococcus, rattus, JH145,
Lyophilized, 10^8 cfu/bottle
Saccharomyces, boulardii, n/a,
n/a, n/a
C-72
Duration Control
LongCategory
Term
Use
3
months
Medium
term
None
Oral
6
months
Medium
term
None
n/a
2
months
Medium
term
None
1 bottle
2 per day
Oral
2
months
Medium
term
None
1 bottle
2 per day
Oral
0.25
months
Short
term
None
Lactobacillus, rhamnosus, n/a,
n/a, n/a
2 per day
Lactobacillus, plantarum, n/a, n/a,
n/a
Lactobacillus, casei, n/a, n/a, n/a
Bifidobacterium, lactis, n/a, n/a,
n/a
Zahradnik, 2009 1
Case Series
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
n/a
2 per day
n/a
n/a
n/a
500 mg
2 per day
None
Medium
term
Oral
0.6
months
Short
term
None
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Burkhardt, 2005 1
Case Study
Perenterol
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Cesaro, 2000
Case Study
Codex
Pill
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
1
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
150 mg
Enteral
1 per day
1
Perenterol
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Conen, 2009
Case Study
1
Aktifit
Drink
Patient
Lactobacillus, n/a, n/a, n/a, n/a
De Groote, 2005 1
Case Study
LGG
Pill
Patient
Lactobacillus, rhamnosus, GG,
n/a, n/a
Force, 1995
Case Study
1
Ultra-Levure
Patient
Saccharomyces, cerevisiae, n/a,
n/a, n/a
Fredenucci,
1998
Case Study
1
Ultra-Levure
Package
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Hennequin,
2000
Case Study
1
n/a
Enteral,
parenteral
(case1,2,4)
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Henry, 2004
Case Study
1
Perenterol
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
300 mg
1 per day
1
Oral
Jensen, 1974
Case Study
1
Kniehl, 2003
Case Study
1
n/a
Patient
Saccharomyces, cerevisiae, n/a,
n/a, 10^7-10^9 /g
Bactisubtil
Varies
Patient
Bacillus, IP, 5832, n/a, n/a
Kunz, 2004
Case Study
1
Infloran Berna
Pill
Patient
Lactobacillus, acidophilus, n/a,
n/a, n/a
Bifidobacterium, infantis, n/a, n/a,
n/a
1
Culturelle; LGG
Pill
Patient
Lactobacillus, rhamnosus, GG,
n/a, n/a
None
Short
term
Enteral
Varies
n/a
n/a
Oral
None
Medium
term
0.07
months
Short
term
0.1
month
Short
term
Oral
None
None
None
Long
term
Varies
None
Short
term
n/a
n/a
None
Medium
term
n/a
1 capsule
1 per day
None
None
n/a
n/a
C-73
1.25
months
Medium
term
Medium
term
n/a
Ku, 2006
Case Study
None
n/a
n/a
4 package
1 per day
None
Medium
term
1/8 capsule Enteral
2 per day
Varies by
participant
Saccharomyces, boulardii, n/a,
Lyophilized, n/a
0.25
months
Short
term
Oral
n/a
Bioflor
Powder
Patient
None
Medium
term
n/a
Hwang, 2009
Case Study
None
Medium
term
n/a
n/a
Cherifi, 2004
Case Study
Duration Control
LongCategory
Term
Use
Enteral
None
Medium
term
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Culturelle
Pill
Patient
Lactobacillus, rhamnosus, GG,
n/a, 10*10^9 cfu/capsule
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
1 capsule
Enteral
1 per day
Land, 2005
Case Study
1
Land, 2005
Case Study
3
n/a
Pill
Patient
Lactobacillus, rhamnosus, GG,
n/a, 10*10^9 cfu/capsule
1 capsule 1 Enteral
per day
LeDoux, 2006
Case Study
1
n/a
Patient
Lactobacillus, acidophilus, n/a,
n/a, n/a
Lestin, 2003
Case Study
1
Perenterol
Pill
Patient
Saccharomyces, cerevisiae
boulardii, Hansen CB55926,
Lyophilized, n/a
Lherm, 2002
Case Study
1
n/a
Packet
Patient
Saccharomyces, boulardii, n/a,
Viable, n/a
1
Ultra-Levure
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
500 mg
4 per day
Enteral
Lungarotti, 2003 1
Case Study
Codex DNB
Pill
Patient
Saccharomyces, boulardii, n/a,
n/a, 2.5*10^9 cfu/0.5 capsule
1/2
capsules
1 per day
n/a
Mackay, 1999
Case Study
n/a
Pill
Patient
Lactobacillus, rhamnosus, n/a,
Lyophilized, 2*10^9 cfu
Lactobacillus, acidophilus, n/a,
n/a, n/a
Streptococcus, faecalis, n/a, n/a,
n/a
n/a, n/a, n/a, n/a, n/a
1-2
capsules
1 per day
Oral
Munakata, 2010 1
Case Study
Lactomin
Patient
Lactobacillus, acidophilus, n/a,
1-2 g
n/a, n/a
1 per day
Lactobacillus, bulgaricus, n/a, n/a, Varies
n/a
over time
Streptococcus, faecalis, n/a, n/a,
n/a
Streptococcus, faecium, n/a, n/a,
n/a
n/a
Muñoz, 2005
Case Study
Ultra-Levure
Pill
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, n/a
n/a
Lolis, 2008
Case Study
1
1
n/a
3 per day
n/a
150 mg
Oral
n/a per day
n/a
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Oggioni, 1998
Case Study
1
Enterogermina
Patient
Bacillus, subtilis, ATCC 9799, n/a,
10^9 spores/dose
1.5 g
1 per day
None
None
None
0.25
months
Short
term
0.13
months
Short
term
None
None
None
Short
term
None
Medium
term
None
Short
term
Enteral
Oral
n/a
C-74
0.75
months
Short
term
0.4
months
Short
term
Medium
term
Varies by
participant
1
None
Medium
term
Enteral
n/a
Niault, 1999
Case Study
Duration Control
LongCategory
Term
Use
0.5
months
Short
term
1 month
Medium
term
None
None
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Oh, 1979
Case Study
1
n/a
Pill
Patient
Lactobacillus, acidophilus, n/a,
n/a, n/a
n/a
Powder
Patient
Bifidobacterium, breve, BBG-01,
Lyophilized, 10^9 cfu/g
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
n/a
Ohishi, 2010
Case Study
1
Perapoch, 2000
Case Study
1
n/a
Sachet
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Piarroux, 1999
Case Study
1
n/a
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
Piechno, 2007
Case Study
1
n/a
Central line
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
n/a
450-600
Vein
mg
n/a per day
Pletinex, 1995
Case Study
1
Perenterol
Pill
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, n/a
3 capsules
4 per day
Oral
Presterl, 2001
Case Study
1
n/a
Yogurt
Sour milk
Patient
Lactobacillus, n/a, n/a, n/a, n/a
1.5 liter
1 per day
Oral
Rautio, 1999
Case Study
1
n/a
Drink
Patient
Lactobacillus, rhamnosus, GG,
n/a, n/a
1/2 liter
1 per day
Oral
Richard, 1988
Case Study
1
Bactisubtil
Pill
Patient
Bacillus, subtilis, n/a, n/a, 10^9
spores/tab
8 tablets
1 per day
Oral
Rijnders, 2000
Case Study
1
Perenterol
Pill
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
2 capsules
6 per day
n/a
Riquelme, 2003
Case Study
1
Perenterol
Patient
Saccharomyces, boulardii, n/a,
Lyophilized, 5*1085*10^10 cells
250 mg
4 per day
Oral
Tommasi, 2008
Case Study
1
n/a
Patient
Lactobacillus, casei, n/a, n/a, n/a
Trautmann,
2008
Case Study
1
Perenterol
Gastric tube
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
n/a
250 mg
2 per day
Viggiano, 1995
Case Study
1
n/a
Gastric tube
Patient
Saccharomyces, boulardii, n/a,
n/a, n/a
4 sachet
4 per day
C-75
Oral
2 per day
n/a
1 Sachet
2 per day
n/a
Duration Control
LongCategory
Term
Use
3
months
Medium
term
0.4
months
Short
term
0.33
months
Short
term
n/a
None
None
None
None
Medium
term
None
Short
term
None
Short
term
None
Medium
term
4
months
Medium
term
None
None
Short
term
None
Short
term
None
Short
term
Oral
Enteral
Enteral
None
Medium
term
1 month
Short
term
0.25
months
Short
term
None
None
Evidence Table C2. Intervention (continued)
Author, Year
Study Design
Arm Product
Genus, Species, Strain, Form,
Delivery Vehicle Potency
Target
Zein, 2008
Case Study
1
Zunic, 1991
Case Study
1
n/a
Patient
Dose
Route of
Number/
Administration
Dose Unit
Frequency
Number
Oral
Bifidobacterium, bifidum, n/a, n/a,
3*10^9 cfu/dose
Bifidobacterium, longum, n/a, n/a, n/a
8*10^7 cfu
Lactobacillus, acidophilus, n/a,
n/a, 7.7*10^8 cfu
Lactobacillus, bulgaricus, n/a, n/a,
7.6*10^8 cfu
Lactobacillus, casei, n/a, n/a,
5.4*10^8 cfu
Lactobacillus, rhamnosus, n/a,
n/a, 8*10^7 cfu
Streptococcus, thermophilus, n/a,
n/a, 8*10^7 cfu
Saccharomyces, boulardii, n/a,
10 g
Lyophilized, n/a
3 per day
Duration Control
LongCategory
Term
Use
None
Medium
term
Ultra
Enteral
None
Gastric tube
Medium
Patient
term
*Abbreviations: C-RCT=Cross-over Randomized Controlled Trial; CCT=Controlled Clinical Trials; cfu=colony forming unit; g=gram; mg
milligram; ml=milliliter; n/a=not available or not applicable; RCT=Randomized Controlled Trial
C-76
Evidence Table C3. Assessment
Author, Year
Study Design
Abrahamsson,
2007
RCT
Agerbaek, 1995
RCT
Aihara, 2005
RCT
Alberda, 2007
RCT
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
Telephone interview
Provider assessment
Medical record
n/a
AE nonspecific
n/a
AE nonspecific; Dry cough; Exanthema;
Dysgeusia;
Headache;
Dizziness/drift;
Constipation; Flatulence; Abdominal discomfort
n/a
Skin itching;
Inappetence;
Duration of
Followup
Long-term
n/a
Provider assessment
Patient record
n/a
Provider assessment
n/a
Allen, 2010
RCT
Infections; AE nonspecific; Hospitalization; Microbiology lab
results to identify Lactobacillus or Bifidobacteria infections
Questionnaire
Telephone interview
Provider assessment
Short
Anderson, 2003
RCT
n/a
Provider assessment
n/a
Andriulli, 2008
RCT
AE nonspecific
Diary
Provider assessment
n/a
Anukam, 2006
RCT
n/a
n/a
n/a
Anukam, 2008
RCT
Diarrhea; n/a
Questionnaire
n/a
Anukam, 2009
RCT
AE nonspecific
Questionnaire
Short
Arunachalam,
2000
RCT
AE nonspecific
n/a
Short
Aso, 1992
RCT
AE nonspecific; Abnormal lab findings
n/a
Aso, 1995
RCT
Lab tests
Japan Society for Cancer
Therapy
Criteria
Provider
assessment
Lab test
Japan Society for Cancer
Therapy Criteria Lab test
Awad, 2010
RCT
n/a
Provider assessment
n/a
Baerheim, 1994
RCT
AE nonspecific
n/a
Short
Bajaj, 2008
RCT
AE nonspecific
n/a
n/a
Banaszkiewicz,
2005
RCT
n/a
Diary
n/a
Barraud, 2010
RCT
AE nonspecific
Provider assessment
Short
C-77
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
n/a
Duration of
Followup
Barreto-Zuniga, 2001
RCT
Basu, 2007
RCT
n/a
Death; Sepsis; Electrolyte imbalance; Renal failure
Diary
Provider assessment
Short
Basu, 2007
RCT
Sepsis;
Electrolyte
imbalance;
Complications of diarrhea
Diary
Provider assessment
n/a
Basu, 2009
RCT
Death; Sepsis; Diarrhea; Electrolyte imbalance
Provider assessment
n/a
Beausoleil, 2007
RCT
AE nonspecific
Provider assessment
n/a
Bellomo, 1979
RCT
Diarrhea; Hematologic controls
n/a
Short
Bertolami, 1999
C-RCT
AE nonspecific
n/a
n/a
Besselink, 2008
RCT
Death; AE nonspecific; Abdominal complaints
Provider assessment
n/a
Bin-Nun, 2005
RCT
Sepsis; Abdominal Pain; Feeding intolerance; Gastric
residuals; Abdominal distension; Heme positive stools;
Vomiting; Sepsis due to administered strains
AE nonspecific
Provider assessment
n/a
n/a
n/a
AE nonspecific; Serious adverse events (death, lifethreatening,
disability,
prolonged
hospitalization,
medically significant)
AE nonspecific; Serious adverse events (death, lifethreatening,
disability,
prolonged
hospitalization,
medically significant)
n/a
Diary
Provider assessment
Short
Diary
Short
Provider assessment
Short
Bousvaros, 2005
RCT
n/a
Provider assessment
n/a
Bravo, 2008
RCT
AE nonspecific; Abdominal distension; Abdominal pain
Telephone interview
Provider assessment
n/a
Brophy, 2008
RCT
Abdominal Pain; Painful spots; Dizzy spells; Stomach
pain; Blood in stools
Questionnaire
n/a
Bruno, 1981
RCT
AE nonspecific; Blood chemistry parameters
Lab test
Short
Bruzzese, 2007
C-RCT
Vomiting
n/a
Short
Bu, 2007
RCT
Acute gastroenteritis
Diary
n/a
Chen, 2005
RCT
n/a
Provider assessment
n/a
Black, 1997
CCT
Boge, 2009
RCT
Boge, 2009
RCT
Borgia, 1982
RCT
C-78
Renal
failure;
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Chen, 2010
RCT
n/a
Published Tool
Method Used to Record
Harms
n/a
Chou, 2010
RCT
Growth; Neurodevelopmental and sensory outcomes
Provider assessment
n/a
Chouraqui, 2004
RCT
Regurgitation; Vomiting
n/a
n/a
Chouraqui, 2008
RCT
AE nonspecific; Illnesses; Signs or symptoms of
illnesses including abnormal lab values
Medical
Dictionary
Regulatory Activities
Diary
Provider assessment
Chui, 2009
RCT
n/a
Provider assessment
Short
Coccorullo, 2010
RCT
n/a
n/a
Short
Connolly, 2005
RCT
n/a
Provider assessment
Lab test
n/a
Cooper, 2006
RCT
n/a
n/a
n/a
Correa, 2005
RCT
n/a
Provider assessment
Short
Cui, 2004
RCT
Diarrhea; AE nonspecific
Lab test
n/a
Cunningham-Rundles,
2000
CCT
n/a
n/a
Short
Czaja, 2007
RCT
Abnormal vaginal discharge; External genital irritation;
Vaginal candidiasis; Cystitis; Vaginal odor; Dysuria;
Headache; Abdominal or pelvic cramps/pain; Low back
pain
n/a
Diary
Provider assessment
Short
Provider assessment
n/a
De Preter, 2006
C-RCT
n/a
n/a
Short
de Roos, 1999
RCT
AE nonspecific
Diary
n/a
De Simone, 1992
RCT
n/a
Provider assessment
Lab test
n/a
De Simone, 2001
CCT
AE nonspecific; Standard blood screening
Provider assessment
Lab test
n/a
Dekker, 2009
RCT
Abdominal Pain; AE nonspecific; Reasons for
hospitalizations; Vomiting; Morphometric measurements;
Wheezing
Questionnaire
n/a
Dadak, 2006
RCT
Assessed Safety Parameters
C-79
for
Duration of
Followup
Short
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Delia, 2002
RCT
AE nonspecific
Published Tool
Method Used to Record
Harms
Provider assessment
Delia, 2007
RCT
Death; Infections; Sepsis
Provider assessment
n/a
Dewan, 2007
RCT
n/a
Provider assessment
Short
Dolin, 2009
RCT
AE nonspecific
Diary
Short
Dubey, 2008
RCT
Abdominal Pain; Blood in stool; Fever; Vomiting;
Abdominal distension; Lethargy; Irritability; Seizures;
Rash
n/a
Provider assessment
n/a
Contact team
Short
Dupont, 2010
RCT
AE nonspecific
Diary
Short
Dylewski, 2010
RCT
AE nonspecific
MedDRA
Diary
Ehrstrom, 2010
RCT
n/a
Provider assessment
Short
Eriksson, 2005
RCT
n/a
Questionnaire
n/a
Falck, 1999
RCT
AE nonspecific
Provider assessment
Case report form
n/a
Felley, 2001
RCT
n/a
Diary
Provider assessment
n/a
Feng, 1999
RCT
Diarrhea; AE nonspecific
n/a
Short
Folster-Holst, 2006
RCT
n/a
Provider assessment
Parent report
Short
Forestier, 2008
RCT
n/a
Provider assessment
n/a
French, 2009
RCT
AE nonspecific
Questionnaire
Short
Frohmader, 2010
RCT
n/a
Provider assessment
Short
Fujimori, 2009
RCT
Blood variables
Lab test
n/a
Gade, 1989
RCT
AE nonspecific
Diary
Short
Galpin, 2005
RCT
AE nonspecific; Vomiting
Care taker questioned
Short
Duman, 2005
RCT
Assessed Safety Parameters
C-80
(version
10.1)
Duration of
Followup
n/a
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
Diary
Provider assessment
Duration of
Followup
Gao, 2010
RCT
Diarrhea; n/a
Garcia Vilela, 2008
RCT
n/a
Provider assessment
n/a
Gerasimou, 2010
RCT
n/a
n/a
Short
Gibson, 2008
RCT
AE nonspecific; Digestive tolerance; Illnesses or signs or
symptoms occurring or worsening; Abnormal lab findings
Provider assessment
Short
Gill, 2001
RCT
n/a
Provider assessment
Short
Gionchetti, 2000
RCT
AE nonspecific; Lab parameters; CBC; Blood chemistry
Provider assessment
Lab test
n/a
Gionchetti, 2003
RCT
AE nonspecific; Laboratory studies (complete blood
count and blood chemistry measurements
Diary
Provider assessment
Short
Goossens, 2003
RCT
n/a;
Questionnaire
Short
Gracheva, 1999
CCT
Abdominal Pain;
Tests
(no
information)
Gruber, 2007
RCT
n/a;
Diary
n/a
Guillemard, 2010
RCT
n/a;
Provider assessment
report
Short
Guyonnet, 2009
RCT
AE nonspecific; Adverse digestive comfort
Diary
Questionnaire
n/a
Habermann, 2001
RCT
Hematologic, clinical chemistry results
Provider assessment
Short
Habermann, 2002
RCT
AE nonspecific; Blood count; Clinical chemistry
Provider assessment
Lab test
Short
Haschke-Becher, 2008
RCT
D-lactate accumulation; Metabolic acidosis
Provider assessment
Short
Hatakka, 2008
C-RCT
AE nonspecific; Gastrointestinal complaints; Any signs
of illness
Diary
Provider assessment
Short
Heimburger, 1994
RCT
n/a;
Provider assessment
n/a
Hemmerling, 2009
RCT
AE nonspecific; Genital tract itching; Vaginal odor;
Abnormal vaginal discharge; Nausea; Cramping;
Headache; Constipation; Common cold symptoms
DAIDS
Toxicity
Table
Addendum
for
Vaginal
Microbicide
Studies;
WHO/CONRAD colposcopy
manual 1994; DAIDS Adult
Toxicity Table Diary
Telephone interview
Provider assessment
Short
C-81
further
n/a
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
Diary
Duration of
Followup
Higashikawa, 2009
RCT
Diarrhea; AE nonspecific
Hilton, 1997
RCT
Abdominal cramps
Diary
Telephone interview
Provider assessment
n/a
Hirata, 2002
CCT
Dry cough; Headache; Vertigo; Digestive symptoms;
Itching
Provider assessment
Short
Hochter,1990
RCT
Diarrhea; n/a;
n/a
n/a
Honeycutt, 2007
RCT
Infections; AE nonspecific;
Provider assessment
Medical record
Short
Hong, 2010
RCT
n/a
n/a
Short
Horvat, 2010
RCT
Constipation; Vomiting; Abdominal cramps; Distention;
Nosocomial infections
Provider assessment
Short
Ishikawa, 2002
RCT
n/a
Diary
Provider assessment
n/a
Ishikawa, 2003
RCT
n/a
n/a
Short
Ishikawa, 2005
RCT
n/a
Provider assessment
n/a
Isolauri, 1991
RCT
Diarrhea; n/a
Provider assessment
Short
Isolauri,1995
RCT
n/a
Lab test, parents' record
Short
Jirapinyo, 2002
RCT
Sepsis; Unexplained worsening of clinical condition
Provider assessment
n/a
Johansson, 1998
RCT
n/a
Recorded
Short
Kadooka, 2010
RCT
Abdominal Pain; Headache; Nausea
Diary
Provider assessment
Short
Kajander, 2005
RCT
n/a
Diary
n/a
Kajander, 2008
RCT
n/a
Diary
Lab test
n/a
Kajimoto, 2002
RCT
Dry cough; Digestive tract symptoms; Exanthema
Provider assessment
Short
Karvonen, 2001
RCT
Abdominal
consistency
Diary
n/a
Pain;
Abdominal
discomfort;
C-82
Stool
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
Provider assessment
Duration of
Followup
Kerac, 2009
RCT
Death; Sepsis; AE nonspecific
Kianifar, 2009
RCT
n/a
Provider assessment
Lab test
Short
Kim, 2006
RCT
AE nonspecific; Lab tests; Physical exam; Blood count;
Blood chemistry panel; Hepatic and renal function;
Exacerbation of symptoms; Blood pressure; Weight; BMI
AE nonspecific; Lab tests; Physical exam; Blood count;
Blood chemistry panel; Hepatic and renal function;
Exacerbation of symptoms; Blood pressure; Weight; BMI
AE nonspecific
Telephone interview
Short
Telephone interview
Short
Provider assessment
n/a
Kirjavainen,2003
RCT
n/a
n/a
n/a
Klarin, 2008
RCT
AE nonspecific
Provider assessment
n/a
Klarin,2005
RCT
n/a
Provider assessment
n/a
Knight, 2007
RCT
Death
Provider assessment
n/a
Koning, 2008
RCT
Bloating; AE nonspecific; Nausea; Abdominal cramps;
Flatulence
Questionnaire
n/a
Kopp, 2008
RCT
Infections
Questionnaire
Provider assessment
Long-term
Kotzampassi, 2006
RCT
Infections
Provider assessment
n/a
Krasse, 2005
RCT
AE nonspecific
Provider assessment
n/a
Kuitunen, 2009
RCT
AE nonspecific; Hemoglobin (Anemia)
Questionnaire
Long-term
Kurugol, 2005
RCT
Diarrhea; n/a
Telephone interview
Short
La Rosa, 2003
RCT
Colic
Diary
Provider assessment
n/a
Laitinen, 2008
RCT
n/a
Provider assessment
n/a
Langhendries, 1995
RCT
Vomiting; Spitting up; Skin problems
Provider assessment
Mother recorded
n/a
Larsen, 2006
RCT
Bloating; Bowel habits; Bloating; Flatulence; Headache
Diary
Short
Larsson, 2008
RCT
AE nonspecific
Telephone interview
n/a
Kim, 2006
RCT
Kim, 2008
RCT
C-83
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Lata, 2009
RCT
n/a
Published Tool
Method Used to Record
Harms
Provider assessment
Lawrence, 2005
RCT
Diarrhea; n/a
n/a
n/a
Li, 2004
RCT
Infections
Provider assessment
n/a
Ligaarden, 2010
C-RCT
AE nonspecific
Diary
Short
Lighthouse, 2004
RCT
n/a
n/a
Short
Lin, 1989
C-RCT
Constipation; Flatulence; Stomach upset
Patient report
n/a
Lin, 2005
RCT
Sepsis; Sepsis due to Lactobacillus or Bifidobacterium
Provider assessment
n/a
Lin, 2008
RCT
Sepsis; Flatulence; Feeding intolerance (based on
presence of gastric aspirate and abdominal distension)
Provider assessment
n/a
Ljungberg, 2006
RCT
Beta cell autoantibodies; Blood samples; Enterovirus
infections
Provider assessment
Long-term
Loguercio, 1987
RCT
Constipation; Meteorism; Abdominal Pain
Provider assessment
Lab test
Short
Lonnermark, 2010
RCT
n/a
Diary
Short
Lu, 2004
CCT
n/a
n/a
n/a
Luoto, 2010
RCT
n/a
Provider assessment
n/a
Mäkeläinen, 2003
RCT
AE nonspecific; Intestinal symptoms; Consistency and
frequency of stools
Lab tests
Short
Malaguarnera, 2007
RCT
Abdominal Pain; Blood tests
Provider assessment
n/a
Malaguarnera, 2010
RCT
Blood tests (hemoglobin, hematocritus, white blood cell
count and thrombocytes); Liver function tests (alanine
amino transferase, aspartate amino transferase,
gamma-glutamyl-transpeptidase, cholinesterase activity,
serum bilirubin concentrations, prothrombin time and
partial thromboplastin time)
AE nonspecific; Clinical examination (weight, length,
head circumference); Spitting up; Vomiting; Night
awakenings; Irritability; Severe crying; Respiratory
infections; Sensitivity to antibiotics
AE nonspecific
Provider assessment
Short
Provider assessment
n/a
Provider assessment
Short
Maldonado, 2009
RCT
Mandel, 2010
RCT
Assessed Safety Parameters
C-84
Duration of
Followup
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Manley, 2007
C-RCT
n/a
Published Tool
Method Used to Record
Harms
Provider assessment
Manzoni, 2006
RCT
Sepsis
Provider assessment
n/a
Margreiter, 2006
RCT
Diarrhea; AE
Tolerability
Diary
Provider assessment
Short
Marotta, 2003
C-RCT
n/a
Lab test
n/a
Marrazzo, 2006
RCT
AE nonspecific; Abnormal vaginal discharge
Questionnaire
Provider assessment
Short
Marseglia, 2007
RCT
AE nonspecific
Provider assessment
n/a
Marteau, 2004
RCT
AE nonspecific
Diary
Provider assessment
n/a
Martiney, 2009
RCT
n/a
Lab, notebook
Short
Martinez, 2008
RCT
n/a
Provider assessment
n/a
Martinez, 2009
RCT
AE nonspecific
Provider assessment
n/a
Mayanagi, 2009
RCT
n/a
n/a
Short
McFarland, 1994
RCT
AE nonspecific
Diary
Telephone interview
Provider assessment
Short
McFarland, 1995
RCT
AE nonspecific; Physical symptoms; Fever; Rash;
Changes in blood chemistries; Urinary indicators
(protein, BUN, Glucose); Changes in liver enzymes
n/a
Provider assessment
AE forms
n/a
Provider assessment
Short
Merenstein, 2009
RCT
Death; AE nonspecific; Life threatening event;
Hospitalization; Prolonged hospital stay; Permanent
disability
Diary
Telephone interview
Provider assessment
Short
Merenstein, 2010
RCT
Death; AE nonspecific; Life-threatening event;
Hospitalization; Prolongation of hospital stay; Permanent
disability; Vomiting; Stomach pain; Constipation; Runny
nose, Cough; Decreased appetite; Fever; Medication
use; Rash
AE nonspecific
Parent report
Short
Provider assessment
Patient report
n/a
AE nonspecific; Significant changes from baseline (lab)
values
Diary
Provider assessment
n/a
McNaught, 2002
RCT
Metts, 2003
RCT
Miele, 2009
RCT
Assessed Safety Parameters
nonspecific;
Physical
C-85
examination;
Duration of
Followup
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Millar, 1993
RCT
Mimura, 2004
RCT
Assessed Safety Parameters
Sepsis; General well being; Abdominal distension;
Vomiting or regurgitation; Feed intolerance; Incidence of
perineal rash; Frequency and consistency of stools;
number of suppositories used; fluid intake; Weight;
Duration of hospital stay
AE nonspecific;
Published Tool
Method Used to Record
Harms
Provider assessment
Duration of
Followup
n/a
Diary
n/a
Miyaji, 2006
RCT
n/a
n/a
Short
Morrow, 2010
RCT
AE nonspecific
Provider assessment
n/a
Mukerji, 2009
RCT
AE nonspecific
Questionnaire
Telephone interview
Short
Naito, 2008
RCT
AE nonspecific
Common
terminology
criteria for adverse events
v2.0 Provider assessment
Long-term
Newcomer, 1983
RCT
Intestinal symptoms; Pain; Gas; Borborygmi
Diary
n/a
Niers, 2009
RCT
AE nonspecific; Feeding difficulties
Diary
Provider assessment
Long-term
Niv, 2005
RCT
Dyspepsia; Headache; Nausea
Diary
n/a
Nobuta, 2009
RCT
n/a
Questionnaire
Short
O'Mahony, 2005
RCT
n/a
Diary
Provider assessment
Short
Ojetti, 2010
RCT
n/a
Diary
Short
Olah, 2005
RCT
Bloating
Provider assessment
n/a
Olivares, 2006
RCT
AE nonspecific
Provider assessment
Short
Osterlund, 2007
RCT
WHO performance status; Weight; Blood cell counts;
Serum chemistry
Common Toxicity Criteria of
the National Cancer Institute
of Canada scale version 2
Provider assessment
n/a
Ouwehand, 2009
RCT
n/a
Diary
Short
Ozkinay, 2005
RCT
AE nonspecific
n/a
n/a
Panigrahi, 2008
RCT
Sepsis; AE nonspecific; Feeding and stooling patterns;
Vital signs
Provider assessment
n/a
C-86
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Parent, 1996
RCT
n/a
Published Tool
Method Used to Record
Harms
Provider assessment
Parfenov, 2005
CCT
Bloating
Provider assessment
n/a
Parfenov, 2005
CCT
AE nonspecific; Allergic reactions
Provider assessment
n/a
Parra, 2004
RCT
Modification in nutritional parameters; General health
problems associated with product
Provider assessment
n/a
Passeron, 2005
RCT
AE nonspecific
Provider assessment
n/a
Peral, 2009
RCT
n/a
Provider assessment
Short
Pereg, 2010
RCT
n/a
n/a
n/a
Petschow, 2005
RCT
AE nonspecific; Stool characteristics;
symptoms; Fussiness; Gas
Diary
Short
Prantera, 2002
RCT
n/a
Provider assessment
n/a
Pregliasco, 2008
RCT
Bloating; AE nonspecific; Decreased bowel movement;
Worsened intestinal function
Diary
Telephone interview
n/a
Pregliasco, 2008
RCT
Bloating; AE nonspecific; Decreased bowel movement;
Worsened intestinal functions
Diary
Telephone interview
n/a
Pregliasco, 2008
RCT
Worsened intestinal functions
Decreased bowel movement)
Telephone interview
n/a
Puccio, 2007
RCT
Cough; Constipation; Respiratory tract infection; Rhinitis;
Wheezing; GI symptoms; Stool characteristics;
Flatulence; Vomiting; Restlessness; Irritability; Colic
AE nonspecific
Diary
n/a
n/a
Short
Ranganathan
C-RCT
AE nonspecific
n/a
Short
Rautava, 2008
RCT
AE nonspecific; Gastrointestinal symptoms; Vomiting
Diary
n/a
Rayes, 2002
RCT
AE nonspecific
Provider assessment
Short
Rayes, 2002
RCT
n/a
Provider assessment
Short
Rayes, 2005
RCT
Abdominal cramps; Abdominal distension
Provider assessment
n/a
Rayes, 2007
RCT
AE nonspecific
Provider assessment
n/a
Rampengan, 2010
RCT
Assessed Safety Parameters
(Increased
C-87
Tolerance
bloating,
Duration of
Followup
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
n/a
Duration of
Followup
Reid, 1992
RCT
Rash; Vomiting; Nausea; Irritation; Discharge
Reid, 1995
RCT
n/a
Diary
Provider assessment
n/a
Ren, 2010
RCT
Gastrointestinal side effects; Skin rash
Provider assessment
Short
Reuman, 1986
RCT
Death; AE nonspecific
Provider assessment
n/a
Richelsen, 1996
RCT
n/a
Telephone interview
n/a
Rio, 2002
RCT
n/a
Provider assessment
n/a
Roos, 1996
RCT
AE nonspecific
Diary
Provider assessment
Short
Roos, 2001
RCT
AE nonspecific
n/a
n/a
Rose, 2010
RCT
Need for medical intervention; Pulmonary deterioration;
Diaper rash; Deterioration of atopic eczema; Lactose
intolerance
Diarrhea; n/a
Diary
Provider assessment
n/a
n/a
Short
Rosenfeldt, 2003
C-RCT
Abdominal Pain; AE nonspecific; Abdominal pain;
Flatulence; Nausea; Medical treatment
n/a
n/a
Rouge, 2009
RCT
n/a
Provider assessment
n/a
Ruiz-Palacios, 1996
RCT
AE nonspecific
n/a
n/a
Saavedra, 2004
RCT
Loose stool; Discomfort with bowel movement; Vomiting;
Colic or irritability; Day care absenteeism; Use of
antibiotics; Healthcare attention for illness; Growth
AE nonspecific
Telephone interview
n/a
Diary
Provider assessment
n/a
Sahagun-flores, 2007
RCT
n/a
n/a
Short
Saint-Marc, 1995
RCT
n/a
n/a
Short
Salminen, 1988
RCT
Abdominal Pain; Tolerance; Flatulence; Meteorism;
Vomiting
Provider assessment
n/a
Salminen, 2004
C-RCT
Infections; Diarrhea; CD4 cell counts; Plasma HIV viral
load levels; serum C-reactive protein; Body temperature;
Lactobacillus infections
Infections; Sepsis; Blood culture
Lab test
n/a
Provider assessment
n/a
Rosenfeldt, 2002
RCT
Safdar, 2008
RCT
Samanta, 2008
RCT
C-88
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
n/a
Duration of
Followup
Satokari, 2001
RCT
n/a
Savino, 2006
RCT
Constipation; Vomiting
Diary
Provider assessment
Short
Sazawal, 2010
RCT
n/a
n/a
n/a
Scalabrin, 2009
RCT
AE nonspecific
Provider assessment
Short
Schrezenmeir, 2004
RCT
Any symptoms of GI intolerance; Constipation; Nausea;
Vomiting or regurgitation; Abdominal distension;
Belching/Burping; Flatulence; Asthma; Bronchitis;
Pneumonia; Severe anorexia; Weight loss; Asthenia
AE nonspecific
Diary
Provider assessment
Short
n/a
n/a
Seppo, 2003
RCT
n/a
Questionnaire
n/a
Sierra, 2010
RCT
Constipation; Fever; Dyspepsia; Headache; Flatulence;
Muscular or bone ache; Maldigestion; Flu symptoms;
Stomachache; Hematologic parameters (red cells,
hemoglobin, hematocrit, mean corpuscular volume,
mean corpuscular hemoglobin, mean cell hemoglobin
concentration, leucocytes, segmented neutrophils,
eosinophils, basophils, lymphocytes, platelets)
AE nonspecific
Questionnaire
Short
Provider assessment
n/a
Simren, 2010
RCT
Biochemistry analysis; Hematology analysis
Telephone interview
Short
Song, 2010
RCT
n/a
Diary
Short
Songisepp, 2005
RCT
Infections; AE nonspecific
Daily questioned
n/a
Songisepp, 2005
CCT
Infections; AE nonspecific
Daily questioned
n/a
Sood, 2009
RCT
n/a
Provider assessment
Short
Spanhaak, 1998
RCT
Body weight; Blood pressure; Heart rate; Temperature;
Hematology; Blood chemistry
Provider assessment
Short
Stockert, 2007
RCT
n/a
Diary
n/a
Stotzer, 1996
C-RCT
Bloating; Abdominal Pain; Flatulence
n/a
n/a
Stratiki, 2007
RCT
Feeding tolerance (vomiting, abdominal distension,
tenderness and stool characteristics)
Provider assessment
n/a
Schultz, 2004
RCT
Simons, 2006
RCT
C-89
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
n/a
Duration of
Followup
Sullivan, 2003
RCT
n/a
Sykora, 2005
RCT
AE nonspecific
Side effect scoring system
for H. pylori (de Boer, 1996)
Questionnaire
Short
Tamura, 2007
RCT
n/a
n/a
Short
Taylor, 2007
RCT
n/a
Provider assessment
n/a
Tempe, 1985
RCT
n/a
n/a
Short
Teran, 2008
RCT
AE nonspecific; Fever; Vomiting
Provider assessment
n/a
Thomas, 2001
RCT
Bloating; Nausea; Abdominal cramps; Gas; Bloating
Diary
Telephone interview
Short
Tomoda, 1991
CCT
AE nonspecific; Blood chemistry
Lab test
n/a
Tsuchiya, 2004
CCT
AE nonspecific
n/a
Turchet, 2003
RCT
n/a
Diary
Provider assessment
Lab test; Specific form
Provider assessment
Tursi, 2004
RCT
AE nonspecific
Diary
n/a
Tursi, 2008
CCT
AE nonspecific
Provider assessment
n/a
Tursi, 2010
RCT
AE nonspecific
Provider assessment
Short
Underwood, 2009
RCT
n/a
Provider assessment
Short
Urban, 2008
RCT
Spitting up; Vomiting; Frequency of hard and loose
stools; Flatulence; Restlessness; Hospital admissions
Provider assessment
n/a
Urbansek, 2001
RCT
Diarrhea; n/a
n/a
n/a
Van der Aa, 2010
RCT
AE nonspecific
Provider assessment
Short
Van Gossum, 2007
RCT
AE nonspecific
Provider assessment
n/a
Velaphi, 2008
RCT
Tolerance of feeds-stools pattern; Stool pattern; Spitting;
Vomiting; Unrest morbidity; Changes in blood chemistry;
Prolonged illness
Provider assessment
Short
C-90
Short
Short
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
Diary
Duration of
Followup
n/a
Vendt, 2006
RCT
Defecation frequency; Stool consistency; Crying, Rash;
Colic pain; Constipation; Excessive breast feeding
Vleggaar, 2008
C-RCT
n/a
Provider assessment
n/a
Vlieger, 2009
RCT
Vomiting; Constipation; Colic; Rash; Eczema
Diary
Provider assessment
n/a
Wada, 2010
RCT
Infections; Blood culture
administered strains
Provider assessment
Daily records, lab
n/a
Wang, 2004
RCT
AE nonspecific
n/a
n/a
Wang, 2007
RCT
n/a
Provider assessment
n/a
Weizman, 2005
RCT
AE nonspecific
Questionnaire
Telephone interview
Provider assessment
Short
Weizman, 2006
RCT
Deviations of growth parameters;
Vomiting; Restlessness; Constipation
Questionnaire
Telephone interview
Provider assessment
n/a
Weston, 2005
RCT
Worsening of condition
Provider assessment
n/a
Wewalka, 2002
RCT
AE nonspecific; Thyroid parameters
Provider assessment
Short
Wheeler, 1997
C-RCT
n/a
n/a
n/a
Wildt, 2006
RCT
Abdominal Pain; AE nonspecific; Constipation
Diary
Provider assessment
Short
Williams, 2008
RCT
n/a
n/a
n/a
Wind, 2010
RCT
AE nonspecific; Change in blood parameters; Nausea;
Vomiting; Burping; Abdominal distension; Flatulence;
Defecation frequency; Stool consistency
Short
Wolf, 1994
RCT
AE nonspecific
Gastrointestinal
symptom
rating scale; King's stool
chart Diary
Questionnaire
Lab test
Questionnaire
Provider assessment
Wolf, 1998
RCT
Nausea; Cramping; Distension; Flatulence; Vomiting;
Constipation; Burping; Reflux; Bowel function
Daily questionnaire
Short
Worthley, 2009
C-RCT
General well-being; Gastrointestinal symptoms
Questionnaire
Provider assessment
Short
Xia, 2010
RCT
AE nonspecific
Provider assessment
Short
/
bacteremia
C-91
due
to
Regurgitation;
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Xiang, 2006
RCT
n/a
Published Tool
Method Used to Record
Harms
Provider assessment
Xiao, 2003
RCT
n/a
Lab test
n/a
Xiao, 2003
RCT
n/a
Diary
n/a
Yang, 2008
RCT
Lab changes (blood, urine, stool, liver, kidney function)
Lab test
Short
Yao-Zong, 2004
RCT
Diarrhea; AE nonspecific; Constipation
Diary
Provider assessment
Short
Yonekura
RCT
Bloating; Abdominal Pain; AE nonspecific; Irritability;
Decreased motivation; Decreased appetite; Fatigue;
Insomnia; Headache; Tinnitus; Vertigo; Itching
(eczema); Vomiting; loose stools; Constipation; Changes
in physical condition; History of present illness
Gastrointestinal side effects
Provider assessment
Short
Provider assessment
Short
Ziegler, 2003
RCT
n/a
Diary
n/a
Zocco, 2003
RCT
AE nonspecific
n/a
n/a
An, 2010
Case series (uncontrolled)
Abdominal Pain; Vomiting
Questionnaire
Provider assessment
Short
Barrett, 2008
Case series (uncontrolled)
n/a
Diary
Questionnaire
n/a
Beck, 1961
Case series (uncontrolled)
n/a
n/a
n/a
Bekkali, 2007
Case series (uncontrolled)
AE nonspecific; Vomiting
Diary
Provider assessment
n/a
Bellomo, 1979
Case series (uncontrolled)
Hematologic controls
n/a
Short
Benchimol, 2004
Case series (uncontrolled)
Diarrhea; n/a
Provider assessment
n/a
Berman, 2006
Case series (uncontrolled)
n/a
Provider assessment
n/a
Bibiloni, 2005
Case series (uncontrolled)
AE nonspecific; Biochemical adverse events
Provider assessment
n/a
Bruce, 1988
Case series (uncontrolled)
n/a
n/a
n/a
Bruni, 2008
Case series (uncontrolled)
Sensitization
Provider assessment
Short
Zhang, 2010
RCT
Assessed Safety Parameters
C-92
Duration of
Followup
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Carlsson, 2009
Case series (uncontrolled)
n/a
Published Tool
Method Used to Record
Harms
n/a
Cobo Sanz, 2006
Case series (uncontrolled)
n/a
Questionnaire
n/a
Colecchia, 2006
Case series (uncontrolled)
AE nonspecific
Neri et al. (2000) IBS
differentiation Questionnaire
Short
Di Pierro, 2009
Case series (uncontrolled)
n/a
n/a
Short
Dughera, 2007
Case series (uncontrolled)
AE nonspecific
Questionnaire
n/a
Elmer, 1995
Case series (uncontrolled)
Diarrhea; n/a
Telephone interview
n/a
Fukuda, 2008
Case series (uncontrolled)
AE nonspecific
Provider assessment
Short
Gabrielli, 2009
Case series (uncontrolled)
AE nonspecific; Clinical findings or patients' complaints
not present 24h before enrollment
n/a
Short
Garrido, 2005
Case series (uncontrolled)
Gastrointestinal symptomatology
n/a
Short
Gionchetti, 2007
Case series (uncontrolled)
AE nonspecific;
measurements
Diary
n/a
Glintborg, 2006
Case series (uncontrolled)
n/a
Provider assessment
n/a
Gniwotta, 1977
Case series (uncontrolled)
Diarrhea; n/a
n/a
n/a
Gotteland, 2003
Case series (uncontrolled)
n/a
n/a
n/a
Gruenwald, 2002
Case series (uncontrolled)
n/a
Questionnaire
Provider assessment
n/a
Hensgens, 1976
Case series (uncontrolled)
n/a
Provider assessment
n/a
Huynh, 2009
Case series (uncontrolled)
AE nonspecific; Serum cytokine levels
Diary
n/a
Karimi, 2005
Case series (uncontrolled)
AE nonspecific
Telephone interview
Short
Kawamura,1981
Case series (uncontrolled)
AE nonspecific
n/a
n/a
Kirchhelle, 1996
Case series (uncontrolled)
AE nonspecific
Provider assessment
Short
Kitajima, 1997
Case series (uncontrolled)
n/a
Provider assessment
n/a
Blood
count;
Blood
C-93
chemistry
Duration of
Followup
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
Diary
Provider assessment
Duration of
Followup
Lamiki, 2010
Case series (uncontrolled)
AE nonspecific
Lee, 2010
Case series (uncontrolled)
AE nonspecific
Provider assessment
Short
Lombardo, 2009
Case series (uncontrolled)
n/a
Diary
Short
Luoto, 2010
Case series (uncontrolled)
Sepsis
Provider assessment
n/a
Malin, 1996
Case series (uncontrolled)
n/a
Provider assessment
Short
Malkov, 2006
Case series (uncontrolled)
n/a
Provider assessment
n/a
Mego, 2005
Case series (uncontrolled)
AE nonspecific
NCI-CTC (2.0) criteria n/a
n/a
Mego, 2006
Case series (uncontrolled)
AE nonspecific
NCI-CTC (2.0) criteria 2
Provider assessment
n/a
Michetti, 1999
Case series (uncontrolled)
n/a
n/a
Short
Muting, 1968
Case series (uncontrolled)
n/a
n/a
n/a
Nobuta, 2009
Case series (uncontrolled)
AE nonspecific
Questionnaire
Interview
Short
Reid, 2001
Case series (uncontrolled)
AE nonspecific; Bladder or vaginal irritation; Discharge;
Intestinal upset; Infections
Patient record
Short
Rosenfeldt, 2003
Case series (uncontrolled)
AE
nonspecific;
Gastrointestinal
inconvenience
(abdominal pain, flatulence, nausea); Medical treatment
n/a
n/a
Sakamoto, 2001
Case series (uncontrolled)
n/a
n/a
Short
Schneider, 2005
Case series (uncontrolled)
n/a
n/a
Short
Shen, 2005
Case series (uncontrolled)
Bloating; AE nonspecific; Intolerable
Bleeding; Worsening abdominal pain
Provider assessment
n/a
Srinivasan, 2006
Case series (uncontrolled)
Cultures from stool, fluid, blood, urine,
cerebrospinal fluid; Endotracheal secretions
Provider assessment
n/a
Tasli, 2006
Case series (uncontrolled)
Nausea; Vomiting; Abdominal fullness
Provider assessment
Short
van Bodegraven, 2004
Case series (uncontrolled)
n/a
n/a
n/a
Weiss, 2010
Case series (uncontrolled)
n/a
Provider assessment
n/a
C-94
constipation;
sputum,
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
Provider assessment
Duration of
Followup
Yim, 2006
Case series (uncontrolled)
n/a
Zahradnik, 2009
Case series (uncontrolled)
AE nonspecific
Diary
Provider assessment
Short
Zahradnik, 2009
Case series (uncontrolled)
AE nonspecific
Diary
Provider assessment
Short
An, 2010
Case series (uncontrolled)
Abdominal Pain; Vomiting
Questionnaire
Provider assessment
Short
Barrett, 2008
Case series (uncontrolled)
n/a
Diary
Questionnaire
n/a
Beck, 1961
Case series (uncontrolled)
n/a
n/a
n/a
Bekkali, 2007
Case series (uncontrolled)
AE nonspecific; Vomiting
Diary
Provider assessment
n/a
Bellomo, 1979
Case series (uncontrolled)
Hematologic controls
n/a
Short
Benchimol, 2004
Case series (uncontrolled)
Diarrhea; n/a
Provider assessment
n/a
Berman, 2006
Case series (uncontrolled)
n/a
Provider assessment
n/a
Bibiloni, 2005
Case series (uncontrolled)
AE nonspecific; Biochemical adverse events
Provider assessment
n/a
Bruce, 1988
Case series (uncontrolled)
n/a
n/a
n/a
Bruni, 2008
Case series (uncontrolled)
Sensitization
Provider assessment
Short
Carlsson, 2009
Case series (uncontrolled)
n/a
n/a
n/a
Cobo Sanz, 2006
Case series (uncontrolled)
n/a
Questionnaire
n/a
Colecchia, 2006
Case series (uncontrolled)
AE nonspecific
Neri et al. (2000) IBS
differentiation Questionnaire
Short
Di Pierro, 2009
Case series (uncontrolled)
n/a
n/a
Short
Dughera, 2007
Case series (uncontrolled)
AE nonspecific
Questionnaire
n/a
Elmer, 1995
Case series (uncontrolled)
Diarrhea; n/a
Telephone interview
n/a
Fukuda, 2008
Case series (uncontrolled)
AE nonspecific
Provider assessment
Short
C-95
n/a
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
n/a
Gabrielli, 2009
Case series (uncontrolled)
AE nonspecific; Clinical findings or patients' complaints
not present 24 hours before enrollment
Garrido, 2005
Case series (uncontrolled)
Gastrointestinal symptomatology
Gionchetti, 2007
Case series (uncontrolled)
AE nonspecific;
measurements
Short
n/a
Short
Diary
n/a
Glintborg, 2006
Case series (uncontrolled)
n/a
Provider assessment
n/a
Gniwotta, 1977
Case series (uncontrolled)
Diarrhea; n/a
n/a
n/a
Gotteland, 2003
Case series (uncontrolled)
n/a
n/a
n/a
Gruenwald, 2002
Case series (uncontrolled)
n/a
Questionnaire
Provider assessment
n/a
Hensgens, 1976
Case series (uncontrolled)
n/a
Provider assessment
n/a
Huynh, 2009
Case series (uncontrolled)
AE nonspecific; Serum cytokine levels
Diary
n/a
Karimi, 2005
Case series (uncontrolled)
AE nonspecific
Telephone interview
Short
Kawamura,1981
Case series (uncontrolled)
AE nonspecific
n/a
n/a
Kirchhelle, 1996
Case series (uncontrolled)
AE nonspecific
Provider assessment
Short
Kitajima, 1997
Case series (uncontrolled)
n/a
Provider assessment
n/a
Lamiki, 2010
Case series (uncontrolled)
AE nonspecific
Diary
Provider assessment
n/a
Lee, 2010
Case series (uncontrolled)
AE nonspecific
Provider assessment
Short
Lombardo, 2009
Case series (uncontrolled)
n/a
Diary
Short
Luoto, 2010
Case series (uncontrolled)
Sepsis
Provider assessment
n/a
Malin, 1996
Case series (uncontrolled)
n/a
Provider assessment
Short
Malkov, 2006
Case series (uncontrolled)
n/a
Provider assessment
n/a
Mego, 2005
Case series (uncontrolled)
AE nonspecific
NCI-CTC (2.0) criteria n/a
n/a
Blood
count;
Blood
C-96
chemistry
Duration of
Followup
Evidence Table C3. Assessment (continued)
Author, Year
Study Design
Assessed Safety Parameters
Published Tool
Method Used to Record
Harms
NCI-CTC (2.0) criteria 2
Provider assessment
Duration of
Followup
Mego, 2006
Case series (uncontrolled)
AE nonspecific
Michetti, 1999
Case series (uncontrolled)
n/a
n/a
Short
Muting, 1968
Case series (uncontrolled)
n/a
n/a
n/a
Nobuta, 2009
Case series (uncontrolled)
AE nonspecific
Questionnaire
Interview
Short
Reid, 2001
Case series (uncontrolled)
AE nonspecific; Bladder or vaginal irritation; Discharge;
Intestinal upset; Infections
Patient record
Short
Rosenfeldt, 2003
Case series (uncontrolled)
AE
nonspecific;
Gastrointestinal
inconvenience
(abdominal pain, flatulence, nausea); Medical treatment
n/a
n/a
Sakamoto, 2001
Case series (uncontrolled)
n/a
n/a
Short
Schneider, 2005
Case series (uncontrolled)
n/a
n/a
Short
Shen, 2005
Case series (uncontrolled)
Bloating; AE nonspecific; Intolerable
Bleeding; Worsening abdominal pain
Provider assessment
n/a
Srinivasan, 2006
Case series (uncontrolled)
Cultures from stool, fluid, blood, urine,
cerebrospinal fluid; Endotracheal secretions
Provider assessment
n/a
Tasli, 2006
Case series (uncontrolled)
Nausea; Vomiting; Abdominal fullness
Provider assessment
Short
van Bodegraven, 2004
Case series (uncontrolled)
n/a
n/a
n/a
Weiss, 2010
Case series (uncontrolled)
n/a
Provider assessment
n/a
Yim, 2006
Case series (uncontrolled)
n/a
Provider assessment
n/a
Zahradnik, 2009
Case series (uncontrolled)
AE nonspecific
Diary
Provider assessment
Short
Zahradnik, 2009
Case series (uncontrolled)
AE nonspecific
Diary
Provider assessment
Short
*Abbreviations
AE=Adverse Events
C-RCT=Cross-over Randomized Controlled Trial
CCT=Controlled Clinical Trials
n/a=not available or not applicable
RCT=Randomized Controlled Trial
C-97
constipation;
sputum,
n/a
Evidence Table C4. Results
Author, Year
Design
Described as
Effective
LTFU
Abrahamsson,
2007
RCT
Effectiveness
unclear
LTFU
Abrahamsson,
2007
RCT
Effectiveness
unclear
LTFU
Agerbaek, 1995
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
La
117
n/a
2
115
VII Constipation n=4
VII Spitting up n=51
VII Colic n=11
XXII Episode of
wheezing (withdrawal)
n=1
VII Constipation n=6
VII Spitting up n=43
VII Colic n=10
XXII Episode of
wheezing n=0
N
Drop
outs,
Due
to AE
22, 1
n/a
22, 0
1
En
29
3
0, 0
Agerbaek, 1995
RCT
Effective
2
29
Aihara, 2005
RCT
Effective
1
La
40
VII Borborygmi n=n/a
VII Loose stools n=n/a
VII Obstipation n=n/a
VII Lactose intolerance
n=0
VII Borborygmi n=0
VII Loose stools n=0
VII Obstipation n=0
VII Lactose intolerance
n=0
XXII Dry cough n=0
XXIII Exanthema n=0
XXIII Skin itching n=0
VII Dysgeusia n=0
XVII Headache n=0
VII Dizziness/drift n=0
VII Inappetence n=0
VII Diarrhea n=2
VII Constipation n=1
VII Flatulence n=0
VII Abdominal discomfort
n=0
1, 0
3
C-98
n/a, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Antibiotics
unclear
Antibiotics
unclear
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Aihara, 2005
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
2
40
Alberda, 2007
RCT
Effectiveness
unclear
1
St
10
Alberda, 2007
RCT
Effectiveness
unclear
2
9
XXII Dry cough n=0
XXIII Exanthema n=0
XXIII Skin itching n=0
VII Dysgeusia n=0
XVII Headache n=0
VII Dizziness/drift n=0
VII Inappetence n=0
VII Diarrhea n=4
VII Constipation n=2
VII Flatulence n=0
VII Abdominal discomfort
n=0
VII Bowel obstruction
(SAE) n=1
XI Lactobacillus-induced
sepsis (SAE) n=0
XXII Respiratory failure
death n=0
II Congestive heart
failure -death (5) n=1
II Myocardial infarction
death (5) n=0
VII Bowel obstruction
(SAE) n=0
XI Lactobacillus-induced
sepsis (SAE) n=0
XXII Respiratory failure
death (SAE) n=0
II Congestive heart
failure -death (5) (SAE)
n=0
II Myocardial infarction
death (5) (SAE) n=1
Other Harms
C-99
Patients
with
AEs
6
N
Dropouts,
Due
to AE
n/a, 0
2
n/a, 2
1
n/a, 1
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Alberda, 2007
RCT
Effectiveness
unclear
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
3
St
9
Allen, 2010
RCT
Effective
1
Bi
220
VII Bowel obstruction
n=0
XI Sepsis due to
lactobacilli (SAE) n=0
XXII Respiratory failure
death (5) (SAE) n=1
II Congestive heart
failure -death (5) (SAE)
n=0
II Myocardial infarct
death (5) (SAE) n=0
XI Infectious and
parasitic diseases (SAE)
n=15
V Endocrine, nutritional
and metabolic diseases
n=0
VI Diseases of the eye
and adnexa n=6
IV Diseases of the ear
and mastoid process
n=3
XI Diseases of the
respiratory system n=24
VII Diseases of the
digestive system n=8
XXIII Diseases of the
skin and subcutaneous
tissue n=12
XX Disease of
genitourinary system
n=0
XXVII Pregnancy,
childbirth and
puerperium n=4
XVIII Perinatal period
conditions (e.g. jaundice)
n=10
III Congenital
malformations,
deformations and
chromosomal
Other Harms
Patients
with
AEs
1
The frequency of
adverse events in
the mothers was
similar in the two
groups
C-100
73
N
Dropouts,
Due
to AE
n/a, 1
Hospitalizations
n/a,
n/a
4
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Allen, 2010
RCT
Effective
Arm
Genera
2
N at
Randomization
234
Reported Harms, SAE
and Number of
Patients
Other Harms
abnormalities (SAE)
n=12
XIII Abnormal clinical
and lab findings n=7
XII Injury, poisoning and
other external causes
n=2
XXVII External causes of
morbidity and mortality
(SAE) n=0
XI Infections due to L. or
B. (SAE) n=0
XI Hospitalization with
respiratory illness (SAE)
n=4
XI Infectious and
parasitic diseases (SAE)
n=12
V Endocrine, nutritional
and metabolic diseases
n=1
VI Diseases of the eye
and adnexa n=12
IV Diseases of the ear
and mastoid process
n=3
XI Diseases of the
respiratory system n=16
VII Diseases of the
digestive system n=12
XXIII Diseases of the
skin and subcutaneous
tissue n=1
XX Disease of
genitourinary system
n=5
XXVII Pregnancy,
childbirth and
puerperium n=18
XVIII Perinatal period
conditions (e.g. jaundice)
n=18
C-101
Patients
with
AEs
N
Dropouts,
Due
to AE
Hospitalizations
75
n/a,
n/a
1
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
III Congenital
malformations,
deformations and
chromosomal
abnormalities (SAE)
n=12
XIII Abnormal clinical
and lab findings n=4
XII Injury, poisoning and
other external causes
n=2
XXVII External causes of
morbidity and mortality
(SAE) n=2
XI Infections due to L. or
B. (SAE) n=0
XI Hospitalization with
respiratory illness (SAE)
n=1
VII Diarrhea n=4 (states
related to oligofructose)
Anderson, 2003
RCT
Not effective
1
St
72
Anderson, 2003
RCT
Not effective
Andriulli, 2008
RCT
Effective
2
65
VII Diarrhea n=0
1
La
132
VII Diarrhea (withdrew)
n=3
VII Abdominal discomfort
(withdrew) n=1
VII Vomiting (withdrew)
n=1
VII Abdominal pain
(withdrew) n=0
XXIII Skin rash n=0
States
adverse
events
are
not
different
between
groups, no further
data
C-102
Patients
with
AEs
N
Dropouts,
Due
to AE
4
n/a, 9
0
n/a, 5
5
25, 5
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Andriulli, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
2
135
Anukam, 2006
RCT
Effective
1
La
65
Anukam, 2006
RCT
Effective
2
60
VII Diarrhea (withdrew)
n=0
VII Abdominal discomfort
(withdrew) n=0
VII Vomiting (withdrew)
n=0
VII Abdominal pain
(withdrew) n=3
XXIII Skin rash
(withdrew) n=1
XVII Persistent
headache n=2
XIV Increased appetite
n=2
XVII Persistent
headache n=0
XIV Increased appetite
n=0
Anukam, 2008
RCT
Effectiveness
unclear
1
St
12
Anukam, 2008
RCT
Effectiveness
unclear
2
Anukam, 2009
RCT
Effectiveness
unclear
Anukam, 2009
RCT
Effectiveness
unclear
Other Harms
4
N
Drop
outs,
Due
to AE
30, 4
2
16, 0
0
3, 0
XI Bacteremia (SAE)
n=0
XXVII Death (SAE) n=0
XXIII Skin rash n=0
0
2, 0
12
XI Bacteremia (SAE)
n=0
XXVII Death (SAE) n=0
XXIII Skin rash n=3
3
n/a, 0
1
La
39
XVII Headache n=n/a
VII Nausea n=n/a
n/a
20,
n/a
2
20
XVII Headache n=n/a
VII Nausea n=n/a
n/a
13,
n/a
C-103
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Yogurt only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Arunachalam,
2000
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
13
VII Digestive problems
n=0
XIV Dietary sensitivities
n=0
XXVII Adverse general
health problems n=0
0
N
Drop
outs,
Due
to AE
0, 0
Arunachalam,
2000
RCT
Effective
2
12
VII Digestive problems
n=0
XIV Dietary sensitivities
n=0
XXVII Adverse general
health problems n=0
0
0, 0
Aso, 1992
RCT
Effective
1
La
29
XIII Abnormal lab
findings n=0
0
6, 0
Aso, 1992
RCT
Effective
2
29
XIII Abnormal lab
findings n=0
0
4, 0
Aso, 1995
RCT
Effective
1
La
68
VII Diarrhea (1) n=1
VII Constipation (1) n=1
XIII Elevation of the
hepatic transaminases
(1) n=1
XIII Elevation of serum
alanine
aminotransferase and
creatinine levels n=0
3
7, n/a
C-104
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
No medication
or placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Aso, 1995
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
70
VII Diarrhea (1) n=2
VII Constipation (1) n=0
XIII Elevation of the
hepatic transaminases
n=0
XIII Elevation of serum
alanine
aminotransferase and
creatinine levels n=1
3
Awad, 2010
RCT
Effective
1
La
60
XXVII Death (SAE) n=5
XI Probiotic bacteria in
blood (SAE) n=0
5
n/a,
n/a
Awad, 2010
RCT
Effective
2
30
XXVII Death (SAE) n=6
XI Probiotic bacteria in
blood n=0
6
n/a,
n/a
Awad, 2010
RCT
Effective
3
La
60
XXVII Death (SAE) n=14
XI Probiotic bacteria in
blood (SAE) n=0
14
n/a,
n/a
Baerheim, 1994
RCT
Not effective
1
La
25
XXI Messy discharge
n=4
4
n/a, 0
Baerheim, 1994
RCT
Not effective
2
22
XXI Messy discharge
n=1
1
n/a, 0
Bajaj, 2008
RCT
Effective
1
St
17
XI Sepsis -death (5)
(SAE) n=1 (states
unrelated)
1
3, 1
Bajaj, 2008
RCT
Effective
2
8
XI Sepsis -death (5)
(SAE) n=0
0
0, 0
C-105
Patients
with
AEs
N
Drop
outs,
Due
to AE
6, n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
No treatment
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Banaszkiewicz,
2005
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
43
VII Abdominal pain n=3
VII Vomiting n=1
XVII Headache n=0
4
N
Drop
outs,
Due
to AE
5, 1
Banaszkiewicz,
2005
RCT
Not effective
2
43
VII Abdominal pain n=5
VII Vomiting n=0
XVII Headache n=1
6
3, 0
Barraud, 2010
RCT
Not effective
1
Bi
87
VII Bowel ischemia
(SAE) n=0
XI Bacteremia due to
Lactobacillus (SAE) n=0
n/a
9, 0
Barraud, 2010
RCT
Not effective
2
80
VII Bowel ischemia
(SAE) n=0
XI Bacteremia due to
Lactobacillus (SAE) n=0
n/a
9, 0
Barreto-Zuniga,
2001
RCT
Effective
1
Bi
12
VII Bloating n=0
VII Loose stools n=0
XIII Routine blood
chemistry changes n=0
0
n/a, 0
Barreto-Zuniga,
2001
RCT
Effective
2
12
VII Bloating n=0
VII Loose stools n=0
XIII Routine blood
chemistry changes n=0
0
n/a, 0
Basu, 2007
RCT
Not effective
1
La
330
XIII Electrolyte
imbalance n=3
XI Septicemia (SAE) n=2
(states no LGG
complications)
XXVII Death (SAE) n=0
n/a
7, 5
Non-severe sepsis
patients in probiotics
group had a higher
mortality
rate
compared to control
(p=0.08)
C-106
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Non-probiotic
Antibiotics
unclear
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Basu, 2007
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
125
XI Septicemia (SAE) n=1
XX Renal failure (SAE)
n=1
n/a
N
Drop
outs,
Due
to AE
8, 2
Basu, 2007
RCT
Not effective
2
332
XIII Electrolyte
imbalance n=3
XI Septicemia (SAE) n=2
XXVII Death (SAE) n=1
n/a
9, 6
Placebo
Basu, 2007
RCT
Effective
2
128
XI Septicemia (SAE) n=3
XX Renal failure (SAE)
n=0
n/a
10, 3
ORS only
Basu, 2009
RCT
Effective
1
La
196
n/a
8, 4
Basu, 2009
RCT
Effective
2
196
n/a
11, 8
Basu, 2009
RCT
Effective
3
La
196
XIII Electrolyte
imbalance n=3
XI Septicemia (SAE) n=1
XXVII Death (SAE) n=0
XIII Electrolyte
imbalance n=4
XI Septicemia (SAE) n=3
XXVII Death (SAE) n=1
XIII Electrolyte
imbalance n=5
XI Septicemia (SAE) n=3
XXVII Death (SAE) n=0
n/a
10, 8
C-107
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Glucoseelectrolyte
rehydration
solution only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Beausoleil, 2007
RCT
Effective
Beausoleil, 2007
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
1
La
44
2
45
VII Softened stools n=8
XVII Taste disorder n=6
VII Abdominal cramps
n=4
VII Bloating n=3
VII Gastroesophageal
reflux n=2
VII Constipation n=2
VII Flatulence n=2
VII Modified stool colon
n=1 (states not related)
VII Nausea n=0
XXVII Death (SAE) n=3
(states unrelated to
preparation)
VII Vomiting n=0
VII Foul-smelling stools
n=0
XIX Hallucination n=0
XXIII Rash n=0
XXIII Pruritus n=1
VII Softened stools n=9
XVII Taste disorder n=7
VII Abdominal cramps
n=5
VII Bloating n=3
VII Gastroesophageal
reflux n=2
VII Constipation n=1
VII Flatulence n=1
VII Modified stool colon
n=2
VII Nausea n=4
XXVII Death (SAE) n=0
VII Vomiting n=1
VII Foul-smelling stools
n=1
XIX Hallucination n=1
XXIII Rash n=1
XXIII Pruritus n=0
Other Harms
Patients
with
AEs
21
20
C-108
N
Dropouts,
Due
to AE
n/a,
n/a
n/a,
n/a
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Bellomo, 1979
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
En
29
I Significant hematologic
change n=0
0
N
Drop
outs,
Due
to AE
0, 0
Bellomo, 1979
RCT
Effective
2
30
I Significant hematologic
change n=0
0
0, 0
Bertolami, 1999
C-RCT
Effectiveness
unclear
1
En
17
VII Nausea n=0
n/a
0, 0
Bertolami, 1999
C-RCT
Effectiveness
unclear
2
15
VII Nausea n=2
Besselink, 2008
RCT
Not effective
1
Bi
153
Besselink, 2008
RCT
Not effective
2
145
VII Bowel ischemia
(SAE) n=9
XXVII Death (SAE) n=24
VII Nausea n=20
VII Abdominal fullness
n=36
VII Diarrhea n=25
XI Infections caused by
administered probiotics
n=0
VII Bowel ischemia
(SAE) n=0
XXVII Death (SAE) n=9
VII Nausea n=23
VII Abdominal fullness
n=43
VII Diarrhea n=28
XI Infections caused by
administered probiotics
n=0
0, 0
n/a
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
3, 0
7, 5
C-109
Hospi
tali
zations
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Bin-Nun, 2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
St
72
XI Sepsis due to
administered probiotics
(SAE) n=0
No differences in
feeding intolerance
(diarrhea,
abdominal
distension,
vomiting),
no
increased
susceptibility
to
infections
Bin-Nun, 2005
RCT
Effective
2
73
XI Sepsis due to
administered probiotics
(SAE) n=0
n/a
n/a,
n/a
Black, 1997
CCT
Effectiveness
unclear
1
Bi
10
XXVII Feeling sick n=0
XXI Candida vaginitis
n=0
VII Diarrhea (severe)
n=0
VII Diarrhea n=0
n/a
0, 0
Black, 1997
CCT
Effectiveness
unclear
2
10
XXVII Feeling sick n=1
XXI Candida vaginitis
n=1
VII Diarrhea (severe)
n=1
VII Diarrhea n=0
Boge, 2009
RCT
Effective
1
St
44
XI Common infectious
diseases n=n/a
28
3, 2
Boge, 2009
RCT
Effective
1
St
113
XI Common infectious
diseases n=n/a
59
n/a, 4
Boge, 2009
RCT
Effective
2
42
XI Common infectious
diseases n=n/a
31
8, 7
n/a
N
Drop
outs,
Due
to AE
n/a,
n/a
1, 1
C-110
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Feeding
supplement
only
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Boge, 2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
109
XXVII Common
infectious diseases
n=n/a
Borgia, 1982
RCT
Effective
1
St
40
Borgia, 1982
RCT
Effective
2
40
Borgia, 1982
RCT
Effective
3
St
40
2, n/a
Borgia, 1982
RCT
Effective
4
St
40
3, n/a
61
2
patients
died
(age>=85,
cardiovascular
cause) but group
unclear
C-111
N
Drop
outs,
Due
to AE
n/a,
12
n/a
1, n/a
n/a
2, n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Antibiotics
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Bousvaros,
2005
RCT
Not effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
1
La
39
VII Perianal abscess
(SAE) n=1 (states not
related to probiotics)
XXVII Perirectal abscess
(SAE) n=1 (states not
related to probiotics)
VII Vomiting/unable to
tolerate n=3
VII Diarrhea (1) n=1
(states unrelated)
XXVII Acute swelling
n=1 (states not related)
VII Nausea n=1 (states
not related)
XXII Sore throat n=0
(states not related)
VII Abdominal pain n=1
(states not related)
XIX Diagnosis of eating
disorder n=1 (states not
related)
XXVII Cervical lymph
nodes n=0
XXVII Headache
dizziness n=0 (states not
related)
XXVII Fatigue n=0
(states not related)
Other Harms
Patients
with
AEs
7
C-112
N
Dropouts,
Due
to AE
14, 2
Hospitalizations
2
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
surgical
drainage
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Bousvaros,
2005
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
36
VII Perianal abscess
(SAE) n=0
VII Perirectal abscess
(SAE) n=0
VII Vomiting/unable to
tolerate n=0
VII Mild diarrhea n=1
XXVII Acute swelling
n=0
VII Nausea n=1
XXII Sore throat n=1
VII Abdominal pain n=2
XIX Diagnosis of eating
disorder n=1
XXVII Cervical lymph
nodes n=1
XXVII Headache
dizziness n=1
XXVII Fatigue n=1
8
Bravo, 2008
RCT
Not effective
1
Sa
41
VII Abdominal distension
or abdominal pain n=2
3
2, n/a
Bravo, 2008
RCT
Not effective
2
45
VII Abdominal distension
or abdominal pain n=n/a
4
2, n/a
Brophy, 2008
RCT
Not effective
1
Bi
71
VII Stomach cramps n=3
VII Indigestion n=1
XXVII Painful spots n=1
XVII Dizzy spells n=1
XXVII General decline in
well-being n=0
6
20, 3
C-113
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
0
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Brophy, 2008
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
76
VII Stomach cramps n=3
VII Indigestion n=1
XXVII Painful spots n=0
XVII Dizzy spells n=0
XXVII General decline in
well-being n=1
5
Bruno, 1981
RCT
Effective
1
En
25
I Blood chemistry
changes n=0
0
n/a,
n/a
Bruno, 1981
RCT
Effective
2
24
I Blood chemistry
changes n=0
0
n/a,
n/a
Bruzzese, 2007
C-RCT
Effective
1
La
19
VII Vomiting n=1
n/a
n/a,
n/a
Bruzzese, 2007
C-RCT
Effective
2
19
VII Vomiting n=0
n/a
n/a,
n/a
Bu, 2007
RCT
Effective
1
La
18
VII Acute gastroenteritis
n=n/a
VII Mild diarrhea n=0
n/a
1, n/a
Bu, 2007
RCT
Effective
2
9
VII Acute gastroenteritis
n=n/a
VII Mild diarrhea n=0
n/a
1, n/a
Chen, 2005
RCT
Effective
1
La
65
XXVII Nostril erosion
n=0
XXII Pneumonia n=0
XI Urinary tract infection
n=1 (states unrelated)
XXII Aspiration
pneumonia n=1 (states
unrelated)
XXII n=
n/a
n/a,
n/a
C-114
Patients
with
AEs
N
Drop
outs,
Due
to AE
19, 3
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Non-probiotic
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Chen, 2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
63
XXVII Nostril erosion
n=1 (states unrelated)
XXII Pneumonia n=1
(states unrelated)
XI Urinary tract infection
n=0
XXII Aspiration
pneumonia n=0
n/a
Chen, 2010
RCT
Effective
1
La
55
XI Upper respiratory
tract infection n=4
4
6, 4
Chen, 2010
RCT
Effective
2
63
XI Upper respiratory
tract infection n=5
5
7, 5
Chou, 2010
RCT
Effective
1
Bi
153
XXVII Growth adverse
effects n=0
XVII
Neurodevelopmental
adverse effects n=0
XVII Sensory adverse
effects n=0
n/a
n/a,
n/a
Chou, 2010
RCT
Effective
2
148
XXVII Growth adverse
effects n=0
XVII
Neurodevelopmental
adverse effects n=0
XVII Sensory adverse
effects n=0
n/a
n/a,
n/a
Chouraqui, 2004
RCT
Effectiveness
unclear
1
St
46
VII Regurgitation and
spitting n=5
VII Vomiting n=0
XV Growth
(suppression) n=0
5
n/a, 0
C-115
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Non-probiotic
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Chouraqui, 2004
RCT
Effectiveness
unclear
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
2
44
VII Regurgitation and
Spitting n=6
VII Vomiting n=0
XV Growth
(suppression) n=0
Chouraqui, 2008
RCT
Effective
1
Bi
70
VII Gastroenteritis (SAE
per author) (SAE) n=1
VII Gastroesophageal
reflux disease (SAE per
author) (SAE) n=0
VII Diarrhea (SAE per
author) n=2
XXVII Milk allergy (SAE
per author) n=2
VII Vomiting (SAE per
author) n=0
XI Febrile infection (SAE
per author) (SAE) n=1
XXV Surgery (SAE per
author) (SAE) n=0
VIII Pyrexia (SAE per
author) n=0
VII Rectal hemorrhage
(SAE per author) (SAE)
n=1
XX Pyelonephritis (SAE
per author) (SAE) n=1
XXII Bronchiolitis (SAE
per author) (SAE) n=2
XXII Cough (SAE per
author) n=1
XXVII Drug toxicity (SAE
per author) (SAE) n=0
XII Inguinal hernia (SAE
per author) (SAE) n=0
Other Harms
C-116
Patients
with
AEs
Hospitalizations
6
N
Dropouts,
Due
to AE
n/a, 0
n/a
10, 1
1
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Antibiotics
unclear
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Chouraqui, 2008
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
2
70
VII Gastroenteritis (SAE
per author) (SAE) n=0
VII Gastroesophageal
reflux disease (SAE per
author) (SAE) n=1
VII Diarrhea (SAE per
author) n=1
XXVII Milk allergy (SAE
per author) n=0
VII Vomiting (SAE per
author) n=1
XI Febrile infection (SAE
per author) (SAE) n=1
XXV Surgery (SAE per
author) (SAE) n=0
VIII Pyrexia (SAE per
author) n=2
VII Rectal hemorrhage
(SAE per author) (SAE)
n=0
XX Pyelonephritis (SAE
per author) (SAE) n=0
XXII Bronchiolitis (SAE
per author) (SAE) n=0
XXII Cough (SAE per
author) n=0
XXVII Drug toxicity (SAE
per author) (SAE) n=1
XII Inguinal hernia (SAE
per author) (SAE) n=0
Other Harms
Patients
with
AEs
n/a
C-117
N
Dropouts,
Due
to AE
17, 2
Hospitalizations
1
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
unclear
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Chouraqui, 2008
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
3
Bi
70
VII Gastroenteritis (SAE
per author) (SAE) n=0
VII Gastroesophageal
reflux disease (SAE per
author) (SAE) n=0
VII Diarrhea (SAE per
author) n=1
XXVII Milk allergy (SAE
per author) n=0
VII Vomiting (SAE per
author) n=0
XI Febrile infection (SAE
per author) (SAE) n=0
XXV Surgery (SAE per
author) (SAE) n=1
VIII Pyrexia (SAE per
author) n=0
VII Rectal hemorrhage
(SAE per author) (SAE)
n=0
XX Pyelonephritis (SAE
per author) (SAE) n=0
XXI Bronchiolitis (SAE
per author) (SAE) n=3
XXI Cough (SAE per
author) n=0
XXVII Drug toxicity (SAE
per author) (SAE) n=0
XII Inguinal hernia (SAE
per author) (SAE) n=2
Other Harms
Patients
with
AEs
n/a
C-118
N
Dropouts,
Due
to AE
16, 1
Hospitalizations
2
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
unclear
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Chouraqui, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
4
Bi
74
VII Gastroenteritis (SAE
per author) (SAE) n=0
VII Gastroesophageal
reflux disease (SAE per
author) (SAE) n=0
VII Diarrhea (SAE per
author) n=0
XXVII Milk allergy (SAE
per author) n=0
VII Vomiting (SAE per
author) n=2
XI Febrile infection (SAE
per author) (SAE) n=0
XXV Surgery (SAE per
author) (SAE) n=0
VIII Pyrexia (SAE per
author) n=0
VII Rectal hemorrhage
(SAE per author) (SAE)
n=0
XX Pyelonephritis (SAE
per author) (SAE) n=1
XXI Bronchiolitis (SAE
per author) (SAE) n=1
XXI Cough (SAE per
author) n=0
XXVII Drug toxicity (SAE
per author) (SAE) n=0
XII Inguinal hernia (SAE
per author) (SAE) n=0
n/a
N
Drop
outs,
Due
to AE
14, 1
Chui, 2009
RCT
Effectiveness
unclear
1
En
20
XXVII Death (SAE) n=1
n/a
0, 0
Chui, 2009
RCT
Effectiveness
unclear
2
25
XXVII Death (SAE) n=2
n/a
0, 0
C-119
Patients
with
AEs
Hospi
tali
zations
0
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Antibiotics
unclear
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Coccorullo,
2010
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
22
VII Vomiting n=0
VII Bloating n=0
VII Increased flatulence
n=0
0
N
Drop
outs,
Due
to AE
0, 0
Coccorullo,
2010
RCT
Effectiveness
unclear
2
22
VII Vomiting n=0
VII Bloating n=0
VII Increased flatulence
n=0
0
0, 0
Connolly, 2005
RCT
Effective
1
La
14
XIV D-lactic acidosis n=0
0
0, 0
Connolly, 2005
RCT
Effective
2
10
XIV D-lactic acidosis n=0
0
0, 0
Cooper, 2006
RCT
Effective
1
Bi
98
n/a
n/a,
n/a
Cooper, 2006
RCT
Effective
2
173
Correa, 2005
RCT
Effective
1
St
87
XI Pneumonia -death (5)
(SAE) n=1 (states
infection not due to
supplemented bacteria)
n/a
7, 1
Correa, 2005
RCT
Effective
2
82
XI Pneumonia -death (5)
(SAE) n=0
n/a
5, 0
No difference in
gastrointestinal
or
respiratory problems
between groups
Patients
with
AEs
n/a,
n/a
C-120
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Formula only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Cui, 2004
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Ba
103
XIII Body weight
changes n=0
VIII Temperature
changes n=0
XXII Respiratory rate
changes n=0
II Heart rate changes
n=0
II Blood pressure
changes n=0
XIII Blood routine
changes n=0
IX Liver function
changes n=0
XX Renal function
changes n=0
0
N
Dropouts,
Due
to AE
n/a, 0
Cui, 2004
RCT
Effective
2
Bi
101
XIII Body weight
changes n=0
VIII Temperature
changes n=0
XXII Respiratory rate
changes n=0
II Heart rate changes
n=0
II Blood pressure
changes n=0
XIII Blood routine
changes n=0
IX Liver function
changes n=0
XX Renal function
changes n=0
0
n/a, 0
CunninghamRundles, 2000
CCT
Effectiveness
unclear
1
La
VII Flatulence n=0
0
n/a, 0
C-121
Patients
with
AEs
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Other
Probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
CunninghamRundles, 2000
CCT
Effectiveness
unclear
Arm
Genera
Czaja, 2007
RCT
Effective
1
La
Czaja, 2007
RCT
Effective
N at
Random
ization
VII Flatulence n=0
0
N
Drop
outs,
Due
to AE
n/a, 0
15
XXI Abnormal vaginal
discharge n=6
XXI External genital
irritation n=1
XI Vaginal candidiasis
n=4
XXI Vaginal odor n=1
VII Abdominal or pelvic
cramps / abdominal pain
n=0
XX Dysuria n=0
n/a
0, 0
2
15
XXI Abnormal vaginal
discharge n=7
XXI External genital
irritation n=5
XI Vaginal candidiasis
n=2
XXI Vaginal odor n=0
VII Abdominal or pelvic
cramps / abdominal pain
n=1
XX Dysuria n=1
Dadak, 2006
RCT
Not effective
1
La
6
Dadak, 2006
RCT
Not effective
2
6
2
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
0, 0
1
death,
unclear
group
n/a
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
n/a,
n/a
1, n/a
C-122
Hospi
tali
zations
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
De Preter, 2006
C-RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Sa
45
VII Flatulence n=0
n/a
N
Drop
outs,
Due
to AE
,
De Preter, 2006
C-RCT
Effectiveness
unclear
2
45
VII Flatulence n=0
n/a
,
de Roos, 1999
RCT
Not effective
1
St
39
n/a
n/a,
n/a
de Roos, 1999
RCT
Not effective
2
39
De
Simone,
1992
RCT
Effective
1
Bi
15
VII Intestinal rumbling
and flatulence (1) n=2
VII Variation in stool
consistency and diarrhea
n=0
2
0, 0
De
Simone,
1992
RCT
Effective
2
10
VII Intestinal rumbling
and flatulence n=0
VII Variation in stool
consistency and diarrhea
n=0
1
0, 0
De
Simone,
2001
CCT
Effective
1
St
130
XIII Blood count changes
n=0
XIII Blood chemistry
changes n=0
n/a
n/a,
n/a
De
Simone,
2001
CCT
Effective
2
En
121
XIII Blood count changes
n=0
XIII Blood chemistry
changes n=0
1
gastrointestinal
complaint,
group
unclear
Patients
with
AEs
n/a,
n/a
n/a,
n/a
C-123
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Antibiotics
unclear
Antibiotics
needed
Placebo
Yogurt only
Placebo
Other
Probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Dekker, 2009
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
170
III Congenital
malformation
hospitalization (SAE)
n=3
XXIII Dermatological
hospitalization (SAE)
n=3
VII Gastrointestinal
hospitalization (SAE)
n=7
XX Genito-urinary
hospitalization (SAE)
n=1
XI Infectious diseases
hospitalization (SAE)
n=6
XXVII Neurology
hospitalization (SAE)
n=0
VI Ophthalmology &
otology hospitalization
(SAE) n=4
XXVII Orthopedics &
rheumatoid
hospitalization (SAE)
n=0
XXII Respiratory
hospitalization (SAE)
n=9
XI Trauma and injury
hospitalization (SAE)
n=1
VII Diarrhea or vomiting
(SAE) n=3
XXVII Other
hospitalizations (SAE)
n=11
No
statistically
significant
differences between
groups for diarrhea
after
antibiotics,
other
diarrhea,
reflux or spilling,
abdominal pain or
vomiting.
Hospitalizations of
mothers 6.4, 6.9
and 3.2% in the 3
arms
C-124
Patients
with
AEs
n/a
N
Dropouts,
Due
to AE
26,
n/a
Hospitalizations
39
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Dekker, 2009
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
2
171
III Congenital
malformation
hospitalization (SAE)
n=2
XXIII Dermatological
hospitalization (SAE)
n=1
VII Gastrointestinal
hospitalization (SAE)
n=7
XX Genito-urinary
hospitalization (SAE)
n=3
XI Infectious diseases
hospitalization (SAE)
n=3
XXVII Neurology
hospitalization (SAE)
n=0
VI Ophthalmology &
otology hospitalization
(SAE) n=6
XXVII Orthopedics &
rheumatoid
hospitalization (SAE)
n=1
XXII Respiratory
hospitalization (SAE)
n=16
XI Trauma and injury
hospitalization (SAE)
n=1
VII Diarrhea or vomiting
(SAE) n=2
XXVII Other
hospitalizations (SAE)
n=4
Other Harms
Patients
with
AEs
n/a
C-125
N
Dropouts,
Due
to AE
21,
n/a
Hospitalizations
39
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Dekker, 2009
RCT
Effective
Delia, 2002
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
3
Bi
171
III Congenital
malformation
hospitalization (SAE)
n=3
XXIII Dermatological
hospitalization (SAE)
n=4
VII Gastrointestinal
hospitalization (SAE)
n=0
XX Genito-urinary
hospitalization (SAE)
n=1
XI Infectious diseases
hospitalization (SAE)
n=7
XXVII Neurology
hospitalization (SAE)
n=1
VI Ophthalmology &
otology hospitalization
(SAE) n=5
XXVII Orthopedics &
rheumatoid
hospitalization (SAE)
n=0
XXII Respiratory
hospitalization (SAE)
n=6
XI Trauma and injury
hospitalization (SAE)
n=4
VII Diarrhea or vomiting
(SAE) n=2
XXVII Other
hospitalizations (SAE)
n=6
1
St
95
VII Gastrointestinal
toxicity n=0
XXVII Death (SAE) n=0
Other Harms
Patients
with
AEs
0
C-126
N
Dropouts,
Due
to AE
19,
n/a
0, 0
Hospitalizations
36
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Delia, 2002
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
2
95
VII Gastrointestinal
toxicity n=2
XXVII Death (SAE) n=0
Delia, 2007
RCT
Effective
1
St
245
XXVI Septic shock
(SAE) n=0
XI Bacteremia (SAE)
n=0
XI Sepsis (SAE) n=0
Delia, 2007
RCT
Effective
2
245
Dewan, 2007
RCT
Effectiveness
unclear
1
St
Dewan, 2007
RCT
Effectiveness
unclear
2
N
Drop
outs,
Due
to AE
2, 2
n/a
2, 1
XXVI Septic shock
(SAE) n=0
XI Bacteremia (SAE)
n=0
XI Sepsis (SAE) n=0
n/a
6, 0
39
XI Bronchopneumonia
death (5) (SAE) n=1
1
7, 1
2
41
XI Bronchopneumonia
death (5) (SAE) n=1
1
5, 1
Dolin, 2009
RCT
Effective
1
Ba
26
XVII Headache n=n/a
5
0, 0
Dolin, 2009
RCT
Effective
2
29
XVII Headache n=1
6
3, 0
Dubey, 2008
RCT
Effective
1
St
113
n/a
n/a, 0
XXIII Rash n=0
Other Harms
1
myocardial
infarction
death,
group unclear
No side effects were
noticed that required
treatment
discontinuation
C-127
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Non-probiotic
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Dubey, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a, 0
2
111
Duman, 2005
RCT
Effective
1
Sa
204
XXIII Skin reaction n=1
II Palpitation n=0
VII Dry mouth n=1
XVII Metallic taste n=1
VII Apthons lesion in
mouth n=0
VI Blurred vision n=0
3
8, 1
Duman, 2005
RCT
Effective
2
185
XXIII Skin reaction n=n/a
II Palpitation n=1
VII Dry mouth n=0
XVII Metallic taste n=0
VII Apthons lesion in
mouth n=1
VI Blurred vision n=n/a
3
13, 1
Dupont, 2010
RCT
Effective
1
Bi
30
VII Vomiting n=1
(feeding-related per
author)
VII Colitis n=1 (feeding
related per author)
VII Constipation n=0
(feeding-related per
author)
VII Regurgitations n=0
(feeding-related per
author)
VII Flatulence n=0
(feeding-related per
author)
n/a
10, 4
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
XXIII Rash n=0
C-128
Triple therapy
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Dupont, 2010
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
2
32
Dylewski, 2010
RCT
Effective
1
La
233
VII Vomiting n=4
(feeding-related per
author)
VII Colitis n=1 (feeding
related per author)
VII Constipation n=5
(feeding-related per
author)
VII Regurgitations n=3
(feeding-related per
author)
VII Flatulence n=1
(feeding-related per
author)
XXVII Death (SAE) n=3
VII Eructation n=0
VII Constipation n=12
VII Flatulence n=7
VII Nausea n=7
VII Vomiting n=5
VII Dyspepsia n=0
VII Dysphagia n=1
VII Fecal incontinence
n=1
XXII Dyspnea n=0
VII Gastro esophageal
adverse events n=1
VII Reflux gastritis n=1
XI Vulvovaginal mycotic
infection n=0
XV Muscle spasms n=0
XXVII Hyperthermia n=0
XIII Pyrexia n=0
XV Arthralgia n=1
XVII Headache n=1
Other Harms
C-129
Patients
with
AEs
n/a
N
Dropouts,
Due
to AE
6, 5
72
17, 0
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Formula only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Dylewski, 2010
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
239
XXVII Death (SAE) n=4
VII Eructation n=1
VII Constipation n=8
VII Flatulence n=13
VII Nausea n=5
VII Vomiting n=0
VII Dyspepsia n=2
VII Dysphagia n=0
VII Fecal incontinence
n=0
XXII Dyspnea n=1
VII Gastro esophageal
adverse events n=0
VII Reflux gastritis n=1
XI Vulvovaginal mycotic
infection n=2
XV Muscle spasms n=2
XXVII Hyperthermia n=1
XIII Pyrexia n=1
XV Arthralgia n=0
XVII Headache n=0
Presence of at least
1
treatmentemergent
non
serious
adverse
event: 76
Ehrstrom, 2010
RCT
Effectiveness
unclear
1
La
60
XXI Vulvovaginal
pruritus n=1
XXI Vaginal bleeding
n=1
XXI Swollen and vulva
n=0
XVII Headache n=0
XXI Vulvar itching n=0
n/a
n/a,
n/a
Ehrstrom, 2010
RCT
Effectiveness
unclear
2
35
XXI Vulvovaginal
pruritus n=5
XXI Vaginal bleeding
n=0
XXI Swollen and vulva
n=1
XVII Headache n=1
XXI Vulvar itching n=1
n/a
n/a,
n/a
C-130
Patients
with
AEs
76
N
Dropouts,
Due
to AE
18, 0
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Eriksson, 2005
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
N
Drop
outs,
Due
to AE
36,
n/a
1
La
127
XI Candida infection
n=n/a (14.2%)
XXI Itching and burning
n=4
n/a
Eriksson, 2005
RCT
Not effective
2
128
XI Candida infection
n=n/a (13.5%)
XXI Itching and burning
n=8
n/a
32,
n/a
Falck, 1999
RCT
Effective
1
St
228
XXII Respiratory related
to common cold n=34
(16%)
77
15, 4
Falck, 1999
RCT
Effective
2
114
XXII Respiratory related
to common cold n=14
(13%)
36
6, 3
Felley, 2001
RCT
Effective
1
La
26
VII Diarrhea (profuse;
withdrew) n=1 (while
taking clarithromycin)
n/a
1, 1
Felley, 2001
RCT
Effective
2
27
VII Diarrhea (profuse)
n=0
Feng, 1999
RCT
Effective
1
St
36
VII Nausea (1) n=2
2
0, 0
Feng, 1999
RCT
Effective
2
36
VII Nausea (1) n=3
3
0, 0
Folster-Holst,
2006
RCT
Not effective
1
La
26
VII Diarrhea (mild) n=4
VII Nausea/vomiting n=3
VIII Fever n=1
XXIII Urticaria n=0
n/a
5, 0
0, 0
C-131
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Other
Probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Folster-Holst,
2006
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
28
VII Diarrhea n=4
VII Nausea/vomiting n=4
VIII Fever n=1
XXIII Urticaria n=1
n/a
N
Drop
outs,
Due
to AE
7, 1
Forestier, 2008
RCT
Effective
1
La
118
XI Lactobacillus-related
sepsis (SAE) n=0
n/a
16, 0
Forestier, 2008
RCT
Effective
2
118
XI Lactobacillus-related
sepsis (SAE) n=0
French, 2009
RCT
Effective
1
La
21
XII Injection site
temporary pain or
redness n=n/a
XXVII Febrile illness n=0
n/a
3, 0
French, 2009
RCT
Effective
2
26
XII Injection site
temporary pain or
redness n=n/a
XXVII Febrile illness n=0
n/a
4, 0
Frohmader,
2010
RCT
Effective
1
St
20
XXVII Death (SAE) n=5
XI Infections due to
probiotic strains (SAE)
n=0
n/a
0, 0
Frohmader,
2010
RCT
Effective
2
25
XXVII Death (SAE) n=3
XI Infections due to
probiotic strains n=0
n/a
0, 0
12, 0
C-132
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Fujimori, 2009
RCT
Effective
Fujimori, 2009
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
40
XIII Blood count changes
n=0
XIII Liver enzyme
changes n=0
XIII Serum urea nitrogen
changes n=0
XIII Creatinine changes
n=0
XIII Electrolytes changes
n=0
XIII Total protein /
cholesterol changes n=0
XIII Albumin changes
n=0
0
N
Dropouts,
Due
to AE
11, 0
2
40
XIII Blood count changes
n=0
XIII Liver enzyme
changes n=0
XIII Serum urea nitrogen
changes n=0
XIII Creatinine changes
n=0
XIII Electrolytes changes
n=0
XIII Total protein /
cholesterol changes n=0
XIII Albumin changes
n=0
0
15, 0
C-133
Patients
with
AEs
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Prebiotics
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Fujimori, 2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
3
Bi
40
XIII Blood counts n=0
XIII Liver enzyme
changes n=0
XIII Serum urea nitrogen
changes n=0
XIII Creatinine changes
n=0
XIII Electrolytes changes
n=0
XIII Total protein / total
cholesterol changes n=0
XIII Albumin changes
n=0
Gade, 1989
RCT
Effective
1
St
32
Gade, 1989
RCT
Effective
2
22
Galpin, 2005
RCT
Not effective
1
La
81
Galpin, 2005
RCT
Not effective
2
Gao, 2010
RCT
Effective
Gao, 2010
RCT
Effective
Other Harms
0
N
Drop
outs,
Due
to AE
11, 0
n/a
n/a, 0
n/a
n/a, 0
VII Vomiting n=0
0
1, 1
83
VII Vomiting n=0
0
2, 0
1
La
85
VIII Fever n=0
VII Hematochezia n=0
0
7, 0
2
84
VIII Fever n=1 (not study
related per author)
VII Hematochezia n=1
(not study related per
author)
2
8, 0
1
polyneuritis
hospitalization
(withdrawal), group
unclear
C-134
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Gao, 2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
3
La
86
XIII Fever n=1(not study
related per author)
VII Hematochezia n=0
1
N
Drop
outs,
Due
to AE
4, 0
Garcia
Vilela,
2008
RCT
Effectiveness
unclear
1
Sa
18
VII Abdominal pain,
vomiting and diarrhea
n=0
0
1, 0
Garcia
Vilela,
2008
RCT
Effectiveness
unclear
2
16
VII Abdominal pain,
vomiting and diarrhea
n=2
Gerasimou,
2010
RCT
Effective
1
Bi
48
XI Upper respiratory
infections n=11
XI Lower respiratory
infection n=4
XXIII Herpetic stomatitis
n=7
VII Diarrhea n=3
VII Constipation n=6
VII Abdominal colic n=5
XXVII Burn (SAE) n=1
(states unrelated)
XXII Croup (SAE) n=1
(states unrelated)
XXVII Head injury (SAE)
n=0
XXVII Food poisoning
n=0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
2, 2
26
C-135
5, 2
Control
Category
Placebo
Antibiotics
needed
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Gerasimou,
2010
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
2
48
XI Upper respiratory
infections n=10
XI Lower respiratory
infection n=5
XXIII Herpetic stomatitis
n=5
VII Diarrhea n=2
VII Constipation n=6
VII Abdominal colic n=4
XXVII Burn (SAE) n=0
XXII Croup (SAE) n=0
XXVII Head injury (SAE)
n=1 (states unrelated)
XXVII Food poisoning
n=2 (states unrelated)
Gibson, 2008
RCT
Not effective
1
Bi
72
XI Intestinal infections
disease n=21
VII Symptoms and signs
involving the digestive
system n=11
VII Feeding problems
n=11
XI Respiratory infections
n=47
XI Candidiasis n=6
XXIII Dermatitis n=13
VII Parent perception of
constipation/irritability (
n=1 (drop out)
XXVII Death (SAE) n=0
Other Harms
C-136
Patients
with
AEs
Hospitalizations
24
N
Dropouts,
Due
to AE
1, 1
61
17, 1
18
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Gibson, 2008
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
70
XI Intestinal infections
disease n=29
VII Symptoms and signs
involving the digestive
system n=8
VII Feeding problems
n=22
XI Respiratory infections
n=49
XI Candidiasis n=9
XXIII Dermatitis n=11
VII Parent perception of
constipation/irritability
n=1 (drop out)
XXVII Death (SAE) n=0
65
N
Drop
outs,
Due
to AE
27, 1
Gill, 2001
RCT
Effective
1
Bi
15
VII Digestive discomfort
n=0
0
0, 0
Gill, 2001
RCT
Effective
2
Bi
15
VII Digestive discomfort
n=1
1
1, 1
Gionchetti, 2000
RCT
Effective
1
St
20
XIII CBC n=0
XIII Blood chemistry
changes n=0
0
0, 0
Gionchetti, 2000
RCT
Effective
2
20
XIII CBC n=0
XIII Blood chemistry
changes n=0
0
0, 0
Gionchetti, 2003
RCT
Effective
1
St
20
XIII Blood count changes
n=0
XIII Blood chemistry
changes n=0
0
0, 0
C-137
Patients
with
AEs
Hospi
tali
zations
11
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Formula only
Other
Probiotic
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Gionchetti, 2003
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
20
XIII Blood count changes
n=0
XIII Blood chemistry
changes n=0
0
N
Drop
outs,
Due
to AE
0, 0
Goossens, 2003
RCT
Effective
1
La
11
VII 5 liquid stools per
day n=0
n/a
0, 0
Goossens, 2003
RCT
Effective
2
11
5 liquid stools per day1
Gracheva, 1999
CCT
Effective
1
Bi
30
VII Abdominal pain
(treatment discontinued)
n=1
1
n/a,
n/a
Gracheva, 1999
CCT
Effective
2
Bi
20
VII Abdominal pain n=0
0
n/a,
n/a
2, 1
C-138
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Other
Probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Gruber, 2007
RCT
Not effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
1
La
56
XI Lower respiratory
tract infections n=24
XI Ear nose and throat
infections n=8
VII Gastrointestinal
complaints n=18
XI Other infections n=22
XXIII Skin disorders n=9
XXVII Conjunctivitis,
dental problems or
unrest n=9
VII Acute enteritis n=1
(states not related to
study medication)
XXIII Eczema
herpeticatum n=1 (states
not related to study
medication)
XXII Spasmodic croup
n=1 (states not related to
study medication)
VII Inguinal hernia n=1
(states not related to
study medication)
XI Pneumonia n=1
(states not related to
study medication)
Other Harms
Patients
with
AEs
46
C-139
N
Dropouts,
Due
to AE
n/a,
n/a
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Gruber, 2007
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
50
XI Lower respiratory
tract infections n=18
XI Ear nose and throat
infections n=15
VII Gastrointestinal
complaints n=10
XI Other infections n=16
XXIII Skin disorders n=5
XXVII Conjunctivitis,
dental problems or
unrest n=7
VII Acute enteritis n=0
XXIII Eczema
herpeticatum n=0
XXII Spasmodic croup
n=0
VII Inguinal hernia n=0
XI Pneumonia n=0
38
Guillemard,
2010
RCT
Effective
1
St
537
XV Muscular-bone
adverse events n=n/a
VII Gastrointestinal
adverse events n=n/a
XI Infections other than
common infectious
diseases n=n/a
137
n/a,
n/a
Guillemard,
2010
RCT
Effective
2
535
XV Muscular-bone
adverse events n=n/a
VII Gastrointestinal
adverse events n=n/a
XI Infections other than
common infectious
diseases n=n/a
139
n/a,
n/a
Guyonnet, 2009
RCT
Effective
1
St
144
VII Adverse digestive
comfort n=0
0
n/a, 0
C-140
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Guyonnet, 2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
2
69
VII Adverse digestive
comfort n=0
Guyonnet, 2009
RCT
Effective
3
St
147
VII Adverse digestive
comfort n=0
Habermann,
2001
RCT
Effective
1
En
70
VII Various
gastrointestinal
complaints n=4
Habermann,
2001
RCT
Effective
2
66
Habermann,
2002
RCT
Effective
1
En
Habermann,
2002
RCT
Effective
2
Other Harms
Patients
with
AEs
0
N
Drop
outs,
Due
to AE
n/a, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
No
intervention
n/a, 0
No difference in
blood and clinical
lab panels between
groups
4
n/a,
n/a
VII Various
gastrointestinal
complaints n=3
3
n/a,
n/a
78
VII Disgust n=n/a
VII Nausea n=n/a
VII Vomiting n=n/a
VII Meteorism n=n/a
I Blood count changes
n=0
XXVII Clinical chemical
panel changes n=0
12
n/a,
n/a
79
VII Disgust n=n/a
VII Nausea n=n/a
VII Vomiting n=n/a
VII Meteorism n=n/a
I Blood count changes
n=0
XXVII Clinical chemical
panel changes n=0
13
n/a,
n/a
C-141
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
HaschkeBecher, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
19
XI Bronchopneumonia
n=0
VII Vomiting n=0
XI Otitis n=0
XVII Neuropathy n=0
Increased D-lactate
excretion
in
probiotic
group
compared
to
breastfed group
HaschkeBecher, 2008
RCT
Effective
2
26
Hatakka, 2008
C-RCT
Not effective
1
La
Hatakka, 2008
C-RCT
Not effective
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
2, 0
XI Bronchopneumonia
n=1
VII Vomiting n=1
XI Otitis n=1
XVII Neuropathy n=1
n/a
8, 4
19
VII Gastrointestinal
complaints n=n/a
XXVII Any signs of
illness n=n/a
n/a
0, 0
2
19
VII Gastrointestinal
complaints n=n/a
XXVII Any signs of
illness n=n/a
Heimburger,
1994
RCT
Not effective
1
La
31
Heimburger,
1994
RCT
Not effective
2
31
0, 0
Discontinuation due
to gastric retention
of feeding, patient
removal of feeding
tube, death, number
and group unclear
n/a
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Antibiotics
unclear
Antibiotics
unclear
Placebo
Placebo
13,
n/a
8, n/a
C-142
Hospi
tali
zations
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Hemmerling,
2009
RCT
Effective
Hemmerling,
2009
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
1
La
3
XXI Vaginal discharge
n=1
VII Abdominal pain n=1
XXI Metrorrhagia n=0
XXI Vulvovaginitis n=0
XVII Headache n=1
XXI Vaginal candidiasis
n=0
XXI Vaginal odor n=1
XXI Erythema n=0
XXI Petechiae n=0
XXI Edema n=0
XXI Abrasion n=0
XXI Laceration n=0
XX Urinary tract infection
n=0
2
3
XXI Vaginal discharge
n=0
VII Abdominal pain n=1
XXI Metrorrhagia n=2
XXI Vulvovaginitis n=1
XVII Headache n=1
XXI Vaginal candidiasis
n=1
XXI Vaginal odor n=0
XXI Erythema n=1
XXI Petechiae n=0
XXI Edema n=1
XXI Abrasion n=0
XXI Laceration n=1
XXI Urinary tract
infection n=1
Other Harms
1 Gastroenteritis, 1
ear pain, 1 upper
respiratory
tract
infection, treatment
group unclear
C-143
Patients
with
AEs
3
N
Dropouts,
Due
to AE
0, 0
3
0, 0
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Hemmerling,
2009
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
3
La
3
XXI Vaginal discharge
n=2
VII Abdominal pain n=2
XXI Metrorrhagia n=0
XXI Vulvovaginitis n=1
XVII Headache n=1
XXI Vaginal candidiasis
n=1
XXI Vaginal odor n=2
XXI Erythema n=0
XXI Petechiae n=1
XXI Edema n=0
XXI Abrasion n=1
XXI Urinary tract
infection n=0
3
N
Dropouts,
Due
to AE
0, 0
Hemmerling,
2009
RCT
Effective
4
La
3
XXI Vaginal discharge
n=2
VII Abdominal pain n=0
XXI Metrorrhagia n=2
XXI Vulvovaginitis n=2
XVII Headache n=0
XXI Vaginal candidiasis
n=1
XXI Vaginal odor n=0
XXI Erythema n=1
XXI Petechiae n=0
XXI Edema n=0
XXI Abrasion n=0
XXI Urinary tract
infection n=0
3
0, 0
Higashikawa,
2009
RCT
Effective
1
La
24
XX Abnormal changes in
urinalysis n=0
XIII Abnormal changes
in serum biochemical
parameters n=0
n/a
0, n/a
C-144
Patients
with
AEs
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Higashikawa,
2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
La
22
XX Abnormal changes in
urinalysis n=0
XIII Abnormal changes
in serum biochemical
parameters n=0
Higashikawa,
2009
RCT
Effective
3
St
22
XX Abnormal changes in
urine analysis n=0
XIII Abnormal changes
in serum biochemical
parameters n=0
Hilton, 1997
RCT
Effective
1
La
200
VII Abdominal cramps
n=2
2
74, 0
Hilton, 1997
RCT
Effective
2
200
VII Abdominal cramps
n=2
n/a
81, 0
Hirata, 2002
CCT
Effective
1
Sa
18
VII Constipation (1) n=1
XVII Exacerbation of
headaches n=0
VIII Dry cough n=0
XVII Dizziness n=0
XVII Other neurological
symptoms n=0
VII Gastrointestinal
symptoms n=0
XXIII Skin symptoms
n=0
n/a
2, 0
n/a
N
Drop
outs,
Due
to AE
3, n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Other
Probiotic
1, n/a
C-145
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Hirata, 2002
CCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
18
VII Constipation (mild)
n=0
XVII Exacerbation of
headaches n=0
VIII Dry cough n=0
XVII Dizziness n=0
XVII Other neurological
symptoms n=0
VII Gastrointestinal
symptoms n=0
XXIII Skin symptoms
n=0
n/a
Hochter,1990
RCT
Effective
1
Sa
43
VII Constipation n=1
1
n/a,
n/a
Hochter,1990
RCT
Effective
2
49
VII Vomiting n=1
1
n/a,
n/a
Honeycutt, 2007
RCT
Not effective
1
La
31
XXVII Death (SAE) n=2
VII Nausea n=1
XI Lactobacillus
bacteremia (SAE) n=0
3
4, 3
Honeycutt, 2007
RCT
Not effective
2
30
XXVII Death (SAE) n=4
VII Nausea n=1
XI Lactobacillus
bacteremia (SAE) n=0
5
5, 5
Hong, 2010
RCT
Effective
1
Bi
36
XXVII Common cold,
headache, cystitis, and /
or low back pain n=8
n/a
1, 1
12 patients reported
common
cold,
headache, cystitis,
low
back
pain,
exacerbation
of
abdominal
pain,
exacerbation
of
constipation
but
group unclear. 8
AEs in each group
C-146
Patients
with
AEs
N
Drop
outs,
Due
to AE
2, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Hong, 2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
34
XXVII Common cold,
headache, cystitis, and /
or low back pain n=8
n/a
Horvat, 2010
RCT
Effective
1
La
20
XI Mild wound infection
with secretion n=0
n/a
n/a,
n/a
Horvat, 2010
RCT
Effective
2
La
20
XI Mild worsened
infection with secretion
n=1
n/a
n/a,
n/a
Horvat, 2010
RCT
Effective
3
28
XI Mild infection with
secretion n=1
1
n/a,
n/a
Ishikawa, 2002
RCT
Effective
1
Sa
11
XI Coryza-like illness
n=1
VII Abdominal pain n=1
VII Diarrhea n=0
VII Vomiting n=0
1
0, 0
Ishikawa, 2002
RCT
Effective
2
10
XI Coryza-like illness
n=0
VII Abdominal pain n=0
VII Diarrhea n=0
VII Vomiting n=0
0
0, 0
Ishikawa, 2003
RCT
Effectiveness
unclear
1
La
28
n/a
n/a,
n/a
Ishikawa, 2003
RCT
Effectiveness
unclear
2
21
0
n/a,
n/a
2 patients with soft
stools
and
abdominal
discomfort,
probiotics group but
unclear which one
VII Abdominal discomfort
n=0
VII Loose stools n=0
C-147
Patients
with
AEs
N
Drop
outs,
Due
to AE
1, 1
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Other
Probiotic
No treatment
No treatment
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Ishikawa, 2003
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
3
La
29
Ishikawa, 2005
RCT
Effective
1
La
99
Ishikawa, 2005
RCT
Effective
2
Ishikawa, 2005
RCT
Effective
3
La
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
XVI Colorectal cancer
(2) (SAE) n=2
XVII Cerebral
hemorrhage -death
(SAE) n=0
VII Peritonitis (3,
surgery) (SAE) n=0
XVI Lung cancer -death
(SAE) n=0
n/a
3, n/a
0
97
XVI Colorectal cancer
(2) (SAE) n=1
XVII Cerebral
hemorrhage -death
(SAE) n=0
VII Peritonitis (3,
surgery) (SAE) n=0
XVI Lung cancer -death
(SAE) n=0
n/a
4, n/a
0
103
XVI Colorectal cancer
(SAE) n=1
XVII Cerebral
hemorrhage -death
(SAE) n=1
XVI Lung cancer -death
(SAE) n=0
VII Peritonitis (SAE) n=1
n/a
7, n/a
1
2 patients taking LS
1
experienced
abdominal
discomfort
and
loose stools but
unclear
which
treatment group
Antibiotic
Therapy
Any Other
Treatment
Control
Category
0
C-148
Dietary
instructions
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Isolauri, 1991
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
La
24
VII Vomiting on day 1
n=14
VII Vomiting on day 2
n=5
VII Vomiting on day 3
n=0
VII Vomiting on day 4 +
5 n=0
Isolauri, 1991
RCT
Effective
2
24
VII Vomiting on day 1
n=13
VII Vomiting on day 2
n=9
VII Vomiting on day 3
n=4
VII Vomiting on day 4 +
5 n=0
0, 0
Isolauri, 1991
RCT
Effective
3
La
23
VII Vomiting on day 1
n=10
VII Vomiting on day 2
n=5
VII Vomiting on day 3
n=2
VII Vomiting on day 4 +
5 n=0
0, 0
Isolauri,1995
RCT
Effective
1
La
30
VIII Fever (>38C) n=n/a
VII Vomiting n=2
VII Loose stool n=n/a
Isolauri,1995
RCT
Effective
2
30
VIII Fever (>38C) n=n/a
VII Vomiting n=0
VII Loose stool n=n/a
n/a
n/a
N
Drop
outs,
Due
to AE
0, 0
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Non-probiotic
n/a,
n/a
n/a,
n/a
C-149
Hospi
tali
zations
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Jirapinyo, 2002
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
8
XXVII Worsening of
clinical condition n=0
XI Sepsis due to
Lactobacillus or
Bifidobacterium (SAE)
n=0
n/a
N
Drop
outs,
Due
to AE
0, 0
Jirapinyo, 2002
RCT
Effectiveness
unclear
2
10
XXVII Worsening of
clinical condition n=0
XI Sepsis due to
Lactobacillus or
Bifidobacterium (SAE)
n=0
n/a
0, 0
Johansson,
1998
RCT
Effective
1
La
26
XXVII Transient nausea,
abdominal discomfort
and flu-like symptoms
n=5
5
0, 0
Johansson,
1998
RCT
Effective
2
22
XXVII Transient nausea,
abdominal discomfort
and flu-like symptoms
n=5
5
0, 0
Kadooka, 2010
RCT
Effective
1
St
43
VII Nausea n=0
XVII Headache n=0
VII Abdominal pain n=0
0
0, 0
Kadooka, 2010
RCT
Effective
2
44
VII Nausea n=0
XVII Headache n=0
VII Abdominal pain n=0
0
0, 0
Kajander, 2005
RCT
Effective
1
Bi
52
XXVII Illness or
hospitalization, not IBS
related n=1
n/a
8, 4
Kajander, 2005
RCT
Effective
2
51
XXVII Illness or
hospitalization, not IBS
related n=3
n/a
9, 4
C-150
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Fermented
milk only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Kajander, 2008
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
1
Bi
43
VII GI symptoms n=n/a
XXII Respiratory tract
n=n/a
VI Eye operation n=n/a
XXVI Atherosclerotic
finding in the carotid
artery n=n/a
XXIII Inflamed mole
n=n/a
XX Cystitis n=n/a
XV Tenosynovitis n=n/a
XI Oral herpes n=0
V Hyperthyroidism n=0
XXII Breathing difficulties
n=0
V Hyperthyroidism n=0
XXVII Backache n=0
XXV Foot operation n=0
XXI Vaginitis n=0
XXVII Intestinal warms
n=0
Other Harms
Patients
with
AEs
10
C-151
N
Dropouts,
Due
to AE
5, 2
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Kajander, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
43
VII GI symptoms n=n/a
XXII Respiratory tract
n=n/a
VI Eye operation n=0
XXVI Atherosclerotic
finding in the carotid
artery n=0
XXIII Inflamed mole n=0
XX Cystitis n=0
XV Tenosynovitis n=0
XI Oral herpes n=0
V Hyperthyroidism n=n/a
Breathing difficultiesn/a
V Hyperthyroidism n=n/a
XXVII Backache n=n/a
XXV Foot operation
n=n/a
XXI Vaginitis n=n/a
XXVII Intestinal warms
n=n/a
15
N
Drop
outs,
Due
to AE
10, 6
Kajimoto, 2002
RCT
Effective
1
St
33
XXII Dry cough n=0
VII Gastrointestinal
symptoms n=0
XXIII Skin symptoms
n=0
0
n/a, 0
Kajimoto, 2002
RCT
Effective
2
33
XXII Dry cough n=0
VII Gastrointestinal
symptoms n=0
XXIII Skin symptoms
n=0
0
n/a, 0
Karvonen, 2001
RCT
Effective
1
La
12
VII Abdominal symptoms
n=n/a (states similar
between groups)
n/a
n/a,
n/a
Karvonen, 2001
RCT
Effective
2
28
VII Abdominal symptoms
n=n/a
n/a
n/a,
n/a
C-152
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Yogurt only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Karvonen, 2001
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
3
La
25
VII Abdominal symptoms
n=n/a
n/a
Karvonen, 2001
RCT
Effective
4
La
25
VII Abdominal symptoms
n=n/a
n/a
n/a,
n/a
Kerac, 2009
RCT
Not effective
1
La
399
XXVII Death (SAE)
n=108
XXVII Not
tolerating/clinically
worsening n=6
XI Probiotics-related
sepsis (SAE) n=0
XXVII Medical visits with
problem n=26
XXVII Readmission
episodes (SAE) n=87
n/a
n/a,
n/a
27
Kerac, 2009
RCT
Not effective
2
396
XXVII Death (SAE)
n=119
XXVII Not
tolerating/clinically
worsening n=5
XI Probiotics-related
sepsis (SAE) n=0
XXVII Medical visits with
problem n=48
XXVII Readmission
episodes (SAE) n=71
n/a
n/a,
n/a
16
Kianifar, 2009
RCT
Effective
1
Bi
34
XIII Bacteremia (SAE)
n=0
XIII Fungemia (SAE) n=0
n/a
2, 0
Kianifar, 2009
RCT
Effective
2
34
XIII Bacteremia (SAE)
n=0
XIII Fungemia (SAE) n=0
n/a
4, 0
17/68
(probiotic
group) versus 23/69
(control
group)
taken blood cultures
positive
C-153
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Kim, 2006
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Ba
12
VII Loose stool, diarrhea
or worsening of GI
symptoms n=0
VII Dehydration n=0
IX Elevated blood
pressure n=0
No
abnormal
changes in blood
chemistry
Kim, 2006
RCT
Effectiveness
unclear
1
Ba
12
Kim, 2006
RCT
Effectiveness
unclear
2
Kim, 2006
RCT
Effectiveness
unclear
Kim, 2006
RCT
Effectiveness
unclear
0
N
Drop
outs,
Due
to AE
3, 0
VII Loose stool, diarrhea
w/ or w/out worsening of
GI symptoms n=1 (states
not related)
VII Dehydration n=1
(states not related)
IX Elevated blood
pressure n=1 (states not
related)
1
2, 1
12
VII Loose stool, diarrhea
or worsening of G1
symptoms n=0
VII Dehydration n=0
IX Elevated blood
pressure n=0
0
3, 0
Placebo
2
Ba
12
VII Loose stool, diarrhea
w/ or w/out worsening of
GI symptoms n=1 (states
not related)
VII Dehydration n=0
(states not related)
IX Elevated blood
pressure n=0 (states not
related)
1
3, 1
Other
Probiotic
3
Ba
12
VII Loose stool, diarrhea
or worsening of GI
symptoms n=1
VII Dehydration n=0
IX Elevated blood
pressure n=0
1
2, 1
C-154
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Kim, 2008
RCT
Effectiveness
unclear
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
St
168
XXVII Metallic taste
n=28
VII Diarrhea n=16
VII Epigastric soreness
n=7
VII Epigastric pain n=4
VII Bloating n=4
VII Epigastric discomfort
n=1
VII Nausea n=3
VII Acid regurgitation
n=2
VIII Headache n=1
VII Constipation n=1
XIV Weight gain n=1
XXIII Pruritus n=1
69
N
Dropouts,
Due
to AE
6, 2
Kim, 2008
RCT
Effectiveness
unclear
2
179
XXVII Metallic taste
n=13
VII Diarrhea n=14
VII Epigastric soreness
n=6
VII Epigastric pain n=5
VII Bloating n=2
VII Epigastric discomfort
n=4
VII Nausea n=n/a
VII Acid regurgitation
n=1
VIII Headache n=1
VII Constipation n=1
XIV Weight gain n=1
XXIII Pruritus n=n/a
47
15, 1
Kirjavainen,2003
RCT
Effectiveness
unclear
1
La
17
VII Diarrhea n=0
0
3, 0
C-155
Patients
with
AEs
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Triple therapy
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Kirjavainen,2003
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
10
VII Diarrhea n=0
0
N
Drop
outs,
Due
to AE
2, 0
Kirjavainen,2003
RCT
Effectiveness
unclear
3
La
16
VII Diarrhea n=5
5
3, 0
Klarin, 2008
RCT
Not effective
1
La
23
XXVII Death (SAE) n=5
n/a
n/a,
n/a
Klarin, 2008
RCT
Not effective
2
21
XXVII Death (in-hospital
mortality) (SAE) n=6
Klarin,2005
RCT
Effective
1
La
9
XXVII Death (SAE) n=2
VII Diarrhea n=n/a
(states no difference
between groups)
VII Gas bloating n=n/a
n/a
1, 0
Klarin,2005
RCT
Effective
2
8
XXVII Death (SAE) n=2
VII Diarrhea n=n/a
VII Gas bloating n=n/a
n/a
1, 0
Knight, 2007
RCT
Not effective
1
La
150
XXVII Death attributable
to probiotics (SAE) n=0
VII Diarrhea n=7
XXVII Colonization
(Leuconostoc, in
tracheal aspirate) n=1
n/a
20, 0
n/a,
n/a
C-156
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Non-probiotic
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Knight, 2007
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
150
XXVII Death attributable
to probiotics (SAE) n=0
VII Diarrhea n=9
XXVII Colonization
(Leuconostoc, in
tracheal aspirate) n=0
n/a
N
Drop
outs,
Due
to AE
21, 0
Koning, 2008
RCT
Effectiveness
unclear
1
En
20
VII Nausea n=n/a
VII Abdominal cramps
n=n/a
VII Bloating n=n/a
VII Flatulence n=n/a
n/a
1, 0
Koning, 2008
RCT
Effectiveness
unclear
2
21
VII Nausea n=n/a
VII Abdominal cramps
n=n/a
VII Bloating n=n/a
VII Flatulence n=n/a
n/a
2, 0
Kopp, 2008
RCT
Not effective
LTFU
Kopp, 2008
RCT
Not effective
LTFU
Kotzampassi,
2006
RCT
Effective
1
La
54
XXII Wheezing
bronchitis (5 or more
episodes) n=13
n/a
4, 0
2
51
XXII Wheezing
bronchitis (5 or more
episodes) n=4
n/a
7, 0
1
La
41
VII Severe constipation
n=4
VII Diarrhea n=5
VII Increased gastric
residuals n=7
XI Infection due to
species contained in
formula (SAE) n=0
n/a
6, 6
90%
mild-mod
symptoms
in
placebo
White blood cell
count,
c-reactive
protein levels and
endotoxin
levels
decreased
compared
to
placebo
C-157
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Kotzampassi,
2006
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
36
VII Severe constipation
n=6
VII Diarrhea n=10
VII Increased gastric
residuals n=15
XI Infection due to
species contained in
formula (SAE) n=0
n/a
N
Drop
outs,
Due
to AE
6, 6
Krasse, 2005
RCT
Effective
1
La
20
VII Increased bowel
movements n=0
0
n/a, 0
Antibiotics
unclear
Krasse, 2005
RCT
Effective
2
18
VII Increased bowel
movements n=0
0
n/a, 0
Antibiotics
needed
Krasse, 2005
RCT
Effective
3
La
21
VII Increased bowel
movements n=1
1
n/a, 0
Antibiotics
unclear
Kuitunen, 2009
RCT
Not effective
LTFU
1
Bi
610
XIII Anemia n=16 (1 at 6
months)
XXVII Excessive crying
n=13
VII Abdominal discomfort
n=35
VII Vomiting n=7
n/a
n/a,
n/a
Kuitunen, 2009
RCT
Not effective
LTFU
2
613
XIII Anemia n=10 (0 at 6
mons; 10 at 2yrs)
XXVII Excessive crying
n=9
VII Abdominal discomfort
n=37
VII Vomiting n=12
n/a
n/a,
n/a
Kurugol, 2005
RCT
Effective
1
Sa
115
VII Meteorism n=1
1
15, 0
C-158
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Kurugol, 2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
117
VII Meteorism n=0
0
La Rosa, 2003
RCT
Effective
1
Ba
60
XXVII Abdominal colic
n=0
0
n/a,
n/a
La Rosa, 2003
RCT
Effective
2
60
VII Abdominal colic n=1
1
n/a, 1
Laitinen, 2008
RCT
Effective
1
Bi
85
VII Flatulence, loose
stools or constipation
n=5
5
12, 9
Laitinen, 2008
RCT
Effective
2
86
VII Flatulence, loose
stools or constipation
n=6
6
17, 7
Langhendries,
1995
RCT
Effective
1
St
20
n/a
n/a,
n/a
Langhendries,
1995
RCT
Effective
2
20
n/a
n/a,
n/a
Larsen, 2006
RCT
Effectiveness
unclear
1
Bi
15
X Hay fever n=n/a
VII Diarrhea n=n/a (1 pat
dropped out before
treatment)
n/a
1, 1
Larsen, 2006
RCT
Effectiveness
unclear
2
15
X Hay fever n=n/a
VII Diarrhea n=n/a
n/a
1, 0
Well accepted (both
groups)
68% in all groups
complained
of
flatulence,
37%
abdominal bloating,
22% headache
C-159
Patients
with
AEs
N
Drop
outs,
Due
to AE
17, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Formula only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Larsen, 2006
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
3
Bi
15
X Hay fever n=n/a
VII Diarrhea n=n/a
Larsen, 2006
RCT
Effectiveness
unclear
4
Bi
15
X Hay fever n=1
VII Diarrhea n=n/a
Larsson, 2008
RCT
Effectiveness
unclear
1
La
50
X Suspected allergy
(vaginal discomfort) n=1
XXIII Itching n=0
XI Candida infection n=5
Larsson, 2008
RCT
Effectiveness
unclear
2
50
Lata, 2009
RCT
Effectiveness
unclear
1
Bi
Lata, 2009
RCT
Effectiveness
unclear
2
Other Harms
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
0, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
0, 0
Headache,
menorrhagia,
hemorrhoids,
influenza, bronchitis,
whiplash, asthma,
urinary
tract
infection occurred,
number and group
unclear
14
n/a, 1
X Suspected allergy
(vaginal discomfort) n=0
XXIII Itching n=0
XI Candida infection n=4
12
n/a, 1
7
XXVII Death (SAE) n=0
n/a
n/a,
n/a
15
XXVII Death (SAE) n=0
n/a
n/a,
n/a
C-160
Antibiotics
needed
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Lawrence, 2005
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
8
VII Bloating n=2
VII Excessive flatulence
n=3
VII Nausea n=0
VII Vomiting n=0
VII Abdominal pain n=0
VII Constipation n=0
XI Lactobacillus
infections (SAE) n=0
Concomitant
antibiotics may have
caused side effects
Lawrence, 2005
RCT
Not effective
2
7
Li, 2004
RCT
Effective
1
Bi
Li, 2004
RCT
Effective
2
5
N
Drop
outs,
Due
to AE
0, 0
VII Bloating n=1
VII Excessive flatulence
n=0
VII Nausea n=0
VII Vomiting n=0
VII Abdominal pain n=0
VII Constipation n=0
XI Lactobacillus
infections (SAE) n=0
1
0, 0
10
VII Flatulence n=0
VII Increased residual
gastric content n=0
VII Diarrhea n=0
VII Constipation n=0
XI Septicemia due to
Bifidobacterium (SAE)
n=0
0
n/a,
n/a
10
VII Flatulence n=0
VII Increased residual
gastric content n=0
VII Diarrhea n=0
VII Constipation n=0
XI Septicemia due to
Bifidobacterium (SAE)
n=0
0
n/a,
n/a
C-161
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
No
supplement
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Ligaarden, 2010
C-RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
1
La
10
Ligaarden, 2010
C-RCT
Not effective
2
9
Lighthouse,
2004
RCT
Effectiveness
unclear
1
Bi
10
VII Bowel abnormalities
n=0
VIII Feverish episode
n=2
VIII Diarrheal syndrome
n=0
Lighthouse,
2004
RCT
Effectiveness
unclear
2
10
VII Bowel abnormalities
n=0
VIII Feverish episode
n=0
VIII Diarrheal syndrome
n=0
Lin, 1989
C-RCT
Not effective
1
La
460
VII Constipation n=6
VII Flatulence n=15
VII Diarrhea n=9
VII Stomach upset n=3
Lin, 1989
C-RCT
Not effective
2
460
VII Constipation n=5
VII Flatulence n=11
VII Diarrhea n=10
VII Stomach upset n=1
Lin, 2005
RCT
Effective
1
Bi
180
XI Sepsis due to
Lactobacillus a
Bifidobacterium (SAE)
n=0
Other Harms
1
pts
was
hospitalized
for
cervicobrachialgia
during washout and
there were 3 minor
adverse
events,
group unclear
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
1, 0
Antibiotic
Therapy
Any Other
Treatment
Control
Category
hospital stay
2, 0
n/a
n/a
Non-probiotic
126,
n/a
126,
n/a
n/a
Placebo
2, 2
0, 0
C-162
Hospi
tali
zations
n/a, 7
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Lin, 2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
187
XI Sepsis due to
Lactobacillus or
Bifidobacterium (SAE)
n=0
n/a
Lin, 2008
RCT
Effective
1
Bi
222
XI Sepsis due to
probiotics (SAE) n=0
VII Flatulence n=0
VII Diarrhea n=0
n/a
5, 2
Lin, 2008
RCT
Effective
2
221
XI Sepsis due to
probiotics (SAE) n=0
VII Flatulence n=0
VII Diarrhea n=0
n/a
4, 3
Ljungberg, 2006
RCT
Effective
LTFU
Ljungberg, 2006
RCT
Effective
LTFU
Loguercio, 1987
RCT
Effective
1
Bi
n/a
n/a,
n/a
1
En
20
Loguercio, 1987
RCT
Effective
2
Lonnermark,
2010
RCT
Effective
1
La
3 samples positive
for
beta
cell
autoantibodies,
group not stated
Patients
with
AEs
2
N
Drop
outs,
Due
to AE
n/a,
20
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Breast
only
1
20
VII Constipation
(switched treatment) n=0
VII Meteorism n=5
VII Abdominal pain n=6
VII Diarrhea n=1
6
2, 2
118
VII Constipation n=3
3
38,
n/a
milk
Placebo
n/a,
n/a
VII Constipation
(switched treatment) n=1
VII Meteorism n=0
VII Abdominal pain n=0
VII Diarrhea n=0
Control
Category
Placebo
1, 1
Lactulose
C-163
Non-probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Lonnermark,
2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
121
VII Constipation n=3
3
Lu, 2004
CCT
Effective
1
La
VII Vomiting n=0
VII Diarrhea n=0
VII Obstipation n=0
XXI Abdominal pain n=0
X Allergic reactions n=0
0
n/a, 0
Lu, 2004
CCT
Effective
2
VII Vomiting n=0
VII Diarrhea n=0
VII Obstipation n=0
XXI Abdominal pain n=0
X Allergic reactions n=0
0
n/a,
n/a
Lu, 2004
CCT
Effective
3
La
VII Vomiting n=0
VII Diarrhea n=0
VII Constipation n=0
VII Abdominal pain n=0
XXI Cough n=0
X Allergic reaction n=0
0
n/a,
n/a
Lu, 2004
CCT
Effective
4
La
VII Vomiting n=0
VII Diarrhea n=0
VII Constipation n=0
VII Abdominal pain n=0
XXI Cough n=0
X Allergic reaction n=0
0
n/a,
n/a
Luoto, 2010
RCT
Effective
1
Bi
85
XXVII Death (SAE) n=0
XI Sepsis (SAE) n=0
XXVII Illness in child n=3
n/a
18,
n/a
Luoto, 2010
RCT
Effective
2
86
XXVII Death (SAE) n=0
XI Sepsis (SAE) n=0
XXVII Illness in child n=1
n/a
23,
n/a
Discontinued
to
illness in mother
(treatment
=
3,
control
=
3);
miscarriage 2 in
both groups
C-164
Patients
with
AEs
N
Drop
outs,
Due
to AE
38,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Dietary
counseling
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Mдkelдinen,
2003
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
1
Bi
19
VII Intestinal complaints
n=0
0
Mдkelдinen,
2003
RCT
Effective
2
20
VII Intestinal complaints
n=0
0
n/a,
n/a
Malaguarnera,
2007
RCT
Effectiveness
unclear
1
Bi
30
VII Nausea n=1
XVII Headache (1) n=1
VII Abdominal pain n=2
VII Diarrhea n=0
XVII Headache
moderate n=0
n/a
0, 0
Malaguarnera,
2007
RCT
Effectiveness
unclear
2
30
VII Nausea n=0
XVII Headache slight
n=0
VII Abdominal pain n=0
VII Diarrhea n=2
XVII Headache
moderate n=1
Malaguarnera,
2010
RCT
Effective
1
Bi
63
VII Abdominal pain n=0
VII Cramping n=0
VII Diarrhea n=0
VII Flatulence n=0
0
n/a,
n/a
Malaguarnera,
2010
RCT
Effective
2
62
VII Abdominal pain
n=n/a
VII Cramping n=n/a
VII Diarrhea n=n/a
VII Flatulence n=n/a
n/a
n/a,
n/a
0, 0
C-165
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Non-probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Maldonado,
2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
40
VII Spitting up n=1
XXVII Night awakenings
n=1
XXVII Irritability n=0
XXVII Severe crying n=0
VII Constipation n=4
n/a
N
Drop
outs,
Due
to AE
0, 0
Maldonado,
2009
RCT
Effective
2
40
VII Spitting up n=2
XXVII Night awakenings
n=3
XXVII Irritability n=1
XXVII Severe crying n=0
VII Constipation n=6
n/a
0, 0
Mandel, 2010
RCT
Effective
1
Ba
22
XXIII Shingles n=1
XXIII Poison ivy n=1
XXII A cold n=1
I Leg edema n=1
VII Gastrointestinal
reflux n=0
XI Upper respiratory
infection n=0
XI Urinary tract infection
n=0
4
n/a,
n/a
Mandel, 2010
RCT
Effective
2
22
XXIII Shingles n=0
XXIII Poison ivy n=0
XXII A cold n=0
I Leg edema n=0
VII Gastrointestinal
reflux n=1
XI Upper respiratory
infection n=1
XI Urinary tract infection
n=1
3
n/a,
n/a
Manley, 2007
C-RCT
Effective
1
La
14
XXVII Death (SAE) n=3
(2 after cross-over to
treatment)
n/a
3, 1
C-166
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Manley, 2007
C-RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
13
XXVII Death (SAE) n=0
Manzoni, 2006
RCT
Effective
1
La
39
XI Sepsis due to LGG
(SAE) n=0
0
0, 0
Manzoni, 2006
RCT
Effective
2
41
XI Sepsis due to LGG
(SAE) n=0
0
0, 0
Margreiter, 2006
RCT
Effective
1
Bi
81
XIII Lab abnormalities
n=0
0
10, 0
Margreiter, 2006
RCT
Effective
2
En
85
XIII Lab abnormalities
n=0
0
8, 0
Marotta, 2003
C-RCT
Effective
1
Bi
26
XXVII Significant dietary
change n=0
XXVII Significant
pharmacological change
n=0
XIII Significant weight
change n=0
VII Abdominal
complaints n=0
VII Changes in bowel
habit n=0
0
0, 0
C-167
Patients
with
AEs
N
Drop
outs,
Due
to AE
5, 2
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Yogurt only
Milk only
Other
Probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Marotta, 2003
C-RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
15
XXVII Significant dietary
change n=0
XXVII Significant
pharmacological change
n=0
XIII Significant weight
change n=0
VII Abdominal
complaints n=0
VII Changes in bowel
habit n=0
Marrazzo, 2006
RCT
Effective
1
La
XXVII Stickiness n=n/a
XXI Abnormal vaginal
discharge n=n/a
Marrazzo, 2006
RCT
Effective
2
XXVII Stickiness n=n/a
XXI Abnormal vaginal
discharge n=n/a
Marseglia, 2007
RCT
Effective
1
Ba
40
Marseglia, 2007
RCT
Effective
2
40
Marteau, 2004
RCT
Not effective
1
La
48
VII Digestive disorder
n=n/a
XXIII Edema n=1
XXIII Cutaneous nevus
n=0
6
13, 0
Marteau, 2004
RCT
Not effective
2
50
VII Digestive disorder
n=n/a
XXIII Edema n=1
XXIII Cutaneous nevus
n=0
6
7, 0
0
Between 3.6% and
7.8% reported SE's
3 cases of diarrhea,
group unclear
N
Drop
outs,
Due
to AE
0, 0
n/a
n/a,
n/a
n/a
n/a,
n/a
n/a
0, 0
0, 0
C-168
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Non-probiotic
Placebo
No treatment
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Martiney, 2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
St
24
XIII Abdominal
hematological
parameters n=0
0
N
Drop
outs,
Due
to AE
3, 0
Martiney, 2009
RCT
Effective
2
25
XIII Abdominal
hematological
parameters n=0
0
2, 0
Martinez, 2008
RCT
Effective
1
La
29
XIV Increased appetite
n=2 (states not due to
probiotics)
XVII Headache n=1
VII Light stool n=1
n/a
n/a,
n/a
Martinez, 2008
RCT
Effective
2
26
XIV Increased appetite
n=0
XVII Headache n=0
VII Light stool n=0
n/a
n/a,
n/a
Martinez, 2009
RCT
Effective
1
La
32
XVII Persistent
headache n=1 (states
not due to probiotics)
n/a
n/a,
n/a
Martinez, 2009
RCT
Effective
2
32
XVII Persistent
headache episode n=0
Mayanagi, 2009
RCT
Effectiveness
unclear
1
La
34
XI Respiratory infection
n=0
0
0, 0
Mayanagi, 2009
RCT
Effectiveness
unclear
2
33
XI Respiratory infection
n=1
1
1, 0
n/a,
n/a
C-169
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Yogurt only
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
McFarland,
1994
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Sa
57
VII Constipation n=8
XI Pneumonia -death (5)
(SAE) n=1
XI Staphylococcus
sepsis -death (5) (SAE)
n=0
XXVII Increased thirst
n=5
1 rash occurred
(withdrew),
group
unclear
McFarland,
1994
RCT
Effectiveness
unclear
2
67
VII Constipation n=2
XI Pneumonia -death (5)
(SAE) n=0
XI Staphylococcus
sepsis -death (5) (SAE)
n=4
XXVII Increased thirst
n=0
McFarland,
1995
RCT
Effective
1
Sa
97
VII Intestinal gas n=0
VIII Fever n=0
McFarland,
1995
RCT
Effective
2
96
McNaught, 2002
RCT
Not effective
1
La
McNaught, 2002
RCT
Not effective
2
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
n/a,
n/a
n/a
n/a,
n/a
n/a
n/a,
n/a
VII Intestinal gas n=7
VIII Fever n=5
n/a
n/a,
n/a
64
VII Nausea n=16
VII Paralytic ileus n=12
n/a
n/a,
n/a
65
VII Nausea n=0 (or not
reported)
VII Paralytic ileus n=0 (or
not reported)
n/a
n/a,
n/a
3 deaths, 4 nausea
or
constipation,
group unclear
C-170
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
No treatment
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Merenstein,
2009
RCT
Not effective
Merenstein,
2009
RCT
Not effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Sa
61
XXVII Emesis n=1
VII Constipation n=0
XXVII Death (SAE) n=0
XXVII Permanent
disability (SAE) n=0
XXVII Life-threatening
event (SAE) n=0
XXVII Hospitalization
(SAE) n=0
XXVII Prolonged hospital
stay (SAE) n=0
1
2
Sa
64
XXVII Emesis n=0
VII Constipation n=1
XXVII Death (SAE) n=0
XXVII Permanent
disability (SAE) n=0
XXVII Life-threatening
event (SAE) n=0
XXVII Hospitalization
(SAE) n=0
XXVII Prolonged hospital
stay (SAE) n=0
1
C-171
Patients
with
AEs
N
Dropouts,
Due
to AE
n/a,
n/a
Hospitalizations
n/a,
n/a
0
Antibiotic
Therapy
Any Other
Treatment
Control
Category
0
Other
Probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Merenstein,
2010
RCT
Effectiveness
unclear
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
1
St
314
VII Diarrhea n=6
VII Gas n=1
VII Vomiting n=0
VII Lack of appetite n=0
VII Constipation n=2
XXIII Hives n=1
XXIII Rash n=7
XI Gastro-intestinal virus
(SAE) n=1
XI Pneumonia leading to
asthma attack (SAE) n=0
XI Viral infection causing
fever (SAE) n=0
XXVII Death (SAE) n=0
XXVII Life-threatening
event (SAE) n=0
XXVII Hospitalization
(SAE) n=1 (unrelated to
study product per
author)
XXVII Prolonged hospital
stay (SAE) n=0
XXVII Permanent
disability (SAE) n=0
Other Harms
Patients
with
AEs
18
C-172
N
Dropouts,
Due
to AE
1, n/a
Hospitalizations
1
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Merenstein,
2010
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
342
VII Diarrhea n=3
VII Gas n=0
VII Vomiting n=3
VII Lack of appetite n=3
VII Constipation n=2
XXIII Hives n=0
XXIII Rash n=10
XI Gastro-intestinal virus
(SAE) n=0
XI Pneumonia leading to
asthma attack (SAE) n=1
XI Viral infection causing
fever (SAE) n=1
XXVII Death (SAE) n=0
XXVII Life-threatening
event (SAE) n=0
XXVII Hospitalization
(SAE) n=2 (unrelated to
study product per
author)
XXVII Prolonged hospital
stay (SAE) n=0
XXVII Permanent
disability (SAE) n=0
22
Metts, 2003
RCT
Effective
1
La
9
XXI Vaginal discharge
n=0
0
n/a,
n/a
Metts, 2003
RCT
Effective
2
10
XXI Vaginal discharge
n=1
1
n/a,
n/a
Metts, 2003
RCT
Effective
3
Bi
8
XXI Vaginal discharge
n=1
1
n/a,
n/a
Miele, 2009
RCT
Effective
1
St
14
XIII Lab value changes
n=0
0
0, 0
C-173
Patients
with
AEs
N
Drop
outs,
Due
to AE
1, n/a
Hospi
tali
zations
2
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Miele, 2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
15
XIII Lab value changes
n=0
0
N
Drop
outs,
Due
to AE
0, 0
Millar, 1993
RCT
Effectiveness
unclear
1
La
10
XI Sepsis (SAE) n=0
XI Perineal Candida
infection n=1
XI Infection attributable
to LGG n=0
1
0, 0
Antibiotics
unclear
Millar, 1993
RCT
Effectiveness
unclear
2
10
XI Sepsis (SAE) n=0
XI Perineal Candida
infection n=1
XI Infection attributable
to LGG n=0
1
0, 0
Antibiotics
needed
Mimura, 2004
RCT
Effective
1
St
20
VII Abdominal cramps
n=1
VII Vomiting n=1
VII Diarrhea n=1
1
1, 1
Antibiotics
needed
Mimura, 2004
RCT
Effective
2
16
VII Abdominal cramps
n=0
VII Vomiting n=0
VII Diarrhea n=0
0
0, 0
Miyaji, 2006
RCT
Effective
1
La
21
VII New gastrointestinal
symptoms n=0
n/a
n/a,
n/a
Miyaji, 2006
RCT
Effective
2
18
VII New gastrointestinal
symptoms n=0
Morrow, 2010
RCT
Effective
1
La
73
XI Lactobacillus
bacteremia (SAE) n=0
XI Lactobacillus
pneumonia (SAE) n=0
n/a,
n/a
n/a
C-174
5, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Milk only
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Morrow, 2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
73
XI Lactobacillus
bacteremia (SAE) n=0
XI Lactobacillus
pneumonia (SAE) n=0
n/a
N
Drop
outs,
Due
to AE
3, 0
Mukerji, 2009
RCT
Not effective
1
La
39
VII Bloating n=7
VII Diarrhea n=8
VII Abdominal pain n=7
VII Loose stools n=9
14
2, n/a
Mukerji, 2009
RCT
Not effective
2
38
VII Bloating n=9
VII Diarrhea n=10
VII Abdominal pain n=7
VII Loose stools n=8
17
3, n/a
Naito, 2008
RCT
Effective
LTFU
1
La
100
XX Pain on micturition
n=31
XX Urinary frequency
adverse events n=25
XX Gross hematuria
n=16
VII Constipation n=6
VII Diarrhea n=2
XXVII Death (SAE) n=4
n/a
24, 0
Naito, 2008
RCT
Effective
LTFU
2
102
XX Pain on micturition
n=42
XX Urinary frequency
adverse events n=31
XX Gross hematuria
n=19
VII Constipation n=4
VII Diarrhea n=0
XXVII Death (SAE) n=3
n/a
7, 0
Newcomer,
1983
RCT
Not effective
1
La
10
VII Diarrhea n=n/a
VII Abdominal pain
n=n/a
VII Gas n=n/a
VII Borborygmi n=n/a
n/a
0, 0
C-175
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Chemotherapy
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Newcomer,
1983
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
10
VII Diarrhea n=n/a
VII Abdominal pain
n=n/a
VII Gas n=n/a
VII Borborygmi n=n/a
Niers, 2009
RCT
Effective
LTFU
1
Bi
78
XXVII Health problems
n=4
XXVII Feeding difficulties
n=9
VII Gastrointestinal colic
n=1
Niers, 2009
RCT
Effective
LTFU
2
78
XXVII Health problems
n=3
XXVII Feeding difficulties
n=7
VII Gastrointestinal colic
n=1
VII n=
Niv, 2005
RCT
Not effective
1
La
27
VII Dyspepsia n=1
XVII Headache n=1
VII Nausea n=0
13
6, 0
Niv, 2005
RCT
Not effective
2
27
VII Dyspepsia n=3
XVII Headache n=0
VII Nausea n=1
13
9, 1
Nobuta, 2009
RCT
Effective
1
La
16
VII Abdominal pain n=1
XI Cold n=0
VII Abdominal pain and
diarrhea n=0
n/a
2, 1
Nobuta, 2009
RCT
Effective
2
16
VII Abdominal pain n=0
XI Cold n=0
VII Abdominal pain and
diarrhea n=0
n/a
0, 0
Health problems mother (4 versus 2
in treatment and
control);
use
of
antibiotics
by
mother
or
child
(both 3)
C-176
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
0, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
28, 19
Antibiotics
unclear
30, 17
Antibiotics
unclear
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Nobuta, 2009
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
3
La
16
VII Abdominal pain n=0
XI Cold n=1
VII Abdominal pain and
diarrhea n=0
n/a
N
Drop
outs,
Due
to AE
1, 1
Nobuta, 2009
RCT
Effective
4
La
16
VII Abdominal pain n=0
XI Cold n=0
VII Abdominal pain and
diarrhea n=1
n/a
2, 1
O'Mahony, 2005
RCT
Effective
1
La
XIII Blood count changes
n=0
XIII Serum chemistry
changes n=0
XIII Serum
immunoglobulin changes
n=0
n/a
n/a,
n/a
O'Mahony, 2005
RCT
Effective
2
XIII Blood count changes
n=0
XIII Serum chemistry
changes n=0
XIII Serum
immunoglobulin changes
n=0
n/a
n/a,
n/a
O'Mahony, 2005
RCT
Effective
3
Bi
XIII Blood count changes
n=0
XIII Serum chemistry
changes n=0
XII Serum
immunoglobulin changes
n=0
n/a
n/a,
n/a
Ojetti, 2010
RCT
Effectiveness
unclear
1
La
VII Constipation n=1
n/a
0, 0
20
Other Harms
1
epistaxis,
1
unstable angina, 1
chest pain due to
anxiety,
1
hospitalized
with
abdominal
pain,
group unclear
C-177
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Ojetti, 2010
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
20
VII Constipation n=0
n/a
N
Drop
outs,
Due
to AE
0, 0
Ojetti, 2010
RCT
Effectiveness
unclear
3
20
VII Diarrhea n=n/a
VII Constipation n=n/a
VII Flatulence n=n/a
VII Bloating n=n/a
VII Abdominal pain
n=n/a
n/a
0, 0
Olah, 2005
RCT
Effective
1
La
33
VII Diarrhea n=n/a
VII Bloating n=n/a
5
n/a,
n/a
Olah, 2005
RCT
Effective
2
29
VII Diarrhea n=n/a
VII Bloating n=n/a
4
n/a,
n/a
Olivares, 2006
RCT
Effective
1
St
15
I Hematological changes
n=0
XXVII Health
disturbances n=0
n/a
n/a, 0
Olivares, 2006
RCT
Effective
2
15
I Hematological changes
n=0
XXVII Health
disturbances n=0
n/a
n/a, 0
Osterlund, 2007
RCT
Effective
1
La
98
XI Lactobacillus growth
in blood n=0
n/a
n/a, 0
Osterlund, 2007
RCT
Effective
2
52
I Lactobacillus growth in
blood n=0
n/a
n/a, 7
Gastrointestinal
discomfort was very
low in both groups
C-178
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Prebiotics
Yogurt only
Chemotherapy
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Ouwehand,
2009
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
Bi
24
XXII Asthma n=2
n/a
N
Drop
outs,
Due
to AE
4, 2
Hospi
tali
zations
Ouwehand,
2009
RCT
Effectiveness
unclear
2
23
XXII Asthma n=1
n/a
2, 1
Ozkinay, 2005
RCT
Effective
1
La
240
VII Diarrhea n=1
VII Nausea n=0
1
4, 0
Ozkinay, 2005
RCT
Effective
2
120
VII Diarrhea n=1
VII Nausea n=1
Panigrahi, 2008
RCT
Effectiveness
unclear
1
La
19
XI Sepsis (SAE) n=0
VII Diarrhea
(hospitalized) n=0
0
n/a, 0
0
Panigrahi, 2008
RCT
Effectiveness
unclear
2
12
XI Sepsis (SAE) n=0
VII Diarrhea
(hospitalized) n=4
4
n/a, 0
4
Parent, 1996
RCT
Effective
1
La
17
XXI Disagreeable
sensations and burning
n=1
1
9, 0
Parent, 1996
RCT
Effective
2
15
XXI Disagreeable
sensations and burning
n=0
0
6, 0
Control
Category
Placebo
2, 0
C-179
Antibiotic
Therapy
Any Other
Treatment
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Parfenov, 2005
CCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
St
30
VII Bloating n=5
5
Parfenov, 2005
CCT
Effective
1
St
20
XXVII Allergic reactions
n=0
0
n/a,
n/a
Parfenov, 2005
CCT
Effective
2
30
VII Bloating n=0
0
,
Parfenov, 2005
CCT
Effective
2
10
XXVII Allergic reactions
n=0
0
n/a,
n/a
Parra, 2004
RCT
Effective
1
La
23
XXVII Modification in
nutritional parameters
n=0
XXVII General Health
problem associated with
consumption of the
product n=0
n/a
0, 0
Parra, 2004
RCT
Effective
2
22
XXVII Modification in
nutritional parameters
n=0
XXVII General Health
problem associated with
consumption of the
product n=0
n/a
0, 0
Passeron, 2005
RCT
Effective
1
La
24
VII Abdominal pain (1)
n=2
2
7, 0
Passeron, 2005
RCT
Effective
2
24
VII Abdominal pain (1)
n=1
1
2, 0
C-180
Patients
with
AEs
N
Drop
outs,
Due
to AE
,
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
No treatment
Milk only
Prebiotics
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Peral, 2009
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
La
38
X Local or systemic
allergic symptoms n=0
XIII Pain (tolerable) n=5
XI Administered
organism in peripheral
blood or wound samples
(SAE) n=0
5
N
Drop
outs,
Due
to AE
0, 0
Peral, 2009
RCT
Effectiveness
unclear
2
42
X Local or systemic
allergic symptoms n=0
XIII Pain (tolerable) n=0
XI Administered
organism in peripheral
blood or wound samples
(SAE) n=0
0
0, 0
Pereg, 2010
RCT
Effectiveness
unclear
1
St
20
XXVII Acute illnesses
not related to liver
disease requiring
hospitalization (SAE)
n=2
n/a
2, 0
Pereg, 2010
RCT
Effectiveness
unclear
2
20
XXVII Acute illnesses
not related to liver
disease requiring
hospitalization n=2
n/a
2, 0
Petschow, 2005
RCT
Effective
1
La
15
XXVII Increased
fussiness n=n/a
VII Increased gas n=n/a
XI Thrush n=n/a
XXII Nasal congestion
n=n/a
XXIII Diaper rash n=n/a
XXII Upper respiratory
events n=n/a
n/a
3, n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Non-probiotic
3
Paracentesis
C-181
3
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Petschow, 2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
15
XXVII Increased
fussiness n=n/a
VII Increased gas n=n/a
XI Thrush n=n/a
XXII Nasal congestion
n=n/a
XXIII Diaper rash n=n/a
XXII Upper respiratory
events n=n/a
Petschow, 2005
RCT
Effective
3
La
14
XXVII Increased
fussiness n=n/a
VII Increased gas n=n/a
XI Thrush n=n/a
XXII Nasal congestion
n=n/a
XXIII Diaper rash n=n/a
XXII Upper respiratory
events n=n/a
0, 0
Petschow, 2005
RCT
Effective
4
La
15
XXVII Increased
fussiness n=n/a
VII Increased gas n=n/a
XI Thrush n=n/a
XXII Nasal congestion
n=n/a
XXIII Diaper rash n=n/a
XXII Upper respiratory
events n=n/a
2, n/a
n/a
C-182
N
Drop
outs,
Due
to AE
0, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Formula only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Prantera, 2002
RCT
Not effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
23
XI Suture stitch
suppuration n=1 (states
not treatment related)
XIII Mild increased
alanine
aminotransferase n=1
(not treatment related
per author)
XXIII Acne n=0
VII Nausea n=0
XX Hematuria n=0
XIX Depressive state
n=0
Diarrhea, bloating,
and meteorism did
not differ between
groups
Prantera, 2002
RCT
Not effective
2
22
Pregliasco, 2008
RCT
Effective
1
Bi
122
2
N
Dropouts,
Due
to AE
5, 0
XI Suture stitch
suppuration n=1 (not
treatment related per
author)
XIII Mild increased
alanine
aminotransferase n=1
(not treatment related
per author)
XXIII Acne n=1 (not
treatment related per
author)
VII Nausea n=1 (not
treatment related per
author)
XX Hematuria n=1 (not
treatment related per
author)
XIX Depressive state
n=1 (not treatment
related per author)
6
3, 0
VII Worsened bowel
function n=9
9
8, 0
C-183
Patients
with
AEs
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Pregliasco, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
115
VII Worsened bowel
function n=9
9
N
Drop
outs,
Due
to AE
10, 0
Pregliasco, 2008
RCT
Effective
1
Bi
79
VII Worsened bowel
function n=6
6
5, 0
Pregliasco, 2008
RCT
Effective
2
76
VII Worsened bowel
function n=10
10
8, 0
Pregliasco, 2008
RCT
Effective
3
Bi
79
VII Worsened bowel
function n=9
9
9, 0
Pregliasco, 2008
RCT
Effective
1
Bi
84
VII Worsened bowel
function n=13
13
8, 0
Pregliasco, 2008
RCT
Effective
2
82
VII Worsened bowel
function n=5
5
7, 0
Pregliasco, 2008
RCT
Effective
3
Bi
84
VII Worsened bowel
function n=9
9
6, 0
C-184
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Puccio, 2007
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
42
XI Respiratory tract
infections n=17
XXVII Sudden infant
death (SAE) n=1
XXVII Congenital
disorder (SAE) n=0
XXVII Adverse event
(illnesses and
symptoms) n=30
XXVII Life-threatening
event (permanent harm,
in-patient treatment)
(SAE) n=12
XXVII Serious adverse
event (fatal, life
thretening, in-patient
treatment) (SAE) n=12
No
significant
difference in dropout
rates (reasons: lifethreatening events,
hospitalizations,
spitting and crying,
other
adverse
events
or
other
reasons;
group
unclear),
crying,
restlessness, colic,
spitting and vomiting
Puccio, 2007
RCT
Effective
2
55
XI Respiratory tract
infections n=27
XXVII Sudden infant
death (SAE) n=0
XXVII Congenital
disorder (SAE) n=1
XXVII Adverse event
(illnesses and
symptoms) (SAE) n=12
XXVII Life-threatening
event (permanent harm,
in-patient treatment)
(SAE) n=10
XXVII Serious adverse
event (fatal, life
thretening, in-patient
treatment) (SAE) n=10
n/a
14,
n/a
Rampengan,
2010
RCT
Effective
1
La
43
XXVII Respiratory or
bowel symptoms n=4
n/a
4, 4
C-185
Patients
with
AEs
n/a
N
Dropouts,
Due
to AE
23,
n/a
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Rampengan,
2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
La
43
XXVII Respiratory or
bowel symptoms n=3
Ranganathan
C-RCT
Effective
1
St
16
Ranganathan
C-RCT
Effective
2
16
Rautava, 2008
RCT
Effective
1
Bi
38
VII Vomiting n=1
VII Flatulence n=0
XXVII Increased fussing
n=0
1
6, 2
Rautava, 2008
RCT
Effective
2
43
VII Vomiting n=n/a
VII Flatulence n=n/a
XXVII Increased fussing
n=n/a
3
2, 1
Rayes, 2002
RCT
Effective
1
La
35
VII Abdominal side
effects (distension,
cramps or diarrhea) n=6
6
4, 0
Rayes, 2002
RCT
Effective
2
36
VII Abdominal side
effects (distension,
cramps or diarrhea) n=8
8
4, 0
n/a
Death due to a
myocardial
infarction and minor
event
such
as
bloating
or
gastrointestinal
of
temporary
nature,
lasting only a few
days, group / phase
unclear
n/a
N
Drop
outs,
Due
to AE
3, 3
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Other
Probiotic
n/a,
n/a
n/a,
n/a
C-186
Hospi
tali
zations
Placebo
Placebo
Parenteral or
enteral
nutrition only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Rayes, 2002
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
3
La
34
VII Abdominal side
effects (distension,
cramps or diarrhea)
n=11
11
N
Drop
outs,
Due
to AE
2, 0
Rayes, 2002
RCT
Effectiveness
unclear
1
La
30
VII Abdominal distension
n=3
VII Abdominal cramps
n=4
VII Diarrhea n=0
n/a
0, 0
Rayes, 2002
RCT
Effectiveness
unclear
2
30
VII Abdominal distension
n=4
VII Abdominal cramps
n=6
VII Diarrhea n=0
0, 0
Rayes, 2002
RCT
Effectiveness
unclear
3
La
30
VII Abdominal distension
n=6
VII Abdominal cramps
n=5
VII Diarrhea n=0
0, 0
Rayes, 2005
RCT
Effective
1
La
33
VII Diarrhea
(disappeared with
temporary treatment
reduction) n=3
VII Abdominal cramps
(disappeared with
temporary treatment
reduction) n=5
VII Abdominal distension
n=0
n/a
C-187
0, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Standard
crystalloid
solution only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Rayes, 2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
33
VII Diarrhea
(disappeared with
temporary treatment
reduction) n=4
VII Abdominal cramps
(disappeared with
temporary treatment
reduction) n=6
VII Abdominal distension
(disappeared with
temporary treatment
reduction) n=6
n/a
N
Drop
outs,
Due
to AE
0, 0
Rayes, 2007
RCT
Effective
1
La
45
VII Diarrhea n=2
VII Abdominal cramps
n=3
VII Abdominal distension
and cramps n=0
n/a
5, 0
Rayes, 2007
RCT
Effective
2
Reid, 1992
RCT
Effectiveness
unclear
1
La
VII Diarrhea n=2
VII Abdominal cramps
n=0
VII Abdominal distension
and cramps n=6
19
XXIII Rash n=0
VII Vomiting n=0
VII Diarrhea n=0
VII Nausea n=0
XX Irritation n=0
XX Discharge n=0
XI Superinfection (SAE)
n=0
,
1 pneumonia, group
unclear
C-188
n/a
n/a, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Reid, 1992
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
21
XXIII Rash n=o
VII Vomiting n=0
VII Diarrhea n=0
VII Nausea n=0
XX Irritation n=0
XX Discharge n=0
XI Superinfection (SAE)
n=n
Reid, 1995
RCT
Effective
1
La
25
XXVII Emergence of
uncommon
uropathogens n=0
XXVII Adverse alteration
of urogenital flora n=0
0
8, 0
Reid, 1995
RCT
Effective
2
24
XXVII emergence of
uncommon
uropathogens n=0
XXVII Adverse alteration
of urogenital flora n=0
0
3, 0
Ren, 2010
RCT
Effective
1
Bi
35
XXIII Skin rash n=0
VII Gastrointestinal side
effects n=0
0
n/a,
n/a
Ren, 2010
RCT
Effective
2
35
XXIII Skin rash n=0
VII Gastrointestinal side
effects n=0
0
n/a,
n/a
Reuman, 1986
RCT
Not effective
1
La
15
XXVII Death (SAE) n=1
n/a
1, 1
No
statistically
significant difference
between groups in
duration
of
hospitalization, days
not
fed
orally,
antibiotics
use,
weight gain, formula
volume, or other
morbidity scores
C-189
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Prebiotics
Non-probiotic
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Reuman, 1986
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
2
15
XXVII Death (SAE) n=3
Richelsen, 1996
RCT
Effectiveness
unclear
1
En
44
Richelsen, 1996
RCT
Effectiveness
unclear
2
43
Rio, 2002
RCT
Effective
1
La
50
Rio, 2002
RCT
Effective
2
Roos, 1996
RCT
Effective
Other Harms
Patients
with
AEs
n/a
1
abdominal
symptoms, 1 weight
gain,
1
hypertriglyceridemia
but unclear which
group
N
Drop
outs,
Due
to AE
3, 3
n/a
n/a,
n/a
n/a
n/a,
n/a
XXVII Death (SAE) n=0
n/a
28,
n/a
50
XXVII Death (SAE) n=0
n/a
14,
n/a
1
St
51
XXII Throat pain n=1
XVII Headache n=0
XXII Coughing n=1
XXII Running nose n=1
VIII Fever n=2
XXII Common cold n=1
13
n/a,
n/a
Roos, 1996
RCT
Effective
2
61
XXII Throat pain n=3
XVII Headache n=3
XXII Coughing n=3
XXII Running nose n=2
VIII Fever n=2
XXII Common cold n=2
18
n/a,
n/a
Roos, 2001
RCT
Effective
1
St
53
XI Pneumonia n=0
22
n/a, 0
C-190
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Roos, 2001
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
2
55
XI Pneumonia n=1
Rose, 2010
RCT
Not effective
1
La
65
XXIII Diaper rash n=2
XXVII Lactose
intolerance (withdrawn)
n=0
Rose, 2010
RCT
Not effective
2
66
Rosenfeldt,
2002
RCT
Effective
1
La
Rosenfeldt,
2002
RCT
Effective
Other Harms
25
N
Drop
outs,
Due
to AE
n/a, 2
n/a
9, 3
XXIII Diaper rash n=0
XXVII Lactose
intolerance (withdrawn)
n=1
0
n/a
20, 6
27
VII Constipation n=1
1
3, 3
2
23
VII Constipation n=n/a
n/a
4, 2
Rosenfeldt,
2003
C-RCT
Effective
1
La
13
VII Abdominal pain (mild,
transitory) n=2
VII Loose stools n=0
2
1, 0
Rosenfeldt,
2003
C-RCT
Effective
2
13
VII Abdominal pain (1)
n=1
VII Loose stools n=1
1
1, 0
LGG recipients with
allergic sensitization
even tended to need
more
medical
intervention.
C-191
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Rouge, 2009
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
45
XI Sepsis (SAE) n=15
XI Sepsis due to
Bifidobacterium and
Lactobacillus (SAE) n=0
XI Nosocomial infection
in infants <=1000g
(SAE) n=12
n/a
N
Drop
outs,
Due
to AE
2, 2
Rouge, 2009
RCT
Effectiveness
unclear
2
49
XI Sepsis (SAE) n=13
XI Sepsis due to
Bifidobacterium and
Lactobacillus (SAE) n=0
XI Nosocomial infection
in infants <=1000g
(SAE) n=14
n/a
4, 4
Ruiz-Palacios,
1996
RCT
Effective
1
Bi
n/a
n/a,
n/a
Ruiz-Palacios,
1996
RCT
Effective
2
n/a
n/a,
n/a
Ruiz-Palacios,
1996
RCT
Effective
3
Bi
n/a
n/a,
n/a
Ruiz-Palacios,
1996
RCT
Effective
4
Bi
n/a
n/a,
n/a
Intake, incidences of
vomiting, abdominal
discomfort, gas and
stool characteristics
were not statistically
different
across
groups
C-192
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Saavedra, 2004
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
St
44
XXIII Viral rash (dropout)
n=1
VII Loose stools
(dropout) n=1
VII Vomiting (dropout)
n=1
Saavedra, 2004
RCT
Effective
2
44
XXIII Viral rash n=0
VII Loose stools n=0
VII Vomiting n=0
Saavedra, 2004
RCT
Effective
3
St
43
XXIII Viral rash n=0
VII Loose stools n=0
VII Vomiting n=0
Safdar, 2008
RCT
Effectiveness
unclear
1
La
23
VIII Fever n=2
VII Nausea n=0
2
0, 0
Safdar, 2008
RCT
Effectiveness
unclear
2
17
VIII Fever n=2
VII Nausea n=3
5
1, 0
Sahagun-flores,
2007
RCT
Effective
1
La
35
VII Diarrhea, metallic
taste, abdominal upset
(withdrawal) n=1
XXVII Allergy n=0
n/a
4, 1
Sahagun-flores,
2007
RCT
Effective
2
36
VII Diarrhea, metallic
taste, abdominal upset
(withdrawal) n=0
XXVII Allergy n=1
n/a
3, 1
No difference in
growth; other data
presented as mean
values
per
100
subject days.
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
5, 3
n/a
5, 1
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
4, 1
C-193
Placebo
Antibiotics
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Saint-Marc,
1995
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Sa
18
XI Infection (SAE) n=0
Potassium
and
hemoglobin levels
were slightly but
significantly
increased in the
treated
group
compared to control
Saint-Marc,
1995
RCT
Effective
2
17
Salminen, 1988
RCT
Effective
1
La
Salminen, 1988
RCT
Effective
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
0, 0
XI Infection (SAE) n=0
n/a
0, 0
12
VII Flatulence n=6
(states due to lactulose)
n/a
1, 0
2
12
VII Flatulence n=7
Salminen, 2004
C-RCT
Effectiveness
unclear
1
La
20
XIII Change in CD4
counts / no effect on
counts n=0
XIII Change in HIV R
copies (SAE) n=0 (no
HIV R copies)
XI Infections due to
Lactobacillus n=0
0
3, 0
Salminen, 2004
C-RCT
Effectiveness
unclear
2
20
XIII Change in CD4
counts / no effect on
counts n=0
XIII Change in HIV R
copies (SAE) n=0
XI infections due to
Lactobacillus n=0
0
3, 0
2, 0
C-194
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Dietary
counseling
only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Samanta, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
91
XI Blood culture grew
Lactobacillus or
Bifidobacterium
(monitored for sepsis)
(SAE) n=0
n/a
Samanta, 2008
RCT
Effective
2
95
XI Blood culture grew
Lactobacillus or
Bifidobacterium
(monitored for sepsis)
(SAE) n=0
n/a
n/a,
n/a
Satokari, 2001
RCT
Not effective
1
Bi
10
VII Abdominal discomfort
n=0
0
n/a, 0
Satokari, 2001
RCT
Not effective
2
9
VII Abdominal discomfort
n=1
n/a
n/a, 0
Savino, 2006
RCT
Effective
1
La
45
n/a
4, 0
Savino, 2006
RCT
Effective
2
45
Sazawal, 2010
RCT
Effective
1
Bi
312
XXVII Death (SAE) n=0
0
16, 0
Sazawal, 2010
RCT
Effective
2
312
XXVII Death (SAE) n=2
2
27, 2
1 participant was
treated
with
antibiotics,
timing
unclear
2 gastroesophageal
reflux, group unclear
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
3, 0
C-195
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Antibiotics
unclear
Prebiotics
Non-probiotic
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Scalabrin, 2009
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
95
XXVII Excessive crying
n=0
XXVII Intolerant to
formula (SAE) n=0 (SAE
per author)
VII Gastroesophageal
reflux (SAE) n=1 (SAE
per author)
VII Vomiting n=n/a
Upper
respiratory
infection
(27%),
nasal
congestion
(21%), gas (17%),
otitis media (16%),
diaper rash (15%),
group unclear; 5
serious
adverse
events per author in
study group, 3 in
control group, 8 in
additional group
Scalabrin, 2009
RCT
Effective
2
95
Scalabrin, 2009
RCT
Effective
3
La
99
n/a
N
Dropouts,
Due
to AE
32, 23
XXVII Excessive crying
n=0
XXVII Intolerant to
formula (SAE) n=0 (SAE
per author)
VII Gastroesophageal
reflux (SAE) n=0 (SAE
per author)
VII Vomiting n=n/a
n/a
25, 14
XXVII Excessive crying
n=0
XXVII Intolerant (SAE)
n=1(SAE per author)
VII Gastroesophageal
reflux (SAE) n=0(SAE
per author)
VII Vomiting n=n/a
n/a
22, 10
C-196
Patients
with
AEs
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Formula only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Schrezenmeir,
2004
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
50
VII Diarrhea n=2 (states
unrelated to treatment in
1 patient)
VII Vomiting (moderate)
n=1
VII Postprandial
abdominal pain n=0
XXII Asthma, bronchitis
and pneumonia n=1
(states unrelated)
XXVII Anorexia (severe)
and weight loss n=0
XXVII Asthenia n=0
4
Schrezenmeir,
2004
RCT
Effectiveness
unclear
2
43
VII Diarrhea n=0
VII Vomiting (moderate)
n=1
VII Postprandial
abdominal pain
(moderate) n=0
XXII Asthma, bronchitis
and pneumonia n=0
XXVII Anorexia (severe)
and weight loss n=0
XXVII Asthenia n=0
1
17,
n/a
Schultz, 2004
RCT
Not effective
1
La
5
VII Bloating (mild) n=n/a
n/a
n/a, 0
Schultz, 2004
RCT
Not effective
2
6
VII Bloating n=n/a
n/a
n/a, 0
Seppo, 2003
RCT
Effective
1
La
22
XXVII Feeling ill
(withdrew) n=n/a
VII Bloating n=0
VII Flatulence n=0
n/a
n/a,
n/a
C-197
Patients
with
AEs
N
Drop
outs,
Due
to AE
24,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Pediasure
only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Seppo, 2003
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
17
XXVII Feeling ill n=n/a
VII Bloating n=1
VII Flatulence n=1
Sierra, 2010
RCT
Effective
1
La
20
VII Diarrhea n=0
VII Constipation n=0
VII Dyspepsia n=0
VII Flatulence n=0
VII Stomach ache n=0
VII Maldigestion n=0
VIII Fever n=0
XVII Headache n=0
XV Muscular or bone
ache n=0
XI Flu symptoms n=0
I Hematological
abnormalities n=0
0
0, 0
Sierra, 2010
RCT
Effective
2
20
VII Diarrhea n=0
VII Constipation n=0
VII Dyspepsia n=0
VII Flatulence n=0
VII Stomach ache n=0
VII Maldigestion n=0
VIII Fever n=0
XVII Headache n=0
XV Muscular or bone
ache n=0
XI Flu symptoms n=0
I Hematological
abnormalities n=0
0
0, 0
Simons, 2006
RCT
Not effective
1
La
24
VII Constipation and
flatulence n=2
2
1, 1
Simons, 2006
RCT
Not effective
2
22
VII Constipation and
flatulence n=1
1
1, 0
C-198
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Milk only
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Simren, 2010
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
St
37
XIII Effects on
biochemistry n=0
XIII Effects on
hematology n=0
0
N
Drop
outs,
Due
to AE
4, 0
Simren, 2010
RCT
Effectiveness
unclear
2
37
XIII Effects on
biochemistry n=0
XIII Effects on
hematology n=0
0
3, 0
Song, 2010
RCT
Effective
1
Sa
330
XI Fungemia due to
Saccharomyces
boulardii (SAE) n=0
0
21, 0
Song, 2010
RCT
Effective
2
331
XI Fungemia due to
Saccharomyces
boulardii (SAE) n=0
0
35, 0
Song, 2010
RCT
Effective
3
Sa
330
XI Fungemia due to
Saccharomyces
boulardii (SAE) n=0
0
11, 0
Songisepp,
2005
CCT
Effective
1
La
16
XI Acute infections n=0
VII Changes in GI
function n=0
XXVII Adverse affects in
general welfare n=0
0
0, 0
Songisepp,
2005
RCT
Effective
1
La
12
VII Change in GI
function n=0
XXVII Adverse effects in
general welfare n=0
n/a
n/a,
n/a
Songisepp,
2005
CCT
Effective
2
5
XI Acute infections n=0
VII Changes in GI
function n=0
XXVII Adverse affects in
general welfare n=0
0
0, 0
1 acute respiratory
viral infection, group
unclear
C-199
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Triple therapy
only
Goat's
only
milk
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Songisepp,
2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
12
VII Change in GI
function n=0
XXVII Adverse effects in
general welfare n=0
n/a
Sood, 2009
RCT
Effective
1
St
77
VII Abdominal bloating
and discomfort n=14
XVII Unpleasant taste
feeling n=7
n/a
22,
n/a
Sood, 2009
RCT
Effective
2
70
VII Abdominal bloating
and discomfort n=0
XVII Unpleasant taste
feeling n=0
n/a
41,
n/a
Spanhaak, 1998
RCT
Effective
1
La
10
XIII Body weight
changes n=0
XIII Blood pressure n=0
II Heart rate n=0
XIII Temperature n=0
XIII Hematology n=0
XIII Blood chemistry
changes n=0
0
n/a, 0
Spanhaak, 1998
RCT
Effective
2
10
XIII Body weight
changes n=0
XIII Blood pressure n=0
II Heart rate n=0
XIII Temperature n=0
XIII Hematology n=0
XIII Blood chemistry
changes n=0
0
n/a, 0
Stockert, 2007
RCT
Effectiveness
unclear
1
En
9
VII Mild flatulence and
diarrhea n=2
n/a
0, 0
C-200
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Stockert, 2007
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
2
8
VII Mild flatulence and
diarrhea n=4
n/a
N
Drop
outs,
Due
to AE
1, 0
Stotzer, 1996
C-RCT
Not effective
1
La
17
XXVII Deteriorated
general condition n=1
(states due to underlying
disease during run-in)
XXVII Side effects
unspecified n=1
n/a
3, 2
Stotzer, 1996
C-RCT
Not effective
2
17
Stratiki, 2007
RCT
Effective
1
Bi
43
VII Feeding intolerance
(Vomiting; Abdominal
distension; Tenderness;
Stool characteristics)
n=0
Stratiki, 2007
RCT
Effective
2
37
Sullivan, 2003
RCT
Effective
1
Bi
Sullivan, 2003
RCT
Effective
2
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Placebo
3, 2
2 intervention, 3
control
infants
excluded due to
NEC,
severe
infection, need for
parenteral nutrition
or inadequate urine
collection
n/a
2, n/a
VII Feeding intolerance
(Vomiting; Abdominal
distension; Tenderness;
Stool characteristics)
n=n/a
0
3, n/a
12
VII Diarrhea n=1
VII Looser stools n=1
2
n/a,
n/a
12
VII Diarrhea n=0
VII Looser stools n=0
0
n/a,
n/a
C-201
Control
Category
Placebo
Placebo
Antibiotics
needed
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Sykora, 2005
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
La
39
VII Nausea n=n/a
XVII Headache n=n/a
VII Recurrent vomiting
n=n/a
VII Diarrhea n=n/a
VII Abdominal pain
n=n/a
VII Heart burn n=n/a
XIV Anorexia n=n/a
XVII Metallic taste n=n/a
VII Flatulence n=n/a
VII Borborygmi n=n/a
13 adverse events
7
N
Drop
outs,
Due
to AE
3, 2
Sykora, 2005
RCT
Effective
2
47
VII Nausea n=n/a
XVII Headache n=n/a
VII Recurrent vomiting
n=n/a
VII Diarrhea n=n/a
VII Abdominal pain
n=n/a
VII Heart burn n=n/a
XIV Anorexia n=n/a
XVII Metallic taste n=n/a
VII Flatulence n=n/a
VII Borborygmi n=n/a
15 adverse events
9
3, 1
Tamura, 2007
RCT
Effectiveness
unclear
1
La
60
XXVII Cold n=10 (states
not related to probiotic)
VII diarrhea n=3 (states
not related to probiotic)
VII Vomiting n=1 (not
related to diarrhea)
n/a
5, 0
Tamura, 2007
RCT
Effectiveness
unclear
2
60
6, 0
C-202
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Taylor, 2007
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
115
VII Colic / abdominal
discomfort n=3
XIX Postnatal
depression n=1
XXVII Unrelated infant
health problem n=1
XXVII Infant refused
supplement n=1
X Allergy sensitization
(skin prick test) n=35
n/a
N
Drop
outs,
Due
to AE
26, 5
Taylor, 2007
RCT
Not effective
2
111
VII Colic / abdominal
discomfort n=1
XIX Postnatal
depression n=1
XXVII Unrelated infant
health problem n=3
XXVII Infant refused
supplement n=0
X Allergy sensitization
(skin prick test) n=21
n/a
22, 5
Tempe, 1985
RCT
Effective
1
Sa
20
XXVII Death (SAE) n=3
(states not attributable to
intervention)
3
n/a, 3
Tempe, 1985
RCT
Effective
2
20
XXVII Death (SAE) n=3
3
n/a, 3
Teran, 2008
RCT
Effective
1
Sa
30
XXVII Staining of
physiologic fluids n=0
n/a
5, 0
Teran, 2008
RCT
Effective
2
29
XXVII Staining of
physiologic fluids n=0
n/a
4, 0
No
significant
difference between
groups for fever,
vomiting
and
number of stools per
day
C-203
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Rehydration
solution only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Thomas, 2001
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
1
La
152
VII Nausea n=n/a
VII Abdominal cramps
n=n/a
VII Gas or bloating n=n/a
Thomas, 2001
RCT
Not effective
2
150
Tomoda, 1991
CCT
Effective
1
St
10
Tomoda, 1991
CCT
Effective
2
Tsuchiya, 2004
CCT
Effective
Other Harms
n/a
N
Drop
outs,
Due
to AE
19, 0
VII Nausea n=n/a
VII Abdominal cramps
n=n/a
VII Gas or bloating n=n/a
n/a
16, 0
I Changes in blood
chemistry n=0
0
,
10
I Changes in blood
chemistry n=0
0
,
1
Bi
34
VII Diarrhea n=n/a (a
few)
XXVII Overt clinical
adverse side-effects n=0
XXVII Biochemical
adverse events n=0
n/a
n/a, 0
Tsuchiya, 2004
CCT
Effective
2
Bi
34
VII Diarrhea n=n/a
XXVII Overt clinical
adverse side-effects n=0
XXVII Biochemical
adverse events n=0
n/a
n/a, 0
Turchet, 2003
RCT
Effectiveness
unclear
1
La
180
VII Dyspepsia n=45
XI Bronchopneumonia
(SAE) n=1 (states not
related)
n/a
n/a, 2
no
statistically
significant difference
in
proportion
of
participants
experiencing
adverse events
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
2
C-204
0
Yogurt only
Synbiotics
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Turchet, 2003
RCT
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
180
VII Dyspepsia n=0 (or
not reported)
XI Bronchopneumonia
(SAE) n=0
n/a
Tursi, 2004
RCT
Effectiveness
unclear
1
St
30
XXIII Cutaneous rash
n=0
VII Diarrhea and
abdominal pain n=0
XXVII Cephalea,
epigastric pain, or
fatigue n=1
1
2, 0
Tursi, 2004
RCT
Effectiveness
unclear
2
30
XXIII Cutaneous rash
n=0
VII Diarrhea and
abdominal pain n=0
XXVII Cephalea,
epigastric pain, or
fatigue n=3
3
4, 0
Tursi, 2008
CCT
Effective
1
La
29
XI Acute bronchial
pneumonia (SAE) n=0
n/a
n/a, 0
Tursi, 2008
CCT
Effective
2
27
XI Acute bronchial
pneumonia (SAE) n=0
n/a
n/a, 0
Tursi, 2008
CCT
Effective
3
La
29
XI Acute bronchial
pneumonia (SAE) n=1
n/a
n/a, 0
2 epigastric pain, 1
nausea, 1 diarrhea,
group unclear
C-205
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
No
study
product
Balsalazide
only
Mesalazine
only
1
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Tursi, 2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
St
71
XVII Dizziness n=1
XI Flue-like syndrome
n=1
VII Abdominal bloating
w/ or w/out discomfort
n=6
VIII Fever n=0
XX Cystitis n=0
XVII Unpleasant taste in
mouth n=0
8
N
Drop
outs,
Due
to AE
6, 0
Tursi, 2010
RCT
Effective
2
73
XVII Dizziness n=0
XI Flue-like syndrome
n=0
VII Abdominal bloating
w/ or w/out discomfort
n=3
VIII Fever n=1
XX Cystitis n=1
XVII Unpleasant taste in
mouth n=4
9
7, 5
Underwood,
2009
RCT
Effectiveness
unclear
1
La
30
VII Feeding intolerance
(emesis, gastric
distention, excessive
gastric residuals;
transient) n=3
3
n/a, 0
Underwood,
2009
RCT
Effectiveness
unclear
2
29
VII Feeding intolerance
(emesis, gastric
distention, excessive
gastric residuals;
transient) n=1
1
n/a, 0
Underwood,
2009
RCT
Effectiveness
unclear
3
Bi
31
VII Feeding intolerance
(emesis, gastric
distention, excessive
gastric residuals;
transient) n=0
0
n/a, 0
C-206
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Urban, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
1
Bi
45
XXVII Serious illness
(SAE) n=7
Urban, 2008
RCT
Effective
2
43
Urbansek, 2001
RCT
Effective
1
La
Urbansek, 2001
RCT
Effective
Other Harms
n/a
N
Drop
outs,
Due
to AE
13, 0
XXVII Serious illness
(SAE) n=4
n/a
9, 0
102
VII Gastrointestinal
problems n=3
XXVII Labial edema n=0
3
n/a,
n/a
2
103
VII Gastrointestinal
problems n=2
XXVII Labial edema n=1
3
n/a,
n/a
Van der Aa,
2010
RCT
Not effective
1
Bi
46
XXII Respiratory
syncytial virus
bronchiolitis
(hospitalized) (SAE) n=1
XXVII Cow's milk allergy
(hospitalized) (SAE) n=0
n/a
6, 2
2
Van der Aa,
2010
RCT
Not effective
2
44
XXII Respiratory
syncytial virus
bronchiolitis
(hospitalized) (SAE) n=0
XXVII Cow's milk allergy
(hospitalized) (SAE) n=1
n/a
2, 1
0
Spitting
up,
vomiting,
hard
stools, loose stools,
flatulence,
restlessness:
no
difference between
groups; 17 hospital
admissions
including 5 cases of
septicemia,
group
unclear
C-207
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Formula only
Antibiotics
unclear
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Van
Gossum,
2007
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
1
La
34
Van
Gossum,
2007
RCT
Not effective
2
36
Velaphi, 2008
RCT
Not effective
1
Bi
53
XI Bronchopneumonia
n=3
VII Gastroenteritis n=1
Velaphi, 2008
RCT
Not effective
2
51
Vendt, 2006
RCT
Effective
1
La
Vendt, 2006
RCT
Effective
2
Other Harms
Feeding intolerance
and
treatment
related
complications
occurred,
number
and group unclear
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
7, n/a
n/a
14,
n/a
n/a
16,
n/a
XI Bronchopneumonia
n=6
VII Gastroenteritis n=0
n/a
15,
n/a
60
VII Colic pain n=1
VII Constipation n=1
VII diarrhea n=2
4
9, 4
60
VII Colic pain n=3
VII Constipation n=1
VII Diarrhea n=0
4
6, 4
5 withdrawals due to
prolonged
illness,
group unclear; No
statistically
significant difference
in number of stools,
spitting,
vomiting,
flatulence,
doctor
visits or hospital
admissions;
congenital syphilis,
ophthalmia
neonatorum,
jaundice,
and
diabetes insipidus
occurred,
group
unclear
C-208
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Maltodextrin
only
Formula only
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Vleggaar, 2008
C-RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
Bi
14
XI Submandibular
abscess n=1
VII Ulcerative colitis
exacerbation n=0
1
N
Drop
outs,
Due
to AE
2, 2
Vleggaar, 2008
C-RCT
Not effective
2
12
XI Submandibular
abscess n=0
VII Ulcerative colitis
exacerbation n=
1
0, 0
Vlieger, 2009
RCT
Effective
1
Bi
69
VII Vomiting n=10
VII Diarrhea n=2
VII Constipation n=4
VII Colic n=17
XI Rash n=15
n/a
28,
n/a
Vlieger, 2009
RCT
Effective
2
64
VII Vomiting n=15
VII Diarrhea n=1
VII Constipation n=7
VII Colic n=13
XI Rash n=19
Wada, 2010
RCT
Effective
1
Bi
19
XI Bacteremia (SAE)
n=0
0
1, 0
Wada, 2010
RCT
Effective
2
23
XI Bacteremia (SAE)
n=0
0
1, 0
Wang, 2004
RCT
Effective
1
St
60
VIII Fever n=0
VII Abdominal pain n=0
VII Diarrhea n=0
n/a
0, 0
Wang, 2004
RCT
Effective
2
20
VIII Fever n=0
VII Abdominal pain n=0
VII Diarrhea n=0
n/a
0, 0
26,
n/a
C-209
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Prebiotics
Placebo
Fermented
milk only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Wang, 2007
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
1
Bi
33
XI Serious infections n=0
XI Positive blood culture
n=0
XIII Elevated c-reactive
protein level n=0
Wang, 2007
RCT
Effective
2
33
XI Serious infections n=0
XI Positive blood culture
n=0
XIII Elevated c-reactive
protein level n=0
Weizman, 2005
RCT
Effective
1
Bi
73
VII Bloody stools n=0
XXVII Hospitalization
(SAE) n=0
Weizman, 2005
RCT
Effective
2
60
Weizman, 2005
RCT
Effective
3
Weizman, 2006
RCT
Effective
Other Harms
Patients
with
AEs
n/a
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
n/a,
n/a
No differences in
growth parameters,
behavior or stooling
parameter
No
supplement
n/a
2, 0
0
Antibiotics
unclear
VII Bloody stools n=0
XXVII Hospitalization
(SAE) n=0
n/a
2, 0
0
Antibiotics
unclear
68
VII Bloody stools n=0
XXVII Hospitalization
(SAE) n=0
n/a
3, 0
0
Antibiotics
unclear
1
Bi
20
IV Otitis media n=0
XI Upper respiratory
infection n=1
1
4, 0
Weizman, 2006
RCT
Effective
2
19
IV Otitis media n=0
XI Upper respiratory
infection n=1
1
3, 0
Weston, 2005
RCT
Effective
1
La
28
VII Vomiting n=0
n/a
2, 0
Weston, 2005
RCT
Effective
2
28
VII Vomiting n=1
n/a
1, 1
C-210
Control
Category
Placebo
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Wewalka, 2002
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
35
XX Pollakiuria
(reversible) n=0
V Increased thyroidstimulating hormone
(TSH) n=0
0
Wewalka, 2002
RCT
Effective
2
35
XX Pollakiuria n=1
V Increased thyroidstimulating hormone
(TSH) n=2
3
n/a,
n/a
Wheeler, 1997
C-RCT
Not effective
1
St
16
VII Gastrointestinal
complications n=0
0
1, 0
Wheeler, 1997
C-RCT
Not effective
2
16
VII Gastrointestinal
complication n=0
0
1, 0
Wildt, 2006
RCT
Not effective
1
Bi
21
VII Gastrointestinal
symptoms n=6
XV Musculoskeletal pain
n=2
XXVII Tiredness,
dizziness, malaise, and
hot flush n=1
XVII Headache n=3
XXVII Cold, flu,
gastroenteritis, and
cystitis n=5
VII Blood in stool n=2
21
n/a,
n/a
C-211
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Non-probiotic
Yogurt only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Wildt, 2006
RCT
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
8
VII Gastrointestinal
symptoms n=4
XV Musculoskeletal pain
n=1
XXVII Tiredness,
dizziness, malaise, and
hot flush n=5
XVII Headache n=2
XXVII Cold, flu,
gastroenteritis, and
cystitis n=2
VII Blood in stool n=2
8
Williams, 2008
RCT
Effective
1
Bi
28
VII Increased flatulence
n=1
1
0, 0
Williams, 2008
RCT
Effective
2
28
VII Increased Flatulence
n=0
0
4, 1
C-212
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Wind, 2010
RCT
Effective
Wind, 2010
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
18
VII Increased flatulence
n=2 (possibly related to
intervention per author)
VII Intermittent
abdominal cramps n=1
(possibly related to
intervention per author)
VII More loose stools
n=1 (possibly related to
intervention per author)
VII Pain in the lower
abdomen n=2 (possibly
related to intervention
per author)
I Clinically relevant
changes in blood
parameters n=0
No
difference
between
groups
regarding heartburn,
acid regurgitation,
sucking sensations
in the epigastrium,
nausea
and
vomiting,
borborygmi,
abdominal
distension,
eructation,
hard
stools, urgent need
for
defecation,
feeling
of
incomplete
evacuation,
dyspeptic
syndrome,
indigestion
syndrome,
bowel
dysfunction
syndrome;
16
adverse events in
treatment, 27 in
control group
2
18
VII Increased flatulence
n=0
VII Intermitted abdominal
cramps n=0
VII More loose stools
n=4 (possibly related to
intervention per author)
VII Pain in the lower
abdomen n=1 (possibly
related to intervention
per author)
I Clinically relevant
changes in blood
parameters n=0
C-213
Patients
with
AEs
n/a
N
Dropouts,
Due
to AE
1, 0
n/a
1, 0
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Wolf, 1994
RCT
Effectiveness
unclear
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
1
La
15
VII Flatulence n=n/a
VII Diarrhea n=1
VII Cramping n=0
Wolf, 1994
RCT
Effectiveness
unclear
2
15
VII Flatulence n=n/a
VII Diarrhea n=n/a
VII Cramping n=n/a
Wolf, 1998
RCT
Effective
1
La
18
XI Bacteria in blood
samples (SAE) n=0
VII Diarrhea (severe)
n=n/a
VII Vomiting (severe)
n=0
VII Flatulence (severe)
n=n/a
VII Burping (sever)
n=n/a
VII Reflux (severe) n=0
VII Nausea (severe)
n=n/a
VII Cramping (severe)
n=n/a
VII Distension (severe)
n=n/a
VII Constipation (severe)
n=0
Other Harms
Patients
with
AEs
n/a
N
Dropouts,
Due
to AE
n/a, 0
n/a, 0
Bacteria
samples
different
groups
in
urine
not
across
C-214
n/a
3, 0
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Wolf, 1998
RCT
Effective
Arm
Genera
N at
Randomization
Reported Harms, SAE
and Number of
Patients
Other Harms
2
21
XI Bacteria in blood
samples (SAE) n=0
VII Diarrhea (severe)
n=n/a
VII Vomiting (severe)
n=0
VII Flatulence 9severe)
n=n/a
VII Burping (severe)
n=n/a
VII Reflux (severe) n=n/a
VII Nausea (severe)
n=n/a
VII Cramping (severe)
n=n/a
VII Distension (severe)
n=n/a
VII Constipation (severe)
n=n/a
n/a
Worthley, 2009
C-RCT
Effectiveness
unclear
1
Bi
19
VII Excessive flatus n=5
VII Abdominal pain n=1
VII Abdominal bloating
n=4
VII Frequent or loose
bowel movements n=7
VII Excessive abdominal
gurgling noises n=2
n/a
n/a,
n/a
Worthley, 2009
C-RCT
Effectiveness
unclear
2
20
VII Excessive flatus
n=n/a
VII Abdominal pain
n=n/a
VII Abdominal bloating
n=n/a
VII Frequent or loose
bowel movements n=n/a
VII Excessive abdominal
gurgling noises n=n/a
n/a
n/a,
n/a
C-215
Patients
with
AEs
N
Dropouts,
Due
to AE
1, 0
Hospitalizations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Prebiotics
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Xia, 2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
30
XI Systemic
inflammatory response
syndrome (SAE) n=26
VII Anastomotic leakage
(SAE) n=2
n/a
N
Drop
outs,
Due
to AE
0, 0
Xia, 2010
RCT
Effective
2
30
XI Systemic
inflammatory response
syndrome (SAE) n=24
VII Anastomotic leakage
(SAE) n=2
n/a
0, 0
Xiang, 2006
RCT
Effective
1
Ba
22
VII Nausea (1) n=1
VIII Headache (1) n=0
VII Vomiting (1) n=0
1
0, 0
Xiang, 2006
RCT
Effective
2
24
VII Nausea (1) n=1
VIII Headache (1) n=1
VII Vomiting (1) n=1
2
0, 0
Xiao, 2003
RCT
Effectiveness
unclear
1
St
16
VII Increased fecal
frequency n=5
5
0, 0
Xiao, 2003
RCT
Effective
1
La
70
VII Vomiting (excessive,
withdrew) n=3
XXVII Insomnia n=0
VII Constipation n=0
3
1, 1
Xiao, 2003
RCT
Effectiveness
unclear
2
16
VII Increased fecal
frequency n=1
1
0, 0
Yogurt only
Xiao, 2003
RCT
Effective
2
La
67
VII Vomiting (excessive,
withdrew) n=1
XXVII Insomnia n=1
VII Constipation n=1
3
3, 3
Other
Probiotic
C-216
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Sulfasalazine
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Yang, 2008
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
St
67
XIII Blood assay
changes n=0
XIII Change in stool
assays n=0
XIII Change in liver
function n=0
XIII Change in urine
assays n=0
0
N
Drop
outs,
Due
to AE
4, 0
Yang, 2008
RCT
Effective
2
68
XIII Blood assay
changes n=0
XIII Change in stool
assays n=0
XIII Change in liver
function n=0
XIII Change in urine
assays n=0
0
5, 0
Yao-Zong, 2004
RCT
Effectiveness
unclear
1
En
202
VII Cessation of bowel
movement for 2 days
n=5
5
9, 5
Yao-Zong, 2004
RCT
Effectiveness
unclear
2
208
VII Cessation of bowel
movement for 2 days
n=8
8
12, 8
Yonekura
RCT
Effectiveness
unclear
1
La
69
VII Loose stools and
diarrhea n=n/a 15%
n/a
11, 0
Yonekura
RCT
Effectiveness
unclear
2
69
VII Loose stools and
diarrhea n=n/a (10%)
n/a
11, 0
Adverse
events
reported were minor
and nonspecific and
their frequency was
not different in the
two groups.
No
significant
difference
in
adverse
events
between groups.
C-217
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Placebo
Dioctahedral
smectite
Placebo
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Zhang, 2010
RCT
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
30
VII Gastrointestinal
discomfort n=3
n/a
N
Drop
outs,
Due
to AE
0, 0
Zhang, 2010
RCT
Effective
2
30
VII Gastrointestinal
discomfort n=6
n/a
0, 0
Ziegler, 2003
RCT
Effective
1
Bi
40
VII Constipation n=n/a
VII Flatulence n=n/a
XI Upper respiratory
infections n=n/a
7
12, 0
Ziegler, 2003
RCT
Effective
2
42
VII Constipation n=n/a
VII Flatulence n=n/a
XI Upper respiratory
infections n=n/a
5
9, 0
Zocco, 2003
RCT
Effective
1
La
65
n/a
n/a, 0
Zocco, 2003
RCT
Effective
2
62
n/a
n/a, 0
Zocco, 2003
RCT
Effective
3
La
n/a
n/a, 0
Most frequent side
effects
were
nausea, epigastric
pain,
and
constipation, group
unclear; side effects
determining
drop
out was observed
only in patients with
Crohn's
disease
consuming
LGG
(group unclear)
C-218
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Non-probiotic
Formula only
Mesalazine
only
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
An, 2010
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
19
VII Vomiting n=0
VII Abdominal pain n=0
VII Diarrhea n=0
0
Barrett, 2008
Case Series
Effective
1
La
18
VII Increased nausea
n=3
3
2, 2
Beck, 1961
Case Series
Effective
1
La
59
VII Constipation (1) n=1
VII Gassy n=1
VII Large amounts of
gas n=1
VII Liquid stool n=1
n/a
0, 0
Bekkali, 2007
Case Series
Effective
1
Bi
20
VII Vomiting n=0
VII Bloating n=0
VII Flatulence n=0
0
0, 0
Bellomo, 1979
Case Series
Effective
1
En
45
I Significant hematologic
changes n=0
0
0, 0
Benchimol, 2004
Case Series
Effective
1
Bi
2
XXIII Erythema around
the anus (1) n=1
1
0, 0
Berman, 2006
Case Series
Effective
1
Bi
10
VII Gastrointestinal gas
n=1
VII Increased
constipation n=1
1
0, 0
Bibiloni, 2005
Case Series
Effectiveness
unclear
1
St
32
XIII Biochemical adverse
events n=0
VII Bloating n=10
10
2, 0
Bruce, 1988
Case Series
Effectiveness
unclear
1
La
5
VII Gastroenteritis n=1
1
0, 0
C-219
Patients
with
AEs
N
Drop
outs,
Due
to AE
n/a,
n/a
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Bruni, 2008
Case Series
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
La
85
XXVII Sensitization (skin
prick test) n=n/a
XXVII Sensitization
(cow's milk) n=n/a
n/a
N
Drop
outs,
Due
to AE
0, 0
Carlsson, 2009
Case Series
Effectiveness
unclear
1
La
15
XXVII Death (SAE) n=2
VII Diarrhea n=1
3
2, 2
Cobo
Sanz,
2006
Case Series
Effective
1
St
381
XI
Otorhinolaryngological
infections n=16
VII Abdominal pain n=11
VII Diarrhea n=7
n/a
n/a,
n/a
Colecchia, 2006
Case Series
Effective
1
Bi
645
VII Diarrhea (1) n=6
6
9, 0
Di Pierro, 2009
Case Series
Effective
1
La
165
XXI Irritation (mild) n=12
12
0, 0
Dughera, 2007
Case Series
Effective
1
Bi
129
VII Dyspepsia (1) n=1
1
n/a,
n/a
Elmer, 1995
Case Series
Effectiveness
unclear
1
Sa
7
XXVII Thirst n=3
XXVII Dry month n=2
VII Gas n=1
XXIII Itching n=1
3
0, 0
Fukuda, 2008
Case Series
Effective
1
Bi
117
VII Diarrhea n=1
1
15, 0
Gabrielli, 2009
Case Series
Effective
1
Ba
40
VII Constipation n=1
1
0, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
reduced
probiotics by
half
C-220
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Garrido, 2005
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Ba
8
VII Mild increases of
borborygmi n=n/a (only
with 500 ml/day)
n/a
N
Drop
outs,
Due
to AE
0, 0
Gionchetti, 2007
Case Series
Effective
1
St
23
VII Transient bloating (1)
n=1
1
0, 0
Glintborg, 2006
Case Series
Not effective
1
La
8
VII Constipation
worsened n=1
n/a
1, 1
Gniwotta, 1977
Case Series
Effective
1
Sa
145
XXVII Allergic reactions
n=0
0
29,
Gotteland, 2003
Case Series
Effective
1
La
12
VII Diarrhea n=1
1
1, 1
Gruenwald,
2002
Case Series
Effectiveness
unclear
1
Bi
42
VII Nausea n=n/a
XXIII Pruritus n=n/a
XXII Dyspnea n=n/a
IX Cholecystitis n=n/a
XXVII Depression n=n/a
VII Uneasiness n=n/a
VII Gastralgia n=n/a
VII Fullness n=n/a
VII Eructation n=n/a
n/a
4, 4
Hensgens, 1976
Case Series
Not effective
1
La
5
VII Gastrointestinal
intolerance n=0
VII Change in stools n=0
0
0, 0
C-221
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Huynh, 2009
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
N
Drop
outs,
Due
to AE
1, n/a
1
St
19
VII Increased nausea
n=7
XIII Biochemical adverse
events n=0
VII Flatulence n=12
VII Vomiting (3) n=1
VII Diarrhea (3) n=1
VII Increased bloating
n=12
n/a
Karimi, 2005
Case Series
Effectiveness
unclear
1
St
29
XXVII Rhinitis (withdrew,
was present before
study strted) n=1
VII Nausea (1/3
withdrew ) n=3
VII Mild to moderate
bloating (withdrew) n=1
VII Nonspecific
gastrointestinal
symptoms (withdrew)
n=1
XXVII Non-IBD
deterioration of well
being n=1
n/a
13, 7
Kawamura,1981
Case Series
Effective
1
La
30
VII GI symptoms n=0
VIII Fever n=0
0
0, 0
Kirchhelle, 1996
Case Series
Effective
1
Sa
98
X Allergic reactions
(medium intensity) n=2
(states unlikely related to
probiotics or link could
not be established)
2
4, 0
Kitajima, 1997
Case Series
Effective
1
Bi
66
VII Functional ileus n=2
2
0, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
1
IV fluids
C-222
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Lamiki, 2010
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Bi
46
VII Diarrhea n=0
VII Abdominal pain n=0
VII Nausea n=0
XIII Biochemical adverse
effects n=0
0
N
Drop
outs,
Due
to AE
1, 0
Lee, 2010
Case Series
Not effective
1
St
12
VII Gastrointestinal
disturbances n=3
XV Flare of rheumatoid
arthritis n=1
4
0, 0
Lombardo, 2009
Case Series
Effective
1
La
100
VII Nausea (slight) n=1
1
n/a, 0
Luoto, 2010
Case Series
Effective
1
La
644
XI LGG Septicemia
(SAE) n=0
n/a
n/a,
n/a
Malin, 1996
Case Series
Effective
1
La
16
VII Watery stools n=1
n/a
n/a,
n/a
Malkov, 2006
Case Series
Effective
1
Ba
10
VII Sicchasia n=1
XXVII Slight blood n=n/a
XVII Intracranial
pressure gain (SAE)
n=n/a
XVII Stroke -death (5)
(SAE) n=1
XXVII Death (SAE) n=7
IX Liver failure -death (5)
(SAE) n=1
XXVII Death due to
pulmonary edema and
stroke (SAE) n=1
n/a
0, 0
C-223
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Mego, 2005
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
En
11
VIII Febrile episode n=0
XI Infection caused by
tested probiotics n=0
XXVII Significant
mucositis n=0
VII Diarrhea n=0
XI Bacteremia (SAE)
n=5
VII Enterocolitis n=2
XI Candidemia (SAE)
n=1
XI Pneumonia n=1
VII Meteorism (mild) n=1
5
N
Drop
outs,
Due
to AE
0, 0
Mego, 2006
Case Series
Not effective
1
En
14
XI Bacteremia caused by
probiotic strain (SAE)
n=0
XI Infection caused by
probiotic strain (SAE)
n=0
VII Diarrhea (1) n=2
XXVII Treatment related
death (SAE) n=0
n/a
0, 0
Michetti, 1999
Case Series
Effectiveness
unclear
1
La
10
VII Diarrhea (1) n=0
VII Abdominal pain n=0
VII Loss of appetite n=0
VII Constipation n=2
VII Pyrosis n=2
VII Nausea n=1
5
0, 0
Muting, 1968
Case Series
Effective
1
Bi
20
XIII Increased blood
sugar n=n/a
VII Stomach pains n=1
XI Severe tooth infection
n=1
n/a
0, 0
C-224
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Nobuta, 2009
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
42
VII Acute enterocolitis
n=1
VII Tenesmus n=n/a
VII Abdominal pain
n=n/a
VII Diarrhea n=n/a
n/a
N
Drop
outs,
Due
to AE
3, 1
Reid, 2001
Case Series
Effective
1
La
10
XX Bladder irritation n=0
XXI Vaginal irritation n=0
XXI Discharge n=0
VII Intestinal upset n=0
XXII Bronchitis n=1
n/a
7, 0
Rosenfeldt,
2003
Case Series
Effective
1
La
11
VII Abdominal pain n=0
VII Loose stools n=0
0
n/a, 0
Sakamoto, 2001
Case Series
Effective
1
La
31
VII Gastrointestinal n=0
0
2, 0
Schneider, 2005
Case Series
Effectiveness
unclear
1
Sa
10
VII Changes in the
number of bowel
movements n=0
VII Changes in stool
consistency n=0
VIII Fever n=0
XI Fungemia (SAE) n=0
VII Diarrhea (1) n=1
1
0, 0
Shen, 2005
Case Series
Not effective
1
St
31
VII Bloody bowel
movements n=1
VII Severe constipation
n=n/a
VII Bloating n=n/a
VII Gas n=n/a
n/a
25, 2
C-225
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Srinivasan, 2006
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
28
XIII Pathologic growth of
lactobacilli n=0
0
N
Drop
outs,
Due
to AE
0, 0
Tasli, 2006
Case Series
Effective
1
La
25
VII Nausea n=n/a 1
withdrew
VII Abdominal fullness
(withdrew) n=1
n/a
2, 1
van
Bodegraven,
2004
Case Series
Effectiveness
unclear
1
St
29
VIII Deterioration of
general well-being n=2
(not IBD related)
VII Gastrointestinal
symptoms n=5
7
12, 9
Weiss, 2010
Case Series
Effective
1
St
10
VII Mild flatulence n=3
n/a
0, 0
Yim, 2006
Case Series
Effective
1
Bi
64
VII Constipation n=1
n/a
14, 3
Zahradnik, 2009
Case Series
Effective
1
St
8
XXVII Tingle in the throat
(1) n=2 (states
unrelated)
XXVII Sore throat (1)
n=2 (unrelated per
author)
XXVII Cold sore/ulcer (1)
n=2 (unrelated per
author)
XVII Headache (1) n=1
(unrelated per author)
VII Stomach ache (1)
n=1 (unrelated per
author)
n/a
0, 0
C-226
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Zahradnik, 2009
Case Series
Effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
St
12
XXVII Sore throat n=2
XXVII Mouth sore/fever
blister n=4
XVII Headache n=1
XXII Cough n=2
XXVII Congestion n=1
n/a
N
Drop
outs,
Due
to AE
1, 0
Barton, 2001
Case Study
Not effective
1
En
1
XI Bacteremia (SAE)
n=1
XI Meningitis (SAE) n=1
1
0, 0
Antibiotics
needed
Bassetti, 1998
Case Study
Not effective
1
Sa
1
XI Fungemia (SAE) n=1
1
0, 0
Antibiotics
needed
Burkhardt, 2005
Case Study
Not effective
1
Sa
1
XI Sepsis (4) (SAE) n=1
1
0, 0
Antibiotics
needed
Cesaro, 2000
Case Study
Not effective
LTFU
Cherifi, 2004
Case Study
Effectiveness
unclear
1
Sa
1
XI Fungemia (4) (SAE)
n=1
1
0, 0
Antibiotics
needed
1
Sa
1
XI Fungemia (SAE) n=1
XXVII Death (SAE) n=1
(states anorexia nervosa
complications)
1
0, 0
Antibiotics
needed
Conen, 2009
Case Study
Not effective
1
La
1
XI Abscess (SAE) n=1
1
0, 0
De Groote, 2005
Case Study
Not effective
1
La
1
XI Bacteremia (SAE)
n=1
1
0, 0
Force, 1995
Case Study
Not effective
1
Sa
2
XI Fungemia (SAE) n=2
2
0, 0
C-227
Patients
with
AEs
Hospi
tali
zations
1
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Antifungal
treatment
Antibiotics
needed
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Fredenucci,
1998
Case Study
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
Patients
with
AEs
1
Sa
1
XI Fungemia (SAE) n=1
1
N
Drop
outs,
Due
to AE
0, 0
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Hennequin,
2000
Case Study
Not effective
1
Sa
4
XI Fungemia (4) (SAE)
n=4
XI Septic shock (SAE)
n=1
XXVI Hypotension n=1
VIII Fever n=2
4
0, 0
Antibiotics
unclear
Henry, 2004
Case Study
Not effective
1
Sa
1
XI Fungemia (SAE) n=1
1
0, 0
Antibiotics
needed
Hwang, 2009
Case Study
Not effective
1
Sa
1
XXVII Food proteininduced enterocolitis
syndrome (SAE) n=1
1
0, 0
Jensen, 1974
Case Study
Not effective
1
Sa
1
VIII Fever n=1
1
0, 0
Kniehl, 2003
Case Study
Effectiveness
unclear
1
Ba
3
VII Diarrhea n=3
3
0, 0
Ku, 2006
Case Study
Not effective
1
Bi
1
XIV D-lactic acidosis (4)
(SAE) n=1
1
0, 0
Kunz, 2004
Case Study
Not effective
1
La
2
XI Sepsis (4) (SAE) n=2
2
0, 0
Antibiotics
needed
1
IV fluid
C-228
1
Antibiotics
needed
supportive
care,
magnesium,
IV
bicarbonate
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Land, 2005
Case Study
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
1
La
2
XI Bacteremia (4) (SAE)
n=2
XI Sepsis (4) (SAE) n=2
LeDoux, 2006
Case Study
Not effective
1
La
1
Lestin, 2003
Case Study
Not effective
1
Sa
Lherm, 2002
Case Study
Not effective
Other Harms
Hospi
tali
zations
2
N
Drop
outs,
Due
to AE
0, 0
XI Bacteremia (SAE)
n=1
1
0, 0
1
1
XI Sepsis (SAE) n=1
VII Toxic megacolon
(SAE) n=1
XXVII Death (SAE) n=1
(organ failure after
bypass)
1
0, 0
Antibiotics
needed
1
Sa
6
XI Fungemia (SAE) n=6
XXVII Death (SAE) n=3
6
0, 0
Antibiotics
needed
Lolis, 2008
Case Study
Not effective
1
Sa
1
XI Fungemia (4) (SAE)
n=1
1
0, 0
Antibiotics
needed
Lungarotti, 2003
Case Study
Not effective
1
Sa
1
XI Fungemia (SAE) n=1
I Methemoglobinemia
(SAE) n=1
1
0, 0
Antibiotics
needed
Mackay, 1999
Case Study
Not effective
1
St
1
XI Endocarditis (4)
(SAE) n=1
1
0, 0
1
Antibiotics
needed
Munakata, 2010
Case Study
Not effective
1
St
1
XXVII D-lactic acidosis
(4) (SAE) n=1
1
0, 0
1
Antibiotics
needed
Muсoz, 2005
Case Study
Not effective
1
Sa
3
XI Sepsis (SAE) n=2
XI Fungemia (SAE) n=3
XXVII Death (unknown
cause, bacteremia,
stroke) (SAE) n=3
3
0, 0
C-229
Patients
with
AEs
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
2
Antibiotics
needed
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Niault, 1999
Case Study
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
1
Sa
1
XI Fungemia (SAE) n=1
Oggioni, 1998
Case Study
Not effective
1
Ba
1
Oh, 1979
Case Study
Not effective
1
La
Ohishi, 2010
Case Study
Not effective
Other Harms
Hospi
tali
zations
1
N
Drop
outs,
Due
to AE
0, 0
XI Septicemia -death
(SAE) n=1
VIII Fever (40C) (2) n=1
XVII Mental confusion
(3) n=1
VII Diarrhea n=1
XXVII Death (central
nervous system related)
(SAE) n=1
1
0, 0
1
Antibiotics
needed
1
XIV D-lactic acidosis
(SAE) n=1
1
0, 0
1
Antibiotics
needed
1
Bi
1
XI Septicemia (SAE) n=1
1
0, 0
Antibiotics
needed
Perapoch, 2000
Case Study
Not effective
1
Sa
1
XI Fungemia (4) - patient
(SAE) n=1
XI Infection also
contracted by second
infant in proximity of
patient (SAE) n=1
1
0, 0
Antibiotics
needed
Piarroux, 1999
Case Study
Not effective
1
Sa
1
XI Fungemia (SAE) n=1
1
0, 0
Antibiotics
needed
A 2nd patient also
developed fungemia
believed
to
be
caused by hand
contact with the
patient #1
C-230
Patients
with
AEs
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Piechno, 2007
Case Study
Effectiveness
unclear
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
Sa
1
XI Fungemia (SAE) n=1
XI Inflammatory bowel
n=1
VII Perforated ulcer
(SAE) n=1
XXVI State of shock n=1
VII Pseudomembranous
colitis (SAE) n=1
1
N
Drop
outs,
Due
to AE
0, 0
Pletinex, 1995
Case Study
Not effective
1
Sa
1
XI Fungemia (SAE) n=1
1
0, 0
Presterl, 2001
Case Study
Not effective
LTFU
1
La
1
XI Endocarditis (4)
(SAE) n=1 (PCR shows
pathogen is not from
yogurt per author)
XI Septic arthritis (4)
(SAE) n=1 (PCR shows
pathogen is not from
yogurt per author)
1
0, 0
1
Rautio, 1999
Case Study
Not effective
1
La
1
XI Liver abscess (SAE)
n=1
1
0, 0
1
Richard, 1988
Case Study
Not effective
1
Ba
4
XI Bacteremia (SAE)
n=4
XXVII Death (SAE) n=2
4
0, 0
Antibiotics
needed
Rijnders, 2000
Case Study
Not effective
1
Sa
1
XI Fungemia -death
(SAE) n=1
VII Colitis n=1
1
0, 0
Antibiotics
needed
Riquelme, 2003
Case Study
Not effective
1
Sa
2
XI Fungemia (4) (SAE)
n=2
2
0, 0
Antibiotics
needed
C-231
Patients
with
AEs
Hospi
tali
zations
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Antifungal
treatment
Antibiotics
needed
acetylsalicylic
acid
Antibiotics
needed
Synovectomy,
valve
replacement
Antibiotics
needed
Control
Category
Evidence Table C4. Results (continued)
Author, Year
Design
Described as
Effective
LTFU
Tommasi, 2008
Case Study
Not effective
Arm
Genera
N at
Random
ization
Reported Harms, SAE
and Number of
Patients
Other Harms
1
La
1
XI Bacteremia (SAE)
n=1
1
N
Drop
outs,
Due
to AE
0, 0
Trautmann,
2008
Case Study
Effectiveness
unclear
1
Sa
1
XI Fungemia (SAE) n=1
XVII Psychomotor
disturbance n=1
1
0, 0
Antibiotics
needed
Viggiano, 1995
Case Study
Not effective
1
Sa
1
VII Gastrointestinal
intolerance n=1
VIII Fever n=1
XXII Respiratory distress
requiring use of
respirator (SAE) n=1
XI Blood cultures
positive for S.
cerevisiae/boulardii n=1
1
0, 0
Antibiotics
needed
Zein, 2008
Case Study
Effectiveness
unclear
1
St
1
XI Lactobacillus
septicemia (SAE) n=1
1
0, 0
Zunic, 1991
Case Study
Effectiveness
unclear
1
Sa
1
XI Fungemia (SAE) n=1
1
0, 0
Abbreviations
I=Blood and lymphatic system disorders
II=Cardiac disorders
III=Congenital, familial and genetic disorders
IV=Ear and labyrinth disorders
V=Endocrine disorders
VI=Eye disorders
VII=Gastrointestinal disorders
VIII=General disorders and administration site conditions
IX=Hepatobiliary disorders
X=Immune system disorders
C-232
Patients
with
AEs
Hospi
tali
zations
1
1
Antibiotic
Therapy
Any Other
Treatment
Antibiotics
needed
Antibiotics
needed
Antibiotics
needed
Control
Category
XI=Infections and infestations
XII=Injury, poisoning and procedural complications
XIII=Investigations
XIV=Metabolism and nutrition disorders
XV=Musculoskeletal and connective tissue disorders
XVI=Neoplasms benign, malignant and unspecified (incl cysts and polyps)
XVII=Nervous system disorders
XVIII=Pregnancy, puerperiumand and perinatal conditions
XIX=Psychiatric disorders
XX=Renal and urinary disorders
XXI=Reproductive system and breast disorders
XXII=Respiratory, thoracic and mediastinal disorders
XXIII=Skin and subcutaneous tissue disorders
XXIV=Social circumstances
XXV=Surgical and medical procedures
XXVI=Vascular disorders
XXVII=Other
AE=Adverse Events
Ba=Bacillus
Bi=Bifidobacterium
C-RCT=Cross-over Randomized Controlled Trial
CCT=Controlled Clinical Trials
Effective=Described as Effective
En=Enterococcus
La=Lactobacillus
LTFU=Long-term follow-up
ml-milliliter
n=number of participants
n/a=not available or not applicable
RCT=Randomized Controlled Trial
a=Saccharomyces
SAE=Serious Adverse Event
St=Streptococcus
C-233
ok
ok
()
ok
ok
ok
ok
()
ok
()
ok
ok
()
()
ok
()
()
ok
ok
()
ok
()
ok
()
()
ok
()
ok
()
()
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
()
()
()
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
()
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
()
ok
ok
()
()
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
Conflict of Interest
Confounding
ITT
ok
()
ok
ok
ok
ok
()
ok
()
ok
()
()
()
ok
ok
()
()
ok
ok
ok
()
()
()
()
()
()
()
()
()
()
ok
ok
ok
()
()
()
()
ok
ok
ok
()
()
()
ok
ok
ok
ok
ok
ok
()
Dropouts
ok
()
ok
Assessor Blinding:
ok
ok
()
Participant Blinding:
()
ok
()
Concealment
()
()
ok
Randomization
Surveillance
Compliance
Power
Comparability
ok
Selection Bias
ok
Harm Reporting
Assessment
Reporting
Abrahamsson,
2007
3970
RCT
Agerbaek, 1995
13296
RCT
Aihara, 2005
2709
RCT
Alberda, 2007
3979
RCT
Allen, 2010
13253
RCT
Anderson, 2003
2226
RCT
Andriulli, 2008
4735
RCT
Anukam, 2006
3319
RCT
Anukam, 2008
4736
RCT
Anukam, 2009
13529
RCT
Arunachalam,
2000
894
RCT
Aso, 1992
12899
RCT
Aso, 1995
12942
RCT
Awad, 2010
13543
RCT
Baerheim, 1994
12960
RCT
Bajaj, 2008
4750
RCT
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality
ok
C-234
ok
ok
()
ok
ok
ok
ok
()
()
()
()
Banaszkiewicz,
2005
2725
RCT
Barraud, 2010
13579
RCT
Barreto-Zuniga,
2001
7806
RCT
Basu, 2007
4007
RCT
Basu, 2007
4008
RCT
Basu, 2009
4762
RCT
Beausoleil, 2007
4012
RCT
Bellomo, 1979
13309
RCT
Bertolami, 1999
13273
C-RCT
Besselink, 2008
4767
RCT
Bin-Nun, 2005
2746
RCT
Black, 1997
13153
CCT
Boge, 2009
13656
RCT
Boge, 2009
15876
RCT
Borgia, 1982
15834
RCT
Bousvaros,
2005
2765
RCT
ok
ok
()
ok
ok
()
ok
()
()
ok
()
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
ok
()
()
()
()
()
()
()
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
()
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
ok
ok
ok
()
()
ok
ok
()
ok
()
ok
ok
ok
()
ok
()
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
ok
ok
()
ok
ok
()
()
()
()
ok
ok
()
ok
ok
ok
ok
C-235
ok
()
()
()
ok
()
ok
()
()
Bravo, 2008
4796
RCT
Brophy, 2008
4800
RCT
Bruno, 1981
12379
RCT
Bruzzese, 2007
4053
C-RCT
Bu, 2007
4054
RCT
Chen, 2005
9337
RCT
Chen, 2010
13804
RCT
Chou, 2010
13817
RCT
Chouraqui, 2004
2291
RCT
Chouraqui, 2008
4846
RCT
Chui, 2009
13870
RCT
Coccorullo,
2010
13833
RCT
Connolly, 2005
2805
RCT
Cooper, 2006
13033
RCT
Correa, 2005
2809
RCT
Cui, 2004
9076
RCT
CunninghamRundles, 2000
919
CCT
()
ok
ok
ok
()
ok
ok
()
ok
()
ok
()
ok
()
ok
ok
ok
ok
ok
ok
ok
()
()
()
ok
()
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
ok
ok
()
()
ok
ok
()
()
()
ok
()
ok
ok
()
ok
ok
ok
()
()
()
ok
ok
()
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
()
()
()
()
ok
ok
()
ok
()
()
()
()
ok
()
ok
ok
()
()
ok
ok
C-236
ok
Conflict of Interest
()
()
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
()
ok
ok
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
ok
ok
ok
()
ok
()
ok
ok
()
ok
()
ok
()
ok
ok
ok
()
ok
ok
ok
Surveillance
Compliance
Power
ok
ok
()
ok
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
ok
()
ok
()
ok
ok
ok
()
()
Czaja, 2007
4116
RCT
Dadak, 2006
13232
RCT
De Preter, 2006
13275
C-RCT
de Roos, 1999
13272
RCT
De
Simone,
1992
13096
RCT
De
Simone,
2001
13264
CCT
Dekker, 2009
12563
RCT
Delia, 2002
1488
RCT
Delia, 2007
4132
RCT
Dewan, 2007
4139
RCT
Dolin, 2009
13961
RCT
Dubey, 2008
4903
RCT
Duman, 2005
2838
RCT
Dupont, 2010
13989
RCT
Dylewski, 2010
13992
RCT
Ehrstrom, 2010
14005
RCT
Eriksson, 2005
2845
RCT
ok
ok
ok
ok
ok
()
ok
ok
()
ok
()
ok
ok
ok
()
ok
ok
()
()
()
ok
ok
()
ok
()
()
()
ok
ok
ok
ok
ok
ok
()
ok
()
ok
()
()
()
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
()
()
()
()
()
()
()
()
()
()
ok
()
()
()
()
()
ok
()
ok
()
()
()
ok
Conflict of Interest
ok
ok
ok
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
ok
ok
ok
()
()
()
()
ok
ok
ok
ok
ok
()
()
()
()
()
ok
ok
ok
()
()
()
ok
ok
ok
()
()
ok
()
()
()
ok
()
()
ok
()
()
ok
ok
ok
()
ok
ok
()
()
ok
ok
()
()
()
ok
()
()
ok
ok
ok
()
()
ok
ok
()
()
ok
ok
ok
()
()
ok
ok
ok
ok
()
ok
()
ok
()
ok
ok
()
()
ok
ok
ok
()
ok
ok
ok
()
ok
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
C-237
ok
()
ok
ok
()
ok
ok
ok
Falck, 1999
13279
RCT
Felley, 2001
12954
RCT
Feng, 1999
12883
RCT
Folster-Holst,
2006
3503
RCT
Forestier, 2008
4929
RCT
French, 2009
13313
RCT
Frohmader,
2010
14075
RCT
Fujimori, 2009
5672
RCT
Gade, 1989
13050
RCT
Galpin, 2005
2875
RCT
Gao, 2010
14095
RCT
Garcia
Vilela,
2008
4941
RCT
Gerasimou,
2010
14116
RCT
Gibson, 2008
5676
RCT
Gill, 2001
1192
RCT
Gionchetti, 2000
944
RCT
()
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
()
ok
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
ok
C-238
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
ok
ok
ok
ok
()
()
()
ok
()
ok
ok
ok
Randomization
Surveillance
Compliance
Power
Comparability
()
ok
ok
ok
ok
ok
ok
ok
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
ok
ok
()
()
()
()
ok
ok
ok
ok
()
()
ok
ok
ok
()
ok
()
Gionchetti, 2003
1923
RCT
Goossens, 2003
1928
RCT
Gracheva, 1999
764
CCT
Gruber, 2007
4223
RCT
Guillemard,
2010
14197
RCT
Guyonnet, 2009
5687
RCT
Habermann,
2001
12892
RCT
Habermann,
2002
1540
RCT
HaschkeBecher, 2008
4993
RCT
Hatakka, 2008
4995
C-RCT
Heimburger,
1994
13228
RCT
Hemmerling,
2009
14262
RCT
Higashikawa,
2009
14278
RCT
Hilton, 1997
548
RCT
Hirata, 2002
12881
CCT
ok
()
ok
ok
()
()
ok
()
ok
ok
()
ok
()
()
ok
()
ok
()
()
()
ok
ok
()
()
ok
()
()
ok
()
()
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
()
ok
()
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
()
()
ok
()
()
()
()
()
ok
ok
ok
()
ok
()
()
ok
ok
ok
()
()
()
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
()
()
ok
()
()
ok
ok
Conflict of Interest
()
()
ok
()
()
()
()
ok
()
()
()
ok
ok
()
()
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
()
ok
()
()
()
ok
()
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
C-239
ok
()
ok
ok
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
ok
ok
ok
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
()
()
()
Hochter,1990
12996
RCT
Honeycutt, 2007
4253
RCT
Hong, 2010
14295
RCT
Horvat, 2010
14304
RCT
Ishikawa, 2002
1968
RCT
Ishikawa, 2003
12937
RCT
Ishikawa, 2005
2922
RCT
Isolauri, 1991
12412
RCT
Isolauri,1995
12826
RCT
Jirapinyo, 2002
1566
RCT
Johansson,
1998
653
RCT
Kadooka, 2010
14403
RCT
Kajander, 2005
2937
RCT
Kajander, 2008
5072
RCT
Kajimoto, 2002
12882
RCT
Karvonen, 2001
13044
RCT
Kerac, 2009
14441
RCT
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
()
()
ok
()
ok
()
()
ok
ok
ok
ok
()
()
()
ok
ok
ok
()
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
()
()
()
ok
ok
()
()
()
()
ok
()
()
ok
()
()
ok
ok
()
()
()
()
()
()
()
()
()
ok
ok
()
ok
ok
ok
()
ok
()
ok
()
()
()
()
()
ok
()
ok
ok
ok
()
()
()
()
()
ok
ok
()
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
()
ok
()
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
C-240
ok
ok
ok
ok
ok
()
ok
ok
Conflict of Interest
()
ok
ok
ok
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
()
ok
()
()
ok
ok
()
ok
()
Kianifar, 2009
14448
RCT
Kim, 2006
13298
RCT
Kim, 2006
3610
RCT
Kim, 2008
5096
RCT
Kirjavainen,2003
1993
RCT
Klarin, 2008
5105
RCT
Klarin,2005
2953
RCT
Knight, 2007
5110
RCT
Koning, 2008
5112
RCT
Kopp, 2008
5117
RCT
Kotzampassi,
2006
3597
RCT
Krasse, 2005
3601
RCT
Kuitunen, 2009
14517
RCT
Kurugol, 2005
2972
RCT
La Rosa, 2003
2008
RCT
Laitinen, 2008
5127
RCT
Langhendries,
1995
13114
RCT
ok
ok
ok
()
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
()
ok
()
ok
ok
ok
ok
()
()
()
ok
ok
ok
()
()
ok
()
()
()
()
ok
ok
ok
()
()
()
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
ok
()
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
()
ok
ok
ok
ok
()
ok
()
()
ok
ok
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
()
()
ok
ok
ok
ok
()
ok
()
()
()
ok
()
()
()
ok
()
ok
()
ok
ok
()
()
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
C-241
ok
()
ok
ok
()
ok
()
ok
ok
()
ok
ok
ok
ok
()
ok
()
ok
ok
ok
()
()
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
()
()
()
ok
()
()
ok
ok
ok
ok
ok
()
ok
()
()
()
ok
()
()
ok
()
()
()
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
()
()
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
()
ok
ok
()
()
ok
ok
()
()
()
()
()
()
()
ok
ok
ok
ok
Conflict of Interest
Confounding
ok
ok
ok
()
ok
ok
()
()
ok
()
ok
()
()
()
()
ok
()
()
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
()
ok
ok
C-242
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
()
ok
ok
()
ok
ok
ok
ok
Power
ok
()
ok
ok
Comparability
ok
Selection Bias
()
Harm Reporting
Assessment
Reporting
Larsen, 2006
3613
RCT
Larsson, 2008
5131
RCT
Lata, 2009
14560
RCT
Lawrence, 2005
2988
RCT
Li, 2004
13042
RCT
Ligaarden, 2010
14622
C-RCT
Lighthouse,
2004
9143
RCT
Lin, 1989
13095
C-RCT
Lin, 2005
3004
RCT
Lin, 2008
5156
RCT
Ljungberg, 2006
3636
RCT
Loguercio, 1987
13116
RCT
Lonnermark,
2010
14668
RCT
Lu, 2004
7077
CCT
Luoto, 2010
14685
RCT
Mäkeläinen,
2003
2031
RCT
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
ok
()
ok
()
()
ok
()
ok
ok
ok
ok
()
ok
ok
ok
ok
()
ok
()
ok
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
()
()
ok
ok
()
()
()
()
ok
()
()
()
()
ok
ok
()
()
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
()
()
()
ok
ok
()
()
()
ok
ok
ok
()
ok
()
()
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
()
ok
ok
ok
ok
()
ok
()
Conflict of Interest
ok
ok
()
Confounding
()
ok
()
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
ok
ok
()
()
Concealment
ok
ok
ok
Randomization
Surveillance
Compliance
Power
Comparability
ok
Selection Bias
ok
Harm Reporting
Assessment
Reporting
Malaguarnera,
2007
4374
RCT
Malaguarnera,
2010
14707
RCT
Maldonado,
2009
14708
RCT
Mandel, 2010
14715
RCT
Manley, 2007
4378
C-RCT
Manzoni, 2006
3654
RCT
Margreiter, 2006
3656
RCT
Marotta, 2003
8348
C-RCT
Marrazzo, 2006
3658
RCT
Marseglia, 2007
4383
RCT
Marteau, 2004
3661
RCT
Martiney, 2009
14747
RCT
Martinez, 2008
5755
RCT
Martinez, 2009
5756
RCT
Mayanagi, 2009
14773
RCT
McFarland,
1994
12403
RCT
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
ok
C-243
()
ok
ok
()
ok
()
()
ok
ok
McFarland,
1995
12753
RCT
McNaught, 2002
1637
RCT
Merenstein,
2009
14810
RCT
Merenstein,
2010
14809
RCT
Metts, 2003
6459
RCT
Miele, 2009
5767
RCT
Millar, 1993
388
RCT
Mimura, 2004
2486
RCT
Miyaji, 2006
10450
RCT
Morrow, 2010
14862
RCT
Mukerji, 2009
5774
RCT
Naito, 2008
5252
RCT
Newcomer,
1983
13137
RCT
Niers, 2009
13237
RCT
Niv, 2005
3096
RCT
Nobuta, 2009
13315
RCT
ok
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
()
()
ok
()
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
()
()
()
Conflict of Interest
Confounding
ITT
Dropouts
ok
ok
ok
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
ok
ok
ok
ok
ok
ok
Power
()
ok
ok
ok
Comparability
ok
ok
ok
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
()
ok
ok
ok
ok
ok
()
()
()
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
()
()
ok
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
C-244
()
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
()
()
ok
()
ok
ok
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
()
ok
()
ok
ok
ok
()
ok
ok
()
()
ok
ok
ok
()
()
ok
()
()
ok
ok
ok
()
ok
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
()
ok
()
()
()
()
()
()
()
()
ok
()
ok
ok
ok
ok
ok
ok
ok
()
()
()
()
ok
()
()
()
ok
()
()
ok
ok
ok
()
ok
ok
()
ok
ok
()
ok
ok
ok
ok
()
ok
()
()
ok
ok
ok
()
()
ok
ok
()
()
ok
ok
ok
()
()
ok
ok
ok
()
ok
()
()
ok
ok
()
()
ok
ok
()
ok
ok
ok
C-245
ok
Confounding
Conflict of Interest
()
()
ok
ok
ok
ok
()
()
()
()
ok
()
ok
ok
ok
()
()
ok
ok
ok
ok
()
ok
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
()
ok
()
Comparability
()
Selection Bias
ok
Harm Reporting
Assessment
Reporting
O'Mahony, 2005
3107
RCT
Ojetti, 2010
14951
RCT
Olah, 2005
3105
RCT
Olivares, 2006
3718
RCT
Osterlund, 2007
4452
RCT
Ouwehand,
2009
14975
RCT
Ozkinay, 2005
13286
RCT
Panigrahi, 2008
5292
RCT
Parent, 1996
13168
RCT
Parfenov, 2005
3114
CCT
Parfenov, 2005
3115
CCT
Parra, 2004
2523
RCT
Passeron, 2005
3733
RCT
Peral, 2009
5801
RCT
Pereg, 2010
15027
RCT
Petschow, 2005
12409
RCT
Prantera, 2002
1692
RCT
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
()
ok
()
ok
()
ok
ok
()
ok
ok
Pregliasco, 2008
13299
RCT
Pregliasco, 2008
13300
RCT
Pregliasco, 2008
5328
RCT
Puccio, 2007
4504
RCT
Rampengan,
2010
15104
RCT
Ranganathan
15107
C-RCT
Rautava, 2008
5350
RCT
Rayes, 2002
12475
RCT
Rayes, 2002
1702
RCT
Rayes, 2005
3152
RCT
Rayes, 2007
4518
RCT
Reid, 1992
12959
RCT
Reid, 1995
12815
RCT
Ren, 2010
15136
RCT
Reuman, 1986
12770
RCT
Richelsen, 1996
12374
RCT
Rio, 2002
1714
RCT
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
()
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
()
ok
ok
ok
ok
()
ok
()
ok
()
()
ok
ok
()
()
()
()
()
()
()
ok
()
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
()
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
()
()
ok
()
()
()
()
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
()
()
()
()
()
()
()
()
()
()
()
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
()
ok
()
()
ok
ok
()
()
()
()
ok
()
C-246
()
ok
ok
()
ok
()
ok
()
ok
ok
()
()
()
ok
ok
()
ok
ok
()
ok
()
Roos, 1996
13278
RCT
Roos, 2001
12970
RCT
Rose, 2010
15187
RCT
Rosenfeldt,
2002
1722
RCT
Rosenfeldt,
2003
6738
C-RCT
Rouge, 2009
5819
RCT
Ruiz-Palacios,
1996
13088
RCT
Saavedra, 2004
2572
RCT
Safdar, 2008
5377
RCT
Sahagun-flores,
2007
15865
RCT
Saint-Marc,
1995
15843
RCT
Salminen, 1988
12816
RCT
Salminen, 2004
2578
C-RCT
Samanta, 2008
5828
RCT
Satokari, 2001
1329
RCT
Savino, 2006
4569
RCT
ok
ok
()
()
ok
ok
ok
()
ok
ok
ok
()
ok
ok
()
()
()
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
()
ok
ok
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
()
()
ok
()
ok
()
ok
ok
()
()
()
()
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
()
()
()
ok
()
ok
ok
()
ok
()
ok
ok
()
()
ok
()
()
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
ok
ok
ok
()
ok
ok
()
()
()
()
ok
ok
()
ok
ok
ok
ok
()
Concealment
()
ok
()
Randomization
()
ok
()
ok
Surveillance
Compliance
()
ok
()
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
ok
C-247
()
()
()
ok
ok
()
()
ok
ok
()
()
()
()
Sazawal, 2010
15858
RCT
Scalabrin, 2009
15253
RCT
Schrezenmeir,
2004
2586
RCT
Schultz, 2004
2588
RCT
Seppo, 2003
12878
RCT
Sierra, 2010
15343
RCT
Simons, 2006
3839
RCT
Simren, 2010
15353
RCT
Song, 2010
15379
RCT
Songisepp,
2005
16079
RCT
Songisepp,
2005
3207
CCT
Sood, 2009
15381
RCT
Spanhaak, 1998
703
RCT
Stockert, 2007
4607
RCT
Stotzer, 1996
515
C-RCT
Stratiki, 2007
4609
RCT
ok
ok
ok
()
ok
()
()
ok
()
ok
ok
ok
ok
()
ok
()
ok
ok
ok
ok
()
()
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
ok
Conflict of Interest
ok
ok
ok
ok
ok
ok
ok
ok
()
()
()
()
()
()
()
ok
ok
()
()
()
()
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
()
()
ok
()
()
ok
()
()
()
ok
()
ok
ok
()
()
()
ok
()
ok
()
()
ok
()
ok
ok
()
ok
()
ok
ok
()
()
ok
ok
ok
Confounding
()
()
ok
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
ok
ok
ok
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
ok
()
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
()
()
ok
()
ok
ok
ok
ok
()
()
()
ok
ok
ok
ok
()
ok
()
()
ok
ok
ok
ok
C-248
ok
ok
()
Sullivan, 2003
2156
RCT
Sykora, 2005
3222
RCT
Tamura, 2007
4626
RCT
Taylor, 2007
4631
RCT
Tempe, 1985
13083
RCT
Teran, 2008
5482
RCT
Thomas, 2001
6623
RCT
Tomoda, 1991
13152
CCT
Tsuchiya, 2004
2648
CCT
Turchet, 2003
2182
RCT
Tursi, 2004
2652
RCT
Tursi, 2008
5505
CCT
Tursi, 2010
15548
RCT
Underwood,
2009
5878
RCT
Urban, 2008
11572
RCT
Urbansek, 2001
1367
RCT
Van der Aa,
2010
15566
RCT
ok
ok
ok
ok
()
ok
()
ok
()
()
()
ok
()
()
ok
ok
()
ok
ok
ok
()
ok
ok
ok
()
()
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
()
ok
ok
ok
ok
ok
ok
()
()
()
ok
()
ok
()
()
()
ok
ok
()
()
ok
()
ok
()
()
()
ok
ok
()
()
ok
ok
ok
ok
()
ok
ok
()
ok
ok
ok
()
ok
()
ok
()
ok
ok
()
ok
()
ok
ok
Conflict of Interest
Confounding
()
ok
ok
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
()
()
ok
ok
Power
()
()
ok
Comparability
()
ok
ok
Selection Bias
ok
ok
ok
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
ok
ok
()
ok
ok
()
()
()
()
ok
ok
()
()
ok
ok
ok
()
ok
ok
()
()
ok
()
()
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
()
ok
()
()
ok
ok
ok
ok
()
ok
ok
ok
()
C-249
()
ok
ok
ok
ok
()
Conflict of Interest
()
()
ok
ok
ok
ok
()
()
ok
ok
()
ok
()
()
ok
ok
ok
()
()
()
ok
ok
ok
()
()
ok
ok
()
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
()
()
()
ok
()
ok
ok
()
()
()
ok
ok
ok
ok
()
ok
ok
()
()
()
()
()
()
ok
()
ok
ok
ok
ok
ok
Confounding
ok
()
ok
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
ok
Concealment
ok
Randomization
ok
()
ok
Surveillance
()
Compliance
ok
ok
Power
ok
Comparability
()
Selection Bias
ok
Harm Reporting
Assessment
Reporting
Van
Gossum,
2007
4658
RCT
Velaphi, 2008
5526
RCT
Vendt, 2006
3908
RCT
Vleggaar, 2008
5531
C-RCT
Vlieger, 2009
5893
RCT
Wada, 2010
15642
RCT
Wang, 2004
2671
RCT
Wang, 2007
11346
RCT
Weizman, 2005
3278
RCT
Weizman, 2006
3925
RCT
Weston, 2005
3280
RCT
Wewalka, 2002
1792
RCT
Wheeler, 1997
12498
C-RCT
Wildt, 2006
3935
RCT
Williams, 2008
5562
RCT
Wind, 2010
15719
RCT
Wolf, 1994
12856
RCT
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
ok
()
ok
ok
()
()
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
ok
()
()
()
()
ok
()
ok
ok
ok
ok
()
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
()
ok
()
ok
ok
ok
()
ok
ok
ok
()
ok
ok
ok
()
()
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
()
()
ok
ok
ok
()
()
C-250
ok
ok
ok
ok
ok
()
ok
ok
()
()
ok
ok
()
ok
ok
ok
ok
ok
()
()
()
()
An, 2010
13513
Case Series
Barrett, 2008
4760
Case Series
Beck, 1961
13117
Case Series
Bekkali, 2007
4013
Case Series
Bellomo, 1979
13195
Case Series
ok
()
ok
ok
ok
ok
()
ok
ok
ok
()
ok
ok
()
()
ok
ok
ok
ok
ok
ok
()
()
()
ok
ok
()
()
()
()
()
ok
ok
()
()
()
()
()
ok
ok
ok
()
()
ok
()
()
()
()
ok
()
ok
ok
ok
ok
()
()
()
()
ok
()
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
ok
()
()
ok
()
C-251
ok
ok
()
ok
()
ok
()
()
ok
ok
()
()
()
()
ok
()
()
ok
()
ok
ok
()
ok
ok
ok
ok
Conflict of Interest
ok
ok
Confounding
ok
ITT
ok
Dropouts
ok
Assessor Blinding:
ok
Participant Blinding:
()
Concealment
()
ok
Randomization
()
Surveillance
ok
Compliance
ok
Power
ok
Comparability
ok
Selection Bias
ok
Harm Reporting
Assessment
Reporting
Wolf, 1998
718
RCT
Worthley, 2009
15730
C-RCT
Xia, 2010
15742
RCT
Xiang, 2006
10102
RCT
Xiao, 2003
2206
RCT
Xiao, 2003
2207
RCT
Yang, 2008
5576
RCT
Yao-Zong, 2004
2684
RCT
Yonekura
15779
RCT
Zhang, 2010
15796
RCT
Ziegler, 2003
8418
RCT
Zocco, 2003
13023
RCT
Author, Year
Genus, Species, and
Strain reporting
Evidence Table C5. Quality (continued)
()
ok
()
ok
()
ok
()
()
()
Benchimol, 2004
2238
Case Series
Berman, 2006
10085
Case Series
Bibiloni, 2005
2745
Case Series
Bruce, 1988
12963
Case Series
Bruni, 2008
5627
Case Series
Carlsson, 2009
13758
Case Series
Cobo
Sanz,
2006
9897
Case Series
Colecchia, 2006
3427
Case Series
Di Pierro, 2009
13935
Case Series
Dughera, 2007
4153
Case Series
Elmer, 1995
13220
Case Series
Fukuda, 2008
11700
Case Series
Gabrielli, 2009
14088
Case Series
Garrido, 2005
2878
Case Series
Gionchetti, 2007
4209
Case Series
Glintborg, 2006
12738
Case Series
Gniwotta, 1977
13081
Case Series
ok
()
ok
ok
ok
()
()
ok
()
ok
ok
()
ok
ok
ok
()
()
ok
Conflict of Interest
Confounding
ITT
ok
()
ok
()
()
()
ok
ok
ok
()
()
ok
()
ok
()
()
ok
ok
ok
ok
ok
()
()
ok
()
()
ok
()
ok
ok
ok
()
ok
ok
ok
ok
Dropouts
ok
()
ok
Assessor Blinding:
ok
()
ok
Participant Blinding:
ok
ok
()
Concealment
()
ok
ok
Randomization
Surveillance
()
ok
ok
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
ok
()
ok
()
()
ok
ok
()
()
ok
ok
()
C-252
Gotteland, 2003
13214
Case Series
Gruenwald,
2002
1533
Case Series
Hensgens, 1976
12902
Case Series
Huynh, 2009
5699
Case Series
Karimi, 2005
2943
Case Series
Kawamura,1981
12842
Case Series
Kirchhelle, 1996
13030
Case Series
Kitajima, 1997
6362
Case Series
Lamiki, 2010
14545
Case Series
Lee, 2010
14586
Case Series
Lombardo, 2009
14662
Case Series
Luoto, 2010
14683
Case Series
Malin, 1996
13109
Case Series
Malkov, 2006
3653
Case Series
Mego, 2005
3051
Case Series
Mego, 2006
3675
Case Series
Michetti, 1999
12400
Case Series
ok
()
()
()
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
()
Conflict of Interest
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Confounding
()
()
ok
()
ok
()
()
()
ok
ok
()
ok
()
ok
()
()
ok
ok
()
ok
ok
ok
()
ok
()
ok
ok
ok
Concealment
()
()
ok
ok
Randomization
ok
ok
ok
Surveillance
Compliance
Power
Comparability
Selection Bias
ok
()
()
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
()
()
()
ok
ok
ok
ok
()
()
()
()
ok
()
()
()
()
ok
()
()
ok
()
ok
ok
ok
ok
()
ok
ok
ok
ok
C-253
()
ok
ok
ok
Muting, 1968
13121
Case Series
Nobuta, 2009
15883
Case Series
Reid, 2001
1309
Case Series
Rosenfeldt,
2003
13297
Case Series
Sakamoto, 2001
1322
Case Series
Schneider, 2005
3191
Case Series
Shen, 2005
3198
Case Series
Srinivasan, 2006
3854
Case Series
Tasli, 2006
10000
Case Series
van
Bodegraven,
2004
8828
Case Series
Weiss, 2010
15681
Case Series
Yim, 2006
9923
Case Series
Zahradnik, 2009
15788
Case Series
Zahradnik, 2009
15877
Case Series
Barton, 2001
1109
Case Study
Bassetti, 1998
12397
Case Study
()
ok
ok
()
()
ok
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
()
ok
ok
()
ok
ok
()
ok
()
()
ok
()
ok
()
()
ok
ok
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
()
ok
ok
()
()
()
ok
()
()
ok
()
()
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
C-254
ok
()
()
()
ok
()
Burkhardt, 2005
13039
Case Study
Cesaro, 2000
12395
Case Study
Cherifi, 2004
2290
Case Study
Conen, 2009
13233
Case Study
De Groote, 2005
2814
Case Study
Force, 1995
12806
Case Study
Fredenucci,
1998
12788
Case Study
Hennequin,
2000
959
Case Study
Henry, 2004
13015
Case Study
Hwang, 2009
14335
Case Study
Jensen, 1974
12870
Case Study
Kniehl, 2003
1996
Case Study
Ku, 2006
10240
Case Study
Kunz, 2004
2424
Case Study
Land, 2005
2984
Case Study
LeDoux, 2006
3617
Case Study
Lestin, 2003
2017
Case Study
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
ok
()
ok
()
ok
ok
ok
Confounding
ITT
Conflict of Interest
()
()
ok
ok
()
()
()
ok
ok
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
()
ok
()
()
ok
()
()
ok
()
()
()
ok
()
()
ok
ok
()
ok
ok
ok
()
()
ok
ok
ok
()
ok
()
ok
()
ok
ok
ok
ok
()
()
ok
ok
ok
ok
()
ok
ok
ok
ok
ok
ok
ok
()
C-255
()
ok
Lherm, 2002
12398
Case Study
Lolis, 2008
5164
Case Study
Lungarotti, 2003
12924
Case Study
Mackay, 1999
812
Case Study
Munakata, 2010
14875
Case Study
Muñoz, 2005
3076
Case Study
NA
14585
NA
NA
15045
NA
NA
4095
NA
NA
4912
NA
Niault, 1999
817
Case Study
Oggioni, 1998
679
Case Study
Oh, 1979
13223
Case Study
Ohishi, 2010
14945
Case Study
Perapoch, 2000
12396
Case Study
Piarroux, 1999
12804
Case Study
Piechno, 2007
4488
Case Study
ok
ok
()
()
ok
ok
()
ok
ok
ok
()
ok
ok
ok
ok
()
()
ok
ok
()
ok
()
ok
()
ok
ok
ok
ok
ok
ok
ok
()
ok
ok
()
ok
ok
()
ok
ok
ok
()
ok
()
ok
ok
ok
ok
()
ok
ok
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
()
ok
ok
C-256
()
()
Conflict of Interest
Confounding
ITT
Dropouts
Assessor Blinding:
Participant Blinding:
Concealment
Randomization
Surveillance
Compliance
Power
Comparability
Selection Bias
Harm Reporting
Assessment
Reporting
Genus, Species, and
Strain reporting
Author, Year
Evidence Table C5. Quality (continued)
Pletinex, 1995
ok
ok
ok
()
()
12363
Case Study
Presterl, 2001
ok
ok
()
1299
Case Study
Rautio, 1999
ok
ok
ok
()
12357
Case Study
Richard, 1988
ok
ok
ok
()
12358
Case Study
Rijnders, 2000
()
ok
ok
ok
()
1033
Case Study
Riquelme, 2003
ok
ok
ok
()
2094
Case Study
Tommasi, 2008
ok
ok
ok
5492
Case Study
Trautmann,
ok
ok
()
ok
()
()
2008
11966
Case Study
Viggiano, 1995
ok
ok
ok
()
()
12787
Case Study
Zein, 2008
ok
ok
ok
ok
()
ok
5583
Case Study
Zunic, 1991
()
()
()
ok
()
ok
ok
12362
Case Study
Note: ( ): quality criterion partially met; ok: quality criterion met
*Abbreviations
ITT=Intention to treat analysis - Was an intention to treat (ITT) analysis described for the effectiveness data? (Were all participants' data included in
the analysis, according to the treatment group to which they were originally assigned, regardless of whether they completed the treatment/study?)
C-257
Evidence Table C6. Nonspecific safety statements
Author, Year
Design
Agarwal, 2002
RCT
Agustina, 2007
RCT
Ahuja, 2001
RCT
Alm, 1983
CT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus* casei DN-114001 , n/a , 10^8 cfu , t.i.d.
Lactobacillus* bulgaricus n/a , n/a , 10^8 cfu , 100 ml t.i.d.
Streptococcus* thermophilus n/a , n/a , 10^8 cfu , 100 ml
t.i.d.
Lactococcus lactis n/a , n/a , 10^8 cfu/g , 100 ml t.i.d.
Lactococcus lactis cremoris , n/a , n/a , n/a
Leuconostoc mesenteroids cremoris , n/a , n/a , n/a
NA
Product Name
*Actimel® #Dahi
Genus, Species, Strain
Lactobacillus rhamnosus LMG P-227 99 , n/a , 5*10^8 cfu ,
ad libitum
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; 1-5 yrs
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus n/a n/a , n/a , n/a , n/a
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Cataract surgery
patients
Genus, Species, Strain
Lactobacillus* acidophilus NCDO 1748 , n/a , 10^9 cfu/ml ,
ad libitum
Lactobacillus# acidophilus NCDO 1748 , n/a , 10^9 cfu/ml ,
200 ml q.d.
Lactobacillus** acidophilus NCDO 1748 , n/a , 10^9 cfu/ml ,
300 ml q.d
Streptococcus** lactis n/a , n/a , 10^9 cfu/ml , 300 ml q.d.
Streptococcus** cremoris n/a , n/a , 10^9 cfu/ml , 300 ml q.d
Streptococcus** diacetylactis n/a , n/a , 10^9 cfu/ml , 300 ml
q.d
NA
Product Name
n/a
Direct Comparison
Timing
Subgroup Analysis
n/a
Cotreatment
n/a
C-258
Safety Assessment
Results
Assessment
n/a
Result Statement
All products were well
accepted.
>65
Assessment
n/a
Result Statement
No treatment failure
or other side effects
occurred.
Assessment
At followup evaluation
a week later…
emergence of any
other new symptoms
attributable to trial
drug therapy.
Result Statement
Very well tolerated.
Assessment
n/a
Result Statement
No adverse effects on
constipation.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Arrola, 1999
RCT
Ataie-Jafari, 2009
RCT
Attar, 1999
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , 2*10^10 cfu/capsule ,
2*10^10 b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs; 2 wks-12.8 yrs
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , n/a , n/a
Bifidobacterium lactis n/a , n/a , n/a , n/a
NA
Product Name
ABY-1
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 1500 mg /day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-259
small bowel bacterial
overgrowth
Safety Assessment
Results
Assessment
The parents kept a
daily symptom diary.
Result Statement
Parents reported no
adverse effects.
Assessment
There was a check up
every week by phone
to ask about
compliance and side
effects.
Result Statement
No adverse effects or
symptoms were
experienced by the
subjects.
Assessment
Other indication taken
and any side effects
were also recorded.
Result Statement
n/a
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Barone, 1999
RCT
Bausserman,
2005
RCT
Bellomo, 1980
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus* delbrueckii Bulgaricus , n/a , 3*10^8/g , n/a
Lactobacillus* acidophilus n/a , n/a , 2*10^9/g , n/a
Lactobacillus* plantarum n/a , n/a , 2.2*10^8/g , n/a
Lactobacillus* casei n/a , n/a , 2.2*10^8/g , n/a
Streptococcus* salivarius thermophilus , n/a , 2.04*10^11/g
, n/a
Streptococcus* faecium n/a , n/a , 3*10^7/g , n/a
Bifidobacterium* longum n/a , n/a , 9.3*10^9/g , n/a
Bifidobacterium (Yovis) breve n/a , n/a , 9.3*10^9cfu/g , n/a
Bifidobacterium (Yovis) infantis n/a , n/a , 9.3*10^9cfu/g ,
n/a
Lactobacillus# acidophilus n/a , n/a , 10^9/vial , n/a
#Bifidobacterium bifidum n/a , n/a , 5*10^8cfu/g , n/a
#Streptococcus thermophilus n/a , n/a , 10^9cfu/vial , n/a
#Lactobacillus bulgaricus n/a , n/a , 10^9cfu/vial , NA
**Saccharomyces boulardii n/a , n/a , 5*10^9cfu/250mg
capsule , n/a
Product Name
*Yovis #Lactogermine **Codex
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , 10^10 cfu , 1 capsule
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus* bulgaricus n/a , Lyophilized , 5*10^8cfu/unit ,
1 unit b.i.d., 2 unit t.i.d.
Streptococcus* lactis n/a , Lyophilized , 4*10^9cfu/unit , 1
unit b.i.d., 2 unit t.i.d.
Lactobacillus* acidophilus n/a , Lyophilized , 5*10^8cfu/unit
, 1 unit b.i.d., 2 unit t.i.d.
Streptococcus# faecium SF68 , Lyophilized , >3.75*10^7cfu
/unit , 1 unit b.i.d., 2 unit t.i.d.
NA
Product Name
*n/a (control)#Bioflorin
Analysis
Direct Comparison
Genera
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
Children
Safety Assessment
Results
Assessment
Following items have
been analyzed during
the clinical courses…
other associated
symptoms.
Result Statement
No associated
symptoms were
recorded in all
subjects.
Direct Comparison
Mode of administration
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
Genera mix
Subgroup Analysis
Age
Cotreatment
Concomitant antibiotics
C-260
n/a
n/a
Assessment
Patients were
withdrawn … based
on … any unexpected
intolerance or side
effect.
Result Statement
There were no
adverse effects noted
with Lactobacillus GG
treatment.
Assessment
n/a
Result Statement
No untoward side
effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Benhamou, 1999
RCT
Billoo, 2006
RCT
Intervention, Form, Potency, Dose
Analysis
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 226 mg/day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , 250mg , b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
<2yrs; antibiotic induced
diarrhea
Safety Assessment
Results
Assessment
n/a
Result Statement
Despite rare cases of
fungemia during
administration of high
doses of
Saccharomyces
boulardii, products
were tolerated, as we
have noted in this
study.
Assessment
The second visit
information variables
included … tolerance
and acceptability of
treatment.
Result Statement
Tolerance and
acceptability of
treatment were
recorded in the study
record forms. S.
boulardii was well
accepted and
tolerated and there
were no reports of
any side effects
during the study
period.
C-261
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Bittner, 2005
RCT
Black, 1988
RCT
Bleichner, 1997
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Blend including Bacillus strains n/a n/a , n/a , n/a , 1 500 mg
capsule b.i.d.
NA
Product Name
Prescript-Assist
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized, live ,
3*10^9cfu/capsule , 1 capsule t.i.d.
Bifidobacterium bifidum n/a , Lyophilized, live ,
3*10^9cfu/capsule , 1 capsule t.i.d
Lactobacillus bulgaricus n/a , Lyophilized, live ,
3*10^9cfu/capsule , 1 capsule t.i.d.
Streptococcus thermophilus n/a , Lyophilized, live ,
3*10^9cfu/capsule , 1 capsule t.i.d
NA
Product Name
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , Lyophilized , n/a , 500mg
b.i.d.
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
: Irritable Bowel
Syndrome
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
Disease or immunologic
status
Cotreatment
n/a
Immune compromised /
critically ill
C-262
Safety Assessment
Results
Assessment
Data on the …
symptoms collected
as part of the 64-item
instrument allowed
basic analysis of the
safety profile, in that
any significant
increase in
a…symptom with
treatment would point
toward an adverse
event or tolerability
concern…
Result Statement
No safety/tolerability
concerns emerged.
Assessment
n/a
Result Statement
No adverse effects
were recorded in any
of the two groups.
Assessment
n/a
Result Statement
Tolerance of S.
boulardii was good
and no adverse effect
was noted.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Bruno, 1983
RCT
Bruns, 1995
RCT
Buydens, 1996
RCT
Cadieux, 2002
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Enterococcus faecium SF 68 , n/a , 7.5*10^7cfu/capsule , 1
capsule t.i.d.
NA
Product Name
Bioflorin
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
Enterocolitis
Genus, Species, Strain
Saccharomyces cerevisiae Hansen CBS 5926 , n/a , n/a ,
150 mg q.i.d.
NA
Product Name
Perenterol
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Enterococcus faecium SF 68 , n/a , 75*10^6 cfu/capsule , 2
capsules t.i.d.
NA
Product Name
Bioflorin
Genus, Species, Strain
Lactobacillus* rhamnosus GR-1 , Lyophilized , 10^9
cfu/capsule , 1 capsule
Lactobacillus fermentum RC-14 , Lyophilized , 10^9
cfu/capsule , 1 capsule /day
Lactobacillus# rhamnosus GG , Lyophilized , 10^9
cfu/capsule , 1 capsule /day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
Strains
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
C-263
Safety Assessment
Results
Assessment
Patients were
assessed daily,
recording the
presence of …
possible side-effects
attributable to the
drugs.
Result Statement
No side effects
attributable to drugs.
Assessment
Undesired events
were assessed and
documented.
Result Statement
There were no
adverse drug
reactions in both
groups.
Assessment
n/a
Result Statement
No side effects.
n/a
Assessment
n/a
Result Statement
No adverse events
reported.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Caglar, 2006
RCT
Camarri, 1981
RCT
Can, 2006
RCT
Canani, 2007
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus reuteri Acid 55730 , n/a , >10^8 cfu/straw ,
1/day
Lactobacillus reuteri Acid 55730 , n/a , 10^8 cfu/tablet , 1
tablet /day
NA
Product Name
(1)Life top straw (BioGaia); (2) ProDenta (BioGaia)
Direct Comparison
Delivery vehicles
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Streptococcus faecium SF 68 , Lyophilized , >7.5*10^7
cfu/capsule , 1 capsule t.i.d.
NA
Product Name
Bioflorin
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
acute enteritis
Genus, Species, Strain
Saccaromyces* boulardii n/a , n/a , 5*10^9 cells , 5*10^9
cells b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus* casei Rhamnosus GG , n/a , 6*10^9 cfu ,
b.i.d.
Saccharomyces# boulardii lt , Live , 5*10^9 cfu , b.i.d.
Bacillus** clausii O/C84, N/R84, T84, SIN84(mix of strains)
, n/a , 10^9 cfu , b.i.d
Lactobacillus## delbrueckii LMG-P17550 Bulgaricus , n/a ,
10^9 cfu , b.i.d
Lactobacillus## acidophilus LMG-P17549 , n/a , 10^9cfu ,
b.i.d
Streptococcus## thermophilus LMG-P17503 , n/a , 10^9 cfu
, b.i.d
Bifidobacterium## bifidum LMG-P17500 , n/a , 5*10^8 cfu ,
b.i.d
Enterococcus*** faecium SF 68 , n/a , 7.5*10^7 cfu , b.i.d
NA
Product Name
*Dicoflor 60; #Codex; **Enterogermina; ##Lactogermina;
***Bioflorin
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
Genera, Genera mix,
Species, Strains
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
C-264
<2yrs; Acute Diarrhea
Safety Assessment
Results
Assessment
n/a
Result Statement
Compliance was
excellent in all
groups, with no drop
outs or reported side
or adverse effects.
Assessment
n/a
Result Statement
No side effects were
observed with either
treatment.
Assessment
n/a
Result Statement
No serious side
effects (per abstract).
Assessment
We also investigated
safety and tolerability.
Result Statement
Probiotic
preparations… were
well received by
nearly all the children
and no adverse
events were
observed.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Carrierol, 2007
CT
Cetina-Sauri,
1994
RCT
Chapoy, 1985
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus plantarum P17630 , n/a , 10^8 cfu/capsule , 1
capsule q.d.
NA
Product Name
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 200mg t.i.d.
NA
Product Name
Ultra-Levure
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 250 mg b.i.d.
NA
Product Name
Ultra-Levure
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-265
High-Risk Population
Candida vulvovaginitis
<2yrs; acute diarrhea
<2yrs; acute diarrhea
Safety Assessment
Results
Assessment
Tolerability and safety
were evaluated by
putting a non leading
question to the patient
to ascertain whether
any adverse events
had occurred; if any
had occurred,
additional information
was to be collected,
i.e. its time of onset,
nature, duration,
outcome, relation to
treatment, severity
and any action taken.
Result Statement
No adverse events
worthy of note were
reported.
Assessment
On the clinical
records were
recorded … and
possible side effects.
Result Statement
Didn't have secondary
effects.
Assessment
n/a
Result Statement
No undesirable effect
was noted and the
acceptability of the
treatment was
excellent.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Chapoy, 1986
CT
Chen, 2010
RCT
Chitapanarux,
2010
RCT
Cildir, 2009
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Saccharomyces cerevisiae Hansen CBS 5926 , , n/a , 500
mg q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; diarrhea
Genus, Species, Strain
Bacillus mesentericus TO-A , n/a , 5*10^7 cfu/mixed sachet
(3*10^8 cfu total) , 2.2*10^6 cfu/kg t.i.d
Enterococcus faecalis T-110 , n/a , 2*10^8 cfu/mixed sachet
, 4.2*10^6 cfu/kg t.i.d
Clostridium butyricum n/a , lyophilized , 5.0*10^7 cfu/mixed
sachet , 2.2*10^6 cfu/kg t.i.d
NA
Product Name
Bio-three
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized , 10^9 /capsule ,
2 capsules b.i.d
Bifidobacterium bifidum n/a , Lyophilized , 10^9 /capsule , 2
capsules b.i.d.
NA
Product Name
Infloran
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Direct Comparison
n/a
Subgroup Analysis
Disease or immunologic
status
Cotreatment
n/a
Immune compromised /
critically ill
Genus, Species, Strain
Bifidobacterium acidophilus Lactis DN 173010 , n/a ,
4*10^10 , 4*10^10 q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-266
Safety Assessment
Results
Assessment
n/a
Result Statement
No undesirable
effects were
measured.
Assessment
n/a
Result Statement
No adverse effects
were recorded.
Adolescents
Assessment
Patients were
evaluated weekly. An
adverse event or
adverse drug reaction
was recorded in each
week of treatment.
Result Statement
There were no
adverse events
attributable to the
study drug.
Assessment
n/a
Result Statement
No side effects or
adverse effects were
registered.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Cindoruk, 2007
RCT
Cohen, 2007
RCT
Costalos, 2003
RCT
Cremonini, 2002
RCT
D'Apuzzo, 1982
CT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , 250 mg/dose , 1 dose,
b.i.d.
NA
Product Name
Reflor
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
n/a
Genus, Species, Strain
Lactobacillus GG n/a , n/a , 2x10^10 organisms / capsule ,
n/a
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 10^9 cfu/kg body
weight b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Preterm
Genus, Species, Strain
Lactobacillus* casei subsp. Rhamnosus GG , n/a , 6*10^9
cfu/sachet , 1 sachet b.i.d.
Saccharomyces# boulardii n/a , n/a , 5*10^9 cfu/sachet , 1
sachet b.i.d.
Lactobacillus** acidophilus n/a , n/a , 5*10^9 cfu/capsule (in
sachet) , 1 capsule b.i.d.
Bifidobacterium** lactis n/a , n/a , n/a , 5*10^9 cfu b.i.d.
NA
Product Name
*Giflorex; #Codex; **Ferzyme
Genus, Species, Strain
Streptococcus faecium SF-68 , Lyophilized , 7.5*10^7 cfu ,
t.i.d.
NA
Product Name
Bioflorin
Direct Comparison
Genera, Genera mix
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Hylicobacter pylori
infection
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; 2-144 mos old
C-267
Safety Assessment
Results
Assessment
n/a
Result Statement
No major side effects
leading to treatment
discontinuation were
observed.
Assessment
n/a
Result Statement
There were no
significant adverse
events recorded.
Assessment
n/a
Result Statement
Drug is well tolerated
by the infants and
caused no side
effects.
Assessment
n/a
Result Statement
No major side effects
leading to treatment
discontinuation were
observed.
Assessment
n/a
Result Statement
No adverse effects
were noticed in either
patient group.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
De Francesco,
2000
CT
Delforge, 1983
RCT
Delia, 2006
RCT
Delia, 2003
CT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus acidophilus LB , Spent culture supernatant ,
Equivalent to 10^10 cfu/0.8 g , 0.8g b.i.d.
NA
Product Name
LB-SCS
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
High-Risk Population
Helicobacter pylori
Genus, Species, Strain
Saccharomyces cerevisiae Hansen CBS 5926 , n/a , n/a , 3
capsules t.i.d.
NA
Product Name
Perenterol
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
IBS
Genus, Species, Strain
Lactobacillus* acidophilus n/a , n/a , n/a , n/a
Lactobacillus# paracasei paracasei F19 , n/a , n/a , n/a
NA
Product Name
*Calagin; #Genefilus
Direct Comparison
Species
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , 3.00*10^6cfu
mixture/gm , n/a
Lactobacillus casei n/a , n/a , n/a ,
Lactobacillus delbrueckii bulgaricus , n/a , n/a ,
Lactobacillus plantarum n/a , n/a , n/a ,
Bifidobacterium longum n/a , n/a , n/a ,
Bifidobacterium infantis n/a , n/a , n/a ,
Bifidobacterium breve n/a , n/a , n/a ,
Streptococcus salivarius thermophilus , n/a , n/a ,
Streptococcus faecium n/a , n/a , n/a ,
NA
Product Name
Yovis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Radiapy
C-268
Safety Assessment
Results
Assessment
Patients were
specifically
questioned
concerning sideeffects during
therapy.
Result Statement
No severe side
effects were reported.
Assessment
n/a
Result Statement
No sign of intolerance
was recorded during
this trial.
Assessment
n/a
Result Statement
All patients tolerated
the treatment well,
and there was not a
single dropout.
Assessment
n/a
Result Statement
Well-tolerated (3
patients excluded due
to intolerance of the
taste of Yovis).
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
DePaula, 2008
RCT
deVrese, 2005
RCT
Diop, 2008
RCT
Falcao, 2004
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Bifidobacterium animalis DN 173010 , n/a , 10^8 cfu/gm ,
116 gm b.i.d.
Lactobacillus bulgaricus n/a , n/a , 10^7cfu/gm , 116 gm
b.i.d.
Streptococcus thermophilus n/a , n/a , 10^7 cfu/gm , 116
gm b.i.d.
NA
Product Name
Activia
Genus, Species, Strain
Lactobacillus gasseri PA 16/8 , Viable , 5*10^7 cfu/tablet ,
q.d.
Bifidobacterium longum SP 07/3 , Viable , 5*10^7 cfu/tablet
, q.d.
Bifidobacterium bifidum MF 20/5 , Viable , 5*10^7 cfu/tablet
, q.d.
NA
Product Name
Tribion harmonis
Genus, Species, Strain
Lactobacillus acidophilus Rosell-52 , n/a , 3*10^9 cfu ,
3*10^9 cfu q.d.
Bifidobacterium longum Rosell-175 , n/a , 3*10^9 cfu/day ,
3*10^9 cfu q.d.
NA
Product Name
Probio-stick
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
constipation
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus johnsonii La1 , n/a , n/a , n/a
NA
Product Name
Nestle LC1
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
Immune compromised /
critically ill
C-269
Safety Assessment
Results
Assessment
… instructed to
withdraw due to
intolerance
Result Statement
No adverse effects
were seen related to
either intervention.
Assessment
n/a
Result Statement
No report of adverse
events.
Assessment
n/a
Result Statement
No adverse reactions
were reported during
the study. The
product was safe and
well tolerated.
Assessment
n/a
Result Statement
No complications
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Fanigliulo, 2006
RCT
Fisberg, 2002
RCT
Francavilla, 2008
RCT
Fukushima, 2007
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Bifidobacterium longum W 11 , n/a , n/a , n/a
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
High-Risk Population
n/a
Genus, Species, Strain
Lactobacillus casei n/a , n/a , 3*10^7 cfu/g , 375-750
ml/daily
Bifidobacterium n/a n/a , n/a , 3*10^7 cfu/g , n/a
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus reuteri ATCC 55730 , Lyophilized , 1*10^8
cfu/tablet , 1 tablet q.d.
NA
Product Name
Reuterin
Genus, Species, Strain
Lactobacillus johnsonii La 1 NCC 533 , n/a , 10^9 cfu/90g ,
90g q.d.
NA
Product Name
LC1
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
Helicobacter pylori
C-270
>65
Safety Assessment
Results
Assessment
Patients who
developed
complications or side
effects, recorded by
means of a structured
clinical interview
during each clinical
evaluation or
whenever necessary,
were withdrawn from
the study.
Result Statement
n/a
Assessment
Adverse events were
monitored throughout
the study.
Result Statement
Both study findings
were well tolerated
and the overall
incidence of adverse
events were very low.
None of the serious
adverse events were
considered study
related.
Assessment
n/a
Result Statement
No adverse events
were reported.
Assessment
n/a
Result Statement
Accepted well; no
adverse health
conditions were
observed.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Furrie, 2005
RCT
Gaon, 2002
RCT
Gaon, 2003
RCT
Gawronska, 2007
RCT
Giralt, 2008
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Bifidobacterium longum n/a , Lyophilized, viable , 2*10^11
cfu b.i.d. , 2x/d for 4 weeks
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus casei n/a , Lyophilized, viable , n/a , 1.5g b.i.d.
Lactobacillus acidophilus n/a , Lyophilized, viable , n/a ,
1.5g b.i.d.
NA
Product Name
CERELA
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Genus, Species, Strain
Lactobacillus* acidophilus CRL 730 , Lyophilized , 10^10
10^12 cfu/g , 175g b.i.d.
Lactobacillus (cerela)* casei CRL 431 , Lyophilized , 10^10
10^12 cfu/g , 175g b.i.d.
Saccharomyces# boulardii n/a , Lyophilized , 10^10 cfu/g ,
175g b.i.d.
NA
Product Name
*CERELA; #n/a
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , n/a , 3*10^9 cfu b.i.d.
NA
Product Name
n/a
Direct Comparison
Genera mix
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus casei DN-114 001 , n/a , 1*10^cfu/g , 96 ml,
t.i.d.
Streptococcus thermophilus n/a , n/a , n/a ,
Lactobacillus delbrueckii bulgaricus n/a , n/a , n/a ,
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-271
Ulcerative colitis
n/a
Safety Assessment
Results
Assessment
n/a
Result Statement
No reports of adverse
reactions.
Assessment
…and any side
effects were also
recorded (by the
patients).
Result Statement
No side effects.
Assessment
n/a
Result Statement
No treatment failures,
neither appearance of
symptoms possibly
related to treatment.
Cancer, receiving
radiation
Assessment
All patients received a
diary to record … any
symptoms they
considered important.
Result Statement
Well tolerated; no
adverse effects were
reported.
Assessment
n/a
Result Statement
The study product
was well tolerated
and none of the
adverse events
reported were
considered related.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Girola, 1995
RCT
Gosselink, 2003
RCT
Grigoriev, 1997
RCT
Grudyanov, 2002
CT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized, live , n/a , 10^9
cfu q.d. in the AM
Lactobacillus bulgaricus n/a , Lyophilized, live , n/a , 10^9
cfu q.d. in the AM
Lactobacillus lactis n/a , Lyophilized, live , n/a , 10^9 cfu
q.d. in the AM
Saccharomyces cerevisiae n/a , Lyophilized, live , n/a ,
10^9 cfu q.d. PM
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus rhamnosus GG , Live , n/a , 1.4*10^10 cfu
q.d.
NA
Product Name
Vifit ®
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Ulcerative Colitis
Genus, Species, Strain
Bifidobacterium n/a n/a , Lyophilized , n/a , 10^6-10^8 cfu
Bifidobacterium n/a n/a , n/a , n/a ,
NA
Product Name
Bifidumbacterin forte
Direct Comparison
Genera
Subgroup Analysis
Age, Disease or
immunologic status
Cotreatment
Concomitant antibiotics
n/a
Genus, Species, Strain
Bifidobacterium bifidum n/a , n/a , n/a , Varies by patients
Lactobacillus acidophilus n/a , n/a , n/a , Varies by patients
NA
Product Name
n/a
Direct Comparison
Genera
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
C-272
Safety Assessment
Results
Assessment
n/a
Result Statement
During the study no
side effect was
observed that could
be associated (or
attributed) to the two
treatments.
Assessment
n/a
Result Statement
None of the patients
had complaints that
were possibly
connected with the
intake of Lactobacillus
rhamnosus.
Assessment
n/a
Result Statement
ADR were not
observed, no there
were no treatment
discontinuations.
Assessment
n/a
Result Statement
The probiotics are
well tolerated and no
side effects, no
contraindications.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Guandalini, 2010
RCT
Guandalini, 2000
RCT
Guslandi, 2000
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized, live , 4.5*10^11
bacteria /sachet , varies by age (1-2 sachets/d)
Lactobacillus casei n/a , Lyophilized, live , 4.5*10^11
bacteria /sachet , varies by age (1-2 sachets/day)
Lactobacillus bulgaricus n/a , Lyophilized, live , 4.5*10^11
bacteria /sachet , varies by age (1-2 sachets /day)
Lactobacillus plantarum n/a , Lyophilized, live , 4.5*10^11
bacteria /sachet , varies by age (1-2 sachets/d)
Bifidobacterium longum n/a , Lyophilized, live , 4.5*10^11
bacteria /sachet , varies by age (1-2 sachets/d)
Bifidobacterium infantis n/a , Lyophilized, live , 4.5*10^11
bacteria /sachet , varies by age (1-2 sachets /day)
Bifidobacterium breve n/a , Lyophilized, live , 4.5*10^11
bacteria /sachet , varies by age (1-2 sachets /day)
Streptococcus salivarius thermophilus n/a , Lyophilized, live
, 4.5*10^11 bacteria /sachet , varies by age (1-2 sachets
/day)
NA
Product Name
VSL#3
Genus, Species, Strain
Lactobacillus casei GG ATCC 53103 , Live , 10^10
cfu/250ml , Single dose
NA
Product Name
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 500 mg b.i.d.
NA
Product Name
n/a
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
C-273
Safety Assessment
Results
Assessment
Data were recorded in
a daily
questionnaire/dairy.
Result Statement
No adverse event
was reported in any of
the participating
patients throughout
the duration of the
study.
Crohn's Disease
Assessment
n/a
Result Statement
Can be safely
administered.
Assessment
n/a
Result Statement
All patients completed
the study without
reporting any side
effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Guyonnet, 2009
RCT
Guyonnet, 2007
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Bifidobacterium lactis DN-173 , n/a , 1.25*10^10 cfu/125 g ,
125g b.i.d
Streptococcus thermophilus I-1630 , n/a , 1.2*10^9 cfu/125g
, 125g b.i.d.
Lactobacillus bulgaricus I-1632, I-1519 , n/a , 1.2*10^9
cfu/125g , 125g b.i.d.
Lactobacillus cremoris CMI-1631 , n/a , 1.25*10^9 cfu/125g
, 125g b.i.d.
NA
Product Name
Activia ®
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Bifidobacterium animalis DN-173010 , n/a , 1.25*10^10
cfu/pot , b.i.d.
Streptococcus thermophilus n/a , n/a , 1.25*10^9 cfu/pot ,
b.i.d.
Lactobacillus bulgaricus n/a , n/a , 1.25*10^9 cfu/pot , b.i.d.
NA
Product Name
Activia
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
adu<s with irritable
bowel syndrome (IBS)
Safety Assessment
Results
Assessment
n/a
Result Statement
These data, taken
together with previous
data obtained on GI
transit and in IBS,
suggest that this
specific probiotic food
may represent a
promising nutritional
and safe solution for
the management of
GI symptoms.
Assessment
Subjects recorded
daily in their diary…
as well as any
adverse events.
Result Statement
Ten subjects from the
control group and 13
from the test product
group reported minor
adverse events
throughout the study.
Four subjects in the
control group and
three in the test group
stopped the
consumption of the
product after an
adverse event. Two
subjects reported
serious adverse
events in the control
group.
C-274
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Hafeez, 2002
RCT
Hatakka, 2001
RCT
Hatakka, 2003
RCT
Hatakka, 2007
RCT
Hickson, 2007
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Saccharomyces boulardii n/a , Lyophilized , 250 mg b.i.d. ,
twice daily for 6 days
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
2-5 yrs
Genus, Species, Strain
Lactobacillus rhamnosus GG ATCC 53103 , n/a , 5-10
*10^5 cfu/ml , t.i.d. to achieve 200 ml daily
NA
Product Name
Gefilus
Genus, Species, Strain
Lactobacillus rhamnosus GG ATCC 53103 , n/a , ?5*10^9
cfu/capsule , 2 b.i.d.
NA
Product Name
Gefilus
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; Children 1-6 yrs
Genus, Species, Strain
Lactobacillus rhamnosus GG ATCC 53103 , n/a , 8-9*10^9
cfu/capsule , 1 q.d.
Lactobacillus rhamnosus LC 705 , n/a , 8-9*10^9
cfu/capsule , 1 q.d.
Bifidobacterium breve 99 , n/a , 8-9*10^9 cfu/capsule , 1
q.d.
Propionibacterium freudenreichii shermanii JS , n/a , 8
9*10^9 cfu/capsule , 1 q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus casei immunitas DN 114-001 , n/a , 10^8
cfu/ml , b.i.d.
Streptococcus thermophilus n/a , n/a , 10^8 cfu/ml , b.i.d.
Lactobacillus delbrueckii Bulgaricus , n/a , 10^7 cfu/ml ,
b.i.d.
NA
Product Name
Actimel ®
Direct Comparison
n/a
Subgroup Analysis
Age
Cotreatment
n/a
<2yrs
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Hospitalized Patients
C-275
Mild RA
Safety Assessment
Results
Assessment
n/a
Result Statement
The drug was
accepted well...and
there were no
reported side effects
in this study
population.
Assessment
n/a
Result Statement
No apparent side
effects.
Assessment
n/a
Result Statement
No clinical relevant
adverse effects were
seen.
Assessment
Reasons for dropout
… adverse effects.
Result Statement
n=1 dropout due to
adverse effects in
probiotics group, n=0
in placebo group.
Assessment
n/a
Result Statement
No reported adverse
events related to the
study drinks.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Hojsak, 2010
RCT
Hojsak, 2010
RCT
Hol, 2008
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , 10^9 cfu/100 ml ,
100ml/day
NA
Product Name
LGG
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , 10^9 cfu/100 ml , 100c
ml q.d.
NA
Product Name
LGG (Dukat)
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
n/a
Genus, Species, Strain
Lactobacillus casei CRL431 paracasei , n/a , 10^7 cfu/gr
formula , n/a
Bifidobacterium animalis lactis Bb-12 , n/a , 10^7 cfu/gr
formula , n/a
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics,
Corticosteroid use
C-276
<2yrs
Safety Assessment
Results
Assessment
Patients were
checked every day by
pediatrician.
Result Statement
No adverse effects
were noted during
study and both
products were well
tolerated.
Assessment
Every 10 days,
investigators
contacted parents to
find out whether their
children had
developed any …
side effects.
Result Statement
No side effects of
adverse effects were
noted during the
study.
Assessment
Structure interviews…
adverse
events…were
performed.
Result Statement
The study formula
with or without the
probiotic
supplementation was
well tolerated.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Hoyos, 1999
CT
Htwe, 2008
RCT
Hun, 2009
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus acidophilus n/a , Live , 10^9 cfu/capsule , 1/4
capsule q.d.
Bifidobacterium infantis n/a , Live , 10^9 cfu/capsule , 1/4
capsule q.d.
NA
Product Name
Infloran Berna 7
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; Immune
compromised / critically
ill
Genus, Species, Strain
Saccharomyces boulardii n/a , Active , n/a , 250 mg b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; 2-10 yrs
Genus, Species, Strain
Bacillus coagulans GBI-30, 6086 , n/a , 8*10^8 cfu/dose , 1
dose q.d.
NA
Product Name
GanedenBC
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
>65
Safety Assessment
Results
Assessment
n/a
Result Statement
No complications
attributed to the use
of the probiotic
preparation were
observed.
Assessment
n/a
Result Statement
No severe side
effects were observed
during the trial.
Assessment
Add adverse events
were reported …
event duration,
severity and causal
relationship to the
study drug were
recorded.
Result Statement
There were 4 adverse
events reported in the
placebo groups and 2
in the study group, all
of which were
unrelated to the
treatments. No
treatment related
adverse events or
serious adverse
events were reported
during the 8-week
study period.
C-277
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Hun, 2009
RCT
Indrio, 2009
RCT
Indrio, 2008
RCT
Jasinski, 2002
RCT
Kalliomaki, 2003
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Bacillus coagulans GB1-30 6086 , n/a , n/a , q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus reuteri n/a , n/a , 10^8 cfu/dose , 1 dose q.d.
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
IBS
<2yrs
Genus, Species, Strain
Lactobacillus reuteri ATCC 55730 , n/a , 10^8 cfu , q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; Preterm
Genus, Species, Strain
Lactobacillus rhamnosus GG ATCC 53103 , Viable , 1*10^9
cfu , Varies
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus rhamnosus GG ATCC 53103 , n/a , 10^10 cfu
, q.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
C-278
Safety Assessment
Results
Assessment
All adverse events
were reported
regardless of whether
they were related to
the study drug. Event
duration, severity, and
causal relationship to
the study drug were
recorded.
Result Statement
No treatment related
or serious adverse
events were reported.
Assessment
Adverse events were
recorded throughout
they study as they
occurred.
Result Statement
No adverse events
were reported.
Assessment
n/a
Result Statement
No adverse events
were reported related
to the trial.
Assessment
n/a
Result Statement
Well tolerated.
Pregnant women
Assessment
n/a
Result Statement
Was promising and
safe.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Kalman, 2009
RCT
Kaplas, 2007
RCT
Katelaris, 1995
RCT
Kato, 2004
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Bacillus coagulans GBI-30,6086 , n/a , 2*10^9 cfu/capsule ,
1 capsule, q.d.
NA
Product Name
GanedenBC
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus rhamnosus GG (ATCC 53103) , n/a , 10^9
cfu/dose , 1 dose q.d.
Bifidobacterium lactis Bb12 , n/a , 10^9 cfu/dose , 1 dose
q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus fermentum KLD , n/a , 10^11 cfu/capsule , 2
capsules q.d.
Lactobacillus acidophilus n/a , n/a , 10^11 cfu/capsule , 2
capsules q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus acidophilus Yakult , Live , 10^10 cfu/100 ml ,
100 ml q.d.
Bifidobacterium breve Yakult , Live , 10^10 cfu/100 ml ,
100ml q.d.
Bifidobacterium bifidum Yakult , Live , 10^10 cfu/100 ml ,
100ml q.d.
NA
Product Name
Yakult BFM
Direct Comparison
Genera
Subgroup Analysis
n/a
Cotreatment
Diet therapies
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Ulcerative Colitis
C-279
Safety Assessment
Results
Assessment
n/a
Result Statement
The Bacillus
coagulans based
probiotic product was
effective and safe for
abating symptoms of
GSRS abdominal
pain and distention
pain in the post
prandial period.
Assessment
n/a
Result Statement
The pregnancies
were uncomplicated
and all infants were
delivered at term.
Assessment
n/a
Result Statement
No adverse effects
were reported.
Assessment
n/a
Result Statement
Well tolerated; …no
subjects reported
adverse events that
might have been
related to BFM.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Kawase, 2009
RCT
Kim, 2010
RCT
Kim, 2005
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus rhamnosus GG(ATCC53103) , n/a , >2*10^10
cfu/2g , 2g q.d.
Lactobacillus gasseri TMC0356 , n/a , >1*10^9 cfu/2g , 2
g/day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Bifidobacterium bifidum BGN4 , n/a , 1.6*10^9 cfu/dose , 1
dose q.d.
Bifidobacterium lactis AD011 , n/a , 1.6*10^9 cfu/dose ,
1/day
Lactobacillus acidophilus AD031 , n/a , 1.6*10^9 cfu , 1 /day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized , 4.5*10^11 cfu
mixture/sachet , 1 sachet b.i.d.
Bifidobacterium infantis n/a , Lyophilized , n/a ,
Bifidobacterium breve n/a , Lyophilized , n/a ,
Bifidobacterium longum n/a , Lyophilized , n/a ,
Lactobacillus casei n/a , Lyophilized , n/a ,
Lactobacillus delbrueckii Bulgaricus , Lyophilized , n/a ,
Lactobacillus plantarum n/a , Lyophilized , n/a ,
Streptococcus salivarius thermophilus , Lyophilized , n/a ,
NA
Product Name
VSL#3
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-280
IBS
Safety Assessment
Results
Assessment
n/a
Result Statement
None of the 35
subjects showed any
disorder related to the
ingestion of LGG and
TMC 0356 during the
trial period.
Assessment
The parents were
asked to report any
adverse effects
whenever they
happen.
Result Statement
No serious adverse
effects developed and
although non-specific
mild symptoms
developed, these
were unlikely to have
been related to the
administration of
probiotics.
Assessment
n/a
Result Statement
There were no
adverse effects
attributable to
treatment with either
VSL#3 or placebo.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Kim, 2003
RCT
Kim, 2006
RCT
Klarin, 2008
CT
Koebnick, 2003
CT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized , 2.25*10^11 cfu
mixture/packet , 1 packet b.i.d.
Lactobacillus casei n/a , Lyophilized , n/a ,
Lactobacillus delbrueckii Bulgaricus , Lyophilized , n/a ,
Lactobacillus plantarum n/a , Lyophilized , n/a ,
Bifidobacterium longum n/a , Lyophilized , n/a ,
Bifidobacterium infantis n/a , Lyophilized , n/a ,
Bifidobacterium breve n/a , Lyophilized , n/a ,
Streptococcus (VSL#3) salivarius thermophilus ,
Lyophilized , n/a ,
NA
Product Name
VSL#3
Genus, Species, Strain
Bacillus subtilis n/a , n/a , n/a , 1*10^9 cfu
Streptococcus faecium n/a , n/a , n/a , 9*10^9 cfu
NA
Product Name
Medilac DS
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Imtable Bowel
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
IBS
Genus, Species, Strain
Lactobacillus plantarum LP 299V , n/a , 8*10^8 cfu/ml , 100
ml b.i.d., then 50 ml b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics,
Corticosteroid use, Diet
therapies
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Immune compromised /
critically ill
Genus, Species, Strain
Lactobacillus casei Shirota , n/a , 10^8 cfu/ml , 65 ml q.d.
NA
Product Name
n/a
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse events
noted.
18-70 yrs; Chronic
Constipation
Assessment
n/a
Result Statement
Medilac DS was well
tolerated without
adverse events... a
safe and useful
probiotic agent.
Assessment
n/a
Result Statement
No adverse impact of
the given probiotic
preparations; well
tolerated.
Assessment
Patients were asked
weekly for product
tolerability during the
intervention phase.
Result Statement
No side effects were
reported.
C-281
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Kollaritsch, 1993
RCT
Kollaritsch, 1989
RCT
Koning, 2010
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 250mg q.d.
Saccharomyces boulardii n/a , n/a , n/a , 1000mg q.d.
NA
Product Name
Perenterol
Direct Comparison
Dose
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , 2*10^8 - 2*10^9 cfu
b.i.d. , 2 per day, duration varies
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Prophylaxis of
traveller's diarrhea
Genus, Species, Strain
Bifidobacterium bifidum NIZO 3804 , n/a , 10^8 cfu/g , 5g
b.i.d
Bifidobacterium lactis NIZO 3680 , n/a , 10^8 cfu/g , 5g
b.i.d.
Enterococcus faecium NIZO 3886 , n/a , 10^8 cfu/g , 5g
b.i.d
Lactobacillus rhamnosus NIZO 3689 , n/a , 10^8 cfu/g , 5g
b.i.d
Lactobacillus paracasei NIZO 3672 , n/a , 10^8 cfu/g , 5g
b.i.d
Lactobacillus plantarum NIZO 3684 , n/a , 10^8 cfu/g , 5g
b.i.d
Lactobacillus acidophilus NIZO 3678 , n/a , 10^8 cfu/g , 5g
b.i.d
Lactobacillus acidophilus NIZO 3887 , n/a , 10^8 cfu/g , 5g
b.i.d
Lactobacillus salivarius NIZO 3675 , n/a , 10^8 cfu/g , 5g
b.i.d
NA
Product Name
Ecologic AAD
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
C-282
n/a
Safety Assessment
Results
Assessment
A questionnaire…
recorded undesirable
side effects.
Result Statement
Serious side effects
or complaints were
not reported.
Assessment
Side effect due to
prophylaxis had to be
listed and
commented.
Result Statement
n/a
Assessment
n/a
Result Statement
There were no
reported adverse
events related to the
study product.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Kontiokari, 2001
RCT
Kotowska, 2005
RCT
Kowalska, 2002
RCT
Kowalska
Duplaga, 2005
RCT
Kuisma, 2003
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus casei GG , n/a , 4*10^10 cfu/100 ml , 50 ml
b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 250 mg b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs; antibiotic
associated diarrhea
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Ulcerative Colitis
patients; who
underwent
protocolectomy
Genus, Species, Strain
Bifidobacterium ruminatium n/a , n/a , 10^9 cfu b.i.d. , twice
daily for 5 days
NA
Product Name
Lactobif
Genus, Species, Strain
lactobacillus acidophilus n/a , Active , n/a , 1.6*10^9 cfu
b.i.d.
Lactbacillus bulgaricus n/a , Active , n/a , 1.6*10^9 cfu b.i.d.
Bifidobacterium bifidum n/a , Active , n/a , 1.6*10^9 cfu
b.i.d.
NA
Product Name
Trilac
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , 0.5-1*10^10
cfu/capsule , 1 capsule q.i.d.
NA
Product Name
n/a
C-283
Acute diarrhea
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse events
were reported except
occasional complaints
about the bitter taste
of the cranberry juice.
Assessment
The secondary
outcomes were…and
adverse events.
Result Statement
Well tolerated and no
adverse events
associated with this
therapy were
reported.
Assessment
n/a
Result Statement
No adverse reactions
were reported.
Assessment
Investigation of …
and safety.
Result Statement
No adverse effects of
the treatment were
noted.
Assessment
n/a
Result Statement
well tolerated and
none of the patients
was withdrawn
because of side
effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Laake, 1999
RCT
Lara, 2007
CT
Larustovskaia,
2008
CT
Lewis, 1998
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus* acidophilus La-5 , Live , >10^8 cfu/ml , 500
ml q.d.
Bifidobacterium* lactis Bb-12 , Live , >10^8cfu/ml , 500 ml
q.d.
Lactobacillus# acidophilus La-5 , Heat-treated ,
Bifidobacterium# lactis Bb-12 , Heat-treated ,
NA
Product Name
*Cultura, #heat-treated Cultura
Genus, Species, Strain
Lactobacillus bulgaricus Delbrueckii , n/a , 2*10^7 cfu/ml ,
200 ml q.d.
Streptococcus thermophilus n/a , n/a , 5*10^5 cfu/ml , 200
ml q.d.
Streptococcus# thermophilus n/a , n/a , 5*10^5 cfu/ml , 80
ml q.d.
Lactobacillus# coryniformis CECT 5711 , n/a , 1.8*10^7
cfu/gm , 80 ml q.d.
Lactobacillus# gasseri CECT 5714 , n/a , 0.2*10^7 cfu/g ,
80 ml q.d.
NA
Product Name
Puleva Max defensas
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , n/a , n/a
Bifidobacterium longum n/a , n/a , n/a , n/a
Bifidobacterium bifidum n/a , n/a , n/a , n/a
NA
Product Name
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 113 mg b.i.d.
NA
Product Name
Ultra-Levure
Analysis
Direct Comparison
Forms
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
Ulcerative colitis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
chronic non-specific
Salpingo-oophoritis and
colon disbacteriosis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
>65
C-284
Safety Assessment
Results
Assessment
… and adverse
events were recorded
by the patients during
the study on a daily
basis in a diary card.
Result Statement
No adverse effects
were recorded.
Assessment
n/a
Result Statement
Well tolerated; No
adverse effects.
Assessment
n/a
Result Statement
Good tolerability by all
treatment group
patients.
Assessment
Subjects were seen
daily…to monitor for
side effects.
Result Statement
No side effects
attributable to S.
boulardii were
observed.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Leyer, 2009
RCT
Ligny, 1976
RCT
Lionetti, 2006
RCT
Luyer, 2010
RCT
Marcone, 2008
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus acidophilus NCFM (ATCC 700396) , n/a ,
5*10^9 cfu/g , 1g, b.i.d.
Lactobacillus acidophilus NCFM , n/a , 5*10^9 cfu/g , 0.5g,
b.i.d.
Bifidobacterium animalis lactis Bi-07 (ATCC PTA-4802) ,
n/a , 5*10^9 cfu/g , 0.5g, b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Saccharomyces hansen CBS 5926 , n/a , n/a , 3-4 capsules
q.d.
NA
Product Name
Perenterol
Direct Comparison
Genera mix
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
side-effect of antibiotics
Genus, Species, Strain
Lactobacillus reuteri ATCC 55 730 , Lyophilized , 10^8
cfu/pill , 1 pill q.d.
NA
Product Name
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , 26 mg/100ml , 200+/-50
mg/day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
n/a
Genus, Species, Strain
Lactobacillus rhamnosus n/a , Lyophilized , 4*10^4
cfu/tablet , 1 tablet once a wk
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Bacterial Vaginosis
C-285
Safety Assessment
Results
Assessment
n/a
Result Statement
No notable adverse
events were attributed
to study probiotic
strains.
<2yrs
Assessment
n/a
Result Statement
In both studies the
safety...was
complete. Its
tolerance was very
good and we found
no contraindication.
Assessment
n/a
Result Statement
No adverse events
were reported.
Assessment
n/a
Result Statement
No undesirable
occurrence was
experienced.
Assessment
n/a
Result Statement
...safe.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Marschan, 2008
RCT
Mastromarino,
2008
RCT
Maupas, 1983
RCT
Mihatsch, 2004
RCT
Miniello, 2010
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus rhamnosus GG ATCC 53103 , n/a , 5*10^9
cfu/capsule , 1 capsule b.i.d. to mothers, q.d. to infants
Bifidobacterium breve Bb99 , n/a , 2*10^8 cfu/capsule , 1
capsule b.i.d. to mothers, q.d. to infants
Lactobacillus rhamnosus LC 705 , n/a , 5*10^9 cfu/capsule ,
1 capsule b.i.d. to mothers, q.d. to infants
Propionibacterium freudenreichii shermanii JS , n/a , 2*10^9
cfu/capsule , 1 capsule b.i.d. to mothers, q.d. to infants
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus brevis CD2 , Viable , 10^9 , 1 tablet daily
Lactobacillus salivarius salicinius FV2 , n/a , 10^9 cfu
mixture /tablet , n/a
Lactobacillus plantarum FV9 , n/a , 10^9 , n/a
NA
Product Name
Florisia
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 1 capsule, t.i.d.
NA
Product Name
Ultra-Levure
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Colitis, irritable colon
Genus, Species, Strain
Bifidobacterium lactis Hansen , n/a , n/a , 6*10^9 cfu/kg/day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs - premature
Genus, Species, Strain
Lactobacillus reuteri ATCC 55730 , Viable , 10^8 cfu/tablet ,
1 tablet q.d.
NA
Product Name
Nóos, BioGaia AB
<2yrs
Result Statement
No major side effects
were observed.
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-286
Safety Assessment
Results
Assessment
n/a
Assessment
At each follow up
visit, patients were
requested to report
any unexpected
symptom.
Result Statement
The tablets caused no
detectable side
effects.
Assessment
n/a
Result Statement
No sign of intolerance
was observed in the
course of the study.
Assessment
n/a
Result Statement
Appeared to be safe.
n/a
Assessment
n/a
Result Statement
Active probiotic
treatment or placebo
was well accepted by
the patients.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Mitra, 1990
RCT
Mohan, 2006
RCT
Montalto, 2010
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Streptococcus faecium SF 68 , Live , 10^8 cfu/capsule , 1
capsule t.i.d.
NA
Product Name
Bioflorin
Genus, Species, Strain
Bifidobacterium lactis Bb12 , n/a , n/a , 5*10^9 cfu
NA
Product Name
Nestle FM 2000A
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized , 9*10^11
bacteria/sachet (4.4g) , 1 sachet q.d.
Lactobacillus casei n/a , Lyophilized , 9*10^11
bacteria/sachet (4.4g) , 1 sachet q.d.
Lactobacillus plantarum n/a , Lyophilized , 9*10^11
bacteria/sachet (4.4g) , 1 sachet q.d.
Lactobacillus bulgaricus n/a , Lyophilized , 9*10^11
bacteria/sachet (4.4g) , 1 sachet q.d.
Bifidobacterium longuum n/a , Lyophilized , 9*10^11
bacteria/sachet (4.4g) , 1 sachet q.d.
Bifidobacterium breve n/a , Lyophilized , 9*10^11
bacteria/sachet (4.4g) , 1 sachet q.d.
Bifidobacterium infantis n/a , Lyophilized , 9*10^11
bacteria/sachet (4.4g) , 1 sachet q.d.
Streptococcus salivarius thermophilus , Lyophilized ,
9*10^11 bacteria/sachet (4.4g) , 1 sachet q.d.
NA
Product Name
VSL #3
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
Adu<s with acute
diarrhea
<2 years; Immune
compromised / critically
ill
n/a
Safety Assessment
Results
Assessment
n/a
Result Statement
Well tolerated; no
unpleasant effects.
Assessment
Routine clinical data
were collected for all
infants and their
mothers.
Result Statement
No adverse effect
was observed in any
of the infants
supplemented with
Bifidobacterium lactis
Bb12.
Assessment
A safety assessment
was performed on
documentation of any
adverse events that
occurred during the
study period.
Result Statement
No adverse events
were reported during
dosing with both
regimens.
C-287
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Morosova, 1996
CT
Myllyluoma, 2007
CT
Narayanappa,
2008
RCT
Naruszewicz,
2002
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Streptococcus salivarius n/a , n/a , n/a , n/a
Streptococcus sanguis n/a , n/a , n/a , n/a
Lactobacillus acidophilus n/a , n/a , n/a , n/a
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
peridontitis
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , n/a , 2.5*10^9 cfu q.d.
Lactobacillus rhamnosus LC705 , n/a , n/a , 2.5*10^9 cfu
q.d.
Propionibacterium freudenreichii Shermanii JS , n/a , n/a ,
2.5*10^9 cfu q.d.
Bifidobacterium lactis Bb12 , n/a , n/a , 2.5*10^9 cfu q.d.
NA
Product Name
n/a
Genus, Species, Strain
Streptococcus faecalis T-110 , Live , 3*10^7 cfu/sachet , 1
sachet t.i.d.
Clostridium butyricum TO-A , Live , 2*10^6 cfu/sachet , 1
sachet t.i.d.
Bacillus mesentericus TO-A , Live , 10^6 cfu/sachet , 1
sachet t.i.d.
Lactobacillus sporogenes 1 sachet t.i.d. up to 14 days , Live
, 5*10^7 cfu/sachet , 1 sachet t.i.d.
NA
Product Name
Bifilac
Genus, Species, Strain
Lactobacillus plantarum 299v , n/a , 5*10^7 cfu/ml , 400ml
q.d.
NA
Product Name
ProViva
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Helicobacter infection
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
<2yrs; 3mos-3yrs acute
viral diarrhea
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Smokers
C-288
Safety Assessment
Results
Assessment
n/a
Result Statement
The developed
treatment
therapy...has no
negative side effects
and was positively
evaluated by patients.
Assessment
n/a
Result Statement
No adverse events
were reported during
ingestion of the
probiotic combination
drink.
Assessment
n/a
Result Statement
None of the patients
had any adverse
events.
Assessment
n/a
Result Statement
Well accepted; no
adverse effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Niedzielin, 2001
RCT
Noback, 2000
RCT
Oksanen, 1990
RCT
Olivares, 2007
RCT
O'Sullivan, 2000
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus plantarum 299V , n/a , 5*10^7 cfu/ml , 200ml
b.i.d.
NA
Product Name
ProViva
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
IBS
Genus, Species, Strain
Lactobacillus plantarum DSM 9843 strain 299v , n/a ,
5*10^7 cfu/400ml , 400ml q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
IBS
Genus, Species, Strain
Lactobacillus casei GG , Lyophilized , 10^9 cfu/sachet , 1
sachet b.i.d.
NA
Product Name
LGG
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
10-80 yrs
Genus, Species, Strain
Lactobacillus fermentum CECT5716 , n/a , 10^10
cfu/capsule , 1 capsule q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus casei GG , Lyophilized , 2.5*10^9 cfu/tablet , 2
tablets b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
IBS
C-289
Safety Assessment
Results
Assessment
n/a
Result Statement
No treatment related
side effects were
observed.
Assessment
n/a
Result Statement
All patients tolerated
the products well, and
no adverse events
were reported during
the period of intake.
Assessment
n/a
Result Statement
No side effects
related to
Lactobacillus GG
were observed.
Assessment
n/a
Result Statement
Capsules were welltolerated…and none
reported any adverse
effect.
Assessment
n/a
Result Statement
No patient developed
a serious illness or
events.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Ouwhand, 2008
RCT
Ozkan, 2007
RCT
Pantoflickova,
2003
RCT
Pedone, 2000
RCT
Peng, 2005
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus acidophilus NCFM , n/a , 2*10^9 cfu /gm, 5
5.5gm/sachet , 1 sachet b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
>65
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 250 mg, b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Genus, Species, Strain
Lactobacillus johnsonii Lj 1 , Live , 10^6-10^7 cfu/gm , 125
gm b.i.d. then q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Helicobacter pylori.
Gastritis
Genus, Species, Strain
Lactobacillus*# bulgaricus n/a , n/a , >10^7 cfu/ml , twice
daily for 5 days a week
Streptococcus*# thermophilus n/a , n/a , >10^7 cfu/ml , n/a
Lactobacillus# casei DN-114 001 , n/a , 3.2*10^8 cfu/ml ,
b.i.d. 5 days a week
NA
Product Name
*n/a, #Actimel
Genus, Species, Strain
Lactobacillus paracasei LP33 , Live , 5*10^9cfu/capsule ,
b.i.d.
Lactobacillus paracasei LP33 , Heat-killed , 5*10^9
cfu/capsule , b.i.d.
NA
Product Name
n/a
Direct Comparison
Delivery vehicles
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Direct Comparison
Forms
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
C-290
Safety Assessment
Results
Assessment
Subjects recorded in
a study dairy… health
status.
Result Statement
No significant
differences in side
effects were observed
between the two
groups.
Assessment
n/a
Result Statement
No adverse reaction
related to S. boulardii
therapy was observed
during the study.
Assessment
Adverse events…
were recorded during
the whole study.
Result Statement
No serious adverse
events were reported.
Assessment
Nursing assistants
recorded daily …
product tolerance.
Result Statement
The acceptability of
the products was
found to be good.
Assessment
n/a
Result Statement
No participants left
the trial prematurely
due to adverse
effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Pereg, 2004
RCT
Piano, 2010
RCT
Pirotta, 2004
RCT
Pitkala, 2007
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus casei DN-114 001 , n/a , 10^8 cfu/ml , 100 ml
q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus (group A) plantarum LP01 (LMG P-21021) ,
Viable , 5*10^9 cfu/sachet , 1 sachet q.d.
Bifidobacterium(group A) breve BR03 (DSM 16604) , Viable
, 5*10^9 cfu/sachet , 1 sachet q.d.
Lactobacillus (group B) plantarum LP01 , Viable , 1*10^9
cfu/sachet , 1 sachet q.d.
Bifidobacterium (group B) breve BR03 , Viable , 1*10^9
cfu/sachet , 1 sachet q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus* rhamnosus n/a , n/a , n/a , n/a
Bifidobacterium* longum n/a , n/a , n/a ,
Lactobacillus# rhamnosus n/a , n/a , n/a ,
Lactobacillus# delbrueckii n/a , n/a , n/a ,
Lactobacillus# acidophilus n/a , n/a , n/a ,
Streptococcus# thermophilus n/a , n/a , n/a ,
NA
Product Name
*Lactobac (oral), #Femilac (vaginal)
Genus, Species, Strain
Bifidobacterium* longum 46 and 2C , Viable , 10^9 cfu , q.d.
Bifidobacterium# lactis Bb12 , Viable , 10^9 cfu , q.d.
NA
Product Name
*n/a, #Yosa
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
Delivery vehicles, Dose
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
Delivery vehicles
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Non pregnant women
18-50 yrs
Direct Comparison
Species
Subgroup Analysis
Disease or immunologic
status
Cotreatment
n/a
>65
C-291
n/a
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse effects
were reported.
Assessment
n/a
Result Statement
No adverse events
were reported.
Assessment
Reasons for
withdrawal…
Result Statement
One participant in the
oral Lactobacillus and
vaginal placebo group
withdrew due to side
effects.
Assessment
n/a
Result Statement
Well accepted.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Rafter, 2007
RCT
Rao, 2009
RCT
Rautava, 2002
RCT
Reid, 2001
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Bifidobacterium lactis Bb12 , Lyophilized , >10^10 cfu/g ,
n/a
Lactobacillus delbrueckii rhamnosus GG , >10^10 cfu/g ,
n/a 7 days ,
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
Colon cancer and
polypectomized patients
Genus, Species, Strain
Lactobacillus casei Shirota , n/a , 8*10^9 cfu/sachet , 1
sachet t.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Adu<s 18-65 yrs with
Chronic Fatigue
Syndrome
Genus, Species, Strain
Bifidobacterium rhamnosus GG(ATCC 53103) , n/a ,
2*10^10 cfu , q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
Disease or immunologic
status
Cotreatment
n/a
<2yrs; m breastfeeding
infants <3 mos
Genus, Species, Strain
Lactobacillus rhamnosus GR-1 , Lyophilized , n/a , 8*10^8
cfu q.d., 6*10^9 cfu q.d., 8*10^8 cfu b.i.d.
Lactobacillus freudenreichii RC-14 , Lyophilized , n/a ,
8*10^8 cfu q.d., 6*10^9 cfu q.d., 8*10^8 cfu b.i.d.
Lactobacillus rhamnosus GG , n/a , 8*10^8 cfu , q.d. (Arm
4)
NA
Product Name
n/a
Direct Comparison
Dose, Species, Strains
Subgroup Analysis
n/a
Cotreatment
n/a
C-292
n/a
Safety Assessment
Results
Assessment
The subjects were
interviewed at time 2
and time 3 … and any
adverse events that
had occurred in each
6-wk period were
recorded.
Result Statement
No adverse effects of
the intervention were
reported.
Assessment
n/a
Result Statement
Well-tolerated; no
significant adverse
events.
Assessment
The infants' clinical …
status were assessed
at scheduled visits at
the ages of 3, 6, 12,
and 24 months.
Result Statement
No adverse reactions
or clinical side effects
were observed during
probiotic
supplementation or
clinical followup.
Assessment
n/a
Result Statement
None of the patients
reported adverse side
effects during the 6
week test period.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Reid, 2003
RCT
Riccia, 2007
CT
Ritchie, 2009
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus rhamnosus GR-1 , Lyophilized , >10^9 cfu
/capsule , 1 capsule q.d.
Lactobacillus fermentum RC-14 , Lyophilized , >10^9
cfu/capsule , 1 capsule q.d.
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
n/a
Genus, Species, Strain
Lactobacillus brevis n/a , Lyophilized , 2*10^7 cfu/lozenge ,
4 lozenges q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
n/a
Genus, Species, Strain
Lactobacillus casei GG , n/a , >5*10^9 cfu/capsule , 1
capsule t.i.d
NA
Product Name
Gelfilus
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs
Safety Assessment
Results
Assessment
The research nurse,
supervised by a
physician, followed
every patient
throughout the study.
This entailed … and
monitor any perceived
adverse events. Upon
completion of the
study, each subject
filled out a
questionnaire to
determine whether
any adverse events ...
occurred.
Result Statement
Patients did not report
any side effects
associated with
probiotic therapy.
Assessment
n/a
Result Statement
The tolerability was
considered as very
good by all patients.
Assessment
Adverse events
related to the study
product and/or
protocol
investigations were
reported to the ethics
committee approving
the study.
Result Statement
No adverse effect
attributable to LGG in
the present study
protocol.
C-293
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Roessler, 2007
RCT
Roggero, 1990
RCT
Romano, 2010
RCT
Intervention, Form, Potency, Dose
Analysis
Genus, Species, Strain
Bifidobacterium animalis Lactis DGCC 420 , Active ,
5.9*10^4 cfu/g , 100ml b.i.d.
Lactobacillus paracasei Lpc-37 , Active , 3.9*10^8 cfu/g ,
100ml b.i.d.
Lactobacillus acidophilus 74-2 , Active , 2.9*10^4 cfu/g ,
100ml b.i.d.
Streptococcus thermophilus n/a , Active , n/a , 100ml b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Streptococcus lactis n/a , Active , 8*10^9 cfu/capsule , b.i.d.
or q.i.d.
Lactobacillus bulgaricus n/a , Active , 1*10^9 cfu , b.i.d. or
q.i.d.
Lactobacillus acidophilus n/a , Active , 1*10^9 cfu , b.i.d. or
q.i.d.
NA
Product Name
Lactipan
Direct Comparison
n/a
Subgroup Analysis
Disease or immunologic
status
Cotreatment
Corticosteroid use
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; chronic diarrhea
Genus, Species, Strain
Lactobacillus reuteri DSM 17938 , Lyophilized , 10^8 cfu/5
drops , 5 drops, b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-294
High-Risk Population
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse effects of
the regular intake of
the probiotic drink
were reported.
n/a
Assessment
Particular attention
was paid to the
detection of any
undesirable effect in
the course of the
treatment.
Result Statement
During the treatment
period no side effect
was observed for both
groups.
Assessment
The patients used a
diary to record… any
other symptoms.
Result Statement
L. reuteri
supplementation was
well tolerated and no
adverse effects or
other unexpected
symptoms were
reported in either
study.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Romeo, 2009
RCT
Roos, 1993
CT
Roos, 1993
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus reuteri ATCC 55730 , n/a , 10^8 cfu/5 drops ,
5 drops, q.d.
Lactobacillus rhamnosus ATCC 53103 , n/a , 6*10^9
cfu/capsule , 1 capsule, q.d.
NA
Product Name
n/a
Direct Comparison
Delivery vehicles,
Species
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Genus, Species, Strain
Streptococcus sanguis 3 strains unspecified , n/a , 10^7 cfu
each strain /treatment , b.i.d.
Streptococcus mitis n/a , n/a , 10^7 cfu /treatment , b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Streptococcus sanguis 3 strains unspecified , Lyophilized ,
10^6 cfu /puff , 3 puffs b.i.d.
Streptococcus mitis n/a , Lyophilized , 10^6 cfu /puff , 3
puffs b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Recurrent streptococcal
tonsillitis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
History of strep infection
(tonsillitis)
C-295
<2yrs
Safety Assessment
Results
Assessment
Nutrition
administrated through
oral access… was
progressively
increased if tolerated.
Result Statement
Both used probiotics
had good safety and
did not show any
adverse reactions or
side effects in preterm
infants.
Assessment
n/a
Result Statement
No adverse effects
have been noted.
Assessment
n/a
Result Statement
No side effects …
were reported and all
patients were able to
complete the 2
treatment regimens.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Ruszczy?ski,
2008
RCT
Saavedra, 1994
RCT
Salazar-Lindo,
2004
RCT
Sazawal, 2010
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus rhamnosus Pen 2593 , n/a , 2*10^9 cfu , b.i.d.
Lactobacillus rhamnosus E/N 2594 , n/a , 2*10^9 cfu , b.i.d.
Lactobacillus rhamnosus Oxy 2595 , n/a , 2*10^9 cfu , b.i.d.
NA
Product Name
Lakcid Forte
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Genus, Species, Strain
Bifidobacterium bifidum n/a , n/a , 1.9*10^8 cfu/g powdered
formula, 3.6*10^8 cfu/100kcal , n/a
Streptococcus thermophilus n/a , n/a , 1.4*10^7 cfu/g or
2.7*10^8 cfu/100kcal , n/a
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Genus, Species, Strain
Lactobacillus casei GG , n/a , 10^9 cfu/ml , 150 ml/kg/d up
to 1L (10^12 cfu) q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Genus, Species, Strain
Bifidobacterium lactis HN019 , n/a , 6.3*10^6 cfu/dose , 1
dose, t.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
Disease or immunologic
status
Cotreatment
n/a
C-296
<2yrs; 2-14 yrs
<2yrs
Safety Assessment
Results
Assessment
The secondary
outcome measures
were… and adverse
events.
Result Statement
Lactobacillus
rhamnosus was welltolerated, and no
adverse event
associated with this
therapy (or with the
use of placebo) was
reported.
Assessment
n/a
Result Statement
No adverse effects
judged to be
associated with the
feeding of the
supplemented
formula.
Assessment
Early withdrawals
defined as patient
who develops a
complicating illnesses
Result Statement
No adverse effects
due to the study
formula.
Assessment
n/a
Result Statement
No adverse effects
were reported or
observed.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Schaafsma, 1998
RCT
Senay, 2009
RCT
Shanahan, 2010
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , 10^7-10^8 cfu/gm , 125
ml t.i.d.
NA
Product Name
Actimel
Genus, Species, Strain
Saccharomyces boulardii n/a , Lyophilized, live , 5*10^6
microorganisms/250 mg , 250 mg, q.d.
NA
Product Name
Reflor
Genus, Species, Strain
Lactobacillus salivarius salivarius UCC118 , Live , 10^9
cfu/dose , 1 dose, q.d.
Bifidobacterium infantis 35624 , Live , 10^9 cfu/dose , 1
dose, q.d.
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Corticosteroid use
C-297
High-Risk Population
n/a
n/a
n/a
Safety Assessment
Results
Assessment
Questionnaire on
well-being
Result Statement
n/a
Assessment
Daily record of… the
side effects of the
treatment. All data
were recorded on a
study record sheet
during the 10 days of
treatment by patients
and patients were
reevaluated after 10
days.
Result Statement
S. boulardii wall
tolerated by all
children and no side
effect was recorded
during the active
treatment period.
Assessment
n/a
Result Statement
Adverse events were
uncommon, unrelated
to the treatment, and
similar across the
groups. Prolonged
feeding with live
probiotics is safe in
patients with
ulcerative colitis.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Sharma, 2008
RCT
Sheu, 2006
RCT
Shimauchi, 2008
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus n/a n/a , n/a , 10^8 cfu/capsule , 1 capsule
t.i.d.
Clostridium butyricum n/a , n/a , 4*10^6 cfu/capsule , 1
capsule t.i.d.
Bacillus mesentericus n/a , n/a , 2*10^6 cfu/capsule , 1
capsule t.i.d.
Streptococcus faecalis n/a , n/a , 6*10^7 cfu/capsule , 1
capsule t.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus acidophilus La 5 , n/a , ?10^9 bacteria/ml ,
200ml b.i.d.
Bifidobacterium lactis Bb 12 , n/a , ?10^9 bacteria/ml , 200
ml b.i.d.
Lactobacillus bulgaricus n/a , n/a , ?10^9 bacteria/ml ,
200ml b.i.d.
Streptococcus thermophilus n/a , n/a , ?10^9 bacteria/ml ,
200 ml b.i.d.
NA
Product Name
AB-yogurt
Direct Comparison
Prebiotic mix
Subgroup Analysis
n/a
Cotreatment
n/a
minimal hepatic
encephalopathy
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Helicobacter pylori
infection
Genus, Species, Strain
Lactobacillus salivarius WB21 , Lyophilized , 6.7*10^8
cfu/tablet , 1 tablet t.i.d.
NA
Product Name
Wakamate D
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
C-298
Safety Assessment
Results
Assessment
n/a
Result Statement
Probiotics treatment
also had no side
effect.
Assessment
n/a
Result Statement
Only 4 patients in the
yogurt-plus-quadruple
therapy group did not
complete the study
design. However, only
1 of the 4 patients
had poor tolerance of
the 4-wk ingestion of
AB-yogurt. This
indicates that the
pretreatment with Abyogurt can be well
tolerated in milktolerant patients who
have residual H.
pylori after failed triple
therapy.
Assessment
n/a
Result Statement
No adverse events
were reported.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Shimizu, 2009
CT
Shornikova, 1997
RCT
Simren, 2007
RCT
Sinn, 2008
RCT
Skovbjerg, 2009
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Bifidobacterium breve Yakult , Live , 10^8 cfu/gm , 3g
mixture q.d.
Lactobacillus casei Shirota , Live , 10^8 cfu/gm , 3g mixture
q.d.
NA
Product Name
Yakult BL
Genus, Species, Strain
Lactobacillus reuteri n/a , Lyophilized, viable , 10^10-10^11
cfu/capsule , 1 capsule q.d.
Lactobacillus reuteri n/a , Lyophilized, viable , 10^7
cfu/capsule , 1capsule q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus paracasei paracasei , Active , ?5*10^7 cfu/ml
yogurt , 400 ml q.d.
Lactobacillus acidophilus n/a , Active , ?5*10^7 cfu/ml
yogurt , 400 ml /day
Bifidobacterium lactis n/a , Active , ?5*10^7 cfu/ml , 400 ml
/day
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus acidophilus SDC 2012 , Lyophilized , 2*10^9
cfu/ml , 1 capsule b.i.d.
Lactobacillus acidophilus SDC 2013 , Lyophilized , 2*10^9
cfu/ml , 1 capsule b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
Immune compromised /
critically ill
Direct Comparison
Dose
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
IBS
Direct Comparison
Genera
Subgroup Analysis
n/a
Cotreatment
n/a
1-8 yrs; Otitis media
with effusion
Genus, Species, Strain
Streptococcus sanguis 89a NCIMB 40104 , Lyophilized ,
5*10^9 cfu/ml , 0.2 ml b.i.d.
Lactobacillus rhamnosus LB21, NCIMB 40564 , Lyophilized
, 5*10^9 cfu/ml , 0.2 ml /day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-299
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse events in
any patients.
Assessment
n/a
Result Statement
Safe.
Assessment
n/a
Result Statement
well tolerated and no
serious adverse
events occurred.
<2yrs Otitis Media With
Effusion
Assessment
Any adverse events
that occurred during
the treatment period
was also recorded.
Result Statement
There were no
adverse events
reported.
Assessment
n/a
Result Statement
No adverse events
were reported.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Stansbridge, 1993
RCT
Steeksen-Blicks,
2009
RCT
Sugawara, 2006
RCT
Sugita, 1994
CT
Sur, 2010
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus casei GG , Lyophilized , 10^8 cfu/dose , b.i.d.
NA
Product Name
n/a
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; Premature
newborns
Genus, Species, Strain
Lactobacillus* casei Shirota , Live , 4*10^10 cfu/bottle , 1
bottle q.d.
Bifidobacterium# breve Yakult , Live , 1*10^10 cfu/bottle , 1
bottle q.d.
Lactobacillus** casei Shirota , Live , 10^8 cfu/g , 3g q.d.
Bifidobacterium** breve Yakult , Live , 10^8 cfu/g , 3g q.d.
NA
Product Name
*Yakult 400; #Bifiel; **Yakult BL
Genus, Species, Strain
Lactobacillus casei n/a , n/a , 10^9-10^10 cfu , 1g
NA
Product Name
n/a
Direct Comparison
Timing
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Immune compromised /
critically ill
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Genus, Species, Strain
Lactobacillus casei Shirota , n/a , 6.5*10^9 cfu/bottle , 1
bottle, q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus rhamnosus LB21 , n/a , 10^7 cfu/ml , 150 ml
q.d.
NA
Product Name
n/a
C-300
<2yrs; day care centers
Safety Assessment
Results
Assessment
n/a
Result Statement
Clinically, there were
no adverse effects.
Assessment
n/a
Result Statement
No harmful side
effects were reported
by any of the
participants in the
study.
Assessment
n/a
Result Statement
No patients had
problems related to
synbiotic treatment.
Assessment
n/a
Result Statement
In two years, no
adverse effects were
found.
Assessment
n/a
Result Statement
No adverse events
was observed in
children of either
probiotic or nutrients
groups.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Surawicz, 2000
RCT
Surawicz, 1989
RCT
Szajewska, 2001
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 500 mg b.i.d.
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
High-Risk Population
Clostridium Difficile
Disease
Genus, Species, Strain
Saccharomyces boulardii n/a , Lyophilized , n/a , 250 mg
b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
Disease or immunologic
status
Cotreatment
n/a
Hospitalized patients
Genus, Species, Strain
Lactobacillus casei GG , n/a , n/a , 6*10^9 cfu b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
C-301
Safety Assessment
Results
Assessment
The patients kept a
standardized diary
of… adverse
reactions.
Result Statement
No significant
differences in the
number of adverse
reactions reported by
patients taking S.
boulardii compared
with those taking
placebo. No specific
type of adverse
reaction was more
common in patients
taking S. boulardii
than in those
receiving placebo, …
no significant adverse
reactions during the
4-week followup.
Assessment
n/a
Result Statement
There were no side
effects of either
Saccharomyces
boulardii or placebo.
Assessment
n/a
Result Statement
Well tolerated and no
adverse effects of the
treatment were noted.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Szajewska, 2007
RCT
Szymanski, 2006
RCT
Szyma?ski, 2008
RCT
Tlaskal, 2007
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , n/a , 3*10^9 cfu b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus rhamnosus 573L/1 , Lyophilized , n/a ,
1.2*10^10cfu b.i.d.
Lactobacillus rhamnosus 573L/2 , Lyophilized , n/a ,
1.2*10^10cfu b.i.d.
Lactobacillus rhamnosus 573L/3 , Lyophilized , n/a ,
1.2*10^10cfu b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus plantarum PL02 , n/a , n/a , 10^8 cfu mixture
b.i.d.
Lactobacillus rhamnosus KL53a , n/a , 10^8 cfu b.i.d. , 10^8
cfu mixture b.i.d.
Bifidobacterium longum PL03 , n/a , n/a , 10^8 cfu mixture
b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus* acidophilus Rossell-52 , n/a , n/a , 1.45*10^8
cfu q.d.
Lactobacillus rhamnosus Rossell-11 , n/a , n/a , 2.755*10^9
cfu q.d.
Streptococcus# faecalis n/a , n/a , n/a , n/a
Lactobacillus# acidophilus n/a , n/a , n/a , n/a
Lactobacillus# helveticus n/a , n/a , n/a , n/a
NA
Product Name
*Lacidofil; #Hylak
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; rectal bleeding
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs; 2-15 yrs
Direct Comparison
Prebiotic mix
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; Acute diarrhea
C-302
<2yrs
Safety Assessment
Results
Assessment
n/a
Result Statement
Well tolerated and no
adverse effects.
Assessment
Secondary outcomes
were… presence of
adverse events.
Result Statement
No adverse events
were noted.
Assessment
Secondary outcomes
were…and adverse
events.
Result Statement
Mixture of probiotics
was well tolerated,
and no adverse
events associated
with this therapy were
reported.
Assessment
n/a
Result Statement
None of the
participants failed to
complete the 10 day
course of therapy
resulting from
untoward effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Tubelius, 2005
RCT
Tursi, 2007
CT
Twetman, 2009
RCT
Vandenplas, 2007
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus reuteri protectus (ATCC 55730) , n/a , n/a ,
10^8 cfu q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus casei n/a , Lyophilized , n/a , 4.5*10^8 cfu/day
Lactobacillus plantarum n/a , Lyophilized , n/a , 4.5*10^8
cfu/day
Lactobacillus bulgaricus n/a , Lyophilized , n/a , 4.5*10^8
cfu /day
Lactobacillus plantarum n/a , Lyophilized , n/a , 4.5*10^8
cfu /day
Bifidobacterium longum n/a , Lyophilized , n/a , 4.5*10^8 cfu
/day
Bifidobacterium infantis n/a , Lyophilized , n/a , 4.5*10^8 cfu
/day
Bifidobacterium breve n/a , Lyophilized , n/a , 4.5*10^8 cfu
/day
Streptococcus salivarius thermophilus n/a , Lyophilized , n/a
, 4.5*10^8 cfu /day
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus reuteri ATCC 55730 , n/a , 10^8 cfu/stick of
gum , 1 stick b.i.d.
Lactobacillus reuteri ATPTA 5289 , n/a , 10^8 cfu/stick , 1
stick b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 500 mg, q.d.
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
High-Risk Population
n/a
n/a
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse events
reported.
Assessment
All patients … were
evaluated for the
presence of possible
side effects.
Result Statement
No side effects were
recorded throughout
the follow up in both
groups.
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs
C-303
Assessment
n/a
Result Statement
No harmful side
effects or adverse
events.
Assessment
n/a
Result Statement
Side effects were not
reported.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Vanderhoof, 1999
RCT
Venturi, 1999
CT
Whorwell, 2006
RCT
Winkler, 2005
RCT
Woodord, 2009
RCT
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus casei rhamnosus GG , Live , 10^10
cfu/capsule , 1 capsule q.d. or b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
2 yrs-10 yrs
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized , 5*10^11 cfu/g
mixture , 3g mixture b.i.d.
Lactobacillus casei casei n/a , Lyophilized , ,
Lactobacillus delbrueckii Bulgaricus , Lyophilized , ,
Lactobacillus plantarum n/a , Lyophilized , n/a ,
Bifidobacterium longum n/a , Lyophilized , ,
Bifidobacterium infantis n/a , Lyophilized , ,
Bifidobacterium breve n/a , Lyophilized , ,
Streptococcus salivarius thermophilus , Lyophilized , n/a ,
NA
Product Name
VSL#3
Genus, Species, Strain
Bifidobacterium infantis 35624 , Live , 1*10^6/ml , q.d.
Bifidobacterium infantis 35624 , Live , 1*10^8/ml , q.d.
Bifidobacterium infantis 35624 , Live , 1*10^10/ml , q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus gasseri PA 16/8 , Spray-dried , 4*10^8
cfu/tablet , 1 tablet q.d.
Bifidobacterium longum SP 07/3 , Spray-dried , 5*10^7
cfu/tablet , 1 tablet q.d.
Bifidobacterium bifidum MF 20/5 , Spray-dried , 5*10^7
cfu/tablet , 1 tablet q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus n/a n/a , Live , 2.4*10^9 cells/pill , 1 pill, q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Ulcerative Colitis In
Remission
Direct Comparison
Dose
Subgroup Analysis
n/a
Cotreatment
n/a
IBS (women)
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
C-304
Safety Assessment
Results
Assessment
n/a
Result Statement
There were no
failures resulting from
untoward effects.
Assessment
n/a
Result Statement
The preparation was
also safe and well
tolerated by patients.
Assessment
n/a
Result Statement
Only 17(
Assessment
n/a
Result Statement
No report of adverse
events.
Assessment
n/a
Result Statement
There were no
probiotic-related
complications.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Wullt, 2003
RCT
Wunderlich, 1989
RCT
Xiao, 2006
RCT
Ya, 2010
RCT
Yamamura, 2009
RCT
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus plantarum 299 V , n/a , n/a , 5*10^10 cfu q.d.
NA
Product Name
n/a
Genus, Species, Strain
Enterococcus n/a SF 68 , Lyophilized , 75*10^6 cfu/capsule
, 2 capsules q.d.
NA
Product Name
n/a
Genus, Species, Strain
Bifidobacterium longum BB 536 , Lyophilized , n/a , 5*10^10
cfu b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus rhamnosus n/a , Lyophilized, live , 6.8x10^9
cfu , daily
Lartobacillus acidophilus n/a , Lyophilized , 4x10^8 cfu ,
daily
Streptococcus thermophilus n/a , Lyophilized , 8x10^8 cfu ,
daily
NA
Product Name
Probaclac Vaginal
Genus, Species, Strain
Lactobacillus helveticus CM4 , n/a , n/a , n/a
NA
Product Name
n/a
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
>18 yrs Hospitalized
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
>65
C-305
Diarrhoea
n/a
Safety Assessment
Results
Assessment
n/a
Result Statement
No apparent side
effects.
Assessment
n/a
Result Statement
No side effects were
reported.
Assessment
n/a
Result Statement
No participants left
the trial prematurely
due to adverse
effects.
Assessment
Follow-up evaluations
included… a report of
adverse events
Result Statement
…no adverse events
were reported in
either group.
Assessment
n/a
Result Statement
None of the subjects
in either group
developed any side
effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Zeng, 2008
RCT
Amati, 2010
CS
Baron, 2009
CS
Bennet, 1992
CS
Bennett, 1996
CS
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Streptococcus thermophilus n/a , Active , 10^8 cfu/ml , 200
ml mixture b.i.d.
Lactobacillus bulgaricus n/a , Active , 10^9 cfu/ml , 200 ml
mixture b.i.d.
Lactobacillus acidophilus n/a , Active , 10^7 cfu/ml , 200 ml
mixture b.i.d.
Bifidobacterium longum n/a , Active , 10^7 cfu/ml , 200 ml
mixture b.i.d.
NA
Product Name
AB100
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus rhamnosus GG , n/a , 10^7 bacteria/90g , 90g
b.i.d.
NA
Product Name
YOMO ABC PLUS
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
>65
Genus, Species, Strain
Bacillus coagulans GBI-30, 6086 , n/a , 2*10^9 cfu , 1
capsule /day
NA
Product Name
Sustenex
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Bifidobacterium longum BB-536 , Lyophilized , 3*10^9 cfu ,
t.i.d 5 days
Bifidobacterium breve BB-576 , Lyophilized , 3*10^9 cfu ,
t.i.d
Lactobacillus acidophilus LAC-343 , Lyophilized , 3*10^9
cfu , t.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus rhamnosus GG , Lyophilized , 10^9
cfu/capsule , q.d., b.i.d. or q.i.d.
NA
Product Name
LGG
Direct Comparison
Genera mix
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
>65
C-306
Safety Assessment
Results
Assessment
n/a
Result Statement
There were no
reported adverse
events related to the
study drinks.
Assessment
n/a
Result Statement
No side effects were
recorded in the
individuals who
terminated that trial.
Assessment
n/a
Result Statement
No serious adverse
events were reported
throughout the study.
Assessment
n/a
Result Statement
No side effects were
noted.
Assessment
n/a
Result Statement
No side effects were
associated with LGG.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Biller, 1995
CS
Bruce, 1992
CS
Ciprandi, 2004
CS
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus rhamnosus GG , Lyophilized , 5*10^9cfu/g ,
125 mg b.i.d.
NA
Product Name
LGG
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; 5-70 mons
Genus, Species, Strain
Lactobacillus casei GR-1 , Lyophilized , >1.6*10^9
organisms/0.5g , 1 suppository/wk
Lactobacillus fermentum B-54 , Lyophilized , >1.6*10^9
organisms/0.5g , 1 suppository/wk
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
Ethnicity
Cotreatment
n/a
n/a
Genus, Species, Strain
Bacillus clausii n/a , n/a , 2*10^9 spores /vial , 2 vials q.d.
NA
Product Name
Enterogermina
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
allergic children with
recurrent respiratory
infections
C-307
Safety Assessment
Results
Assessment
n/a
Result Statement
No side effects were
noted during the
course of treatment.
Assessment
n/a
Result Statement
The suppositories
caused no detectable
side effects. Two
patients were not
compliant. The
reasons appropriate
treatment were
suffering from other
types of ailments not
related to UTI.
Assessment
n/a
Result Statement
All children assumed
the prescribed
treatment with B.
clausii spores without
any side-effect.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Drago, 2007
CS
Erzsébet, 1988
CS
Fan, 2006
CS
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized , 10^9 cfu/ml , 1
douche (100 ml)/day
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
High-Risk Population
n/a
Genus, Species, Strain
Lactobacillus n/a n/a , n/a , n/a , 0.14gm tablet
NA
Product Name
Lactobact
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Vaginal infection
Genus, Species, Strain
Bifidobacterium n/a n/a , Live , 5*10^7cfu/gm , 420 mg
mixture t.i.d.
Lactobacillus n/a n/a , Live , 5*10^7cfu/gm , 420 mg mixture
t.i.d.
Enterococcus n/a n/a , Live , 5*10^7cfu/gm , 420 mg
mixture t.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
IBS patients
C-308
Safety Assessment
Results
Assessment
The treatment kit
included a
questionnaire to
determine whether
any adverse events
occurred during the
treatment and in the
following period.
Result Statement
The treatment kit
included a
questionnaire to
determine whether
any adverse events
occurred during the
treatment and in the
following period.
Assessment
n/a
Result Statement
Using the vaginal
tablet did not cause
subject complaints,
side effect.
Assessment
Side effects were
recorded at the same
time as symptoms
Result Statement
All tolerated the
products well; no
adverse events were
reported.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Federico, 2009
CS
Ferraz, 2009
CS
Friedlander, 1986
CS
Fujimori, 2007
CS
Fukushima, 1998
CS
Gee, 2010
CS
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus paracasei B 21060 , Lyophilized , 5*10^9
cfu/bag , 1 bag b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus casei Shirota , Lyophilized , 2*10^7-10^9
cfu/50 mg , 50mg, t.i.d.
Bifidobacterium breve n/a , Lyophilized , 5*10^7-10^9 cfu ,
50mg, t.i.d.
NA
Product Name
Yakult SA
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , 10^8-10^9/100 ml , 100
ml, b.i.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus* casei n/a , n/a , n/a , 3*10^10 q.d.
Bifidobacterium* breve n/a , n/a , n/a , 3*10^10 q.d.
Bifidobacterium# longum n/a , n/a , 1.5*10^10 q.d. ,
NA
Product Name
*Yakult BL; #ISAGOL 5 billion
Genus, Species, Strain
Bifidobacterium lactis Bb-12 , Viable , n/a , 10^9cfu q.d.
NA
Product Name
Nan BF
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Corticosteroid use, Diet
therapies
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus paracasei NFBC 338 , Stored at 22 degree
centigrade , 1*10^9 cfu/dose , 1 single dose
NA
Product Name
n/a
C-309
Safety Assessment
Results
Assessment
n/a
Result Statement
The preparation was
well-tolerated and
well accepted, no
adverse events were
observed.
Assessment
n/a
Result Statement
No adverse effects
were observed while
on the use of LAB.
Crohn's Disease
<2yrs; 15-31 mos
Assessment
n/a
Result Statement
In no case were side
effects observed.
Assessment
n/a
Result Statement
Synbiotic therapy can
safely reduce Crohn's
disease activity.
Assessment
n/a
Result Statement
Well Accepted
<2yrs
Assessment
n/a
Result Statement
No adverse effects
were observed with
probiotic
administration.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Giacarri, 1993
CS
Gill, 2001
CS; Pre-Post
Gracheva, 1996
CS
Guandalini, 2002
CS
Gupta, 2000
CS
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus n/a n/a , n/a , n/a , 2 capsules q.d.
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
High-Risk Population
n/a
Genus, Species, Strain
Lactobacillus rhamnosus HN 001 (DR 20) , n/a , 1.25*10^8
cfu/ml , 5*10^10 cfu q.d.
NA
Product Name
DR 20 ™
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
>65
Genus, Species, Strain
Bacillus subtilis n/a , Live , n/a , 2*10^9 cfu
Bacillus licheniformis n/a , Live , , 2*10^6 cfu
Lactobacillus n/a n/a , n/a , n/a ,
NA
Product Name
Biosporin
Genus, Species, Strain
Lactobacillus n/a GG , n/a , n/a , n/a
NA
Product Name
n/a
Direct Comparison
Dose
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics,
Corticosteroid use,
Immune suppressants
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics,
Corticosteroid use,
Immune suppressants
Pediatric Crohn's
Genus, Species, Strain
Lactobacillus casei GG , n/a , n/a , 10^10 cfu b.i.d.
NA
Product Name
n/a
C-310
Safety Assessment
Results
Assessment
Throughout the period
of observation the
appearance of any
undesired effect was
monitored.
Result Statement
Tolerability of the
treatment was
excellent; no side
effects.
Assessment
n/a
Result Statement
No reports of adverse
effects on health and
no general health
problems.
Assessment
n/a
Result Statement
Well tolerated; no
adverse reactions
observed.
Assessment
n/a
Result Statement
No patient reported
any adverse effects.
Crohn's Disease
Assessment
n/a
Result Statement
No patient reported
any adverse effects.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Guslandi, 2003
CS
Kanamori, 2010
CS
Kerk, 2002
CS
Kocian, 1994
CS
Laake, 2003
CS; Pre-Post
Intervention, Form, Potency, Dose
Analysis
Genus, Species, Strain
Saccharomyces boulardii n/a , n/a , n/a , 250 mg t.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
Adu<s 19-47 yrs
Ulcerative Colitis
Safety Assessment
Results
Assessment
n/a
Genus, Species, Strain
Bifidobacterium breve Yakult , n/a , 10^9 - 10^10 cfu/g ,
0.03g, q.i.d.-1g, t.i.d.
Lactobacillus casei Shirota , n/a , 10^9 - 10^10 cfu/g ,
0.03g, q.i.d.-1g, t.i.d.
NA
Product Name
BiolActis, Yakult
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , n/a , n/a
NA
Product Name
Acidosalus
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
severe congenital
anormality
Result Statement
No side effects
induced by the
probiotic agent.
Assessment
n/a
Direct Comparison
n/a
Subgroup Analysis
Age
Cotreatment
n/a
Colpitis
Genus, Species, Strain
Lactobacillus acidophilus n/a , Live , 10^9 cfu/capsule , n/a
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Dyspepsia
Genus, Species, Strain
Lactobacillus acidophilus La-5 , Live , 10^8 cfu/ml , 500ml
q.d.
Bifidobacterium lactis Bb-12 , Live , 10^8 cfu/ml , 500 ml
q.d.
NA
Product Name
Cultura
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Pouchitis
C-311
High-Risk Population
Result Statement
Tolerated feeding
very well
Assessment
n/a
Result Statement
Proved especially
tolerable since not
one…experienced
side effects.
Assessment
n/a
Result Statement
No side effects were
observed, the
preparation was very
well tolerated.
Assessment
n/a
Result Statement
No adverse effects
were recorded.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Laake, 2004
CS
Levy, 1997
CS
Lieske, 2005
CS
Lozhardzkaya(?),
1984
CS
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus acidophilus La-5 , Live , 10^8 cfu/ml , 500 ml
q.d.
Bifidobacterium lactis Bb-12 , Live , 10^8 cfu/ ml , 500 ml
q.d.
NA
Product Name
Cultura
Genus, Species, Strain
Lactobacillus plantarum 299v , n/a , n/a , n/a
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , 2*10^11 cfu/gm , 0.4g
to 1.2g q.d.
Lactobacillus brevis n/a , n/a , 2*10^11cfu/gm , 0.4g to 1.2g
q.d.
Streptococcus thermophilus n/a , n/a , 2*10^11cfu/g , 1.6g
to 4.8g q.d.
Bifidobacterium infantis n/a , n/a , 2*10^11cfu/g , 1.6g to
4.8g q.d.
NA
Product Name
Oxadrop
Genus, Species, Strain
Lactobacillus acidophilis n/a , Live, Lyophilized , n/a , pills
(powder) 2-3/day and injection 2-3 every time
NA
Product Name
Acilact
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
“IPAA"(Colectomy/ileost
omy)
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; Clostridium
difficile infection
Direct Comparison
n/a
Subgroup Analysis
Disease or immunologic
status
Cotreatment
n/a
n/a
C-312
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse effects
were recorded.
Assessment
n/a
Result Statement
Well tolerated.
>65, IBD
Assessment
n/a
Result Statement
No adverse events
were noted.
Assessment
n/a
Result Statement
Product is well
tolerated by the
patients and induces
no side effects, there
are no
contraindications
against its
administration.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Matsuzaki, 2005
CS
Monden, 2002
CS
Morita, 2006
CS
Nasirova, 2007
CS
Nobuta, 2009
CS
Intervention, Form, Potency, Dose
Genus, Species, Strain
Lactobacillus casei Shirota , Live , 4*10^10 cfu , b.i.d.
NA
Product Name
n/a
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Corticosteroid use
HTLV-1 associated
myelopathy
Genus, Species, Strain
Lactobacillus* n/a n/a , n/a , 0.5gm/vaginal suppository , n/a
Lactobacillus# crispatus GAI 98322 , n/a , 10^8 cfu , n/a,
NA
Product Name
*LacB, #n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus gasseri TMC0356 , n/a , 4.3*10^8 cfu/ml ,
200ml, q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus n/a n/a , n/a , n/a , n/a
Bifidobacterium forte n/a , n/a , n/a ,
NA
Product Name
n/a
Direct Comparison
Genera
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
<2yrs
Genus, Species, Strain
Lactobacillus brevis KB290 , n/a , 2x10^9 cfu / tablets , per
day
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
C-313
Safety Assessment
Results
Assessment
Assessments were
performed on … and
adverse effects.
Result Statement
No adverse effect and
laboratory findings
were observed.
Assessment
n/a
Result Statement
…no adverse effects
in clinical
examination.
Assessment
n/a
Result Statement
No clinical problems
have been observed
in the medical
examination during
the intervention of the
tested fermented milk.
Assessment
n/a
Result Statement
The application of
probiotics did not
influence on an
organism negatively.
Assessment
Daily questionnaire
and health status.
Result Statement
No relevant adverse
events were reported.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Okombo, 2010
CS
Rossi, 2010
CS
Sanges, 2009
CS
Simenhoff, 1996
CS
Intervention, Form, Potency, Dose
Analysis
High-Risk Population
Genus, Species, Strain
Lactobacillus acidophilus n/a , Lyophilized, live , 8*10^11
bacteria /sachet , 1 sachet, q.d.
Lactobacillus casei n/a , Lyophilized, live , 8*10^11 bacteria
/sachet , 1 sachet, q.d.
Lactobacillus bulgaricus n/a , Lyophilized, live , 8*10^11
bacteria /sachet , 1 sachet, q.d.
Lactobacillus plantarum n/a , Lyophilized, live , 8*10^11
bacteria /sachet , 1 sachet, q.d.
Bifidobacterium longum n/a , Lyophilized, live , 8*10^11
bacteria /sachet , 1 sachet, q.d.
Bifidobacterium infantis n/a , Lyophilized, live , 8*10^11
bacteria /sachet , 1 sachet, q.d.
Bifidobacterium breve n/a , Lyophilized, live , 8*10^11
bacteria /sachet , 1 sachet, q.d.
Streptococcus salivarius thermophilus n/a , Lyophilized, live
, 8*10^11 bacteria /sachet , 1 sachet, q.d.
NA
Product Name
VSL#3
Genus, Species, Strain
Lactobacillus rhamnosus n/a , Lyophilized , >=10^6
cfu/tablet , 1 tablet, b.i.d., then reduced
NA
Product Name
Normogin
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus acidophilus n/a , n/a , 10^9 bacteria/dose , 1
dose, b.i.d.
Lactobacillus salivarius n/a , n/a , 10^9 bacteria/dose , 1
dose, b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus acidophilus NCFM , Lyophilized , 10^9 cfu/ml ,
1 capsule b.i.d.
Lactobacillus acidophilus BG2F04 , Lyophilized , 10^9
cfu/ml , 1 capsule b.i.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Immune compromised /
critically ill
C-314
Safety Assessment
Results
Assessment
n/a
Result Statement
No subject reported
experiencing any
noticeable effects
from the use of this
probiotic.
Assessment
n/a
Result Statement
Tolerability of the
local therapy was
good.
Assessment
n/a
Result Statement
During the study no
one of the patients
had a relapse of UC
or relevant adverse
effects.
Assessment
n/a
Result Statement
No one experienced
any side effects from
the LBA.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Sprunt, 1980
CS
Tandan, 2009
CS
Thompson, 1982
CS
Uehara, 2006
CS
Intervention, Form, Potency, Dose
Analysis
Genus, Species, Strain
Alpha Streptococcus n/a n/a , Active , n/a , 2*10^5-5*10^6
cfu/kg body weight
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs; newborns in
neonatal ICU
Safety Assessment
Results
Assessment
n/a
Genus, Species, Strain
Lactobacillus n/a n/a (4 strains) , Lyophilized, viable ,
9*10^11 cfu/sachet , 2 sachets, b.i.d.
Bifidobacterium n/a n/a (3 strains) , Lyophilized, viable ,
9*10^11 cfu/sachet , 2 sachets, b.i.d
Streptococcus salivarius thermophilus n/a , Lyophilized,
viable , 9*10^11 , 2 sachets b.i.d.
NA
Product Name
VSL#3
Genus, Species, Strain
Streptococcus* cremoris n/a , n/a , n/a , 1L q.d.
Streptococcus* lactis n/a , n/a , n/a , 1L q.d.
Lactobacillus# bulgaricus n/a , n/a , n/a , 1L q.d.
Streptococcus# thermophilus n/a , n/a , n/a , 1L q.d.
Lactobacillus** acidophilus n/a , n/a , n/a , 1L q.d.
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Immune compromised /
critically ill
Result Statement
There has been no
evidence of disease
or other adverse
reaction caused by
the implant strain.
Assessment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
n/a
Genus, Species, Strain
Lactobacillus crispatus GAI 98332 , Lyophilized , 1*10^8
cfu/suppository , 1 suppository on alternating days
NA
Product Name
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
C-315
High-Risk Population
Result Statement
No adverse events
were noted.
recurrent urinary tract
infection
Assessment
To test their
tolerance, individuals
were also asked to
take a day's
supplementation of
the milk product.
Result Statement
In general, the
supplements were
well tolerated.
Assessment
n/a
Result Statement
Patients did not report
any side effects
associated with the
study treatment.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Wang, 1984
CS
Wendakoon, 2002
CS
Korvyakova, 2000
Coh
Marieke, 2010
Coh
Intervention, Form, Potency, Dose
Genus, Species, Strain
Bacillus cereus DM423 , n/a , n/a , 0.5g t.i.d. (
NA
Product Name
n/a
Analysis
High-Risk Population
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
n/a
<2yrs
Genus, Species, Strain
Bifidobacterium n/a n/a , Lyophilized , n/a , n/a
NA
Product Name
Bifidumbacterin forte
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Diet therapies
n/a
Genus, Species, Strain
Bifidobacterium bifidum n/a , n/a , 10^8 cfu/g , 5g b.i.d.
Bifidobacterium lactis 2 strains , n/a , 10^8 cfu/g , 5g b.i.d
Enterococcus faecium n/a , n/a , 10^8 cfu/g , 5g b.i.d
Lactobacillus acidophilus 2 strains , n/a , 10^8 cfu/g each ,
5g b.i.d
Lactobacillus paracasei n/a , n/a , 10^8 cfu/g , 5g b.i.d
Lactobacillus plantarum n/a , n/a , 10^8 cfu/g , 5g b.i.d
Lactobacillus rhamnosus n/a , n/a , 10^8 cfu/g , 5g b.i.d
Lactobacillus salivarius n/a , n/a , 10^8 cfu/g , 5g b.i.d
NA
Product Name
Ecologic AAD
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
n/a
Genus, Species, Strain
Lactobacillus casei 03 , n/a , 1.6*10^9 cfu/g , t.i.d.
Lactobacillus acidophilus 2412 , n/a , 1.6*10^9 cfu/g , t.i.d.
Lactobacillus acidophilus ACDI , n/a , 1.6*10^9 cfu/g , t.i.d.
Lactobacillus* bulgaricus n/a , n/a , n/a , n/a
Streptococcus* thermophilus n/a , n/a , n/a , n/a
Lactobacillus* acidophilus n/a , n/a , n/a , n/a
NA
Product Name
n/a, *Commercial starter mix
C-316
n/a
Safety Assessment
Results
Assessment
n/a
Result Statement
No adverse events of
side effects.
Assessment
n/a
Result Statement
Well tolerated… no
adverse effects or any
other complications.
Assessment
n/a
Result Statement
Was well tolerated, no
adverse drug
reaction.
Assessment
n/a
Result Statement
There was no
evidence that
probiotic use, given
orally in addition to a
normal diet, was
unsafe in our
population of patients
who were not critically
ill.
Evidence Table C6. Nonspecific safety statements (continued)
Author, Year
Design
Nagasaki, 2010
Case
Yangco, 2009
Case
Intervention, Form, Potency, Dose
Genus, Species, Strain
Bifidobacterium n/a n/a , n/a , n/a , 6 mg, q.d.
NA
Product Name
n/a
Genus, Species, Strain
Lactobacillus n/a n/a , n/a , n/a , n/a
Saccharomyces n/a n/a , n/a , n/a , n/a
NA
Product Name
n/a
Analysis
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics,
Corticosteroid use
Direct Comparison
n/a
Subgroup Analysis
n/a
Cotreatment
Concomitant antibiotics
*Abbreviations
b.i.d.=two times per day
Case=Case Studies
cfu: colony forming unit
Coh=Cohort
CS=Case Series
CT=Controlled Trial
g=grams
mg=milligram
ml=milliliter
q.d.=one time per day
q.i.d.=four times per day
t.i.d.=three times per day
yrs=years
RCT=Randomized Controlled Trial
C-317
High-Risk Population
>65
Immune compromised /
critically ill
Safety Assessment
Results
Assessment
n/a
Result Statement
Bifidobacterium was
used safely without
any side effects.
Assessment
n/a
Result Statement
Overall the regimen
was well tolerated.
Appendix D. Excluded Studies and Background
Papers
Excluded Studies
Exclude-NoAE (does not address safety); Exclude-Design (lacks primary data or
uncontrolled studies that are not linked to adverse events); Exclude-Duplicate (duplicates a study
already reviewed); Exclude-Genus (does not address specific genera); Exclude-Intervention
(does not address specific interventions); Exclude-Participants (does not address humans). Please
note Rec means the reviewers had different decisions and had to reconcile.
D-1
“1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected
with human immunodeficiency virus: disease-specific recommendations. USPHS/IDSA
Prevention of Opportunistic Infections Working Group. U.S. Public Health Services/Infectious
Diseases Society of America.” Clin Infect Dis 1997;25 Suppl 3: S313-335. Exclude-Intervention
Aaltonen, J., T. Ojala, et al. (2008). "Evidence of infant blood pressure programming by
maternal nutrition during pregnancy: a prospective randomized controlled intervention study." J
Pediatr 152(1): 79-84, 84 e71-72. Exclude-NoAE
Aas, J., C. E. Gessert, et al. (2003). "Recurrent Clostridium difficile colitis: case series involving
18 patients treated with donor stool administered via a nasogastric tube." Clin Infect Dis 36(5):
580-585. Exclude-Intervention
Abbas, Z. and W. Jafri (1992). "Yoghurt (dahi): a probiotic and therapeutic view." J Pak Med
Assoc 42(9): 221-224. Exclude-Design
Abd El-Atti, S., K. Wasicek, et al. (2009). "Use of probiotics in the management of
chemotherapy-induced diarrhea: a case study." JPEN J Parenter Enteral Nutr 33(5): 569-570.
Exclude-Genus
Abgrall, S., V. Joly, et al. (1997). "Lactobacillus casei infection in an AIDS patient." Eur J Clin
Microbiol Infect Dis 16(2): 180-182. Exclude-Intervention
Abrams, S. A., I. J. Griffin, et al. (2007). "Effect of prebiotic supplementation and calcium intake
on body mass index." J Pediatr 151(3): 293-298. Exclude-Intervention
Adam, J., A. Barret, et al. (1977). "Essais cliniques controles en double insu de l'ultra-levure
lyphilisee: etude multicentrique par 25 medicins de 388 cas." Gaz Med Fr 84: 2072-2078.
Exclude-NoAE (French)
Adam, J., C. Barret, et al. (1977). "Controlled doubleblind clinical trials of Ultra-Levure:
Multicentre study by 25 physicians in 388 cases. ." Gaz Med Fr 84: 2072–2078. Exclude
NoAE(French)
Adams, M. R. and P. Marteau (1995). "On the safety of lactic acid bacteria from food." Int J
Food Microbiol 27(2-3): 263-264. Exclude-Rec NoAE
Adawi, D., S. Ahrne, et al. (2001). "Effects of different probiotic strains of Lactobacillus and
Bifidobacterium on bacterial translocation and liver injury in an acute liver injury model." Int J
Food Microbiol 70(3): 213-220. Exclude-Participants
Adler, S. N. (2006). "The probiotic agent Escherichia coli M-17 has a healing effect in patients
with IBS with proximal inflammation of the small bowel." Dig Liver Dis 38(9): 713. ExcludeGenus
Agadjanyan, M., V. Vasilevko, et al. (2003). "Nutritional Supplement (NT Factor(TM)) Restores
Mitochondrial Function and Reduces Moderately Severe Fatigue in Aged Subjects." Journal of
Chronic Fatigue Syndrome 11(3): 23-36. Exclude-Intervention
Agarwal, R., N. Sharma, et al. (2003). "Effects of oral Lactobacillus GG on enteric microflora in
low-birth-weight neonates." J Pediatr Gastroenterol Nutr 36(3): 397-402. Exclude-Intervention
D-2
Agerholm-Larsen, L., M. L. Bell, et al. (2000). "The effect of a probiotic milk product on plasma
cholesterol: a meta-analysis of short-term intervention studies." Eur J Clin Nutr 54(11): 856-860.
Exclude-NoAE
Agerholm-Larsen, L., A. Raben, et al. (2000). "Effect of 8 week intake of probiotic milk
products on risk factors for cardiovascular diseases." Eur J Clin Nutr 54(4): 288-297. ExcludeNoAE
Aggett, P. J., J. M. Antoine, et al. (2005). "PASSCLAIM: consensus on criteria." Eur J Nutr 44
Suppl 1: i5-30. Exclude-Design
Agrawal, A., L. A. Houghton, et al. (2008). "Clinical trial: the effects of a fermented milk
product containing Bifidobacterium lactis DN-173-010 on abdominal distension and
gastrointestinal transit in irritable bowel syndrome with constipation." Aliment Pharmacol Ther.
Exclude-NoAE
Agrawal, A., L. A. Houghton, et al. (2009). "Clinical trial: The effects of a fermented milk
product containing Bifidobacterium lactis DN-173 010 on abdominal distension and
gastrointestinal transit in irritable bowel syndrome with constipation." Alimentary Pharmacology
and Therapeutics 29(1): 104-114. Exclude-Duplicates 4724
Aguirre, M. and M. Collins (1993). "Lactic acid bacteria and human clinical infection." J Appl
Bacteriol 75(2): 95-107. Exclude-Rec Intervention
Ahmed, M., J. Prasad, et al. (2007). "Impact of consumption of different levels of
Bifidobacterium lactis HN019 on the intestinal microflora of elderly human subjects." J Nutr
Health Aging 11(1): 26-31. Exclude-NoAE
Ahola, A. J., H. Yli-Knuuttila, et al. (2002). "Short-term consumption of probiotic-containing
cheese and its effect on dental caries risk factors." Arch Oral Biol 47(11): 799-804. ExcludeNoAE
Al Samaraee, A., I. J. McCallum, et al. (2010). "Nutritional strategies in severe acute
pancreatitis: a systematic review of the evidence." Surgeon 8(2): 105-110. Exclude-Participants
Alander, M. and T. Mattila-Sandholm (1996). "Selection and Safety Criteria of Probiotics.
Workshop Demonstration of the Nutritional Functionality of Probiotic Foods (1st).". ExcludeRec NoAE
Alander, M., R. Satokari, et al. (1999). "Persistence of colonization of human colonic mucosa by
a probiotic strain, Lactobacillus rhamnosus GG, after oral consumption." Appl Environ
Microbiol 65(1): 351-354. Exclude-Participants
Aldinucci, C., L. Bellussi, et al. (2002). "Effects of dietary yoghurt on immunological and
clinical parameters of rhinopathic patients." Eur J Clin Nutr 56(12): 1155-1161. Exclude-NoAE
Alenfall, J., M. Astrom, et al. (2004). "Early Enteral supply of Lactobacillus plantarum 299
reduce the incidence of infections in severely ill patients: a meta analysis of three randomized
controlled trials." Clin Nutr 23: S1474. Exclude-Design
AlFaleh Khalid, M. and D. Bassler (2008). "Probiotics for prevention of necrotizing enterocolitis
in preterm infants." Cochrane Database of Systematic Reviews(1). Exclude-Duplicates 4728
D-3
Allen, S. J., B. Okoko, et al. (2004). "Probiotics for treating infectious diarrhoea." Cochrane
Database Syst Rev(2): CD003048. Exclude-Duplicate 6083
Alliet, P., P. Scholtens, et al. (2007). "Effect of prebiotic galacto-oligosaccharide, long-chain
fructo-oligosaccharide infant formula on serum cholesterol and triacylglycerol levels." Nutrition
23(10): 719-723. Exclude-NoAE
Alm, L. (1982). "Effect of fermentation on lactose, glucose, and galactose content in milk and
suitability of fermented milk products for lactose intolerant individuals." J Dairy Sci 65(3): 346
352. Exclude-Intervention
Amenta, M., M. T. Cascio, et al. (2006). "Diet and chronic constipation. Benefits of oral
supplementation with symbiotic zir fos (Bifidobacterium longum W11 + FOS Actilight)." Acta
Biomed 77(3): 157-162. Exclude-NoAE
Anaissie, E., G. P. Bodey, et al. (1989). "New spectrum of fungal infections in patients with
cancer." Rev Infect Dis 11(3): 369-378. Exclude-Intervention
Anderson, J. W. and S. E. Gilliland (1999). "Effect of fermented milk (yogurt) containing
Lactobacillus acidophilus L1 on serum cholesterol in hypercholesterolemic humans." J Am Coll
Nutr 18(1): 43-50. Exclude-NoAE
Andreeva, P. M. and H. A. Omar (2002). "Effectiveness of current therapy of bacterial
vaginosis." Int J Adolesc Med Health 14(2): 145-148. Exclude-Intervention
Anikhovskaia, I. A., I. Vyshegurov, et al. (2004). "[Bifidobacteria as a means of prevention or
treatment of endotoxin aggression in patients with chronic diseases during remission or
exacerbation]." Fiziol Cheloveka 30(6): 125-127. Exclude-NoAE
Antonio, M. A. and S. L. Hillier (2003). "DNA fingerprinting of Lactobacillus crispatus strain
CTV-05 by repetitive element sequence-based PCR analysis in a pilot study of vaginal
colonization." J Clin Microbiol 41(5): 1881-1887. Exclude-Participants
Antony, S. J., C. W. Stratton, et al. (1996). "Lactobacillus bacteremia: description of the clinical
course in adult patients without endocarditis." Clin Infect Dis 23(4): 773-778. ExcludeIntervention
Anukam, K. C., K. Hayes, et al. (2009). "Probiotic Lactobacillus rhamnosus GR-1 and
Lactobacillus reuteri RC-14 may help downregulate TNF-Alpha, IL-6, IL-8, IL-10 and IL-12
(p70) in the neurogenic bladder of spinal cord injured patient with urinary tract infections: a twocase study." Adv Urol: 680363. Exclude-NoAE
Anukam, K. C., E. Osazuwa, et al. (2006). "Clinical study comparing probiotic Lactobacillus
GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis."
Microbes Infect 8(12-13): 2772-2776. Exclude-NoAE
Aponte, G. B., M. C. A. B., et al. (2008). "Probiotics for treating persistent diarrhoea in
children." Cochrane Database of Systematic Reviews 4. Exclude-NoAE
Apostolou, E., P. V. Kirjavainen, et al. (2001). "Good adhesion properties of probiotics: a
potential risk for bacteremia?" FEMS Immunol Med Microbiol 31(1): 35-39. ExcludeParticipants
D-4
Arciero, J. C., G. B. Ermentrout, et al. (2010). "Using a mathematical model to analyze the role
of probiotics and inflammation in necrotizing enterocolitis." PLoS One 5(4): e10066. ExcludeNoAE
"Are probiotics safe?" Contemporary OB/GYN 2007;52(4): 20. Exclude-Design
Armuzzi, A., F. Cremonini, et al. (2001). "The effect of oral administration of Lactobacillus GG
on antibiotic-associated gastrointestinal side-effects during Helicobacter pylori eradication
therapy." Aliment Pharmacol Ther 15(2): 163-169. Exclude-NoAE
Armuzzi, A., F. Cremonini, et al. (2001). "Effect of Lactobacillus GG supplementation on
antibiotic-associated gastrointestinal side effects during Helicobacter pylori eradication therapy:
a pilot study." Digestion 63(1): 1-7. Exclude-NoAE
Aronsson, B., P. Barany, et al. (1987). "Clostridium difficile-associated diarrhoea in uremic
patients." Eur J Clin Microbiol 6(3): 352-356. Exclude-NoAE
Arpi, M., M. Vancanneyt, et al. (2003). "Six cases of Lactobacillus bacteraemia: identification of
organisms and antibiotic susceptibility and therapy." Scand J Infect Dis 35(6-7): 404-408.
Exclude-Intervention
Arroyo, R., V. Martin, et al. (2010). "Treatment of infectious mastitis during lactation:
antibiotics versus oral administration of Lactobacilli isolated from breast milk." Clin Infect Dis
50(12): 1551-1558. Exclude-NoAE
Arshad, S., K. V. Gopalakrishna, et al. (2010). "Lactobacillus-cause of death." Infectious
Diseases in Clinical Practice 18(3): 219-220. Exclude-Intervention
Arslanoglu, S., G. E. Moro, et al. (2007). "Early supplementation of prebiotic oligosaccharides
protects formula-fed infants against infections during the first 6 months of life." J Nutr 137(11):
2420-2424. Exclude-Intervention
Arslanoglu, S., G. E. Moro, et al. (2008). "Early dietary intervention with a mixture of prebiotic
oligosaccharides reduces the incidence of allergic manifestations and infections during the first
two years of life." J Nutr 138(6): 1091-1095. Exclude-Intervention
Arzumanian, V. G., A. Y. Sergeev, et al. (2009). "Antagonistic activity of Malassezia Spp.
towards other clinically signifi cant yeast genera." Bulletin of Experimental Biology and
Medicine 148(3): 410-415. Exclude-Participants
Asahara, T., M. Takahashi, et al. (2003). "Assessment of safety of lactobacillus strains based on
resistance to host innate defense mechanisms." Clin Diagn Lab Immunol 10(1): 169-173.
Exclude-Participants
Ascioglu, S., J. H. Rex, et al. (2002). "Defining opportunistic invasive fungal infections in
immunocompromised patients with cancer and hematopoietic stem cell transplants: an
international consensus." Clin Infect Dis 34(1): 7-14. Exclude-Intervention
Ataie-Jafari, A., S. Hosseini, et al. (2007). "Effects of milk replacement with regular yogurt and
probiotic yogurt on blood lipid profiles of hypercholesterolemic and normocholesterolemic
individuals." Iranian Journal of Diabetes and Lipid Disorders 7(2): 239-244+E224. ExcludeNoAE (Foreign Language)
D-5
Aucott, J. N., J. Fayen, et al. (1990). "Invasive infection with Saccharomyces cerevisiae: report
of three cases and review." Rev Infect Dis 12(3): 406-411. Exclude-Intervention
Aureli, P., A. Fiore, et al. (2010). "National survey outcomes on commercial probiotic food
supplements in Italy." Int J Food Microbiol 137(2-3): 265-273. Exclude-Participants
Avlami, A., T. Kordossis, et al. (2001). "Lactobacillus rhamnosus endocarditis complicating
colonoscopy." J Infect 42(4): 283-285. Exclude-Rec Genus
Awasthi, S. (2000). "Lactobacillus GG reduced diarrhoea incidence in children treated with
antibiotics." Evid Based Med(5): 113. Exclude-NoAE
Axelrod, J., G. T. Keusch, et al. (1973). "Endocarditis caused by Lactobacillus plantarum." Ann
Intern Med 78(1): 33-37. Exclude-Intervention
Bahar, R. J., B. S. Collins, et al. (2008). "Double-blind placebo-controlled trial of amitriptyline
for the treatment of irritable bowel syndrome in adolescents." J Pediatr 152(5): 685-689.
Exclude-Intervention
Bakker-Zierikzee, A. M., E. A. Tol, et al. (2006). "Faecal SIgA secretion in infants fed on pre- or
probiotic infant formula." Pediatr Allergy Immunol 17(2): 134-140. Exclude-NoAE
Baldassarre, M. E., N. Laforgia, et al. (2010). "Lactobacillus GG improves recovery in infants
with blood in the stools and presumptive allergic colitis compared with extensively hydrolyzed
formula alone." J Pediatr 156(3): 397-401. Exclude-NoAE
Balli, F., P. Bertolani, et al. (1992). "[High-dose oral bacteria-therapy for chronic non-specific
diarrhea of infancy]." Pediatr Med Chir 14(1): 13-15. Exclude-NoAE (Italian)
Barbara, G. and R. Corinaldesi (2000). "Probiotics: could they turn out to be ineffective in
irritable bowel syndrome?" Dig Liver Dis 32(4): 302-304. Exclude-Design
Barbes, C. and S. Boris (1999). "Potential role of lactobacilli as prophylactic agents against
genital pathogens." AIDS Patient Care STDS 13(12): 747-751. Exclude-NoAE
Barbi, M., M. Bardare, et al. (1992). "Antibody response to inactivated polio vaccine (E-IPV) in
children born to HIV positive mothers." Eur J Epidemiol 8(2): 211-216. Exclude-Intervention
Barker, P., C. McNaught, et al. (2003). "Synbiotic in irritable bowel syndrome: a double blind
prospective randomised controlled trial." Gut 52: A11. Exclude-NoAE
Barreto, R., Y. Naito, et al. (2000). "Gut flora manipulation mitigates ethanol-induced liver
damage and endotoxinemia: experimental comparison between a novel probiotic and
metronidazole." Intern Med J 7: 121-128. Exclude-Participants
Barrett, J. F. (2006). "Potential risk of probiotic usage." Expert Opin Drug Saf 5(1): 3-4.
Exclude-Intervention
Bartlett, J. G. (2006). "Narrative review: the new epidemic of Clostridium difficile-associated
enteric disease." Ann Intern Med 145(10): 758-764. Exclude-Rec NoAE
Basu, S., D. K. Paul, et al. (2009). "Efficacy of high-dose Lactobacillus rhamnosus GG in
controlling acute watery diarrhea in Indian children: a randomized controlled trial." J Clin
Gastroenterol 43(3): 208-213. Exclude-Duplicate 4762
D-6
Batac MaCR, G. M., Caparas-de Castro C, Gutierrez-Santos K, Tondoc A (2005). "Effects of a
probiotic formula on measles, mumps and rubella IgG production and on anthropometric
measurements of infants aged 11-15 months in a tertiary hospital." Santo Tomas Journal of
Medicine 52(4): 124-130. Exclude-NoAE
Baughan, C. A., P. A. Canney, et al. (1993). "A randomized trial to assess the efficacy of 5
aminosalicylic acid for the prevention of radiation enteritis." Clin Oncol (R Coll Radiol) 5(1):
19-24. Exclude-Intervention
Bayer, A. S., A. W. Chow, et al. (1978). "Lactobacillemia--report of nine cases. Important
clinical and therapeutic considerations." Am J Med 64(5): 808-813. Exclude-Intervention
Bayona-Gonzalez, A., V. Lopez-Camara, et al. (1990). "Final results of a dental caries clinical
trial using heat killed lactic bacteria (Streptococci and Lactobacilli) orally." Pract Odontol 11(6):
41-47. Exclude-Rec Genus
Bazzarre, T., S. Liu-Wu, et al. (1983). "Total and HDL-cholesterol concentrations: yogurt and
calcium supplementation " Nutr Rep Int 28: 17-24. Exclude-NoAE
Bazzocchi, G., P. Gionchetti, et al. (2002). "Intestinal microflora and oral bacteriotherapy in
irritable bowel syndrome." Dig Liver Dis 34 Suppl 2: S48-53. Exclude-NoAE
Beerepoot, M. A., G. ter Riet, et al. (2006). "[Non-antibiotic prophylaxis for recurrent urinarytract infections]." Ned Tijdschr Geneeskd 150(10): 541-544. Exclude-Rec NoAE (Dutch)
Bell, M. J. (1985). "Perforation of the gastrointestinal tract and peritonitis in the neonate." Surg
Gynecol Obstet 160(1): 20-26. Exclude-Intervention
Bellete, B. (2006). "Molecular confirmation of an absidiomycosis following treatment with a
probiotic supplement in a child with leukemia." Exclude-Rec Genus
Bellizzi, A., V. Barucca, et al. (2010). "Early years of biological agents therapy in Crohn's
disease and risk of the human polyomavirus JC reactivation." Journal of Cellular Physiology
224(2): 316-326. Exclude-NoAE
Bengmark, S. (1998). "Ecological control of the gastrointestinal tract. The role of probiotic
flora." Gut 42(1): 2-7. Exclude-Design
Bennett, R., S. L. Gorbach, et al. (1993). "Treatment of relasping Clostridium difficile diarrhea
with Lactobacillus GG." Nutr Today 31: 35S-42S. Exclude-Duplicate 12844
Benno, P., I. Ernberg, et al. (2010). "[Probiotics--friends or enemies of the intestine?]."
Lakartidningen 107(13-14): 907-909. Exclude-Design
Benno, Y. and T. Mitsuoka (1992). "Impact of Bifidobacterium longum on human fecal
microflora." Microbiol Immunol 36(7): 683-694. Exclude-NoAE
Benton, D., C. Williams, et al. (2007). "Impact of consuming a milk drink containing a probiotic
on mood and cognition." Eur J Clin Nutr 61(3): 355-361. Exclude-NoAE
Berg, R. D. (1992). "Translocation of enteric bacteria in health and disease." Curr Stud Hematol
Blood Transfus(59): 44-65. Exclude-Intervention
Bergogne-Berezin, E. (2000). "Treatment and prevention of antibiotic associated diarrhea." Int J
Antimicrob Agents 16(4): 521-526. Exclude-NoAE
D-7
Berrada, N., J. F. Lemeland, et al. (1991). "Bifidobacterium from fermented milks: survival
during gastric transit." J Dairy Sci 74(2): 409-413. Exclude-NoAE
Besirbellioglu, B. A., A. Ulcay, et al. (2006). "Saccharomyces boulardii and infection due to
Giardia lamblia." Scand J Infect Dis 38(6-7): 479-481. Exclude-NoAE
Besselink, M. G., H. M. Timmerman, et al. (2004). "Probiotic prophylaxis in patients with
predicted severe acute pancreatitis (PROPATRIA): design and rationale of a double-blind,
placebo-controlled randomised multicenter trial [ISRCTN38327949]." BMC Surg 4: 12.
Exclude-NoAE
Besselink, M. G., H. C. van Santvoort, et al. (2009). "Timing and impact of infections in acute
pancreatitis." Br J Surg 96(3): 267-273. Exclude-Intervention
Besselink, M. G., H. C. van Santvoort, et al. (2008). "[Probiotic prophylaxis in patients with
predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial]." Ned
Tijdschr Geneeskd 152(12): 685-696. Exclude-Duplicate 4767(Dutch)
Besselink, M. G., H. C. van Santvoort, et al. (2009). "Intestinal barrier dysfunction in a
randomized trial of a specific probiotic composition in acute pancreatitis." Ann Surg 250(5):
712-719. Exclude-NoAE
Bessis, D., A. Le Quellec, et al. (1995). "Lactobacillus acidophilus endocarditis after an
appendectomy." Clin Infect Dis 20(3): 724-725. Exclude-Design
Betsi, G. I., E. Papadavid, et al. (2008). "Probiotics for the treatment or prevention of atopic
dermatitis: a review of the evidence from randomized controlled trials." Am J Clin Dermatol
9(2): 93-103. Exclude-Rec NoAE
Bettler, J. and A. Euler (2004). "An evaluation of the growth of term infants fed formula
supplemented with fructo-oligosaccharide." Exclude-Rec Intervention
Bhutta, Z. A., A. M. Molla, et al. (1994). "Nutrient absorption and weight gain in persistent
diarrhea: comparison of a traditional rice-lentil/yogurt/milk diet with soy formula." J Pediatr
Gastroenterol Nutr 18(1): 45-52. Exclude-Intervention
Billot-Klein, D., L. Gutmann, et al. (1994). "Modification of peptidoglycan precursors is a
common feature of the low-level vancomycin-resistant VANB-type Enterococcus D366 and of
the naturally glycopeptide-resistant species Lactobacillus casei, Pediococcus pentosaceus,
Leuconostoc mesenteroides, and Enterococcus gallinarum." J Bacteriol 176(8): 2398-2405.
Exclude-Participants
Binns, C. W., A. H. Lee, et al. (2007). "The CUPDAY Study: prebiotic-probiotic milk product in
1-3-year-old children attending childcare centres." Acta Paediatr 96(11): 1646-1650. ExcludeRec NoAE
Birch, E. E., S. Garfield, et al. (2007). "Visual acuity and cognitive outcomes at 4 years of age in
a double-blind, randomized trial of long-chain polyunsaturated fatty acid-supplemented infant
formula." Early Hum Dev 83(5): 279-284. Exclude-Intervention
Bisson, J. F., S. Hidalgo, et al. (2010). "Preventive effects of different probiotic formulations on
travelers' diarrhea model in wistar rats : preventive effects of probiotics on TD." Dig Dis Sci
55(4): 911-919. Exclude-Participants
D-8
Bittner, A., B. Caicedo, et al. (2007). "Probiotic-prebiotic Prescript-Assist(TM) treatment for
bacterial diarrhea." Prensa Medica Argentina 94(3): 195-202. Exclude-NoAE (Spanish)
Blaire, E. and B. Tull (1968). "Multiple infections among newborns resulting from colonization
with Staphylococcus aureus 502a." Am J Clin Pathol 52: 42. Exclude-Genus
Bodmann, K. F. and F. Vogel (2001). "Antimikrobielle Therapie der Sepsis.": 43-55. ExcludeIntervention (German)
Boehm, G., M. Lidestri, et al. (2002). "Supplementation of a bovine milk formula with an
oligosaccharide mixture increases counts of faecal bifidobacteria in preterm infants." Arch Dis
Child Fetal Neonatal Ed 86(3): F178-181. Exclude-Intervention
Bongaerts, G. (2007). "Lactobacillus Fermentum Bacteremia In A Seriously Ill Premature Short
Small Bowel Patient During Probiotic Lactobacillus Casei Therapy." International Journal of
probiotics 1(2): 145-158. Exclude-Rec Design
Bongaerts, G., R. Severijnen, et al. (2005). "Yeast mediates lactic acidosis suppression after
antibiotic cocktail treatment in short small bowel?" Scand J Gastroenterol 40(10): 1246-1250.
Exclude-Intervention
Bongaerts, G., R. Severijnen, et al. (2005). "Effect of antibiotics, prebiotics and probiotics in
treatment for hepatic encephalopathy." Med Hypotheses 64(1): 64-68. Exclude-NoAE
Bongaerts, G. P., J. J. Tolboom, et al. (1997). "Role of bacteria in the pathogenesis of short
bowel syndrome-associated D-lactic acidemia." Microb Pathog 22(5): 285-293. ExcludeIntervention
Bongers, M. E., F. de Lorijn, et al. (2007). "The clinical effect of a new infant formula in term
infants with constipation: a double-blind, randomized cross-over trial." Nutr J 6: 8. ExcludeIntervention
Bonnay, S., J. Darchis, et al. (1991). "Saccharomyces cerevisiae septicaemia in a cancer patient "
Med Malad Infect 21: 73. Exclude-Intervention (French)
Bonorden, M. J., K. A. Greany, et al. (2004). "Consumption of Lactobacillus acidophilus and
Bifidobacterium longum do not alter urinary equol excretion and plasma reproductive hormones
in premenopausal women." Eur J Clin Nutr 58(12): 1635-1642. Exclude-Rec NoAE
Boonyaritichaikij, S., K. Kuwabara, et al. (2009). "Long-term administration of probiotics to
asymptomatic pre-school children for either the eradication or the prevention of Helicobacter
pylori infection." Helicobacter 14(3): 202-207. Exclude-NoAE
Borruel, N., M. Carol, et al. (2002). "Increased mucosal tumour necrosis factor alpha production
in Crohn's disease can be downregulated ex vivo by probiotic bacteria." Gut 51(5): 659-664.
Exclude-Participants
Bosques-Padilla, F. J. and A. R. Flores-Rendon (2005). "[Treatment of hepatic encephalopathy
with probiotics and prebiotics]." Rev Gastroenterol Mex 70(3): 372-374. Exclude-NoAE
Boudraa, G., M. Touhami, et al. (1990). "Effect of feeding yogurt versus milk in children with
persistent diarrhea." J Pediatr Gastroenterol Nutr 11(4): 509-512. Exclude-NoAE
D-9
Bouhnik, Y., A. Attar, et al. (2004). "Lactulose ingestion increases faecal bifidobacterial counts:
a randomised double-blind study in healthy humans." Eur J Clin Nutr 58(3): 462-466. ExcludeRec Intervention
Bouhnik, Y., P. Marteau, et al. (1993). "[The use of probiotics in humans]." Ann Gastroenterol
Hepatol (Paris) 29(5): 241-249. Exclude-Rec NoAE
Bouhnik, Y., C. Neut, et al. (2004). "Prospective, randomized, parallel-group trial to evaluate the
effects of lactulose and polyethylene glycol-4000 on colonic flora in chronic idiopathic
constipation." Aliment Pharmacol Ther 19(8): 889-899. Exclude-Genus
Bouilly-Gauthier, D., C. Jeannes, et al. (2010). "Clinical evidence of benefits of a dietary
supplement containing probiotic and carotenoids on ultraviolet-induced skin damage." Br J
Dermatol. Exclude-NoAE
Boulloche, J., O. Mouterde, et al. (1994). "Management of acute diarrhoea in infants and young
children. Controlled study of the antidiarrhoeal efficacy of killed L/ acidophilus (LB strain)
versus a placebo and a reference drug (Loperamide)." Ann Pediatr 41: 1-7. Exclude-Rec Genus
(Foreign Language)
Bourne, K. A., J. L. Beebe, et al. (1978). "Bacteremia due to Bifidobacterium, Eubacterium or
Lactobacillus; twenty-one cases and review of the literature." Yale J Biol Med 51(5): 505-512.
Exclude-Intervention
Bowden, T. A., Jr., A. R. Mansberger, Jr., et al. (1981). "Pseudomembraneous enterocolitis:
mechanism for restoring floral homeostasis." Am Surg 47(4): 178-183. Exclude-Intervention
Boyce, J. M., S. M. Opal, et al. (1994). "Outbreak of multidrug-resistant Enterococcus faecium
with transferable vanB class vancomycin resistance." J Clin Microbiol 32(5): 1148-1153.
Exclude-Intervention
Boyle, R. J., L. Mah, et al. (2009). "In vivo, in vitro and transplacental immune effects of a
probiotic bacterium lactobacillus rhamnosus GG in humans." Journal of Allergy and Clinical
Immunology 123(2): S200. Exclude-NoAE
Brady, L. J., D. D. Gallaher, et al. (2000). "The role of probiotic cultures in the prevention of
colon cancer." J Nutr 130(2S Suppl): 410S-414S. Exclude-NoAE
Braegger, C. (2002). "Probiotics in the prevention and treatment of acute infectious diarrhea in
children." (150): 824-828. Exclude-Rec Design (German)
Brand, S. and H. Reinecker (2002). "An enhanced barrier is a better defense: effects of probiotics
on intestinal barrier function." Inflammatory Bowel Diseases 8: 67-69. Exclude-Participants
Briand, V., P. Buffet, et al. (2006). "Absence of efficacy of nonviable Lactobacillus acidophilus
for the prevention of traveler's diarrhea: a randomized, double-blind, controlled study." Clin
Infect Dis 43(9): 1170-1175. Exclude-Genus
Brigidi, P., B. Vitali, et al. (2001). "Effects of probiotic administration upon the composition and
enzymatic activity of human fecal microbiota in patients with irritable bowel syndrome or
functional diarrhea." Res Microbiol 152(8): 735-741. Exclude-NoAE
D-10
Brinkhaus, B., K. Stockert, et al. (2007). "The effect of acupuncture and probiotics in children
with asthma." Focus on Alternative & Complementary Therapies 12(3): 194-196. ExcludeDesign
Brook, I. (1996). "Isolation of non-sporing anaerobic rods from infections in children." J Med
Microbiol 45(1): 21-26. Exclude-Intervention
Broughton, R., W. Gruber, et al. (1983). "Neonatal meningitis due to Lactobacillus." Pediatr
Infect Dis 2: 382--384. Exclude-Duplicate 12439
Broughton, R. A., W. C. Gruber, et al. (1983). "Neonatal meningitis due to Lactobacillus."
Pediatr Infect Dis 2(5): 382-384. Exclude-Intervention
Brouwer, M. L., S. A. Wolt-Plompen, et al. (2006). "No effects of probiotics on atopic dermatitis
in infancy: a randomized placebo-controlled trial." Clin Exp Allergy 36(7): 899-906. ExcludeNoAE
Bruck, W. M., M. Redgrave, et al. (2006). "Effects of bovine alpha-lactalbumin and casein
glycomacropeptide-enriched infant formulae on faecal microbiota in healthy term infants." J
Pediatr Gastroenterol Nutr 43(5): 673-679. Exclude-Intervention
Bruhn, C. (2003). "Prevention of atopic disease with lactobacillus." Deutsche Apotheker Zeitung
143(35): 44. Exclude-Design
Brunser, O., M. Araya, et al. (1989). "Effect of an acidified milk on diarrhoea and the carrier
state in infants of low socio-economic stratum." Acta Paediatr Scand 78(2): 259-264. ExcludeNoAE
Brunser, O., G. Figueroa, et al. (2006). "Effects of probiotic or prebiotic supplemented milk
formulas on fecal microbiota composition of infants." Asia Pac J Clin Nutr 15(3): 368-376.
Exclude-Rec NoAE
Brunser, O., M. Gotteland, et al. (2006). "Effect of a milk formula with prebiotics on the
intestinal microbiota of infants after an antibiotic treatment." Pediatr Res 59(3): 451-456.
Exclude-Intervention
Bruzzese, E., V. Raia, et al. (2004). "Intestinal inflammation is a frequent feature of cystic
fibrosis and is reduced by probiotic administration." Aliment Pharmacol Ther 20(7): 813-819.
Exclude-NoAE
Bruzzese, E., M. Volpicelli, et al. (2009). "A formula containing galacto- and fructo
oligosaccharides prevents intestinal and extra-intestinal infections: an observational study." Clin
Nutr 28(2): 156-161. Exclude-Intervention
Buchner, A. M. and A. Sonnenberg (2002). "Epidemiology of Clostridium difficile infection in a
large population of hospitalized US military veterans." Dig Dis Sci 47(1): 201-207. ExcludeIntervention
Burton, J. P., P. A. Cadieux, et al. (2003). "Improved understanding of the bacterial vaginal
microbiota of women before and after probiotic instillation." Appl Environ Microbiol 69(1): 97
101. Exclude-Participants
D-11
Burton, J. P., C. N. Chilcott, et al. (2006). "A preliminary study of the effect of probiotic
Streptococcus salivarius K12 on oral malodour parameters." J Appl Microbiol 100(4): 754-764.
Exclude-NoAE
Burton, J. P., P. A. Wescombe, et al. (2006). "Safety assessment of the oral cavity probiotic
Streptococcus salivarius K12." Appl Environ Microbiol 72(4): 3050-3053. Exclude-Design
Buts, J. P., G. Corthier, et al. (1993). "Saccharomyces boulardii for Clostridium difficile
associated enteropathies in infants." J Pediatr Gastroenterol Nutr 16(4): 419-425. Exclude-NoAE
Byun, R., M. A. Nadkarni, et al. (2004). "Quantitative analysis of diverse Lactobacillus species
present in advanced dental caries." J Clin Microbiol 42(7): 3128-3136. Exclude-Participants
Cabana, M. D., M. McKean, et al. (2007). "Examining the hygiene hypothesis: the Trial of Infant
Probiotic Supplementation." Paediatr Perinat Epidemiol 21 Suppl 3: 23-28. Exclude-Design
Cafaro, D., L. Onofrio, et al. (2007). "Combination therapy with symbiotics and local anti
inflammatories for red anusitis." Minerva Gastroenterol Dietol 53(2): 117-123. Exclude-NoAE
Caglar, E., B. Kargul, et al. (2005). "Bacteriotherapy and probiotics' role on oral health." Oral
Dis 11(3): 131-137. Exclude-Design
Caglar, E., O. O. Kuscu, et al. (2008). "A probiotic lozenge administered medical device and its
effect on salivary mutans streptococci and lactobacilli." Int J Paediatr Dent 18(1): 35-39.
Exclude-NoAE
Cairoli, R., P. Marenco, et al. (1995). "Saccharomyces cerevisiae fungemia with granulomas in
the bone marrow in a patient undergoing BMT." Bone Marrow Transplant 15(5): 785-786.
Exclude-Intervention
Camilleri, M., A. R. Northcutt, et al. (2000). "Efficacy and safety of alosetron in women with
irritable bowel syndrome: a randomised, placebo-controlled trial." Lancet 355(9209): 1035-1040.
Exclude-Genus
Campbell, J. M., G. C. Fahey, Jr., et al. (1997). "Metabolic characteristics of healthy adult males
as affected by ingestion of a liquid nutritional formula containing fish oil, oligosaccharides, gum
arabic and antioxidant vitamins." Food Chem Toxicol 35(12): 1165-1176. Exclude-Intervention
Campeotto, F. (2003). "Effects of administration of Bifidobacteria on fecal microflora and
clinical symptoms in infants with atopic dermatitis." Coh Nutr Diet 38(6): 371-375. ExcludeNoAE (French)
Campeotto, F. (2003). "Probiotics during pregnancy: A protection against atopic disease in the
infant?" Medicine and Nutrition. Exclude-Rec Design
Campieri, C., M. Campieri, et al. (2001). "Reduction of oxaluria after an oral course of lactic
acid bacteria at high concentration." Kidney Int 60(3): 1097-1105. Exclude-NoAE
Campieri, M., F. Rizzello, et al. (2000). "Combination of antibiotic and probiotic treatment is
efficacious in prophylaxis of post-operative recurrence of Crohn's disease: a randomized
controlled study vs mesalamine." Gastroenterology 118: A781. Exclude-NoAE
Canani, R., F. Albano, et al. (2001). "Probiotics for acute diarrhea: a comparative study." J
Pediatr Gastroenterol Nutr 32: 347. Exclude-NoAE
D-12
Candelli, M., E. C. Nista, et al. (2003). "Saccharomyces cerevisiae-associated diarrhea in an
immunocompetent patient with ulcerative colitis." J Clin Gastroenterol 36(1): 39-40. ExcludeIntervention
Canducci, F., A. Armuzzi, et al. (2000). "A lyophilized and inactivated culture of Lactobacillus
acidophilus increases Helicobacter pylori eradication rates." Aliment Pharmacol Ther 14(12):
1625-1629. Exclude-Genus
Candy, D. C., L. Densham, et al. (2001). "Effect of administration of Lactobacillus casei shirota
on sodium balance in an infant with short bowel syndrome." J Pediatr Gastroenterol Nutr 32(4):
506-508. Exclude-NoAE
Cao, Y. J., C. M. Qu, et al. (2005). "Control of intestinal flora alteration induced by eradication
therapy of Helicobacter pylori infection in the elders." Chin J Gastroenterol Hepatol 14: 195-199.
Exclude-NoAE
Caplan, M., M. Lickerman, et al. (1995). "Bifidobacteria supplementation reduces the incidence
and severity of neonatal necrotizing enterocolitis (NEC) in newborn rats." Pediatr Res(37):
A198. Exclude-Participants
"Capsule & comment Lactobacilli for allergy: calling Dr Metchnikoff Kalliomäki M et al
Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial Lancet
357:1076, 2001." Hospital Practice 2001;36(6): 24. Exclude-NoAE
Capurso, G., M. Marignani, et al. (2008). "Probiotics and severe acute pancreatitis." J Clin
Gastroenterol 42 Suppl 3 Pt 1: S148-151. Exclude-NoAE
Capurso, L., G. Delle Fave, et al. (2008). "Probiotics, prebiotics, and new foods." J Clin
Gastroenterol 42 Suppl 3 Pt 2: S155. Exclude-NoAE
Carmona-Sanchez, R. (2010). "[Clinical trial: the effects of a fermented milk containing three
probiotic bacteria in patients with irritable bowel syndrome - a randomized, doubleblind,
controlled study.]." Rev Gastroenterol Mex 75(1): 123. Exclude-Design
Caropreso, E. (1998). "I microorganismi probiotici: effetti sul trattamento e sulla prevenzione
delle diarree acute." Aggiorn Pediatr 1: 81-85. Exclude-Design (Italian)
Caropreso, E. (1998). "Probiotics micro-organisms: Effects on the treatment and prevention of
acute diarrhea." Aggiornamento Pediatrico 1(3-4): 81-85. Exclude-Design
Carroll, D., A. Corfield, et al. (2003). "Faecal calprotectin concentrations and diagnosis of
necrotising enterocolitis." Lancet 361(9354): 310-311. Exclude-Intervention
Cartwright-Shamoon, J., G. R. Dickson, et al. (1996). "Uptake of yeast (Saccharomyces
boulardii) in normal and rotavirus treated intestine." Gut 39(2): 204-209. Exclude-Participants
Casey, P. H., L. Whiteside-Mansell, et al. (2006). "Impact of prenatal and/or postnatal growth
problems in low birth weight preterm infants on school-age outcomes: an 8-year longitudinal
evaluation." Pediatrics 118(3): 1078-1086. Exclude-Intervention
Castex, F., G. Corthier, et al. (1990). "Prevention of Clostridium difficile-induced experimental
pseudomembranous colitis by Saccharomyces boulardii: a scanning electron microscopic and
microbiological study." J Gen Microbiol 136(6): 1085-1089. Exclude-Participants
D-13
Cats, A., E. J. Kuipers, et al. (2003). "Effect of frequent consumption of a Lactobacillus casei
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429-435. Exclude-Rec Participants
Cerny, A. (1996). "[Side effects and consequences of frequently used antibiotics in clinical
practice]." Schweiz Med Wochenschr 126(13): 528-534. Exclude-Intervention
Chaiken, B. H. (1994). "Yogurt and autoimmune liver disease." Am J Gastroenterol 89(10):
1916-1917. Exclude-Rec Genus
Chandra, R. (2002). "Effect of Lactobacillus on the incidence and severity of acute rotavirus
diarrhoea in infants. A prospective placebo-controlled double-blind study." Nutr Res 22: 65-69.
Exclude-NoAE
Charteris, W. P., P. M. Kelly, et al. (1997). "Selective detection, enumeration and identification
of potentially probiotic Lactobacillus and Bifidobacterium species in mixed bacterial
populations." Int J Food Microbiol 35(1): 1-27. Exclude-Participants
Charteris, W. P., P. M. Kelly, et al. (1998). "Antibiotic susceptibility of potentially probiotic
Lactobacillus species." J Food Prot 61(12): 1636-1643. Exclude-Participants
Cheng, J., D. Chen, et al. (2008). "Dietary probiotic supplementation for allergic rhinitis."
Cochrance Database of Systematic Reviews. Exclude-Design
Chermesh, I., A. Tamir, et al. (2007). "Failure of Synbiotic 2000 to prevent postoperative
recurrence of Crohn's disease." Dig Dis Sci 52(2): 385-389. Exclude-NoAE
Chernyshov, P. V. (2009). "Randomized, placebo-controlled trial on clinical and immunologic
effects of probiotic containing Lactobacillus rhamnosus R0011 and L. helveticus R0052 in
infants with atopic dermatitis." Microbial Ecology in Health and Disease 21(3-4): 228-232.
Exclude-NoAE
Chiang, B. L., Y. H. Sheih, et al. (2000). "Enhancing immunity by dietary consumption of a
probiotic lactic acid bacterium (Bifidobacterium lactis HN019): optimization and definition of
cellular immune responses." Eur J Clin Nutr 54(11): 849-855. Exclude-NoAE
Choi, S. S., B. Y. Kang, et al. (2005). "Safety assessment of potential lactic acid bacteria
Bifidobacterium longum SPM1205 isolated from healthy Koreans." J Microbiol 43(6): 493-498.
Exclude-Participants
Chomarat, M. and D. Espinouse (1991). "Lactobacillus rhamnosus septicemia in patients with
prolonged aplasia receiving ceftazidime-vancomycin." Eur J Clin Microbiol Infect Dis 10(1): 44.
Exclude-Intervention
Chouragqui, J., L. Van Egroo, et al. (1998). "Prevention of diarrhea by feeding infants with an
acidified milk formula containing Bifidobacterium bifidum (Bb)." J Pediatr Gastroenterol Nutr
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with probiotics: a dose-response study in healthy young adults." FEMS Immunol Med Microbiol
47(3): 380-390. Exclude-NoAE
Christmann, W. (1967). "Gleichzeitige Gabe eines Breitbandantibiotikums und Hefepraparates."
Arztliche Praxis 19(13): 451-452. Exclude-NoAE (Foreign Language)
D-14
Chuang, L. C., C. S. Huang, et al. (2010). "Probiotic Lactobacillus paracasei effect on cariogenic
bacterial flora." Clin Oral Investig. Exclude-NoAE
Chui, D. (1992). "The efficacy of bifidobacteria on interstinal obstruction and blood endotoxin."
Chinese Journal of Microecology 4(3): 7. Exclude-Participants (Chinese)
Cianci, A., R. Giordano, et al. (2008). "[Efficacy of Lactobacillus Rhamnosus GR-1 and of
Lactobacillus Reuteri RC-14 in the treatment and prevention of vaginoses and bacterial vaginitis
relapses]." Minerva Ginecol 60(5): 369-376. Exclude-NoAE
Cimolai, N., M. J. Gill, et al. (1987). "Saccharomyces cerevisiae fungemia: case report and
review of the literature." Diagn Microbiol Infect Dis 8(2): 113-117. Exclude-Intervention
Clancy, R. L., M. Gleeson, et al. (2006). "Reversal in fatigued athletes of a defect in interferon
gamma secretion after administration of Lactobacillus acidophilus." Br J Sports Med 40(4): 351
354. Exclude-NoAE
Clements, M. L., M. M. Levine, et al. (1983). "Exogenous lactobacilli fed to man - their fate and
ability to prevent diarrheal disease." Prog Food Nutr Sci 7(3-4): 29-37. Exclude-Rec NoAE
Cobo Sanz, J. M., J. A. Mateos, et al. (2006). "[Effect of Lactobacillus casei on the incidence of
infectious conditions in children]." Nutr Hosp 21(4): 547-551. Exclude-NoAE
Coconnier, M. H., V. Lievin, et al. (1998). "Antagonistic activity against Helicobacter infection
in vitro and in vivo by the human Lactobacillus acidophilus strain LB." Appl Environ Microbiol
64(11): 4573-4580. Exclude-Participants
Colbere-Garapin, F., S. Martin-Latil, et al. (2007). "Prevention and treatment of enteric viral
infections: possible benefits of probiotic bacteria." Microbes Infect 9(14-15): 1623-1631.
Exclude-NoAE
Collado, M. C., E. Isolauri, et al. (2009). "The impact of probiotic on gut health." Curr Drug
Metab 10(1): 68-78. Exclude-NoAE
Collins JK, D. C., Murphy L, Morrissey D, O'Mahony L, O'Sullivan E, Fitzgerald G, Kiely B,
O'Sullivan GC, Daly C, Marteau P, Shanahan F (2002). "A randomised controlled trial of a
probiotic Lactobacillus strain in healthy adults: Assessment of its delivery, transit and influence
on microbial flora and enteric immunity." Microbial Ecology in Health & Disease 14(2): 81-89.
Exclude-NoAE
Colodner, R., H. Edelstein, et al. (2003). "Vaginal colonization by orally administered
Lactobacillus rhamnosus GG." Isr Med Assoc J 5(11): 767-769. Exclude-NoAE
Colombel, J. F., A. Cortot, et al. (1987). "Yoghurt with Bifidobacterium longum reduces
erythromycin-induced gastrointestinal effects." Lancet 2(8549): 43. Exclude-NoAE
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childhood]." Clin Ter 136(6): 409-413. Exclude-Rec NoAE (Foreign Language)
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A placebo-controlled randomised controlled trial in general practice." Br J Gen Pract 57(545):
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Cooper, C. D., A. Vincent, et al. (1998). "Lactobacillus bacteremia in febrile neutropenic patients
in a cancer hospital." Clin Infect Dis 26(5): 1247-1248. Exclude-Intervention
D-15
Coronado, B. E., S. M. Opal, et al. (1995). "Antibiotic-induced D-lactic acidosis." Ann Intern
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Costalos, C., A. Kapiki, et al. (2008). "The effect of a prebiotic supplemented formula on growth
and stool microbiology of term infants." Early Hum Dev 84(1): 45-49. Exclude-Intervention
Costa-Ribeiro, H., T. C. Ribeiro, et al. (2003). "Limitations of probiotic therapy in acute, severe
dehydrating diarrhea." J Pediatr Gastroenterol Nutr 36(1): 112-115. Exclude-NoAE
Cote, G. L. and S. M. Holt (2006.). "Probiotics in food : health and nutritional properties and
guidelines for evaluation. Corp Author(s): Food and Agriculture Organization of the United
Nations. ; World Health Organization
Prebiotic oligosaccharides via alternansucrase acceptor reactions." FAO food and nutrition
paper, 85; 2007(no.): 10. Exclude-Participants
Cotton, D. J., V. J. Gill, et al. (1987). "Clinical features and therapeutic interventions in 17 cases
of Bacillus bacteremia in an immunosuppressed patient population." J Clin Microbiol 25(4): 672
674. Exclude-Intervention
Cox, A. J., D. B. Pyne, et al. (2008). "Oral administration of the probiotic Lactobacillus
fermentum VRI-003 and mucosal immunity in endurance athletes." Br J Sports Med. ExcludeNoAE
Cox, A. J., D. B. Pyne, et al. (2010). "Oral administration of the probiotic Lactobacillus
fermentum VRI-003 and mucosal immunity in endurance athletes." Br J Sports Med 44(4): 222
226. Exclude-Duplicate 4867
Cox, M. J., Y. J. Huang, et al. (2010). "Lactobacillus casei abundance is associated with
profound shifts in the infant gut microbiome." PLoS One 5(1): e8745. Exclude-NoAE
Cremonini, F., S. Di Caro, et al. (2001). "The impact of probiotics in antibiotic-associated
diarrhea: A meta-analysis of placebo-controlled trials." Gastroenterology(120): A215. ExcludeNoAE
Cremonini, F., S. Di Caro, et al. (2002). "Meta-analysis: the effect of probiotic administration on
antibiotic-associated diarrhoea." Aliment Pharmacol Ther 16(8): 1461-1467. Exclude-NoAE
Crosby, Z. and I. Williamson (2009). "Probiotics for the prevention of acute otitis media in
children [Protocol." Exclude-Design
Cross, M. L. and H. S. Gill (2001). "Can immunoregulatory lactic acid bacteria be used as
dietary supplements to limit allergies?" Int Arch Allergy Immunol 125(2): 112-119. Exclude-Rec
NoAE
Cross, M. L., L. M. Stevenson, et al. (2001). "Anti-allergy properties of fermented foods: an
important immunoregulatory mechanism of lactic acid bacteria?" Int Immunopharmacol 1(5):
891-901. Exclude-NoAE
Cruchet, S., M. C. Obregon, et al. (2003). "Effect of the ingestion of a dietary product containing
Lactobacillus johnsonii La1 on Helicobacter pylori colonization in children." Nutrition 19(9):
716-721. Exclude-NoAE
Cui, H. H., C. L. Chen, et al. (2004). "Effects of probiotic on intestinal mucosa of patients with
ulcerative colitis." World J Gastroenterol 10(10): 1521-1525. Exclude-NoAE
D-16
Cukrowska, B., A. Ceregra, et al. (2008). "The influence of probiotic Lactobacillus casei and
paracasei strains on clinical status of atopic eczema in children with food allergy on cow's milk
proteins." Pediatria Wspolczesna 10(2): 67-70. Exclude-NoAE (Polish)
Cukrowska, B., I. Rosiak, et al. (2010). "Impact of heat-inactivated Lactobacillus casei and
Lactobacillus paracasei strains on cytokine responses in whole blood cell cultures of children
with atopic dermatitis." Folia Microbiol (Praha) 55(3): 277-280. Exclude-Participants
Cummings, J. H. and G. T. Macfarlane (2002). "Gastrointestinal effects of prebiotics." Br J Nutr
87 Suppl 2: S145-151. Exclude-Intervention
Cummings, J. H., G. T. Macfarlane, et al. (2001). "Prebiotic digestion and fermentation." Am J
Clin Nutr 73(2 Suppl): 415S-420S. Exclude-Intervention
Cummins, J. and M. Ho (2005). "Genetically modified probiotics should be banned." Microbial
Ecology in Health and Disease 17(2): 66-68. Exclude-Design
Curragh, H. and M. Collins (1992). "High levels of spontaneous drug resistance in Lactobacillus
" Journal of Applied Bacteriology 73: 31-36. Exclude-Participants
Czajkowska-Kozik, J. and A. Szymanski (2009). "[The influence of probiotic supplementation
on girls' red blood cell characteristics]." Rocz Panstw Zakl Hig 60(4): 367-370. Exclude-NoAE
(Polish)
Czerucka, D. and P. Rampal (2002). "Experimental effects of Saccharomyces boulardii on
diarrheal pathogens." Microbes Infect 4(7): 733-739. Exclude-Participants
Czerwionka-Szaflarska, M., R. Kuczynska, et al. (2006). "Effect of probiotic bacteria
supplementation on the tolerance of Helicobacter pylori eradication therapy in children and
youth." Pediatria Polska 81(5): 334-341. Exclude-NoAE (Polish)
Czerwionka-Szaflarska, M. and S. Murawska (2006). "Probiotics importance in tolerance of
eradication therapy of Helicobacter pylori in children." Przeglad Peditryczny 36(4): 287-290.
Exclude-Design
Czerwionka-Szaflarska, M., S. Murawska, et al. (2009). "Evaluation of influence of oral
treatment with probiotic and/or oral rehydration solution on course of acute diarrhoea in
children." Przeglad Gastroenterologiczny 4(3): 166-172. Exclude-NoAE
Dani, C., R. Biadaioli, et al. (2002). "Probiotics feeding in prevention of urinary tract infection,
bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind
study." Biol Neonate 82(2): 103-108. Exclude-NoAE
de Boer, A. S. and B. Diderichsen (1991). "On the safety of Bacillus subtilis and B.
amyloliquefaciens: a review." Appl Microbiol Biotechnol 36(1): 1-4. Exclude-Intervention
De Boisiambert, P. (1966). "Accidents et incidents digestifs de l'antibiotherapie. Leur prevention
par des levures ultra-hautes " Semaine des Hopitaux (Therapeutique) 1: 36-40. Exclude-NoAE
(Foreign Language)
de Bortoli, N., G. Leonardi, et al. (2007). "Helicobacter pylori eradication: a randomized
prospective study of triple therapy versus triple therapy plus lactoferrin and probiotics." Am J
Gastroenterol 102(5): 951-956. Exclude-Rec NoAE
D-17
de dios Pozo-Olano, J., J. H. Warram, Jr., et al. (1978). "Effect of a lactobacilli preparation on
traveler's diarrhea. A randomized, double blind clinical trial." Gastroenterology 74(5 Pt 1): 829
830. Exclude-NoAE
de Felippe Junior, J., M. da Rocha e Silva Junior, et al. (1993). "Infection prevention in patients
with severe multiple trauma with the immunomodulator beta 1-3 polyglucose (glucan)." Surg
Gynecol Obstet 177(4): 383-388. Exclude-Intervention
de Llanos, R., M. T. Fernandez-Espinar, et al. (2006). "A comparison of clinical and food
Saccharomyces cerevisiae isolates on the basis of potential virulence factors." Antonie Van
Leeuwenhoek 90(3): 221-231. Exclude-Participants
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De Preter, V., K. Geboes, et al. (2004). "The in vivo use of the stable isotope-labelled biomarkers
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D-18
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D-19
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D-20
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D-21
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D-22
Faber, S., S. Rigden, et al. (2005). "The use of probiotics in the treatment of irritable bowel
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D-23
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D-24
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D-25
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Helicobacter pylori eradication treatment side effects; A placebo-controlled, double-blind
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Giraffa, G., D. Carminati, et al. (1997). "Enterococci isolated from dairy products: A review of
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Gluck, U. and J. O. Gebbers (2003). "Ingested probiotics reduce nasal colonization with
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D-26
Goerg, K. J. and E. Schlorer (1998). "[Probiotic therapy of pseudomembranous colitis.
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Goldin, B. R. and S. L. Gorbach (1984). "The effect of milk and lactobacillus feeding on human
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Infect Dis 46 Suppl 2: S96-100; discussion S144-151. Exclude-NoAE
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Exclude-NoAE
Golledge, C. L. and T. V. Riley (1996). ""Natural" therapy for infectious diseases." Med J Aust
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Microbiologie Aliments Nutrit 8: 349-354. Exclude-NoAE
Gonzalez, S., R. Cardoza, et al. (1995). "Biotherapeutic role of fermented milk." Biotherapy 8:
129-134. Exclude-NoAE
Gopal, P., J. Dekker, et al. (2005). "Development adn commercialisation of Fonterra's probiotic
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Gorbach, S. L., T. W. Chang, et al. (1987). "Successful treatment of relapsing Clostridium
difficile colitis with Lactobacillus GG." Lancet 2(8574): 1519. Exclude-NoAE
Gorbach, S. L. and B. R. Goldin (1990). "The intestinal microflora and the colon cancer
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Gotoh, M., T. Sashihara, et al. (2009). "Efficacy of oral administration of a heat-killed
Lactobacillus gasseri OLL2809 on patients of japanese cedar pollinosis with high japanese-cedar
pollen-specific IgE." Bioscience, Biotechnology and Biochemistry 73(9): 1971-1977. ExcludeGenus
D-27
Gotteland, M., M. Andrews, et al. (2008). "Modulation of Helicobacter pylori colonization with
cranberry juice and Lactobacillus johnsonii La1 in children." Nutrition 24(5): 421-426. ExcludeNoAE
Gotteland, M., O. Brunser, et al. (2006). "Systematic review: are probiotics useful in controlling
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Exclude-NoAE
Gotteland, M., L. Poliak, et al. (2005). "Effect of regular ingestion of Saccharomyces boulardii
plus inulin or Lactobacillus acidophilus LB in children colonized by Helicobacter pylori." Acta
Paediatr 94(12): 1747-1751. Exclude-NoAE
Gotz, V., J. A. Romankiewicz, et al. (1979). "Prophylaxis against ampicillin-associated diarrhea
with a lactobacillus preparation." Am J Hosp Pharm 36(6): 754-757. Exclude-NoAE
Graf, C. and G. Gavazzi (2007). "Saccharomyces cerevisiae fungemia in an
immunocompromised patient not treated with Saccharomyces boulardii preparation." J Infect
54(3): 310-311. Exclude-Intervention
Grathwohl, D. (2008). "Early supplementation of prebiotic oligosaccharides protects formula-fed
infants against infections during the first six months of life." J Nutr 138(8): 1520; author reply
1521. Exclude-Intervention
Graul, T., A. M. Cain, et al. (2009). "Lactobacillus and bifidobacteria combinations: A strategy
to reduce hospital-acquired Clostridium difficile diarrhea incidence and mortality." Med
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Greany, K. A., M. J. Bonorden, et al. (2008). "Probiotic capsules do not lower plasma lipids in
young women and men." Eur J Clin Nutr 62(2): 232-237. Exclude-Rec NoAE
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Exclude-Rec NoAE
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Exclude-Intervention
Griffiths, J. K., J. S. Daly, et al. (1992). "Two cases of endocarditis due to Lactobacillus species:
antimicrobial susceptibility, review, and discussion of therapy." Clin Infect Dis 15(2): 250-255.
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Gronlund, M. M., O. P. Lehtonen, et al. (1997). "Lactobacillus GG supplementation does not
reduce faecal colonization of Klebsiella oxytoca in preterm infants." Acta Paediatr 86(7): 785
786. Exclude-NoAE
"Growth, weight gain composition and mineral accretion in term infants fed a new experimental
formula containing hydrolysed protein, beta-palmitate and prebiotics." Ciencia Pediatrika
2001;21(10): 387-396. Exclude-Intervention
D-28
Guandalini, S. (1998). "Probiotics in the treatment of diarrheal diseases in children."
Gastroenterol Int(11): 87-90. Exclude-Intervention
Guarino, A., R. B. Canani, et al. (1997). "Oral bacterial therapy reduces the duration of
symptoms and of viral excretion in children with mild diarrhea." J Pediatr Gastroenterol Nutr
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Guarner, F. and J. R. Malagelada (2003). "Gut flora in health and disease." Lancet 361(9356):
512-519. Exclude-NoAE
Guarner, F., G. Perdigon, et al. (2005). "Should yoghurt cultures be considered probiotic?" Br J
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Gueimonde, M., S. Sakata, et al. (2006). "Effect of maternal consumption of lactobacillus GG on
transfer and establishment of fecal bifidobacterial microbiota in neonates." J Pediatr
Gastroenterol Nutr 42(2): 166-170. Exclude-NoAE
Gueniche, A., P. Bastien, et al. (2010). "Bifidobacterium longum lysate, a new ingredient for
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Guenther, K., E. Straube, et al. (2010). "Sever sepsis after probiotic treatment with Escherichia
coli NISSLE 1917." Pediatr Infect Dis J 29(2): 188-189. Exclude-Genus
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Lactobacillus casei compared with yogurt and gelled milk: influence on intestinal microflora in
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Helicobacter pylori." Chin J Celiopathy 4: 163-165. Exclude-Genus
Guslandi, M. (2006). "Are probiotics effective for treating Clostridium difficile disease and
antibiotic-associated diarrhea?" Nat Clin Pract Gastroenterol Hepatol 3(11): 606-607. ExcludeDesign
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Habermann, W. and K. Zimmerman (2002). "Reduction of acute relapses in patients with chronic
recurrent hypertrophic sinusitis during treatment with a bacterial immunostimulant
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Exclude-Duplicate 1540 (German)
Hafer, A., S. Kramer, et al. (2007). "Effect of oral lactulose on clinical and
immunohistochemical parameters in patients with inflammatory bowel disease: a pilot study."
BMC Gastroenterol 7: 36. Exclude-Intervention
Hallen, A., C. Jarstrand, et al. (1992). "Treatment of bacterial vaginosis with lactobacilli." Sex
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Haller, J. and H. Kraeubig (1960). "[On the modification of the radiation reaction of the
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D-29
Halpern, G. M., T. Prindiville, et al. (1996). "Treatment of irritable bowel syndrome with Lacteol
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Harty, D. W., M. Patrikakis, et al. (1993). "Identification of lactobacillus strains isolated from
patients with infective endocarditis and comparison of their surface-associated properties with
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Exclude-NoAE (Foreign Language)
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Hayatsu, H. and T. Hayatsu (1993). "Suppressing effect of Lactobacillus casei administration on
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D-30
He, Y. (1990). "The efficacy of Bifidobacterium on adult diarrhea." Chinese Journal of
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Heath, C. H., A. Jaksic, et al. (2000). "Disseminated Saccharomyces cerevisiae infection
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Heilpern, D. and A. Szilagyi (2008). "Manipulation of intestinal microbial flora for therapeutic
benefit in inflammatory bowel diseases: review of clinical trials of probiotics, pre-biotics and
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Heimbach, J. (2004). "European Food Safety Authority Scientific Colluquium on Micro
organisms in Food and Feed Qualified Presumption of Safety - QPS." Exclude-Participants
Helin, T., S. Haahtela, et al. (2002). "No effect of oral treatment with an intestinal bacterial
strain, Lactobacillus rhamnosus (ATCC 53103), on birch-pollen allergy: a placebo-controlled
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Henker, J., B. Blokhin, et al. (2008). "Acute diarrhoea in infants and small children. Successful
adjuvant therapy with the probiotic Mutaflor." Padiatrische Praxis 71(4): 605-610. Exclude-Rec
Genus (Foreign Language)
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Hennequin, C., A. Thierry, et al. (2001). "Microsatellite typing as a new tool for identification of
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Henriksson, R., L. Franzen, et al. (1991). "Prevention of irradiation-induced bowel discomfort by
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fermented milk to patients with chronic bowel discomfort following irradiation." Support Care
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Hepner, G., R. Fried, et al. (1979). "Hypocholesterolemic effect of yogurt and milk." Am J Clin
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D-31
Hernando-Harder, A. C., R. von Bunau, et al. (2008). "Influence of E. coli strain Nissle 1917
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NoAE
Hilton, E., H. D. Isenberg, et al. (1992). "Ingestion of yogurt containing Lactobacillus
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Hinze, J. and T. Mahan (2000). "Probiotics and their effect on leaky gut syndrome and associated
diseases." International Journal of Pharmaceutical Compounding 4(5): 349-350. Exclude-NoAE
Hlivak, P., J. Odraska, et al. (2005). "One-year application of probiotic strain Enterococcus
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Expertenrunde Darmerkrankungen, Garmisch-Partenkirchen1.-5.3.89, Munch Med Wschr
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Noorvosok Lapja 67(2): 85-91. Exclude-Rec NoAE (Hungarian)
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D-32
Hosoda, M., H. Hashimoto, et al. (1996). "Effect of administration of milk fermented with
Lactobacillus acidophilus LA-2 on fecal mutagenicity and microflora in the human intestine." J
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probiotics, lactitol and rifaximin on intestinal flora and fecal excretion of organic acids in
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Exclude-Duplicate 5694
Howard, J. C., G. Reid, et al. (2004). "Probiotics in surgical wound infections: current status."
Clin Invest Med 27(5): 274-281. Exclude-Participants
Hoyme, U. B. and E. Saling (2004). "Efficient prematurity prevention is possible by pH-self
measurement and immediate therapy of threatening ascending infection." Eur J Obstet Gynecol
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Huang, J. S., A. Bousvaros, et al. (2002). "Efficacy of probiotic use in acute diarrhea in children:
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Huertas-Ceballos, A., S. Logan, et al. (2008). "Dietary interventions for recurrent abdominal pain
(RAP) and irritable bowel syndrome (IBS) in childhood." Cochrane Database Syst Rev(1):
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used for colonization of the vagina." Obstet Gynecol 75(2): 244-248. Exclude-Participants
Huntley, A. L. (2003). "Four-year follow-up shows continued benefit of perinatal Lactobacillus
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Huntley, A. L. and K. W. Martin (2002). "Probiotics show promise for prevention and treatment
of diarrhoea." Focus on Alternative & Complementary Therapies 7(4): 358-359. Exclude-Design
Hurduc, V., D. Plesca, et al. (2009). "A randomized, open trial evaluating the effect of
Saccharomyces boulardii on the eradication rate of Helicobacter pylori infection in children."
Acta Paediatr 98(1): 127-131. Exclude-NoAE
Husni, R. N., S. M. Gordon, et al. (1997). "Lactobacillus bacteremia and endocarditis: review of
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D-33
Huurre, A., K. Laitinen, et al. (2008). "Impact of maternal atopy and probiotic supplementation
during pregnancy on infant sensitization: a double-blind placebo-controlled study." Clin Exp
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(Russian)
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concomitantly with Helicobacter pylori eradication therapy in relation to changes in the intestinal
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infection--a double-blind randomised placebo-controlled cross-over clinical study."
Kansenshogaku Zasshi 81(4): 387-393. Exclude-NoAE
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healthy term infants." Pediatr Res 62(1): 98-100. Exclude-NoAE
Indrio, F., G. Riezzo, et al. (2009). "Prebiotics improve gastric motility and gastric electrical
activity in preterm newborns." J Pediatr Gastroenterol Nutr 49(2): 258-261. Exclude-Genus
Infante Pina, D., S. Redecillas Ferreiro, et al. (2008). "[Improvement of intestinal function in
cystic fibrosis patients using probiotics]." An Pediatr (Barc) 69(6): 501-505. Exclude-NoAE
Iovieno, A., A. Lambiase, et al. (2008). "Preliminary evidence of the efficacy of probiotic eyedrop treatment in patients with vernal keratoconjunctivitis." Graefes Arch Clin Exp Ophthalmol
246(3): 435-441. Exclude-Genus
Ipson, M. A. and C. L. Blanco (2001). "Saccharomyces cerevisiae sepsis in a 35-week-old
premature infant. A case report." J Perinatol 21(7): 459-460. Exclude-Design
Ishida, Y., F. Nakamura, et al. (2005). "Clinical effects of Lactobacillus acidophilus strain L-92
on perennial allergic rhinitis: a double-blind, placebo-controlled study." J Dairy Sci 88(2): 527
533. Exclude-NoAE
Ishida, Y., F. Nakamura, et al. (2005). "Effect of milk fermented with Lactobacillus acidophilus
strain L-92 on symptoms of Japanese cedar pollen allergy: a randomized placebo-controlled
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therapy for HCC." Am J Gastroenterol 85(12): 1646-1648. Exclude-Intervention
Isolauri, E. (2001). "Probiotics in human disease." Am J Clin Nutr 73(6): 1142S-1146S.
Exclude-NoAE
Isolauri, E., T. Arvola, et al. (2000). "Probiotics in the management of atopic eczema." Clin Exp
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D-34
Isolauri, E., M. Kaila, et al. (1994). "Oral bacteriotherapy for viral gastroenteritis." Dig Dis Sci
39(12): 2595-2600. Exclude-NoAE
Isolauri, E., M. Kalliomaki, et al. (2009). "Obesity - extending the hygiene hypothesis." Nestle
Nutr Workshop Ser Pediatr Program 64: 75-85; discussion 85-79, 251-257. Exclude-Design
Isolauri, E., H. Majamaa, et al. (1993). "Lactobacillus casei strain GG reverses increased
intestinal permeability induced by cow milk in suckling rats." Gastroenterology 105(6): 1643
1650. Exclude-Participants
Isolauri, E., Y. Sutas, et al. (2001). "Probiotics: effects on immunity." Am J Clin Nutr 73(2
Suppl): 444S-450S. Exclude-NoAE
Ivory, K., S. J. Chambers, et al. (2008). "Oral delivery of Lactobacillus casei Shirota modifies
allergen-induced immune responses in allergic rhinitis." Clin Exp Allergy 38(8): 1282-1289.
Exclude-NoAE
Iwabuchi, N., N. Takahashi, et al. (2009). "Suppressive effects of Bifidobacterium longum on the
production of Th2-attracting chemokines induced with T cell-antigen-presenting cell
interactions." FEMS Immunol Med Microbiol 55(3): 324-334. Exclude-Participants
Iwamoto, T., N. Suzuki, et al. (2010). "Effects of probiotic Lactobacillus salivarius WB21 on
halitosis and oral health: an open-label pilot trial." Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 110(2): 201-208. Exclude-NoAE
Jaafari, A., F. Tahbaz, et al. (2005). "Comparison of the effect of a probiotic yoghurt and
ordinary yoghurt on serum cholesterol levels in subjects with mild to moderate
hypercholesterolemia." Iranian Journal of Diabetes and Lipid Disorders 4(3): E6+E6i-E6vi.
Exclude-NoAE (Foreign Language)
Jabra-Rizk, M. A., S. M. Ferreira, et al. (2001). "Recovery of Candida dubliniensis and other
yeasts from human immunodeficiency virus-associated periodontal lesions." J Clin Microbiol
39(12): 4520-4522. Exclude-Intervention
Jaspers, D., L. Massey, et al. (1984). "Effect of consuming yogurts prepared with 3 culture
strains on human serum lipoproteins." J Food Sci 49: 1178-1181. Exclude-NoAE
Jeun, J., S. Kim, et al. (2010). "Hypocholesterolemic effects of Lactobacillus plantarum
KCTC3928 by increased bile acid excretion in C57BL/6 mice." Nutrition 26(3): 321-330.
Exclude-Participants
Jiang, T., A. Mustapha, et al. (1996). "Improvement of lactose digestion in humans by ingestion
of unfermented milk containing Bifidobacterium longum." J Dairy Sci 79(5): 750-757. ExcludeNoAE
Jimenez, E., L. Fernandez, et al. (2008). "Oral administration of Lactobacillus strains isolated
from breast milk as an alternative for the treatment of infectious mastitis during lactation." Appl
Environ Microbiol 74(15): 4650-4655. Exclude-NoAE
Johansson, M. L., G. Molin, et al. (1993). "Administration of different Lactobacillus strains in
fermented oatmeal soup: in vivo colonization of human intestinal mucosa and effect on the
indigenous flora." Appl Environ Microbiol 59(1): 15-20. Exclude-NoAE
D-35
Jonkers, D. and R. Stockbrugger (2007). "Review article: Probiotics in gastrointestinal and liver
diseases." Aliment Pharmacol Ther 26 Suppl 2: 133-148. Exclude-NoAE
Kaila, M., E. Isolauri, et al. (1995). "Viable versus inactivated lactobacillus strain GG in acute
rotavirus diarrhoea." Arch Dis Child 72(1): 51-53. Exclude-NoAE
Kaila, M., E. Isolauri, et al. (1992). "Enhancement of the circulating antibody secreting cell
response in human diarrhea by a human Lactobacillus strain." Pediatr Res 32(2): 141-144.
Exclude-NoAE
Kajander, K., L. Krogius-Kurikka, et al. (2007). "Effects of multispecies probiotic
supplementation on intestinal microbiota in irritable bowel syndrome." Aliment Pharmacol Ther
26(3): 463-473. Exclude-NoAE
Kajimoto, O., K. Aihara, et al. (2001). "Hypotensive effects of the tablets containing
"lactotripeptides (VPP, IPP)" " J Nutr Food 4: 51-61. Exclude-Intervention
Kajimoto, O., K. Aihara, et al. (2001). "Safety evaluation of excessive intake of the tablet
containing "lactotripeptides (VPP, IPP) in healthy volunteers." J Nutr Food 4: 37-46. ExcludeIntervention
Kalima, P., R. G. Masterton, et al. (1996). "Lactobacillus rhamnosus infection in a child
following bone marrow transplant." J Infect 32(2): 165-167. Exclude-Design
Kalliomaki, M., P. Kirjavainen, et al. (2001). "Distinct patterns of neonatal gut microflora in
infants in whom atopy was and was not developing." J Allergy Clin Immunol 107(1): 129-134.
Exclude-Intervention
Kalliomaki, M., S. Salminen, et al. (2001). "Prenatal and postnatal administration of
Lactobacillus GG reduced the occurence of atopic disease in offspring." Evidence-Based
Medicine 6(6): 178. Exclude-Rec NoAE
Kalliomaki, M., S. Salminen, et al. (2007). "Probiotics during the first 7 years of life: a
cumulative risk reduction of eczema in a randomized, placebo-controlled trial." J Allergy Clin
Immunol 119(4): 1019-1021. Exclude-NoAE
Kamiya, T., M. Shikano, et al. (2008). "[The efficacy of probiotics in gastrointestinal disease]."
Nippon Rinsho 66(7): 1385-1390. Exclude-Rec NoAE (Chinese)
Kanamori, U. (2007). "SYNBIOTIC THERAPY: AN IMPORTANT SUPPORTIVE THERAPY
FOR PEDIATRIC PATIENTS WITH SEVERE RESPIRATORY DISTRESS." International
journal of probiotics 1(3 ): 161. Exclude-NoAE
Kanamori, Y., K. Hashizume, et al. (2001). "Combination therapy with Bifidobacterium breve,
Lactobacillus casei, and galactooligosaccharides dramatically improved the intestinal function in
a girl with short bowel syndrome: a novel synbiotics therapy for intestinal failure." Dig Dis Sci
46(9): 2010-2016. Exclude-NoAE
Kanamori, Y., K. Hashizume, et al. (2002). "A novel synbiotic therapy dramatically improved
the intestinal function of a pediatric patient with laryngotracheo-esophageal cleft (LTEC) in the
intensive care unit." Clin Nutr 21(6): 527-530. Exclude-NoAE
D-36
Kanamori, Y., M. Sugiyama, et al. (2004). "Experience of long-term synbiotic therapy in seven
short bowel patients with refractory enterocolitis." J Pediatr Surg 39(11): 1686-1692. ExcludeNoAE
Kanauchi, O., K. Mitsuyama, et al. (2003). "Treatment of ulcerative colitis patients by long-term
administration of germinated barley foodstuff: multi-center open trial." Int J Mol Med 12(5):
701-704. Exclude-Intervention
Kanazawa, H., M. Nagino, et al. (2005). "Synbiotics reduce postoperative infectious
complications: a randomized controlled trial in biliary cancer patients undergoing hepatectomy."
Langenbecks Arch Surg 390(2): 104-113. Exclude-NoAE
Kang, B. (1984). "Report on Probiotics." Journal of Dalian Medical College 6(1): 46. ExcludeParticipants (Chinese)
Kang, M. S., B. G. Kim, et al. (2006). "Inhibitory effect of Weissella cibaria isolates on the
production of volatile sulphur compounds." J Clin Periodontol 33(3): 226-232. Exclude-NoAE
Karakan, T., M. Ergun, et al. (2007). "Comparison of early enteral nutrition in severe acute
pancreatitis with prebiotic fiber supplementation versus standard enteral solution: a prospective
randomized double-blind study." World J Gastroenterol 13(19): 2733-2737. ExcludeIntervention
Karlsson, C., S. Ahrne, et al. (2010). "Probiotic therapy to men with incipient arteriosclerosis
initiates increased bacterial diversity in colon: a randomized controlled trial." Atherosclerosis
208(1): 228-233. Exclude-NoAE
Kastner, S., V. Perreten, et al. (2006). "Antibiotic susceptibility patterns and resistance genes of
starter cultures and probiotic bacteria used in food." Syst Appl Microbiol 29(2): 145-155.
Exclude-Participants
Katamura, K., N. Shintaku, et al. (1995). "Prostaglandin E2 at priming of naive CD4+ T cells
inhibits acquisition of ability to produce IFN-gamma and IL-2, but not IL-4 and IL-5." J
Immunol 155(10): 4604-4612. Exclude-Participants
Katan, M. B. (2008). "[The probiotic yogurt Activia shortens intestinal transit, but has not been
shown to promote defecation]." Ned Tijdschr Geneeskd 152(13): 727-730. Exclude-Rec Design
(German)
Kato, I., T. Yokokura, et al. (1984). "Augmentation of mouse natural killer cell activity by
Lactobacillus casei and its surface antigens." Microbiol Immunol 28(2): 209-217. ExcludeParticipants
Kaur, S., T. Kullisaar, et al. (2008). "Successful management of mild atopic dermatitis in adults
with probiotics and emollients." European Journal of Medicine 3(2): 215-220. Exclude-NoAE
Kawase, M., H. Hashimoto, et al. (2000). "Effect of administration of fermented milk containing
whey protein concentrate to rats and healthy men on serum lipids and blood pressure." J Dairy
Sci 83(2): 255-263. Exclude-NoAE
Kawase, M., F. He, et al. (2009). "Effect of fermented milk prepared with two probiotic strains
on Japanese cedar pollinosis in a double-blind placebo-controlled clinical study." Int J Food
Microbiol 128(3): 429-434. Exclude-NoAE
D-37
Kecskes, G., T. Belagyi, et al. (2003). "[Early jejunal nutrition with combined pre- and probiotics
in acute pancreatitis--prospective, randomized, double-blind investigations]." Magy Seb 56(1):
3-8. Exclude-Rec NoAE (Hungarian)
Keegan, B., Y. P. Chan, et al. (2006). "An interdisciplinary approach including probiotic in the
reduction of Clostridium difficile infection on an acute geriatric ward British Geriatrics Society:
Abstracts of papers presented at the Spring Scientific Meeting, 6-7 April 2006." Age & Ageing
35: Supplement 3: i12. Exclude-NoAE
Kekkonen, R. A., N. Lummela, et al. (2008). "Probiotic intervention has strain-specific antiinflammatory effects in healthy adults." World J Gastroenterol 14(13): 2029-2036. ExcludeNoAE
Kekkonen, R. A., M. Sysi-Aho, et al. (2008). "Effect of probiotic Lactobacillus rhamnosus GG
intervention on global serum lipidomic profiles in healthy adults." World J Gastroenterol 14(20):
3188-3194. Exclude-NoAE
Kekkonen, R. A., T. J. Vasankari, et al. (2007). "The effect of probiotics on respiratory
infections and gastrointestinal symptoms during training in marathon runners." Int J Sport Nutr
Exerc Metab 17(4): 352-363. Exclude-Rec NoAE
Kelly, G. S. (1999). "Nutritional and botanical interventions to assist with the adaptation to
stress." Altern Med Rev 4(4): 249-265. Exclude-Intervention
Kennedy, R. J., S. J. Kirk, et al. (2002). "Mucosal barrier function and the commensal flora." Gut
50(3): 441-442. Exclude-Rec NoAE
Khanna, V., S. Alam, et al. (2005). "Efficacy of tyndalized Lactobacillus acidophilus in acute
diarrhea." Indian J Pediatr 72(11): 935-938. Exclude-Rec NoAE
Kiessling, G., J. Schneider, et al. (2002). "Long-term consumption of fermented dairy products
over 6 months increases HDL cholesterol." Eur J Clin Nutr 56(9): 843-849. Exclude-NoAE
Kim, H., K. Kwack, et al. (2005). "Oral probiotic bacterial administration suppressed allergic
responses in an ovalbumin-induced allergy mouse model." FEMS Immunol Med Microbiol
45(2): 259-267. Exclude-Participants
Kim, H., S. Y. Lee, et al. (2005). "Timing of bifidobacterium administration influences the
development of allergy to ovalbumin in mice." Biotechnol Lett 27(18): 1361-1367. ExcludeParticipants
Kim, H. S. and S. E. Gilliland (1983). "Lactobacillus acidophilus as a dietary adjunct for milk to
aid lactose digestion in humans." J Dairy Sci 66(5): 959-966. Exclude-NoAE
Kim, S. H., H. Lee da, et al. (2007). "Supplementation of baby formula with native inulin has a
prebiotic effect in formula-fed babies." Asia Pac J Clin Nutr 16(1): 172-177. ExcludeIntervention
Kim, S. H., S. J. Yang, et al. (2001). "Inhibitory activity of Bifidobacterium longum HY8001
against Vero cytotoxin of Escherichia coli O157:H7." J Food Prot 64(11): 1667-1673. ExcludeParticipants
Kimmey, M. B., G. W. Elmer, et al. (1990). "Prevention of further recurrences of Clostridium
difficile colitis with Saccharomyces boulardii." Dig Dis Sci 35(7): 897-901. Exclude-NoAE
D-38
Kirjavainen, P. V., E. Apostolou, et al. (2001). "Characterizing the composition of intestinal
microflora as a prospective treatment target in infant allergic disease." FEMS Immunol Med
Microbiol 32(1): 1-7. Exclude-Intervention
Kirpich, I. A., N. V. Solovieva, et al. (2008). "Probiotics restore bowel flora and improve liver
enzymes in human alcohol-induced liver injury: a pilot study." Alcohol 42(8): 675-682. ExcludeNoAE
Klein, A., U. Friedrich, et al. (2008). "Lactobacillus acidophilus 74-2 and Bifidobacterium
animalis subsp lactis DGCC 420 modulate unspecific cellular immune response in healthy
adults." Eur J Clin Nutr 62(5): 584-593. Exclude-NoAE
Klein, N., P. Schoch, et al. (1991). "Lactobacillus acidophilus liver abscess." Infectious Diseases
Newsletter 10: 101-102. Exclude-Intervention
Klein, V., C. Bonaparte, et al. (1992). "Lactobazillen als Starterkulturen fur die Milchwirtschaft
unter dem Gesichtspunkt der Sicheren Biotechnologie." Milchwissenschaft 47: 632-636.
Exclude-Rec Intervention
Kliegman, R. and R. Willoughby (2005). "Prevention of Necrotizing Enterocolitis With
Probiotics." Pediatrics 115-172: 171. Exclude-Duplicate 2956
Kliegman, R. M. (2005). "Oral probiotics reduce the incidence and severity of necrotizing
enterocolitis in very low birth weight infants." J Pediatr 146(5): 710. Exclude-NoAE
Kloster Smerrud, H., C. Ramstak Kleiveland, et al. (2008). "Effect of a probiotic milk product on
gastrointestinal and respiratory infections in children attending day-care." Microbial Ecology in
Health and Disease 20(2): 80-85. Exclude-NoAE
Kluytmans, J. (1998). "Reduction of surgical site infections in major surgery by elimination of
nasal carriage of Staphylococcus aureus." J Hosp Infect 40 Suppl B: S25-29. ExcludeIntervention
Knight, D. J. (2003). "Immunonutrition: increased mortality is associated with immunonutrition
in sepsis." BMJ 327(7416): 682-683; author reply 683. Exclude-Design
Knight, D. J., D. Gardiner, et al. (2009). "Effect of synbiotic therapy on the incidence of
ventilator associated pneumonia in critically ill patients: a randomised, double-blind, placebocontrolled trial." Intensive Care Med 35(5): 854-861. Exclude-Duplicates 5110
Kocourkova, I., R. Ladnikova, et al. (2007). "Effect of oral application of a probiotic E. coli
strain on the intestinal microflora of children of allergic mothers during the first year of life."
Folia Microbiol (Praha) 52(2): 189-193. Exclude-NoAE
Kok, R. G., A. de Waal, et al. (1996). "Specific detection and analysis of a probiotic
Bifidobacterium strain in infant feces." Appl Environ Microbiol 62(10): 3668-3672. ExcludeNoAE
Kolars, J. C., M. D. Levitt, et al. (1984). "Yogurt--an autodigesting source of lactose." N Engl J
Med 310(1): 1-3. Exclude-NoAE
Koletzko, S. (2004). "Does lactobacillus GG lower the risk of atopic eczema?" Tagliche Praxis
45(3): 661-662. Exclude-NoAE (Foreign Language)
D-39
Kollaritsch, H. (1989). "Prophylaxe der Reisediarrhomit Saccharomyces cerevisiae Hansen CBS
5929." Munch Med Wschr, Beilage 81 (Expertenrunde Darmerkrankungen, Garmisch
Partenkirchen1.-5.3.89 131: 5-6. Exclude-Duplicate 13031
Koretz, R. L. (2009). "Invited review: Probiotics, critical illness, and methodologic bias."
Nutrition in Clinical Practice 24(1): 45-49. Exclude-NoAE
Korschunov, V. M., V. V. Smeianov, et al. (1996). "Therapeutic use of an antibiotic-resistant
Bifidobacterium preparation in men exposed to high-dose gamma-irradiation." J Med Microbiol
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Kotz, C. M., J. K. Furne, et al. (1994). "Factors affecting the ability of a high beta-galactosidase
yogurt to enhance lactose absorption." J Dairy Sci 77(12): 3538-3544. Exclude-NoAE
Koutelidakis, I. M., E. Bezirtzoglou, et al. (2010). "Impact of synbiotics on the intestinal flora of
critically ill patients with multiple injuries." Int J Antimicrob Agents 36(1): 90-91. ExcludeNoAE
Kralovicova, K., S. Spanik, et al. (1997). "Fungemia in cancer patients undergoing chemotherapy
versus surgery: risk factors, etiology and outcome." Scand J Infect Dis 29(3): 301-304. ExcludeIntervention
Krause, W., H. Matheis, et al. (1969). "Fungaemia and funguria after oral administration of
Candida albicans." Lancet 1(7595): 598-599. Exclude-Genus
Krauss-Silva, L., M. E. Moreira, et al. (2010). "Randomized controlled trial of probiotics for the
prevention of spontaneous preterm delivery associated with intrauterine infection: study
protocol." Reprod Health 7: 14. Exclude-NoAE
Krogh, P., P. Holmstrup, et al. (1986). "Yeast organisms associated with human oral
leukoplakia." Acta Derm Venereol Suppl (Stockh) 121: 51-55. Exclude-Intervention
Kroon, F. P., J. T. van Dissel, et al. (1994). "Antibody response to influenza, tetanus and
pneumococcal vaccines in HIV-seropositive individuals in relation to the number of CD4+
lymphocytes." AIDS 8(4): 469-476. Exclude-Intervention
Kroon, F. P., J. T. van Dissel, et al. (1995). "Antibody response to diphtheria, tetanus, and
poliomyelitis vaccines in relation to the number of CD4+ T lymphocytes in adults infected with
human immunodeficiency virus." Clin Infect Dis 21(5): 1197-1203. Exclude-Intervention
Kruis, W., P. Fric, et al. (2004). "Maintaining remission of ulcerative colitis with the probiotic
Escherichia coli Nissle 1917 is as effective as with standard mesalazine." Gut 53(11): 1617
1623. Exclude-Genus
Kruis, W., E. Schutz, et al. (1997). "Double-blind comparison of an oral Escherichia coli
preparation and mesalazine in maintaining remission of ulcerative colitis." Aliment Pharmacol
Ther 11(5): 853-858. Exclude-Genus
Ksiazyk (2002). "Probiotics and prebiotics in carcinogenesis." 4(1): 61-62. Exclude-Design
(Polish)
Kubota, A., F. He, et al. (2010). "Diversity of Intestinal Bifidobacteria in Patients with Japanese
Cedar Pollinosis and Possible Influence of Probiotic Intervention." Curr Microbiol. ExcludeNoAE
D-40
Kubota, A., F. He, et al. (2009). "Lactobacillus strains stabilize intestinal microbiota in Japanese
cedar pollinosis patients." Microbiol Immunol 53(4): 198-205. Exclude-NoAE
Kubota, A., H. Kawahara, et al. (2007). "The efficacy of synbiotics on chronic intestinal pseudoobstruction syndrome in children." J Parenter Ent Nutr 31: S63-64. Exclude-NoAE
Kuhbacher, T., S. J. Ott, et al. (2006). "Bacterial and fungal microbiota in relation to probiotic
therapy (VSL#3) in pouchitis." Gut 55(6): 833-841. Exclude-NoAE
Kuitunen, M. (2007). "Probiotics And Intestinal Permeability In Infants With Cow’s Milk
Allergy And Eczema " International journal of probiotics 2(4): 239-244. Exclude-NoAE
Kuitunen, M. (2009). "Probiotics prevent allergic diseases in high-risk children." Expert Rev
Clin Immunol 5(3): 221-224. Exclude-NoAE
Kuitunen, M., K. Kukkonen, et al. (2009). "Probiotics prevent IgE-associated allergy until age 5
years in cesarean-delivered children but not in the total cohort." J Allergy Clin Immunol 123(2):
335-341. Exclude-Rec NoAE
Kukkonen, K., M. Kuitunen, et al. (2010). "High intestinal IgA associates with reduced risk of
IgE-associated allergic diseases." Pediatr Allergy Immunol 21(1 Pt 1): 67-73. Exclude-NoAE
Kullisaar, T., E. Songisepp, et al. (2003). "Antioxidative probiotic fermented goats' milk
decreases oxidative stress-mediated atherogenicity in human subjects." Br J Nutr 90(2): 449-456.
Exclude-NoAE
Kyne, L., S. Sougioultzis, et al. (2002). "Underlying disease severity as a major risk factor for
nosocomial Clostridium difficile diarrhea." Infect Control Hosp Epidemiol 23(11): 653-659.
Exclude-Intervention
Laake, K. O., A. Bjorneklett, et al. (2005). "Outcome of four weeks' intervention with probiotics
on symptoms and endoscopic appearance after surgical reconstruction with a J-configurated
ileal-pouch-anal-anastomosis in ulcerative colitis." Scand J Gastroenterol 40(1): 43-51. ExcludeNoAE
Ladenheim, D., O. Horn, et al. (2008). "Potential health risks of complementary alternative
medicines in HIV patients." HIV Medicine 9(8): 653-659. Exclude-Design
Lahtinen, S. J., R. J. Boyle, et al. (2009). "Prenatal probiotic administration can influence
Bifidobacterium microbiota development in infants at high risk of allergy." J Allergy Clin
Immunol 123(2): 499-501. Exclude-NoAE
Laitinen, K., T. Poussa, et al. (2009). "Probiotics and dietary counselling contribute to glucose
regulation during and after pregnancy: a randomised controlled trial." Br J Nutr 101(11): 1679
1687. Exclude-Duplicate 5127
Lanco, S., M. Guillot, et al. (1997). "[Severe systemic infections with Bacillus cereus: current
aspects of the pathogenicity of the genus Bacillus]." Arch Pediatr 4(11): 1144-1145. ExcludeRec Intervention (French)
Lara-Villoslada, F., S. Sierra, et al. (2009). "Safety Assessment of Lactobacillus fermentum
CECT5716, a probiotic strain isolated from human milk." J Dairy Res 76(2): 216-221. ExcludeParticipants
D-41
Larkin, T. A., L. B. Astheimer, et al. (2009). "Dietary combination of soy with a probiotic or
prebiotic food significantly reduces total and LDL cholesterol in mildly hypercholesterolaemic
subjects." Eur J Clin Nutr 63(2): 238-245. Exclude-NoAE
Larkin, T. A., W. E. Price, et al. (2007). "Increased probiotic yogurt or resistant starch intake
does not affect isoflavone bioavailability in subjects consuming a high soy diet." Nutrition
23(10): 709-718. Exclude-NoAE
Larvol, L., A. Monier, et al. (1996). "[Liver abscess caused by Lactobacillus acidophilus]."
Gastroenterol Clin Biol 20(2): 193-195. Exclude-Intervention (French)
Lata, J., J. Jurankova, et al. (2006). "[Effect of administration of Escherichia coli Nissle
(Mutaflor) on intestinal colonisation, endo-toxemia, liver function and minimal hepatic
encephalopathy in patients with liver cirrhosis]." Vnitr Lek 52(3): 215-219. Exclude-Genus
(Czech)
Lata, J., I. Novotny, et al. (2007). "The effect of probiotics on gut flora, level of endotoxin and
Child-Pugh score in cirrhotic patients: results of a double-blind randomized study." Eur J
Gastroenterol Hepatol 19(12): 1111-1113. Exclude-Intervention
Lata, J., V. Pribramska, et al. (2006). "Bowel premeability, endotoxin level and bacterial flora
changes in patients suffering from liver cirrhosis after Escherichia Coli Nissle (Mutaflor)
administration." Ceska a Slovenska, Gasatoenterologie a Hepatologie 60(2): 70-72. ExcludeGenus
Lata, J. and O. Stiburek (2010). "[Antibiotics and probiotics in acute pancreatitis]." Vnitr Lek
56(6): 582-584. Exclude-Design
Laviano, A., M. Pennacchiotti, et al. (2004). "Reduced need for parenteral nutrition in intensive
care unit by enteral nutrition supplemented with probiotic " Clin Nutr 23: S1466. Exclude-NoAE
Le, M. G., L. H. Moulton, et al. (1986). "Consumption of dairy produce and alcohol in a casecontrol study of breast cancer." J Natl Cancer Inst 77(3): 633-636. Exclude-Rec NoAE
Lee do, K., S. Jang, et al. (2009). "Lactic acid bacteria affect serum cholesterol levels, harmful
fecal enzyme activity, and fecal water content." Lipids Health Dis 8: 21. Exclude-Participants
Lee, H., Y. H. Kim, et al. (2010). "A feasibility study of probiotics pretreatment as a bowel
preparation for colonoscopy in constipated patients." Dig Dis Sci 55(8): 2344-2351. ExcludeNoAE
Lee, J., D. Seto, et al. (2008). "Meta-analysis of clinical trials of probiotics for prevention and
treatment of pediatric atopic dermatitis." J Allergy Clin Immunol 121(1): 116-121 e111.
Exclude-NoAE
Lee, K., M. Lee, et al. (2008). "Safety assessment of commercial Enterococcus probiotics in
Korea." J Microbiol Biotechnol 18(5): 942-945. Exclude-Participants
Lee, M. C., L. H. Lin, et al. (2001). "Oral bacterial therapy promotes recovery from acute
diarrhea in children." Acta Paediatr Taiwan 42(5): 301-305. Exclude-NoAE
Lee, P. and L. V. Campbell (2009). "Vitamin D deficiency: the invisible accomplice of metabolic
endotoxemia?" Curr Pharm Des 15(23): 2751-2758. Exclude-Genus
D-42
Lee, S., H. S. Lillehoj, et al. (2007). "Effects of Pediococcus- and Saccharomyces-based
probiotic (MitoMax) on coccidiosis in broiler chickens." Comp Immunol Microbiol Infect Dis
30(4): 261-268. Exclude-Participants
Lee, S. J., S. J. Cho, et al. (2007). "Effects of probiotics on enteric flora and feeding tolerance in
preterm infants." Neonatology 91(3): 174-179. Exclude-Rec NoAE
Lee, S. J., Y. H. Shim, et al. (2007). "Probiotics prophylaxis in children with persistent primary
vesicoureteral reflux." Pediatr Nephrol 22(9): 1315-1320. Exclude-NoAE
Lee, S. Y., C. T. Chang, et al. (2004). "Lactobacillus peritonitis: a rare cause of peritonitis in
peritoneal dialysis patients." Ren Fail 26(4): 419-423. Exclude-Intervention
Lee, T. T., M. Morisset, et al. (2007). "Contamination of probiotic preparations with milk
allergens can cause anaphylaxis in children with cow's milk allergy." J Allergy Clin Immunol
119(3): 746-747. Exclude-Rec Intervention
Lei, V., H. Friis, et al. (2006). "Spontaneously fermented millet product as a natural probiotic
treatment for diarrhoea in young children: an intervention study in Northern Ghana." Int J Food
Microbiol 110(3): 246-253. Exclude-NoAE
Leonard, F., A. Andremont, et al. (1989). "Use of beta-lactamase-producing anaerobes to prevent
ceftriaxone from degrading intestinal resistance to colonization." J Infect Dis 160(2): 274-280.
Exclude-Intervention
Lerebours, E., C. N'Djitoyap Ndam, et al. (1989). "Yogurt and fermented-then-pasteurized milk:
effects of short-term and long-term ingestion on lactose absorption and mucosal lactase activity
in lactase-deficient subjects." Am J Clin Nutr 49(5): 823-827. Exclude-Rec Intervention
Lessard, M., M. Dupuis, et al. (2009). "Administration of Pediococcus acidilactici or
Saccharomyces cerevisiae boulardii modulates development of porcine mucosal immunity and
reduces intestinal bacterial translocation after Escherichia coli challenge." J Anim Sci 87(3):
922-934. Exclude-Participants
Lestin, F. (2003). "Fungemia after oral treatment with Saccharomyces boulardii in a patient with
multiple co-morbidities." Exclude-Duplicate 2017
Lewis, S. (2007). "Response to the article: McFarland LV. Meta-analysis of probiotics for the
prevention of antibiotic-associated diarrhea and the treatment of Clostridium difficile disease.
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D-43
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D-44
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D-45
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D-46
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D-47
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D-48
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D-49
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D-51
Miraglia del Giudice, M. and M. G. De Luca (2004). "The role of probiotics in the clinical
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Exclude-Design
Moayyedi, P., A. C. Ford, et al. (2010). "The efficacy of probiotics in the treatment of irritable
bowel syndrome: a systematic review." Gut 59(3): 325-332. Exclude-Duplicate 5233
Modi, N., S. Uthaya, et al. (2010). "A randomised, double-blind, controlled trial of the effect of
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Moneret-Vautrin, D. A., M. Morisset, et al. (2006). "Probiotics may be unsafe in infants allergic
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D-52
Montineri, A., C. Iacobello, et al. (2008). "[Saccharomyces cerevisiae fungaemia associated to
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Moreira, A., R. Kekkonen, et al. (2007). "Allergy in marathon runners and effect of
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Morelli, L. and E. Campominosi (2002). "Genetic stability of Lactobacillus paracasei subsp
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819. Exclude-Rec Intervention
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coincides with promotion of Bifidobacterium longum-infantis and Bifidobacterium breve in
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nigerooligosaccharides and heat-killed Lactobacillus plantarum L-137 on skin symptom and
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Exclude-NoAE
Mustapha, A., T. Jiang, et al. (1997). "Improvement of lactose digestion by humans following
ingestion of unfermented acidophilus milk: influence of bile sensitivity, lactose transport, and
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D-53
Myllyluoma, E., L. Veijola, et al. (2005). "Probiotic supplementation improves tolerance to
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Nakajima, S., Y. Setoguchi, et al. (2005). "[Effect of probiotics on the prevention of diarrhea in
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D-54
Nikitenko, V. I., G. N. Zolotareva, et al. (2010). "[Sporobakterin impact on atherogenic
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Exclude-NoAE
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Nonaka, Y., T. Izumo, et al. (2008). "Antiallergic effects of Lactobacillus pentosus strain S-PT84
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Exclude-NoAE
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Ogier, J.-C. and P. Serror (2008). "Safety assessment of dairy microorganisms: The
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D-55
Ohno, H., S. Tsunemine, et al. (2005). "Oral administration of Bifidobacterium bifidum G9-1
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Exclude-NoAE
Olah, A., T. Belagyi, et al. (2002). "Randomized clinical trial of specific lactobacillus and fibre
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D-56
Osipova, I. G., I. B. Sorokulova, et al. (1998). "[Safety of bacteria of the genus Bacillus, forming
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combination of Lactobacillus rhamnosus GG and antibodies." BMC Microbiol 7: 86. ExcludeParticipants
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Am J Clin Nutr 89(6): 1751-1759. Exclude-Intervention
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D-57
Pawlowska, J., E. Klewicka, et al. (2007). "Effect of Lactobacillus casei DN-114001 application
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Peng, S., J. Y. Lin, et al. (2007). "Antiallergic effect of milk fermented with lactic acid bacteria
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Peral, M. C., M. M. Rachid, et al. (2010). "Interleukin-8 production by polymorphonuclear
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Clin Microbiol Infect 16(3): 281-286. Exclude-NoAE
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Peret Filho, L. A., F. J. Penna, et al. (1998). "Dose effect of oral Saccharomyces boulardii
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D-58
Pessi, T., Y. Sutas, et al. (2000). "Interleukin-10 generation in atopic children following oral
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Phuapradit, P., W. Varavithya, et al. (1999). "Reduction of rotavirus infection in children
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Exclude-NoAE
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Pichkhadze, G. M., V. P. Rusanov, et al. (2000). "[The antagonistic activity of the eubiotic
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Pilipenko, V. I., E. A. Burliaeva, et al. (2009). "[Efficacy of using inulin fortified fermented milk
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(Russian)
Pirotta, M., J. Gunn, et al. (2004). "The PAV trial: does lactobacillus prevent post-antibiotic
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postoperative infections in patients undergoing abdominal surgery? A meta-analysis of
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Pitzurra, R., R. Steffen, et al. (2010). "Diarrhoea in a large prospective cohort of European
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Planeta-Malecka, I., L. Bak-Romaniszyn, et al. (2004). "Probiotics in the treatment of
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Exclude-Design (Polish)
Plein, K. and J. Hotz (1993). "Therapeutic effects of Saccharomyces boulardii on mild residual
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12363
Plewinska, E. M., P.-M. I., et al. (2006). "Probiotics in the treatment of Helicobacter pylori
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D-59
Plummer, S., M. A. Weaver, et al. (2004). "Clostridium difficile pilot study: effects of probiotic
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Pochapin, M. (2000). "The effect of probiotics on Clostridium difficile diarrhea." Am J
Gastroenterol 95(1 Suppl): S11-13. Exclude-NoAE
Pohjavuori, E., M. Viljanen, et al. (2004). "Lactobacillus GG effect in increasing IFN-gamma
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Exclude-NoAE
Pool-Zobel, B. L. (2005). "Inulin-type fructans and reduction in colon cancer risk: review of
experimental and human data." Br J Nutr 93 Suppl 1: S73-90. Exclude-Intervention
Posteraro, B., M. Sanguinetti, et al. (1999). "Molecular and epidemiological characterization of
vaginal Saccharomyces cerevisiae isolates." J Clin Microbiol 37(7): 2230-2235. ExcludeIntervention
Pothoulakis, C., C. P. Kelly, et al. (1993). "Saccharomyces boulardii inhibits Clostridium
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Exclude-Participants
Poty, F. C. and J. A. Poty (1979). "[Urinary tract infections caused by Lactobacillus (author's
transl)]." Nouv Presse Med 8(45): 3755-3756. Exclude-Rec Intervention (Foreign Language)
Prajapati, J., R. Shah, et al. (1986). "Nutritional and therapeutic benefits of a blended-spray dried
acidophilus preparation " Cultured Dairy Prod J: 16-21. Exclude-NoAE
Prantera, C. (2006). "Should probiotics be given as an adjunct to standard maintenance therapy
for children with Crohn's disease?" Nat Clin Pract Gastroenterol Hepatol 3: 130-131. ExcludeRec Design
Prantera, C., F. Zannoni, et al. (1996). "An antibiotic regimen for the treatment of active Crohn's
disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin." Am J
Gastroenterol 91(2): 328-332. Exclude-Intervention
Prescott, S. L., J. A. Dunstan, et al. (2005). "Clinical effects of probiotics are associated with
increased interferon-gamma responses in very young children with atopic dermatitis." Clin Exp
Allergy 35(12): 1557-1564. Exclude-NoAE
Prescott, S. L., K. Wickens, et al. (2008). "Supplementation with Lactobacillus rhamnosus or
Bifidobacterium lactis probiotics in pregnancy increases cord blood interferon-gamma and breast
milk transforming growth factor-beta and immunoglobin A detection." Clin Exp Allergy 38(10):
1606-1614. Exclude-NoAE
Prescott, S. L., J. Wiltschut, et al. (2008). "Early markers of allergic disease in a primary
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Preter, V. d., H. Raemen, et al. (2008). "Effect of dietary intervention with different pre- and
probiotics on intestinal bacterial enzyme activities." European journal of clinical nutrition 62(2):
225-231. Exclude-NoAE
D-60
"Probiotic blocks HIV transmission via breastfeeding." AIDS Patient Care STDS 2008;22(8):
687. Exclude-NoAE
"Probiotic normalizes bowel function in IBS." Clinical Infectious Diseases 2006;42(1): iii.
Exclude-NoAE
"A probiotic strain of Escherichia coli, Nissle 1917, given orally exerts local and systemic antiinflammatory effects in lipopolysaccharide-induced sepsis in mice." 2009. Exclude-Participants
"Probiotic supplements improve atopic dermatitis in infants." Anonymous Nurs Times
2005;101(23): 7. Exclude-Rec Design
"Probiotic therapy may prevent necrotizing enterocolitis in preterm infants." Clinical Infectious
Diseases 2005;41(2): IV. Exclude-NoAE
"Probiotics and eczema prevention: a randomized study." Nutrition & the M D 2004;30(8): 5-6.
Exclude-Design
"Probiotics for antibiotic-associated diarrhoea." Bandolier 2002; 9(10): 1-2. Exclude-NoAE
"Probiotics in late pregnancy/early infancy confer antiallergy protection." Alternative &
Complementary Therapies 2003;9(4): 155-156. Exclude-NoAE
Pronio, A., C. Montesani, et al. (2008). "Probiotic administration in patients with ileal pouchanal anastomosis for ulcerative colitis is associated with expansion of mucosal regulatory cells."
Inflamm Bowel Dis 14(5): 662-668. Exclude-NoAE
Qin, H., J. Zheng, et al. (2008). "Effect of Lactobacillus plantarum enteral feeding on the gut
permeability and septic complications in the patients with acute pancreatitis." European Journal
of Clinical Nutrion 62(7): 923-930. Exclude-Rec NoAE
Qualia, C. and A. Bousvaros (2010). "Probiotic for new onset ulcerative colitis in children:
baby's got bac(teria)." Inflamm Bowel Dis 16(1): 177-178. Exclude-Design
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Quliyev, N. and N. Huseynova (2007). "Dynamics of immune indices at newborn with intestinal
dysbacteriosis during treatment by probiotics." Azerbaijan Medical Journal 4: 110-112. ExcludeNoAE (Azerbaijani)
Radke, M. (2009). "Pro- and prebiotics for nutrition of preterm infants and newborns."
Padiatrische Praxis 73(1): 49-57. Exclude-NoAE (Foreign Language)
Rafeey, M., A. Ostadrahimi, et al. (2008). "Lactobacillus acidophilus yogurt and supplement in
children with acute diarrhea: A clinical trial." Research Journal of Medical Sciences 2(1): 13-18.
Exclude-NoAE
Rafter, J. (2003). "Probiotics and colon cancer." Best Pract Res Clin Gastroenterol 17(5): 849
859. Exclude-Design
Rahimi, R., S. Nikfar, et al. (2008). "A meta-analysis on the efficacy of probiotics for
maintenance of remission and prevention of clinical and endoscopic relapse in Crohn's disease."
Dig Dis Sci 53(9): 2524-2531. Exclude-NoAE
D-61
Rahman, M. (1982). "Chest infection caused by Lactobacillus casei ss rhamnosus." Br Med J
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lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis (Br
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Rajala, S. A., S. J. Salminen, et al. (1988). "Treatment of chronic constipation with lactitol
sweetened yoghurt supplemented with guar gum and wheat bran in elderly hospital in-patients."
Compr Gerontol A 2(2): 83-86. Exclude-Rec Intervention
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treatment of called-up servicemen with community-acquired pneumonia]." Voen Med Zh 327(4):
15-22. Exclude-Rec Intervention (Russian)
Rapoport, L. and W. I. Levine (1965). "Treatment of oral ulceration with lactobacillus tablets.
Report of forty cases." Oral Surg Oral Med Oral Pathol 20(5): 591-593. Exclude-NoAE
Rautanen, T., E. Isolauri, et al. (1998). "Management of acute diarrhoea with low osmolarity oral
rehydration solutions and Lactobacillus strain GG." Arch Dis Child 79(2): 157-160. ExcludeNoAE
Rautava, S., H. Arvilommi, et al. (2006). "Specific probiotics in enhancing maturation of IgA
responses in formula-fed infants." Pediatr Res 60(2): 221-224. Exclude-NoAE
Rautava, S., S. Salminen, et al. (2009). "Specific probiotics in reducing the risk of acute
infections in infancy--a randomised, double-blind, placebo-controlled study." Br J Nutr 101(11):
1722-1726. Exclude-Duplicate 3761
Rayes, N. (2004). "Lactobacilli and fibers -- a strong couple against bacterial infections in
patients with major abdominal surgery." Nutrition 20(6): 579-580. Exclude-NoAE
Raza, S., S. M. Graham, et al. (1995). "Lactobacillus GG promotes recovery from acute
nonbloody diarrhea in Pakistan." Pediatr Infect Dis J 14(2): 107-111. Exclude-NoAE
"Recurrent septicemia in an immunocompromised patient due to probiotic strains of Bacillus
subtilis [2]." Journal of Clinical Microbiology 1998;36(1): 32. Exclude-Duplicate 679
Reddy, B. S., J. Macfie, et al. (2007). "Randomized clinical trial of effect of synbiotics,
neomycin and mechanical bowel preparation on intestinal barrier function in patients undergoing
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Reddy, B. S. and A. Rivenson (1993). "Inhibitory effect of Bifidobacterium longum on colon,
mammary, and liver carcinogenesis induced by 2-amino-3-methylimidazo[4,5-f]quinoline, a
food mutagen." Cancer Res 53(17): 3914-3918. Exclude-Participants
Reid, G. (1999). "Testing the efficacy of probiotics in: Probiotics: a Critical Review." Horizon
Scientific Press: 129-140. Exclude-NoAE
Reid, G. (2001). "Probiotic agents to protect the urogenital tract against infection." Am J Clin
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D-62
Reid, G. and J. Burton (2002). "Use of Lactobacillus to prevent infection by pathogenic
bacteria." Microbes Infect 4(3): 319-324. Exclude-NoAE
Reid, G., J. Burton, et al. (2004). "Nucleic acid-based diagnosis of bacterial vaginosis and
improved management using probiotic lactobacilli." J Med Food 7(2): 223-228. Exclude-NoAE
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1081. Exclude-NoAE
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pathways by VSL#3, a biotherapeutic agent, in the treatment of inflammatory bowel disease."
Inflamm Bowel Dis 15(11): 1721-1736. Exclude-Participants
Rembacken, B. J., A. M. Snelling, et al. (1999). "Non-pathogenic Escherichia coli versus
mesalazine for the treatment of ulcerative colitis: a randomised trial." Lancet 354(9179): 635
639. Exclude-Genus
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44(1): 59-63. Exclude-Intervention
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adminstration of Lactobacillus plantarum 299V in a day care facility, Abstract #P162." 5th Joint
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Rincon Sanchez, A. R. and A. M. Rivas-Estilla (2006). "Role of probiotics in hepatic ischemia
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Gastroenterol Nutr 43(2): 200-205. Exclude-NoAE
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improves breath-hydrogen status and short-chain fatty acid profiles: a controlled study in healthy
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D-63
Robertson, J. (2000). "In children receiving antibiotics, does coadministration of Lactobacillus
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microbiota and growth of infants." J Pediatr Gastroenterol Nutr 41: 508. Exclude-Intervention
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Rosenfeldt, V., K. F. Michaelsen, et al. (2002). "Effect of probiotic Lactobacillus strains in
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D-64
Rossouw, J. E., E. M. Burger, et al. (1981). "The effect of skim milk, yoghurt, and full cream
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D-65
Sakata, T., T. Kojima, et al. (1999). "Probiotic preparations dose-dependently increase net
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D-66
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D-67
Sazawal, S., U. Dhingra, et al. (2007). "Effects of fortified milk on morbidity in young children
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D-68
Scholtens, P. A., M. S. Alles, et al. (2006). "Bifidogenic effects of solid weaning foods with
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Scribano, M. L. and P. C. (2004). "Use of antibiotics and probiotics in inflammatory bowel
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Gastroenterology 107(3): 643-649. Exclude-Intervention
See, J. (2006). "Lactobacillus endocarditis: Case report and literature review." Exclude-Rec
Genus
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Gastoenterologie 45(11): 1110. Exclude-Rec Design (Foreign Language)
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Database of Systematic Reviews 4. Exclude-Design
D-69
Senok, A. C., A. Y. Ismaeel, et al. (2005). "Probiotics: facts and myths." Clin Microbiol Infect
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Sentongo, T. A., V. Cohran, et al. (2008). "Intestinal permeability and effects of Lactobacillus
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309-314. Exclude-NoAE
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fructooligosaccharide supplementation during pregnancy on maternal and neonatal microbiota
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Shah, U. and W. A. Walker (2000). "Adverse host responses to bacterial toxins in human
infants." J Nutr 130(2S Suppl): 420S-425S. Exclude-Design
Shalev, E. (2002). "Ingestion of probiotics: optional treatment of bacterial vaginosis in
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Shanahan, F. (2002). "Probiotics and inflammatory bowel disease: from fads and fantasy to facts
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Exclude-NoAE
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D-70
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16: 1669-1675. Exclude-Duplicate 1749
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Aliment Pharmacol Ther 16(9): 1669-1675. Exclude-NoAE
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Sicherer, S. H. and L. S. Ford (2009). "Probiotic supplementation in the first 6 months of life in
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D-71
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Exclude-Design
Simren, M., A. Syrous, et al. (2006). "Effects of Lactobacillus Plantarum 299V on symptoms and
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Soh, S. E., M. Aw, et al. (2009). "Probiotic supplementation in the first 6 months of life in at risk
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Soh, S. E., M. Aw, et al. (2009). "Probiotic supplementation in the first 6 months of life in at risk
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D-72
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Sorokulova, I. B. (1998). "[The safety and reactogenicity of the new probiotic subalin for
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D-73
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D-74
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D-75
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D-76
Tiollier, E., M. Chennaoui, et al. (2007). "Effect of a probiotics supplementation on respiratory
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Torii, A., S. Torii, et al. (2007). "Lactobacillus Acidophilus strain L-92 regulates the production
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Microbiologie Aliments Nutrition 4(2): 101-106. Exclude-Participants
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Tsangalis, D., G. Wilcox, et al. (2007). "Urinary excretion of equol by postmenopausal women
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Exclude-NoAE
Tsangalis, D., G. Wilcox, et al. (2005). "Bioavailability of isoflavone phytoestrogens in
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D-77
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D-79
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D-80
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D-81
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D-82
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D-83
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D-84
Zubadalashvili, N. G., M. A. Makhviladze, et al. (2009). "[The comparative study of Linex and
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D-85
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Appendix E. Technical Expert Panel and Peer
Reviewers
Technical Expert Panel
Michael D. Cabana, M.D., M.A., M.P.H.
Division of General Pediatrics
University of California San Francisco Benioff Children’s Hospital
San Francisco, CA
Cara Fiore, Ph.D.
Center for Biologics Evaluation and Research
Food and Drug Administration
Rockville, MD
Barry R. Goldin, M.S., Ph.D.
Department of Public Health and Community Medicine
Tufts University School of Medicine
Boston, MA
Patricia Hibberd, M.D., Ph.D.
Center for Global Health Research
Tufts University School of Medicine
Boston, MA
David Mills, M.S., Ph.D.
Department of Viticulture and Enology
University of California, Davis
Davis, CA
Mary Ellen Sanders, Ph.D.
Dairy and Food Culture Technologies
Centennial, CO
Maija-Liisa Saxelin, Ph.D.
Formerly Valio Ltd., R&D00101
Helsinki, Finland
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Alain L. Servin, Ph.D.
Faculty of Pharmacy
French National Institute of Health and Medical Research
Paris, France
Jon A. Vanderhoof, M.D.
Boys Town National Research Hospital, Mead Johnson Nutrition
Boys Town, NE
Peer Reviewers
Ger Rijkers, Ph.D.
Department of Surgery
University Medical Center Utrecht
Utrecht, Netherlands
Louis M.A. Akkermans, Ph.D.
Gastrointestinal Research Unit
University Medical Center Utrecht
Utrecht, Netherlands
Marc G.H. Besselink, M.D., Ph.D.
Department of Surgery
University Medical Center Utrecht
Utrecht, Netherlands
Daniel Buijs, M.Sc.
Natural Health Products Directorate, Health Products and Food Branch
Health Canada
Ottawa, Ontario, Canada
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