Interventions for Tuberculosis Control and Elimination 2002

Tuberculosis Interventions 

Interventions for 

Tuberculosis Control 

and Elimination 

2002 

International Union Against Tuberculosis 

and Lung Disease

Interventions for 

Tuberculosis Control and 

Elimination 

2002 

Hans L Rieder 

International Union Against Tuberculosis and Lung 

Disease 

68, boulevard Saint Michel, 75006 Paris, France 

The publication of this guide was made possible thanks to the support of the United 

States Centers for Disease Control and Prevention, the British Columbia Lung 

Association, the French Ministry of Foreign Affairs, and the Norwegian Royal Ministry 

of Foreign Affairs.

Editor 

International Union Against Tuberculosis and Lung Disease (IUATLD), 

68 boulevard Saint Michel, 75006 Paris, France 

Author : H. L. Rieder 

© International Union Against Tuberculosis 

and Lung Disease (IUATLD) 

March 2002 

All rights reserved 

No part of this publication may be reproduced without the prior permission 

of the authors, and the publisher. 

ISBN : 2-914365-11-X 

II

Table of contents 

Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 

Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 

Summary – the role of specific interventions . . . . . . . . . . . . . . . . . . . . . . . 9 

1. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 

Essential drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 

Isoniazid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 

Rifampicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 

Pyrazinamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 

Ethambutol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 

Streptomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 

Thioacetazone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 

Fixed-dose combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 

Principal prerequisites for an efficacious anti-tuberculosis drug. . . . . . . . . . . 50 

Early bactericidal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 

Sterilizing activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 

Ability to prevent emergence of resistance to the companion drug . . . . . . 53 

Emergence of anti-tuberculosis drug resistance . . . . . . . . . . . . . . . . . . . . . 54 

Effective or functional monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . 55 

Monotherapy during sterilization of special populations . . . . . . . . . . . . . 56 

Differences in bactericidal activity . . . . . . . . . . . . . . . . . . . . . . . . . . 57 

Sub-inhibitory concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 

Differences in post-antibiotic effect (lag phase) . . . . . . . . . . . . . . . . . . 59 

Clinical trials in the treatment of pulmonary tuberculosis . . . . . . . . . . . . . . 59 

Streptomycin monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 

Streptomycin plus para-aminosalicylic acid . . . . . . . . . . . . . . . . . . . . . 61 

Streptomycin plus para-aminosalicylic acid plus isoniazid. . . . . . . . . . . . 62 

Isoniazid plus ethambutol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 

Isoniazid plus thioacetazone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 

Isoniazid plus rifampicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 

III

Isoniazid plus rifampicin plus pyrazinamide (plus a fourth drug) . . . . . . . 66 

Rifampicin-containing continuation phase . . . . . . . . . . . . . . . . . . . . 67 

Non-rifampicin-containing continuation phase . . . . . . . . . . . . . . . . . 68 

Intermittent regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 

Treatment regimens of less than six months’ duration . . . . . . . . . . . . . . 70 

Clinical trials in extrapulmonary tuberculosis . . . . . . . . . . . . . . . . . . . . . . 71 

Tuberculosis of peripheral lymph nodes . . . . . . . . . . . . . . . . . . . . . . . 71 

Tuberculosis of the spine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 

Tuberculosis of the central nervous system . . . . . . . . . . . . . . . . . . . . . 73 

Influence of HIV infection on the choice of a regimen. . . . . . . . . . . . . . . . 74 

Adverse drug events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 

Treatment efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 

Influence of isoniazid resistance on the choice of a regimen . . . . . . . . . . . . 77 

Influence of isoniazid plus rifampicin resistance on the choice of a regimen . . 78 

Strategic considerations, indications, and recommendations for the choice 

of treatment regimens in a national tuberculosis control program . . . . . . . 78 

Choice of first-line regimen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 

8-month regimens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 

6-month regimens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 

12-month regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 

Choice of re-treatment regimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 

Treatment of patients with organisms resistant to isoniazid and rifampicin . 82 

Case holding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 

Directly observed treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 

Can emergence of drug resistance be outpaced in a national tuberculosis 

program? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 

The approach to management of adverse drug events . . . . . . . . . . . . . . . . . 86 

The patient with hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 

The patient with gastrointestinal symptoms . . . . . . . . . . . . . . . . . . . . . 88 

The patient with impaired vision . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 

The patient with vestibulo-cochlear toxicity . . . . . . . . . . . . . . . . . . . . 89 

The patient with neurologic symptoms. . . . . . . . . . . . . . . . . . . . . . . . 89 

The patient with hypersensitivity reactions or muco-cutaneous signs 

and symptoms of toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 

The patient with hematologic abnormalities. . . . . . . . . . . . . . . . . . . . . 90 

The patient with acute renal toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 91 

The patient with osteo-articular pain . . . . . . . . . . . . . . . . . . . . . . . . . 91 

The approach to the patient with pre-existing medical conditions . . . . . . . . . 91 

The patient with liver injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 

The patient with renal failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 

IV

The patient with impaired hearing or impaired balance . . . . . . . . . . . . . 92 

The patient with impaired vision . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 

The patient with gastrointestinal malabsorption . . . . . . . . . . . . . . . . . . 92 

The pregnant patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 

2. Prophylactic treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 

Rationale and experiences with prophylactic treatment . . . . . . . . . . . . . . . . 95 

Indications and recommendations for the use of prophylactic treatment . . . . . 96 

3. Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 

Early vaccine development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 

Vaccination with Mycobacterium bovis . . . . . . . . . . . . . . . . . . . . . . . 97 

Vaccination with Mycobacterium chelonae . . . . . . . . . . . . . . . . . . . . . 97 

Vaccination with BCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 

Vaccine development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 

The BCG strain family. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 

Safety record of BCG vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . 101 

Management of adverse reactions due to BCG vaccination . . . . . . . . . . . 104 

Efficacy and effectiveness of BCG vaccination . . . . . . . . . . . . . . . . . . 104 

Prospective and retrospective studies on BCG vaccination . . . . . . . . . . . 107 

Protection conferred by BCG vaccination against disseminated 

and meningeal tuberculosis, and against death from tuberculosis . . . 108 

Protection conferred by BCG vaccination of newborns and infants . . . 109 

Protection conferred by BCG vaccination of children over one year 

of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 

Protection conferred by BCG vaccination among adolescents and adults . . 112 

Protection conferred by BCG vaccination across various age groups . . 114 

Hypotheses about the variation in the efficacy of BCG vaccination . . . . . 115 

Differences in methodological stringency . . . . . . . . . . . . . . . . . . . . 116 

Differences in vaccine strains . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 

Differences in vaccine dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 

Differences in virulence of M. tuberculosis strains . . . . . . . . . . . . . . 117 

Differences in risk attributable to exogenous re-infection tuberculosis. . 118 

Differences in genetic make-up of vaccinees. . . . . . . . . . . . . . . . . . 118 

Differences in nutritional status of vaccinees . . . . . . . . . . . . . . . . . 118 

Differences in prevalence of infection with environmental mycobacteria . . 119 

Other factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 

BCG revaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 

Effects of BCG other than those directed against tuberculosis . . . . . . . . . . . 123 

Indications and recommendations for the use of BCG vaccination. . . . . . . . . 123 

V

4. Preventive chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 

Prevention of disease in tuberculin skin test reactors . . . . . . . . . . . . . . . . . 128 

Prevention of disease in persons with risk factors . . . . . . . . . . . . . . . . . . . 130 

Recently acquired infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 

Infection with the human immunodeficiency virus . . . . . . . . . . . . . . . . 131 

Spontaneously healed tuberculosis with fibrotic residuals . . . . . . . . . . . . 134 

Silicosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 

Renal failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 

Prevention of disease following cessation of preventive chemotherapy . . . . . . 136 

Prevention of disease with different durations of treatment . . . . . . . . . . . . . 136 

Prevention of disease with alternatives to isoniazid . . . . . . . . . . . . . . . . . . 138 

Rifampicin and rifampicin combinations in comparison to placebo . . . . . . 140 

Rifampicin and rifampicin combinations in comparison to isoniazid . . . . . 141 

Effectiveness of preventive chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . 143 

Indications and recommendations for the use of preventive chemotherapy . . . . 145 

Appendix 1 – Adjunctive treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 

Adjunctive therapy with corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . 147 

Pulmonary tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 

Extrapulmonary tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 

Tuberculosis of serous membranes . . . . . . . . . . . . . . . . . . . . . . . . . . 148 

Pleural tuberculosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 

Pericardial tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 

Peritoneal tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 

Meningeal tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 

Corticosteroid treatment in other forms of tuberculosis . . . . . . . . . . . . . 150 

The role of surgery in the chemotherapy era . . . . . . . . . . . . . . . . . . . . . . 150 

Surgical treatment in respiratory tract tuberculosis . . . . . . . . . . . . . . . . . . . 151 

Tuberculous pyopneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 

Pleural tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 

Surgical treatment in tuberculosis of the spine . . . . . . . . . . . . . . . . . . . . . 152 

Appendix 2 – Active agents other than essential drugs and drug classes 

(second-line drugs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 

Aminoglycosides (other than streptomycin) . . . . . . . . . . . . . . . . . . . . . 153 

Amikacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 

Kanamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 

Capreomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 

Cycloserine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 

VI

Para-aminosalicylic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 

Quinolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 

Rifamycins other than rifampicin . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 

Rifabutin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 

Rifapentine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 

Thioamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 

Drugs and drug classes with potential activity against M. tuberculosis 

under investigation and development . . . . . . . . . . . . . . . . . . . . . . . . . 161 

Acetamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 

Amoxicillin plus clavulanic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 

Clarithromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 

Fullerene derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 

Nitroimidazopyrans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 

Oxazolidinones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 

Paromomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 

Phenothiazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 

Tuberactinomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 

Appendix 3 – Current vaccine development strategies . . . . . . . . . . . . . . . . . 167 

Immunotherapy with M. vaccae . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 

Vaccination with saprophytic (environmental) mycobacteria . . . . . . . . . . 168 

Auxotrophs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 

DNA vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 

Recombinants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 

Subunits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 

VII

Acknowledgments 

It would not have been possible to compile this review of currently available 

interventions without the help of numerous colleagues who dedicated 

time and effort to review chapters that touched upon their specific field of 

expertise. 

Particular appreciation goes to Richard J O’Brien, Donald A Enarson, 

and Arnaud Trébucq who reviewed the entire monograph, offered critical 

advise, proposed corrections and, most importantly, suggested improvements 

in the structure and flow of argumentation. Thuridur Arnadottir, José A 

Caminero, Bernard Fourie, Denis A Mitchison, Mario C Raviglione, Victoria 

Romanus, Dean E Schraufnagel, Amalio Telenti, and Jean-Pierre Zellweger 

made specific comments on various chapters, pointed out errors and inaccuracies, 

and provided additional references to complete the picture. Anne 

Fanning, Giovanni-Battista Migliori, Robert Loddenkemper, and Li-Xing 

Zhang offered helpful comments on the manuscript. Masashi Suchi provided 

access to some Japanese literature and offered translation of relevant 

parts thereof. Uwe Molkentin unearthed literature to close gaps on the 

understanding of the Lübeck disaster. 

Clare Pierard provided editorial assistance in improving the readability 

of the manuscript. 

1

Preface 

This monograph adds a module to the series on the scientific basis of tuberculosis 

control (figure 1). 1 The International Tuberculosis Courses of the 

International Union Against Tuberculosis and Lung Disease (IUATLD) follow 

a logical sequence with these five modules. These courses are directed 

principally at managers of national tuberculosis control programs, largely 

in low-income countries. 

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Figure 1. Modules and flow of teaching in the international tuberculosis courses 

of the IUATLD. 1 

The courses start with the bacteriologic basis of tuberculosis control, 

for which several documents are available. 2-6 In a second module, the 

effect of tubercle bacilli on the human host, the clinical presentation and 

diagnosis of tuberculosis is presented for which the book by Sir John Crofton 

and collaborators is used as background material. 7 Following this second 

module, the impact of tubercle bacilli on the community is presented, i.e., 

the epidemiologic basis of tuberculosis control. 1 Once these three facets 

– the agent, the individual, and the community – are understood, the various 

available interventions are discussed, and finally it needs to be specifically 

demonstrated how this knowledge can be integrated into the practice 

of a national tuberculosis control program. 8 The time allotted to each of 

these modules is determined by the requirements of the audience. 

3

This monograph deals with the fourth module, interventions directed 

against Mycobacterium tuberculosis complex. There are numerous excellent 

reviews on the various available interventions. Often, they deal with 

one specific intervention. This monograph tries to assemble information 

about each available intervention and to weigh the role of each in current 

practice. Appendices provide additional information on current developments. 

The presentation should make it easy for the reader to select individual 

chapters of particular interest. 

It is hoped that this module offers the review of currently available 

interventions that participants have been requesting since the inception of 

the IUATLD courses. 

Paris, November 2001 

4

Introduction 

The aim of interventions in tuberculosis control or elimination strategies is 

to reduce or eliminate the adverse impact of epidemiological risk factors 

that promote the progression from one step to the next in the pathogenetically 

based model (figure 2). 9 

There are four principal interventions at our disposal to accomplish 

this task (figure 3): 10 

• Treatment of tuberculosis reduces the risk of death from tuberculosis, 

aims at restoring health and curing patients, and reduces the risk of 

transmission of tubercle bacilli in the community. 

• Prophylactic treatment aims at preventing infection with Mycobacterium 

tuberculosis from occurring. 

• Vaccination with Bacille Calmette-Guérin (BCG) before acquisition of 

infection with M. tuberculosis aims at priming the immune system, so 

that the risk of progression from sub-clinical, latent tuberculous infection 

to clinically overt tuberculosis is reduced should such infection be 

acquired. 

• Preventive chemotherapy is treatment of sub-clinical, latent 

Mycobacterium tuberculosis populations in the human host, given to 

reduce the risk of progression to clinically overt tuberculosis. 

The key to improving the epidemiologic situation is linked to the specifics 

of the transmission (incidence) and prevalence of infection with M. tuberculosis. 

1 This has consequences for the role of the interventions. 

The principal strategy aims at reducing the incidence infection with 

M. tuberculosis. A reduction in incidence of tuberculous infection is 

achieved by as swift as possible identification of potential transmitters of 

tubercle bacilli, i.e., the identification of persons with tuberculosis of the 

respiratory tract. Amongst these the most infectious are the patients with 

such a high bacillary load that the bacilli can be identified using sputum 

smear microscopy. While these patients account for only roughly half of 

all cases of pulmonary tuberculosis, they are the most potent sources of 

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Figure 2. Pathogenetically-based model of the epidemiology of tuberculosis. 1 

Reproduced from 9 by the permission of the publisher Urban & Vogel. 

transmission (figure 4). 11 Once identified, they should be quickly and permanently 

rendered non-infectious through chemotherapy. In the terminology 

used in this monograph, this approach is called “tuberculosis control”. 

Thus, tuberculosis control is the strategy aimed at reducing the incidence 

of tuberculous infection. This strategy also includes prophylactic treatment, 

defined as the provision of chemotherapy to persons exposed to, but not 

yet infected with M. tuberculosis. 

The second strategy aims at reducing the prevalence infection with 

M. tuberculosis. Because M. tuberculosis probably survives in a large 

proportion of persons for years following acquisition, tuberculosis will 

continue to emerge from the pool of persons who are already infected. 

A strategy to reduce the prevalence of infection in the community will 

be designated “tuberculosis elimination strategy” in the context of this 

monograph. Tuberculous infection is highly prevalent in virtually every 

country’s population, but varies demographically in important ways. 1 

To be epidemiologically effective, preventive chemotherapy to reduce 

the prevalence of infection must target groups that are both easily identifiable 

and that potentially contribute a large fraction of future morbidity. 

Vaccination with BCG varies somewhat from this concept, as it aims 

at reducing the risk of progression from infection to disease. Consequently, 

its effect is expected to be similar to that of the strategy to reduce the 

prevalence of infection. 

The options available to address the tuberculosis problem in a community 

will first aim at reducing the incidence of tuberculous infection 

(case-finding and treatment of the most infectious cases, supplemented by

prophylactic treatment of special populations). Where this has been achieved 

and maintained over a substantial period of time, a reduction of the prevalence 

of tuberculous infection by preventive chemotherapy must be considered 

as the next logical step. Vaccination with BCG will supplement 

tuberculosis control efforts, particularly in high-burden countries, mainly by 

reducing disability and death in young children. 

In this monograph, the approach chosen to discuss the various interventions 

follows the sequence in the epidemiological model presented 

elsewhere (figure 2). 1,9 Interventions aim at reducing the impact of 

those risk factors recognized to promote the progression from one step 

to the next in the chain of events in the pathogenesis of tuberculosis 

(figure 3). 10 

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Figure 3. Model of interventions based on the epidemiology of tuberculosis. 

Reproduced from 10 by the permission of the publisher Marcel Dekker.

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Figure 4. Sensitivity of sputum smear microscopy in identifying pulmonary tuberculosis 

among culture-confirmed cases and sensitivity of sputum smear microscopy 

in identifying transmitters of M. tuberculosis. 11

Chemotherapy 

Summary – the role 

of specific interventions 

Chemotherapy of tuberculosis is universally indicated for all newly identified 

tuberculosis patients. No patient with newly diagnosed tuberculosis 

should be denied treatment. 

Chemotherapy is the most powerful weapon in tuberculosis control. 

It carries individual benefit by reducing morbidity and fatality. It has epidemiologic 

impact by cutting the chain of transmission effectively if effective 

treatment leading to cure of individual patients can be assured. 

A national tuberculosis program must choose and recommend efficacious, 

standardized treatment regimens and must ensure both that they are 

administered carefully to prevent emergence of drug resistance and the cure 

of the patient. 

The limited armamentarium of available anti-tuberculosis medications 

imposes particular constraints on the use of the most efficacious drugs. 

Regimens and their administration should be designed to prevent the emergence 

of chronic excretors with incurable, multidrug-resistant tuberculosis. 

The following six drugs are currently on the essential drug list: 

• Isoniazid is the cornerstone of every first-line regimen. It has the most 

potent early bactericidal activity of all known drugs. It rarely causes 

adverse drug events, the most important of which is hepatic injury, 

which may result in hepatitis in a small fraction of patients. It interacts 

with several medications, but the single most important is its 

enhancement of the effect of anti-epileptics. 

• Rifampicin has unique relapse-preventing properties that allowed the 

duration of chemotherapy to be shortened to nine months or fewer. It 

is a superbly tolerated drug that may, however, complicate isoniazidassociated 

hepatitis, mainly by supporting cholestasis. Immunologicallylinked 

events might be serious and life-threatening, but are very rare. 

Rifampicin interacts with a multitude of other medications: the most 

important interactions in practice are reduction of the efficacy of oral 

9

contraceptives and anti-retroviral medications, which preclude any such 

combination. 

• Pyrazinamide also has particular relapse-preventing properties that have 

allowed the duration of required chemotherapy to be further reduced. 

In the currently recommended dosages, it is also a very well tolerated 

drug. Arthralgias are the most frequently reported adverse event that 

can be alleviated by the administration of acetylic salicylic acid or 

intermittent administration. There are no practically important interactions 

with other medications. 

• Ethambutol’s main purpose is to reduce the risk of emergence of resistance 

to isoniazid. It is a very well tolerated drug, and optic neuritis, 

its main adverse drug event, occurs infrequently with the currently recommended 

dosages. It does not interact with any other drug, but its 

absorption might be reduced if patients take certain antacids. 

• Streptomycin might add bactericidal activity to a regimen in the intensive 

phase and may add additional protection against the emergence of 

drug resistance, particularly in patients receiving a re-treatment regimen. 

It is reasonably well tolerated by young patients, but its vestibulocochlear 

toxicity and hypersensitivity reactions make its prolonged use 

an unpleasant experience for many patients. The only potentially important 

interaction in daily practice is that its toxic effects are enhanced 

by some diuretics. 

• Thioacetazone’s main purpose is to reduce the risk of emergence of 

drug resistance to isoniazid and to reduce the risk of failure and relapse 

where there is resistance to the latter. More than any other drug it 

has the potential of multi-system adverse drug events. Among human 

immunodeficiency virus (HIV) infected patients, the most prominent is 

a muco-cutaneous syndrome that may progress to toxic epidermal 

necrolysis. This precludes its use in an increasing number of countries. 

No important interactions with other medications are known. 

The treatment of previously untreated tuberculosis patients begins with the 

direct observation of intake of a four-drug regimen (isoniazid, rifampicin, 

pyrazinamide, and ethambutol, preferably in a fixed-dose combination tablet) 

during a two-month intensive phase. To facilitate the organization of 

directly observed therapy, treatment may be given thrice-weekly after a 

10

two-week to one-month daily phase. The continuation phase cannot usually 

be directly observed, thus a non-rifampicin-containing continuation 

phase of six months is the rule in most low-income countries. The continuation 

phase associates isoniazid plus ethambutol (or, increasingly rarely, 

isoniazid plus thioacetazone). These drugs are usually given in one-month 

supplies for self-administration. Where resources permit a directly observed 

continuation phase and second-line drugs in case of treatment failure, the 

continuation phase can be shortened to four months by giving isoniazid and 

rifampicin throughout. Twelve-month regimens based on isoniazid plus 

ethambutol or isoniazid plus thioacetazone, supplemented by streptomycin 

during the first two months, were efficacious in patients not infected with 

HIV, and have been widely used in the treatment of bacteriologically unconfirmed 

tuberculosis. Evidence is accumulating that these twelve-month regimens 

result in a high relapse rate in HIV-infected patients and are thus 

being phased out in an increasing number of countries. 

Patients presenting again with tuberculosis after prior treatment are 

known to have an increased risk of harboring bacilli resistant to at least 

isoniazid. Patients whose first-line treatment regimen did not include 

rifampicin can be successfully treated with a re-treatment regimen of eight 

months duration, containing rifampicin throughout. Patients who fail (remain 

or become again bacteriologically positive) on a first-line regimen containing 

rifampicin throughout cannot usually be treated successfully with 

the above re-treatment regimen, and recourse to second-line drugs must 

necessarily be taken. In most high-burden countries, however, the resources 

required to appropriately treat all patients who need such a regimen are not 

available. 

The immediate prospects for the development of new, high-quality 

drugs that would have nation-wide availability, be well tolerated, and affordable 

are slim for most high-burden countries. Consequently, the preservation 

of the activity of the currently available medications, particularly isoniazid, 

rifampicin, and pyrazinamide, must be accorded the highest priority. 

Directly observed therapy reduces the risk of acquisition of drug resistance 

and relapse, and is thus of both individual and public health benefit. 

Prophylactic treatment 

The evidence for the efficacy of prophylactic treatment in preventing acquisition 

of tuberculous infection among persons exposed to an infectious case 

11

is scant. However, the limited evidence would suggest that a child born 

into a household with an infectious tuberculosis patient only recently placed 

on chemotherapy should receive prophylactic treatment with isoniazid, continued 

for probably at least three months following cessation of relevant 

exposure. Should the bacteriologic response of the index case be poor 

(failing to convert sputum smears), prophylactic treatment should probably 

be prolonged (or adjusted where feasible if the index case has a drug-resistant 

strain). 

Prophylactic treatment is an individual intervention primarily to protect 

the child without separation from the mother. No great epidemiologic 

or public health impact of this measure is to be anticipated. 

Vaccination 

Vaccination with BCG provides considerable protection against death from 

tuberculosis, and the development of disseminated and meningeal tuberculosis, 

particularly in infants. Neonatal BCG vaccination (or as early in life 

as possible) is thus indicated where tuberculosis is frequent, childhood tuberculosis 

rarely diagnosed, and adequate contact examinations rarely feasible. 

There is insufficient evidence to recommend vaccination beyond infancy, 

or re-vaccination. 

BCG vaccination is an individual measure that is not expected to 

improve the epidemiologic situation in a country. It is of public health 

importance to the extent that it reduces disability and death from tuberculosis 

in the target population. 

Preventive chemotherapy 

Preventive chemotherapy using nine to twelve months of isoniazid is efficacious 

but operationally inefficient. In adults it carries the danger of 

monotherapy of clinically active tuberculosis which might not be recognized 

if mycobacterial culture facilities and chest radiography are not routinely 

available. This is of particular concern in HIV infected patients who 

would be most likely to benefit, because such patients frequently have active 

tuberculosis that cannot be identified on sputum smear microscopy alone. 

The drug of choice is isoniazid, although shorter regimens based on 

rifampicin can be used where resources permit. Logistically and adminis- 

12

tratively easiest, and also of least concern for the development of drug resistance, 

is preventive chemotherapy for asymptomatic children under the age 

of five years who live in the household (not all of whom are necessarily 

infected) of a newly identified sputum smear-positive index case. It may 

be pragmatic to adjust the duration of isoniazid preventive chemotherapy 

in such cases to the length of treatment for the adult index case. 

Preventive chemotherapy is an individual intervention, not shown to 

have as great an epidemiologic impact as chemotherapy of tuberculosis. 

Even if safeguards could be taken to prevent inadvertent monotherapy for 

patients with active tuberculosis, it remains an inefficient tool that reaches 

only a fraction of persons infected with M. tuberculosis. 

13

1. Chemotherapy 

The primary intervention must aim at reducing the incidence of infection 

with M. tuberculosis. 12 Subsequent events will reflect what happens if this 

primary prevention has not been properly applied. Efficacious and effective 

chemotherapy for patients transmitting tubercle bacilli is thus paramount 

to the success of a national tuberculosis program. The following 

major areas of concern are addressed in this chapter: 

• The absolute prerequisite to effective chemotherapy is the availability 

of high-quality anti-tuberculosis drugs. With these drugs, optimum 

combination regimens have been identified. Regimens must be prescribed 

in a way that simultaneously prevents the emergence of resistant 

strains and cures the affected patient. 

• Regimens suitable for use in national tuberculosis programs have been 

identified. The HIV epidemic has complicated tuberculosis control in 

general and chemotherapy in particular, and not all issues relating to 

treatment in the presence of HIV infection have yet been resolved. 

• Administering chemotherapy through self-administered medication often 

gives poor results. Directly observed therapy, sometimes incorporating 

intermittent administration, increases the chances for a successful 

treatment outcome and has been shown to reduce the chance of emergence 

of drug resistant populations of bacilli. 

• While the course of chemotherapy is uneventful in most patients and 

leads to complete restoration of health, some patients experience adverse 

drug events that need to be addressed without compromising the efficacy 

of treatment. 

Essential drugs 

There are six essential drugs that are active against M. tuberculosis: isoniazid, 

rifampicin, pyrazinamide, ethambutol, streptomycin, and thioacetazone. 

13 For each essential drug with activity against M. tuberculosis, a 

15

standard summary of the major aspects of interest is presented. These 

include, notably: 

Discovery. A brief history of the discovery of the drug. 

Activity, mechanism of action and resistance. Activity, mechanism of 

action, and mechanisms that allow M. tuberculosis to become resistant to 

anti-tuberculosis agents are intrinsically linked. In contrast to many other 

microorganisms, the susceptibility of virtually all wild strains of M. tuberculosis 

to the major anti-tuberculosis agents is identical. Any apparent 

variation in susceptibility is a misconception due to technical errors of the 

method used to demonstrate it. This means that an approach using the 

minimum inhibitory concentration (MIC) of the initial strain (in the absence 

of resistance) as a guide to treatment is theoretically invalid. 

Pharmacokinetics. In treatment of tuberculosis (as in other diseases), concentration 

of the drug in the target organ determines whether the drug will 

have the desired effect or not. The maximum concentration that can be 

achieved is that which provides the highest concentration and the longest 

period the drug is above the MIC without being toxic. 14 There are four 

key pharmacokinetic parameters that are of particular interest (table 1): 

• C max : The maximum serum concentration of the drug that can be 

achieved; 

• T max : the point in time when the maximum serum concentration is 

achieved following administration of the drug; 

• AUC: the area under the serum concentration-versus-time curve. This 

is an informative parameter that summarizes the overall avail- 

Table 1. Pharmacokinetic parameters (rounded values) of essential anti-tuberculosis 

drugs. 

Pharmacokinetic parameters in serum 

Drug C max T max AUC 0-∞ βt 1/2 

(mg/L) (h) (mg × hr/L) (h) 

Isoniazid 4 1-2 17 2-3 

Rifampicin 14 1-3 71 2-4 

Pyrazinamide (1,500 mg) 25-30 1.2 420 10 

Streptomycin (1 g) 25-50 1-2 2-3 

Ethambutol (25 mg/kg) 5 3 30 12 

Thioacetazone (150 mg) 1.8 4 13 

16

ability of the drug in the serum of the person to whom the 

drug is administered; 

• βt 1/2 : the serum elimination half-life (in hours) of the drug. It indicates 

the time required to reduce the blood serum (or plasma) 

concentration to half of its maximum value. 

Dosage. This is the recommended dosage in the treatment of tuberculosis 

in daily or thrice-weekly treatment. Because neither WHO nor the IUATLD 

recommend twice-weekly treatment, the dosages recommended for such an 

administration schedule are not presented. 

Adverse drug events. No drug is without side effects or adverse drug 

events. Four types of adverse drug events might be distinguished: 15 

1) toxic, 2) idiosyncratic, 3) hypersensitivity reactions, and 4) adverse drug 

events that cannot be classified into one of the three preceding groups. 

Toxic reactions are effects that will occur in the majority of patients at a 

given dose. Idiosyncrasy denotes an individual genetic defect that causes 

a qualitative abnormal response. 16 Hypersensitivity reactions are untoward 

immunologic reactions to a drug. 

Interactions. Some drugs interact with other medications. Such interactions 

are listed here, to the extent known. 

Isoniazid 

Discovery. Isoniazid was synthesized in 1912 at the German University 

of Prague by Meyer and Mally (figure 5). 17 In 1952 it was independently 

re-discovered by the Bayer Laboratories in Germany, 18 Hoffmann-La Roche 

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Figure 5. Chemical structure of isoniazid, synthesized by Meyer and Malley in 

1912. 17 

17

Laboratories in Switzerland / United States, 19 and Squibb Laboratories in 

the United States, 20 without the knowledge of the other groups working on 

the drug. 

Activity, mechanism of action and resistance. Isoniazid is only active 

against mycobacteria. Within the genus, its effect is mainly against 

M. tuberculosis complex and to a lesser extent against a few species of 

environmental mycobacteria, e.g., M. kansasii. The MIC of M. tuberculosis 

is 0.025 to 0.05 mg/L in broth and 0.1 to 0.2 mg/L in agar plates, 21-23 

showing the uncertainty surrounding MIC determinations. Isoniazid has 

the most potent early bactericidal activity of all of the anti-tuberculosis 

drugs. 24-27 Adding other drugs will not increase this activity. 24,25 Thus, 

the rapid reduction in infectiousness observed following initiation of 

chemotherapy 28-30 is most likely attributable to a considerable extent to the 

bactericidal activity of isoniazid. 

Early reports have suggested that the effect of isoniazid is on cell wall 

integrity. It was observed that acid-fastness was lost shortly after treatment 

with isoniazid. 31 Winder and Collins demonstrated that isoniazid 

inhibits the synthesis of mycolic acids. 32 Sacchettini and Blanchard 33 have 

traced the history of development in the understanding of the mechanisms 

of action of isoniazid. The next step in understanding was the direct correlation 

between isoniazid uptake, viability and mycolic acid biosynthesis. 34,35 

A specific inhibitory effect was observed on the synthesis of saturated fatty 

acids greater than 26 carbons, 36 and the synthesis of monounsaturated longchain 

fatty acids in vivo. 37 These and subsequent observations strongly 

implicated enzymatic steps in the elongation of fatty acids, and the biosynthesis 

of the very long fatty acyl chains of mycolic acids as the site of 

action of isoniazid. 33 Early studies by Middlebrook et al. and others noted 

the correlation between resistance and loss of catalase-peroxidase activity. 38-40 

The molecular basis for these early observations has now been documented 

with the demonstration that isoniazid-resistant strains could be sensitized to 

the drug by transformation with the M. tuberculosis katG-encoded catalase 

peroxidase. 41,42 Additional evidence in support of the role of catalase-peroxidase 

stems from the observation that deletions and missense mutations 

within the katG gene are common in isoniazid-resistant clinical isolates of 

M. tuberculosis. 43,44 

The current concept classifies isoniazid as a pro-drug which requires 

the katG gene product for activation by the catalase, 33,45 targeting the last 

steps in mycolic acid synthesis. 46 While details of the mode of action still 

18

emain elusive, 47 the general mechanism of action is fairly well understood 

(figure 6). 46 Several mutations have been identified which confer resistance 

in M. tuberculosis. Important mutations are located on the katG 

gene, 41 and the inhA gene, 48 of which the latter is responsible for approximately 

25% of clinical isolates that demonstrate resistance, generally associated 

with low-levels of resistance. Susceptibility to isoniazid is dependent 

on the presence of the catalase-peroxidase enzyme encoded by the 

katG gene. 44,49 Mutations in catalase-peroxidase lead to high-level isoniazid 

resistance. 41,50 The ahpC gene encodes the alkyl hydroperoxide reductase, 

and its absence leads to isoniazid resistance. 51 Approximately 60% 

to 70% of isoniazid resistant strains carry mutations in one of several genes 

involved in its activation from pro-drug (katG and possibly ahpC) or in the 

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Figure 6. The proposed action of isoniazid. Reproduced from 46 by the permission 

of the publisher ASM Press.

drug target (inhA). However, the mechanism of resistance for one third of 

isoniazid-resistant strains remains to be elucidated. 

The maximum proportion of isoniazid resistant mutants able to grow 

during isoniazid monotherapy of an isoniazid susceptible strain is estimated 

to be approximately 1 in 10 6 . 52-54 

Pharmacokinetics. The serum concentrations achieved by administering 

300 mg isoniazid (approximately 5 mg/kg body weight) are well above the 

MIC (figure 7). 55-57 The pharmacokinetics of isoniazid are influenced by 

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Figure 7. Maximum serum concentrations (hollow circles) and range of minimum 

inhibitory concentrations (lines) for isoniazid (INH), rifampicin (RMP), pyrazinamide 

(PZA), ethambutol (EMB), streptomycin (SM), and thioacetazone 

(TH). 55,56,180,182,301,422 

acetylator type (slow versus rapid), 55 food intake, 55 and age. 57 A comparative 

pharmacokinetic profile of isoniazid by type of food (fasting versus 

high-fat meal) is shown in figure 8. 55 The distribution volume of isoniazid 

diminishes with increasing age as shown in figure 9. 57 The 

elimination of isoniazid from serum is determined by the acetylator status 

of the individual. 58 There are three groups of acetylator types. 

Homozygous rapid activators are found in 40% of European and African 

populations and in most of those with a Mongolian ancestry. There is a 

heterozygous group with mutations in only one of the two alleles, and 

finally a homozygous group of slow inactivators with mutations in both 

alleles. The old “rapid inactivator group” from earlier publications consisted, 

in most populations, of a majority of heterozygous and a minority 

of homozygous rapid inactivators (Mitchison DA, personal written communication, 

May 22, 2001). The serum half-life, βt 1/2 , in slow acetylators 

is about three hours following a dose of 5 mg/kg body weight, and about 

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Figure 8. Pharmacokinetics of isoniazid following fasting and a high-fat meal. 55 

Original data kindly provided by Charles A Peloquin. 

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half as long for rapid acetylators. 59,60 The AUC is similarly affected by 

acetylator type which is approximately 14.2 mg/h/L in slow eliminators as 

compared to 2.3 mg/h/L in rapid eliminators. 60 The acetylator type is important 

for widely spaced intermittent therapy. It explains to a large extent 

why once-weekly therapy with isoniazid is particularly ineffective in rapid 

acetylators. For thrice-weekly treatment, the acetylator type is not impor- 

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Figure 9. Clearance of isoniazid from serum, by acetylator type and age among 

tuberculosis patients. 57 

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tant. Isoniazid also has excellent penetration into cerebrospinal fluid, 

although the peak concentrations achieved are much lower in rapid than in 

slow acetylators. 61 

Dosage. The recommended dosage of isoniazid is 5 mg/kg body weight 

(usually up to a maximum of 300 mg) in daily, and 10 mg/kg body weight 

in thrice-weekly treatment. 8,13 

Adverse drug events (table 2). Toxic reactions include peripheral neuropathy, 

62 seizures, 62-68 and other central nervous system toxic reactions, 

such as hallucinosis, 69 psychosis, 70 memory loss, 71 optic neuropathy, 72 and 

pellagra. 73,74 Other toxic reactions from isoniazid include pyridoxine responsive 

anemia, 15,75,76 metabolic acidosis. 77 Pyridoxine is effective in both 

treatment and prevention of these reactions, 78-80 but pyridoxine non-responsive 

psychosis has also been reported. 81 In case of accidental or intentional 

overdose both charcoal treatment, if given early, 82,83 and hemodialysis 

84 have proved useful. 

Table 2. Summary of adverse reactions from isoniazid with estimated frequencies 

of occurrence. Note that these are estimates of frequencies which may vary 

across population groups. 

Frequent Common Infrequent Rare 

(� 5 per 100) (� 1 per 100 and (� 1 per 1,000 (< 1 per 1,000) 

< 5 per 100) and < 1 per 100) 

Liver enzyme Hepatitis Seizures 

elevations Peripheral Hallucinosis 

neuropathy Psychosis 

Drug fever Memory loss 

Optic neuropathy 

Pellagra 

Pyridoxine responsive 

anemia 

Metabolic acidosis 

Pyridoxine non-responsive 

psychosis 

Lupus erythematosus 

Hemolytic anemia 

Agranulocytosis 

Pure red cell aplasia 

Alopecia 

Asthma 

Dermatitis 

22

Idiosyncratic reactions from isoniazid include lupus erythematosus, 85,86 

rheumatic-like syndromes and various hematologic disorders, such as 

hemolytic anemia, 87 agranulocytosis, 88,89 pure red cell aplasia, 90-92 and other 

blood dyscrasias. 93 Other rare, probably idiosyncratic reactions, include 

alopecia. 94 These reactions are reported to subside promptly with withdrawal 

of the drug. 15 

Hypersensitivity reactions from isoniazid include drug fever, 95 asthma, 96,97 

dermatitis, 98-100 and hepatitis. 77,101,102 Hepatotoxicity might be increased with 

the concomitant use of acetaminophen. 103-105 

Clinically, the most relevant and frequent adverse drug events from 

isoniazid are neuropathy and liver injury. 

Routine use of pyridoxine (vitamin B6) for prevention of neuropathy 

is not indicated. 79 Preventive treatment with small dosages of pyridoxine 

(6 mg/day, not to exceed 10 to 15 mg 106,107 ) is indicated for patients with 

increased requirements (e.g., during pregnancy), patients with nutritional 

deficiencies (alcoholics and aged patients), patients with a history of seizure 

disorder, and patients otherwise predisposed to the development of peripheral 

neuropathy, such as uremic patients or patients with diabetes. 79 

Treatment of isoniazid-associated peripheral neuropathy (paresthesia) is with 

100 to 200 mg pyridoxine per day. 79 It should be noted that there is antagonism 

between isoniazid and pyridoxine, 108 and thus the potential of inactivation 

of isoniazid with very high doses of pyridoxine. Therefore many 

clinicians prefer lower dosages (50 mg per day). 

Liver enzyme elevations are frequent, but overt clinical hepatitis (with 

symptoms such as gastrointestinal distress, nausea, vomiting, and jaundice) 

occurs in less than five per cent of patients 109 and is age-dependent, 110-114 

and may differ in frequency in different populations, 114 being virtually absent 

among, e.g., Filipinos, 115 and is increased in patients with pre-existent liver 

injury. 110 The hepatic damage caused by isoniazid is predominantly cytolysis. 

116 The AUC for monoacetyl hydrazine, the putative precursor of the 

responsible agent, was greater in slow acetylators in a pharmacokinetic 

study, though the AUCs for acetyl isoniazid and diacetyl hydrazine were 

higher in rapid acetylators. 117 The association of differences in pharamcokinetics 

of isoniazid and its metabolites with hepatitis risk is poorly understood, 

118 and has not been shown to be of great importance. 119 Indeed, 

evidence obtained from patients in Hong Kong and Singapore showed that 

elevated transaminase levels during treatment with isoniazid-containing regimens 

were no higher in rapid than in slow acetylators. 120-122 In the 

IUATLD trial on preventive chemotherapy with isoniazid in patients with 

23

fibrotic lesions, 123 the risk of hepatitis due to isoniazid alone could be 

assessed. Among patients receiving isoniazid for one year, the risk of 

hepatitis was 5.8 per 1,000 persons. 110 It increased from 2.8 per 1,000 for 

subjects aged less than 35 years to 7.7 per 1,000 for those aged 55 years 

or more, but risk was much lower in those without pre-existing liver damage 

(figure 10). 110 The hepatitis risk was highest in the first two months 

of treatment (figure 11). In a US Public Health Service survey, the hepati- 

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Figure 10. Hepatotoxicity from isoniazid during preventive therapy by age and 

pre-existing liver damage. 110 

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Figure 11. Hepatotoxicity from isoniazid during preventive therapy by length of 

exposure. 110

tis risk per 1,000 subjects was zero for those aged less than 20 years, 2.4 

for those aged 20 to 34 years, 9.2 for those aged 35 to 49 years, and 19.2 

for those aged 50 to 64 years. 111 Isoniazid and rifampicin given together 

may potentiate the risk of hepatitis, and cases of hepatitis caused by the 

two drugs in combination have been reported. 124,125 

Patients abusing alcohol may be treated with isoniazid provided they 

do not display signs of overt alcoholic hepatitis. Careful clinical control, 

limitation of alcohol consumption and (where feasible) control of liver 

enzymes in such patients are recommended. 

Interactions. Isoniazid is an inhibitor of oxidative and demethylation metabolism 

as well as other cytochrome P-450 dependent microsomal pathways. 

126,127 It is also a monoamine and diamine oxidase inhibitor. 128,129 

These properties bear on the various interactions that have been reported, 130 

in that the most important interaction leads to a potentiation of the companion 

drug (opposite to the usual interactions seen with rifampicin). 

Scombroid fishes (such as mackerel, tuna and salmon) have a high histidin 

content which is converted to histamine by bacteria, if improperly 

refrigerated. Eating such fish while taking isoniazid may lead to the typical 

signs of scombroid fish poisoning, with erythematous and urticarial 

rash, facial flushing, diarrhea, palpitations, headache, nausea, paresthesias, 

abdominal cramps, and dizziness. 131-134 It may progress to bronchospasm 

and hypotensison. 

Certain types of cheeses rich in monoamines may also lead to hypersensitivity 

reactions. 135-138 With wine, such reactions have also been 

reported. 128 

Effects of isoniazid potentiated: para-aminosalicylic acid, 139 insulin, 140 carbamazepine, 

141 valproic acid (a single report, usually the effect is the opposite), 

142 theophylline. 143 

Effects of isoniazid opposed: prednisolone, 59 ketoconazole. 144 After intake 

of ethanol, most is metabolized to acetaldehyde in the liver. Acetaldehyde 

appears to form acetaldehyde-adducts with isoniazid in vitro, and thus may 

lower its bioavailability, but the adduct itself may increase the toxicity of 

either drug. 145 

Effect of drug potentiated by isoniazid: 

• acetominophen hepatotoxicity is increased by isoniazid; 103,104 

25

• anti-coagulants such as warfarin; 146 

• anti-epileptics such as phenobarbital, diphenylhydantoin, 147 and phenytoin, 

148,149 carbamazepine, 150-153 ethosuximide, 154 epanutin, 155 and valproic 

acid; 142,156,157 

• anti-neoplastics such as vincristine; 158 

• benzodiazepines which are oxidatively metabolized (not through glucorination), 

159 such as diazepam 160 and triazolam; 161 

• haloperidol 162 and tricyclic anti-depressants; 163 

• theophylline. 143,164 The effect on theophylline pharmacokinetics might 

be such that even in combination with rifampicin (which has the opposite 

effect), theophylline clearance might be lowered, requiring a lower 

dose of theophylline in patients simultaneously treated with isoniazid 

and rifampicin. 165 

Because of its monoamine oxidase inhibiting activity, isoniazid may potentiate 

the effect of monamine oxidase inhibitor anti-depressants, 166,167 meperidine 

168 and levodopa. 169 

Effects of drug opposed by isoniazid: enflurane, 170 cyclosporine 155 (disputed). 

Rifampicin 

Discovery. In 1957, a Streptomyces strain, designated strain ME / 83, later 

named Streptomyces mediterranei was isolated in the Lepetit Research 

Laboratories from a soil sample collected at a pine arboretum near Saint 

Raphaël, France. 171,172 From this strain several rifamycins, whose structure 

was elucidated by Oppolzer and collaborators, 173 were isolated. By reduction 

of one of these, rifamycin S and rifamycin SV were obtained. 

Rifamycin SV was only effective parenterally, as it was not absorbed to a 

significant degree when administered orally. Further chemical modification 

led to an orally active substance, rifampicin (figure 12). 174 

Activity, mechanism of action and resistance. The minimum inhibitory 

concentration of rifampicin for M. tuberculosis is about 0.25 mg/L in broth 

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and 0.5 mg/L in agar. 21-23 Rifampicin is active against a wide range of 

micro-organisms including M. leprae, S. aureus, N. meningitidis, and L. pneumophila. 

Rifampicin, like all naphthalenic ansamycins (the class to which 

rifampicin belongs), is a specific inhibitor of DNA-dependent RNA polymerase. 

175 

Rifampicin acts by interfering with the synthesis of mRNA by binding 

to the RNA polymerase. 176 Mycobacteria develop resistance to 

rifampicin by mutations in a defined region for the RNA polymerase subunit 

β. Mutations in the rpoB gene of M. tuberculosis are responsible for 

most of the resistance. 177 Mutations have been found in more than 97% 

of resistant isolates. 178,179 

The maximum proportion of rifampicin-resistant mutants able to grow 

during rifampicin monotherapy of an isoniazid-susceptible strain is estimated 

to be approximately 1 in 10 8 . 53 

Pharmacokinetics. After oral administration of rifampicin on an empty 

stomach, the absorption is rapid and practically complete. 180 With a dose 

of 8.1 (± 0.7) mg/kg body weight, a peak level of 6.3 (± 0.5) mg/L is 

achieved 3.2 hours after oral administration. After oral intake of 600 mg 

27 

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Figure 12. Chemical structure of rifampicin, isolated and semi-synthesized by 

Maggi and collaborators in 1966. 174

ifampicin, a peak level of 12 to 14 mg/L is achieved after one to three 

hours (figure 13). 181,182 The AUC (between 0 and 12 hours) is 36 mg/L/hr, 

and the half-life is estimated to be 4.7 (± 1.9) hours, 183 but has been found 

to be shorter in three studies (3.8 to 4.1 hours) after a single dose of 

10 mg/kg body weight. 175 A drug-concentration – time profile is shown 

in figure 49. 175 Rifampicin is excreted unchanged in urine and bile and is 

also metabolized. Its major metabolite, desacetyl-rifampicin, is excreted 

principally in bile, but also in urine. 184 It appears that there are differences 

between men and women in the blood levels achieved, with women 

achieving significantly higher levels than men, a difference not explained 

by differences in body weight. 185 The pharmacokinetics of rifampicin are 

influenced by meals, 186,187 but depend on the type of constituents. 

Carbohydrates and proteins seem to have virtually no influence, while a 

fatty meal reduces serum concentrations considerably, as shown in four 

groups of 35 patients each (figure 14). 188 The major differences in pharmacokinetics 

following a meal include a reduced total amount absorbed 

(area under the curve) and delayed achievement of peak serum levels. 175 

Tissue penetration of rifampicin is excellent into cavity linings, lung 

parenchyma and kidneys, with levels above the serum levels (figure 15). 175 

Levels below the serum levels but well above the minimum inhibitory concentration 

are achieved in pyogenic bone lesions and the pleura. Critical 

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Figure 13. Pharmacokinetics of rifampicin in healthy volunteers. Reproduced 

from 181 by the permission of the publisher ASM Press.

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concentrations close to the minimum inhibitory concentration were measured 

in caseum and cerebrospinal fluid in meningitis. 

The cerebrospinal fluid to plasma concentration level ratio is between 

0.52 and 1.17 over 12 hours in the experimental (healthy) rabbit model. 189 

In comparative studies, mean peak rifampicin concentrations in the cerebrospinal 

fluid of patients with tuberculous meningitis of 2.4 mg/L were 

29 

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Figure 14. Pharmacokinetics of rifampicin following meals compared to fasting. 

Reproduced from 188 by the permission of the publisher Churchill Livingstone. 

Figure 15. Tissue penetration of rifampicin with tissue-to-serum ratios. 175

obtained six hours after administration of 600 mg rifampicin, while a delayed 

mean peak of only 0.81 mg/L was reached nine hours after drug ingestion 

in normal subjects. 175 

The quality of rifampicin is very susceptible to the manufacturing 

process. The same amount on a weight basis can lead to markedly reduced 

bioavailability if the particle size in the manufacturing process or the excipient 

are changed. 190 A particularly critical issue in the manufacture of 

rifampicin is its crystalline structure, which might be affected during the 

mixing process (particularly if there is a failure to properly control temperature 

and the grinding process), especially in fixed-dose combination 

preparations. 191-193 

Dosage. The recommended dosage of rifampicin is 10 mg/kg body weight 

in daily treatment. 13 The recommended dosage in thrice-weekly treatment 

is the same as the daily dosage, because an increased frequency of a flulike 

syndrome has been observed with intermittent treatment at higher 

dosages. 194 

Adverse drug events (table 3). Serum bilirubin levels increase above normal 

values with the usual dosage of rifampicin on the first day of treatment, 

but normalize within two weeks (figure 16). 195,196 The most frequent hepatic 

abnormality caused by rifampicin is cholestasis. Rifampicin induces isoniazid 

hydrolase, leading to increased formation of hydrazine, a finding that 

could explain the increased hepatotoxicity observed in patients receiving both 

rifampicin and isoniazid (figure 17). 124,197,198 Hepatitis as a result of combination 

therapy with rifampicin and isoniazid is the most important adverse 

drug event in adults 120,194,199,200 and occurs also in children, albeit less frequently. 

109,201-203 Patients with HIV infection appear to be at particularly high 

risk of hepatotoxicity. 204-206 Whether hepatitis B HBsAg carriers are at 

increased risk appears to be equivocal. 207,208 In contrast, hepatitis C carriers 

appear to be at greatly increased risk of drug-induced hepatitis. 206 

Rifampicin has been reported to cause acute interstitial nephritis 209 and 

glomerulonephritis. 210 

Hypersensitivity reactions are infrequent or rare, and include pruritus, 

211 and rarely severe muco-cutaneous toxicity, such as toxic epidermal 

necrolysis, 212-214 particularly in HIV-infected patients. 215,216 

Rifampicin may cause menstrual disturbances such as oligomenorrhea 

and amenorrhea. 217 Anaphylactic shock has been reported among HIVinfected 

patients. 218,219 

30

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Among hematologic abnormalities, rifampicin has been reported to 

cause leukopenia, 220 hemolytic crisis, 221 and thrombocytopenia, 222 the latter 

being perhaps one of the more frequent adverse drug events. 

Rifampicin reduces pruritus in patients with primary biliary cirrhosis, 

similar to the effect of phenobarbitone. 223 

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Figure 16. Total serum bilirubin levels in adults with normal liver function after ingestion 

of rifampicin at the beginning of treatment and after two weeks. Reproduced 

from 195 by the permission of the publisher Monaldi Archives for Chest Disease.

Table 3. Summary of adverse reactions from rifampicin with estimated frequencies 

of occurrence. Note that these are estimates of frequencies which may vary 

across population groups. 




Bilirubin elevations Hepatitis Interstitial nephritis 

in the beginning Pruritus Glomerulonephritis 

of treatment Flu syndrome Renal failure 

Orange discoloration Drug fever Toxic epidermal 

of urine and tears* necrolysis 

Liver enzyme Oligomenorrhea 

elevations Amenorrhea 

Anaphylactic shock 

Neutropenia 

Leukopenia 

Hemolytic anemia 

Pseudomembranous 

colitis 

Eosinophilic colitis 

Lupus erythematosus 

Myopathy 

* Not an adverse drug event, but a normal occurrence that might cause anxiety in patients. 

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Figure 17. Hepatitis frequency following isoniazid alone or in combination with 

rifampicin. 198

Rifampicin may rarely cause pseudomembranous colitis 224,225 and 

eosinophilc colitis. 226 

Rifampicin has also been reported to induce lupus erythematosus. 227 

Rifampicin has also been reported to cause myopathy. 228 

With intermittent therapy, when higher doses than the now-recommended 

daily dose equivalent have been used, a “flu” syndrome has frequently 

been reported. 194,229 Also shortness of breath, hemolytic anemia, 

and renal failure usually occur only if rifampicin is given intermittently. 194 

Although not an adverse drug event, it should be noted that rifampicin 

leads to orange discoloration of urine and tears, 230 and may permanently 

damage soft contact lenses. 231 Intoxication leads to the “red man syndrome”. 

232-234 

Interactions. Rifampicin is an inducer of several enzymes in the 

cytochrome P-450 system, 235 leading to numerous interactions with multiple 

drugs. This action leads most frequently to faster elimination and lower 

concentrations of the companion drug, an effect opposite to that seen with 

the most common isoniazid interactions. 

No important interactions between rifampicin and other anti-tuberculosis 

drugs have been found, with the exception of para-aminosalicylic acid 

preparations 139 containing a bentonite excipient. 175 Rifampicin reduces the 

incidence of pyrazinamide-associated arthralgia, not by increasing pyrazinamide 

elimination, but presumably through increased excretion of uric 

acid. 236 Numerous interactions with other medications have been 

described, 140,237-240 as detailed below. 

Effect of rifampicin potentiated: Cotrimoxazole. 241 A pharmacokinetic study 

reported an inhibitory effect of the anti-retroviral indinavir on the metabolism 

of rifampicin. 242 

Effect of rifampicin opposed: No drug has been identified yet that opposes 

the action of rifampicin. 

Effect of drug potentiated by rifampicin: Acetominophen hepatic failure and 

encephalopathy as a result of suspected potentiation by rifampicin has been 

reported. 105 

Effect of drug opposed by rifampicin: 

• anti-arrhythmics such as quinidine, 243, 244 phenytoin, 148 and lorcainide; 245 

33

• anti-asthmatics such as theophylline. 246-248 The effect on theophylline 

pharmacokinetics might be opposed if rifampicin is given in combination 

with isoniazid (which has the opposite effect), so that theophylline 

clearance might be lowered, requiring a lower dose of theophylline in 

patients simultaneously treated with isoniazid and rifampicin; 165 

• anti-coagulants such as acenocoumarol, 249,250 phenprocoumon, 251,252 and 

warfarin; 253-257 

• anti-diabetics such as tolbutamide, 258,259 glidazide 260 or, to a lesser extent, 

glimeripide 261 and glyburide; 262 

• anti-fungals such as the imidazol derivatives fluconazol 263,263 and ketoconazol; 

144 

• anti-malarials such as hydroxychloroquine 264 and quinine 265 and mefloquine; 

266 

• antimicrobial agents such as chloramphenicol; 267 

• anti-retroviral agents such as protease inhibitors (saquinavir, ritonavir, 

indinavir, nelfinavir), 268,269 nevirapine (inconsistent), 270 and other antiviral 

agents such as zidovudine; 271,272 

• barbiturates such as hexobarbital; 259 

• benzodiazepins such as diazepam; 273 

• beta-blockers such as propranolol; 274 

• calcium blockers or antagonists such as verapamil 275-277 and nifedipine; 

278 

• cardiac glycosides such as digoxin; 244,279,280 

• haloperidol; 162 

• hormones such as oral contraceptives, 281 gluococorticoids, 282,283 , 

insulin, 284,285 , and thyroxine; 286 

• immunosuppressants such as azathioprine, 140 cyclosporin, 287-290 and 

tacrolimus; 291 

34

• opioids; 292-294 

• vitamin K 295 , vitamin D metabolism; 296 

• sulphasalazine. 297 

Pyrazinamide 

Discovery. Following up on the anti-tuberculosis activity of nicotinamide 

(a vitamin B3 precursor), further experimentation led to the synthesis of 

pyrazinamide by Kushner at the Lederle Laboratories, communicated in 

1952 (figure 18) 298 and by Solotorovski at the Merck laboratories in the 

same year. 299 The synthesis of pyrazinoic acid, the active metabolite of 

pyrazinamide, had already been patented in 1934. 300 

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Figure 18. Chemical structure of pyrazinamide, synthesized by Kushner and collaborators 

in 1952. 298 

Activity, mechanism of action and resistance. Pyrazinamide is only active 

against mycobacteria, and among the genus, mycobacteria other than 

M. tuberculosis (including M. bovis) are naturally resistant. 301 It was recognized 

early on that pyrazinamide acts only in an acid environment. 302 

The active derivative of pyrazinamide is pyrazinoic acid, which is preferentially 

accumulated in an acidic pH. 303 Pyrazinamide itself is not active 

against intracellularly growing M. tuberculosis: 304 only the accumulation of 

pyrazinoic acid through the action of the amidase pyrazinamidase by susceptible 

M. tuberculosis leads to its intracellular bactericidal action. 305 

The presence of both a functional pyrazinamidase and pyrazinamide 

transport system into M. tuberculosis have been postulated as prerequisites 

for drug susceptibility. 306 Relatively little is known about the actual drug 

target, although the NAD metabolic pathway has been postulated as one of 

the potential targets. 307 

Mutations in pncA, a gene encoding pyrazinamidase, cause resistance 

to pyrazinamide. 308,309 Resistance against pyrazinamide appears to develop 

rapidly if given as a single effective agent. 310 M. bovis is naturally resistant 

to pyrazinamide. 311 

35

Pharmacokinetics. After oral intake of 1500 mg of pyrazinamide, a peak 

level of 25 to 30 mg/L is achieved after one to one and a half hours (figure 

19). 181 Pyrazinamide has one of the best penetrations into cerebrospinal 

fluid among the anti-tuberculosis medications. 312,313 About four per cent 

of pyrazinamide is excreted unchanged in urine and about 30% as pyrazinoic 

acid. 314 It is only slightly influenced by ingestion of antacids, but 

with a fatty meal T max is delayed and C max slightly lowered, although these 

effects are unlikely to bear clinical relevance. 315 Absorption of pyrazinamide 

is not influenced by food intake. 

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Figure 19. Pharmacokinetics of pyrazinamide in healthy volunteers. Reproduced 

from 181 by the permission of the publisher ASM Press. 

Dosage. The dosages of pyrazinamide have varied greatly since its introduction. 

In early periods, the usual dosage was around 40 to 50 mg/kg 

body weight 316,317 and up to eight grams were given per day. 310 Such 

dosages frequently resulted in hepatotoxicity 317 and its early withdrawal 

from chemotherapy regimens. The current recommendations are to give 

25 mg/kg body weight per day. 8,13 

Adverse drug events (table 4). The two major adverse drug events of pyrazinamide 

are hepatotoxicity 115,120,200,310,317-324 and interference with the metabolism 

of purine. The latter leads to decreased excretion and accumulation 

of uric acid, occasionally accompanied by gout-like arthralgia. 310,325,326 The 

suppressive effect of pyrazinoic acid on uric acid excretion is maximal for

Table 4. Summary of adverse reactions from pyrazinamide with estimated frequencies 

of occurrence. Note that these are estimates of frequencies which may 

vary across population groups. 




Arthralgias Nausea Hepatitis Sideroblastic anemia 

Rash Lupus erythematosus 

Nausea Convulsions 

Photodermatitis 

24 hours. 327 Thus, uric acid retention could be reduced by intermittent 

administration. 

Relatively frequent events include rash 200,328,329 and nausea. 200 Rarer 

adverse drug events include sideroblastic anemia, 75,93 lupus erythematosus, 330 

convulsions, 331 and photodermatitis. 332 

Interactions 

Effect of pyrazinamide potentiated: Allopurinol increases plasma concentrations 

of pyrazinoic acid which is directly responsible for the inhibition 

of renal urate secretion. 333 Therefore, pyrazinamide-induced arthralgias are 

unresponsive to allopurinol. 

Effect of pyrazinamide opposed: A potentially serious interaction may exist 

with zidovudin, with combination treatment leading to barely detectable 

pyrazinamide levels. 334 However, these findings have not been confirmed. 

Effect of drug potentiated by pyrazinamide: None identified. 

Effect of drug opposed by pyrazinamide: Pyrazinamide might antagonistically 

affect the action of medications that have a uricosuric effect such as 

acetylic salicylic acid, ascorbic acid, probenecid, and iodine containing radiocontrast 

offering preparations. 335,336 

Ethambutol 

Discovery. The synthesis of ethambutol (figure 20) was reported in 

1961. 337 Its excellent activity in vitro and in vivo against M. tuberculosis 

was reported in the same year. 338-340 

37

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Activity, mechanism of action and resistance. Ethambutol is only active 

against mycobacteria. 340 Ethambutol is bactericidal on both extracellular 

and intracellular tubercle bacilli. 341 The MIC of ethambutol for 

M. tuberculosis is about 0.95 to 7.5 mg/L in broth and 1.9 to 7.5 mg/L 

on agar. 21,23 

Ethambutol specifically inhibits biosynthesis of the mycobacterial cell 

wall. 46 It acts on the biosynthesis of arabinogalactan, the major polysaccharide 

of the mycobacterial cell wall. 342 It inhibits the polymerization of 

cell wall arabinogalactan and of lipoarabinomannan. 343,344 It indirectly 

inhibits mycolic acid synthesis (by limiting the availability of arabinan for 

the mycolic acids to attach to) 345 and triggers a cascade of changes in the 

lipid metabolism of mycobacteria, leading to the disaggregation of bacteria 

clumps into smaller clusters. 346 It appears to be able to break down 

the “exclusion barrier” located in the M. avium cell wall and thus significantly 

enables the activity of other drugs, both intracellularly and extracellularly. 

347,348 

The maximum proportion of ethambutol-resistant mutants able to grow 

during ethambutol monotherapy of an isoniazid-susceptible strain is estimated 

to be approximately 1 in 10 8 . 53 

Pharmacokinetics. The absorption of ethambutol is rapid. Following a 

dosage of 25 mg/kg body weight, a peak serum concentration of 4 to 5 mg/L 

is achieved approximately two to four hours after administration (figure 

21). 349,350 The drug is not extensively metabolized. Roughly 80% of 

ethambutol is eliminated by glomerular filtration and tubular secretion. 349-351 

38 

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Figure 20. Chemical structure of ethambutol, reported by Thomas and collaborators 

in 1961. 337

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Ethambutol penetrates tissues rapidly and in high concentrations, including 

lung, liver and kidney in experimental tuberculosis. 352,353 It has poor penetration 

into cerebrospinal fluid and brain. 352 Renal failure decreases body 

clearance and increases serum half-life, and dose adjustment in such patients 

is mandatory. 354 High-fat meals alter the pharmacokinetics of ethambutol 

somewhat, but probably not importantly. 355 

Dosage. Although 15 mg/kg body weight in the continuation phase and 

25 mg/kg body weight in the intensive phase have been recommended, 356 

international consensus recommends 15 mg/kg (range 15 to 20 mg/kg) 

throughout 8,13 to obviate operational difficulties in changing the dosage and 

to further reduce toxicity. 

Adverse drug events (table 5). The most important adverse drug event of 

ethambutol is ocular toxicity, first reported in 1962, 357 and followed by 

numerous accounts. 358-376 It is postulated that many instances of ethambutol’s 

ocular toxicity might be explained by its binding to zinc or copper. 

152,377 Two types of ocular toxicity (optic neuropathy) from ethambutol 

have been described. 372,378 The more common form is a noninflammatory 

axial fiber disease involving central fibers of the optic nerve. 378 Patients 

with central or axial toxicity have reduced visual acuity, central scotoma, 

39 

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Figure 21. Pharmacokinetics of ethambutol in healthy volunteers. Reproduced 

from 349 by the permission of the publisher American Thoracic Society at the American 

Lung Association.

Table 5. Summary of adverse reactions from ethambutol with estimated frequencies 

of occurrence. Note that these are estimates of frequencies, which may 





Retrobulbar Aplastic anemia 

neuritis Eosinophilic pneumonia 

Periaxial ocular Thrompocytopenia 

toxicity Hyperuricemia 

and loss of ability to see green (reported as white or gray). The ability to 

see red, which has been reported as pink, has occasionally been affected. 

Those with periaxal toxicity have a defect in the peripheral isopters of their 

field of vision, with little or no decrease in visual acuity and normal redgreen 

color discrimination. The optic discs and the fundi appeared normal 

in both types of toxicity. The incidence of ocular toxicity is dose dependent. 

372,379 The chance of visual recovery appears to be related to the total 

dose administered and the initial degree of loss of vision. 370 It has been 

recommended not to use ethambutol in children too young for objective 

tests for visual acuity. 363 There is, however, no evidence that children are 

particularly prone to ocular toxicity, 380 and ethambutol may thus be used 

in children. However, as children might be less likely to report ocular toxicity, 

particular caution may be warranted. Ocular toxicity is usually 

reversible upon cessation of ethambutol administration, but recovery might 

be protracted. 368 Compared to the frequency of fatal outcome resulting 

from anti-tuberculosis medication, the occurrence of blindness from ethambutol 

is rare. 367 

Ethambutol may cause aplastic anemia, 367 but this is exceedingly rare. 

Ethambutol is a rare cause of pulmonary infiltrates with eosinophilia, 381 

rash, 367,382 exacerbation of lupus erythematosus, 330 thrombocytopenia 383 and 

hyperuricemia. 384 

Interactions 

Effect of ethambutol potentiated: Although listed in some text books, ethionamide 

and isoniazid have not been conclusively shown to increase ethambutol 

ocular toxicity. 

Effect of ethambutol opposed: Aluminum-magnesium antacid reduces 

ethambutol resorption, and lowers and delays, respectively, C max and T max . 355 

40

Effect of drug potentiated by ethambutol: None identified. 

Effect of drug opposed by ethambutol: None identified. 

Streptomycin 

Discovery. Selman A Waksman isolated Actinomyces griseus from soil in 

1916, 385 later termed Streptomyces griseus. 386 In 1939, Waksman’s research 

group started an extensive study of substances produced by soil organisms 

which destroyed other soil organisms (termed antibiotics by Waksman). 387 

The first antibiotic isolated from an Actinomyces species was actinomycin 

in 1940. 386 In 1942, streptothricin was isolated. 386 In September 1943 

Streptomyces griseus was re-identified. 388 and the isolation of streptomycin 

was reported in January 1944 (figure 22). 389 It is noteworthy that the original 

table presenting the antimicrobial activity of streptomycin accorded a 

single, inconspicuous line to its effect on M. tuberculosis and this finding 

found no mention in the text (figure 23). 390 But in the same year Schatz 

and Waksman published a paper devoted particularly to the action of streptomycin 

on M. tuberculosis. 391 In 1952, Waksman received the Nobel Prize 

for Physiology or Medicine. 386,387 

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Figure 22. Chemical structure of streptomycin, isolated by Schatz, Bugie, and 

Waksman and reported in 1944. 390

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Activity, mechanism of action and resistance. Streptomycin has a broadspectrum 

activity against many gram-positive and gram-negative microorganisms 

and against various species of mycobacteria. Its effect on M. tuberculosis 

in vitro and in the guinea pig was reported as early as December 

1944, 392 and a preliminary report on its usefulness in the treatment of tuberculosis 

in man in September 1945 by Feldman and Hinshaw, 393,394 followed by 

a more extensive report in 1946. 395 The MIC of M. tuberculosis is 0.25 

to 2.0 mg/L. 21,56 It had been surmised that streptomycin is active only 

against extracellularly growing tubercle bacilli, but this notion has not been 

42 

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Figure 23. Original table published when the isolation of streptomycin was 

reported. Reproduced from 389 by the permission of the publisher Society for 

Experimental Biology and Medicine.

orne out by experiments which have demonstrated its activity against bacilli 

residing inside macrophages as well. 396 

Streptomycin inhibits protein synthesis of M. tuberculosis. Streptomycin 

acts on ribosomes and causes misreading of the genetic code, inhibition of 

translation of mRNA, and aberrant proofreading. 397 

It was demonstrated a half century ago that a strain may contain different 

variants with different levels of susceptibility (or resistance) to streptomycin. 

398 Interestingly, problems with molecular techniques to properly 

identify clinically relevant resistance led some authors to conclude that the 

seemingly outdated use of drug-containing media described in these early 

reports 398 may again become a valid procedure. 399 Resistance results from 

a limited number of missense mutations in the rrs gene (16S rRNA) or in 

the rpsL gene (ribosomal protein S12). 400 

The maximum proportion of streptomycin resistant mutants able to 

grow during streptomycin monotherapy of an isoniazid susceptible strain is 

estimated to be approximately 1 in 10 8 . 53 

Pharmacokinetics. Streptomycin is not at all, or only insignificantly, 

absorbed from the gut and its administration is parenteral. Following intramuscular 

administration, resorption is rapid and maximum serum concentrations 

are achieved within one to two hours (figure 24). 183,401 Streptomycin, 

like all aminoglycosides, is excreted by glomerular filtration. When kid- 

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Figure 24. Pharmacokinetics of streptomycin in tuberculosis patients. Reproduced 

from183 by the permission of the publisher American Thoracic Society at the 

American Lung Association. 

43

ney function is impaired, the dosage must be adjusted, as excretion is exclusively 

renal. 56 Streptomycin has a limited ability to penetrate membranes, 

resulting in low concentrations of cerebrospinal fluid. 402 

Dosage. After large doses (up to three grams daily were given in the early 

trials 395 ) toxicity was frequent and dosage reductions were sought that would 

not compromise efficacy. 403 The current recommendation is to give 

15 mg/kg body weight (range 12 to 18), 8, 13 with a usual maximal dose of 

one gram in adults. The dosage is reduced in elderly patients. It has to 

be administered parenterally, usually by intramuscular injection, but intravenous 

application is preferred by some because of higher peak but lower 

trough levels. 404 

Adverse drug events (table 6). The main adverse effect of streptomycin is 

vestibulo-cochlear toxicity, which is usually 323,403,405 but not always, dosedependent. 

406 Hypersensitivity reactions are also relatively frequent and 

important, 56 not only in patients, but also in health care personnel administering 

the medication. 407 Because of its penetration into amniotic fluid 

and its ototoxic effect on the fetus, 408 streptomycin should never be administered 

to pregnant women. 56 Streptomycin may cause neuromuscular blockade, 

409 not reversed by neostigmine. 410 

Table 6. Summary of adverse reactions from streptomycin with estimated frequencies 






Vestibular Cochlear toxicity Renal damage Neuromuscular 

toxicity Hypersensitivity blockade 

reactions 

Interactions 

Effect of streptomycin potentiated: Ototoxicity of streptomycin is increased 

by diuretics such as furosemide 411 and ethacrynic acid. 412 

Effect of streptomycin opposed: None identified. 

Effect of drug potentiated by streptomycin: Like other aminoglycosides, 

streptomycin has a neuromuscular blocking effect 413 and may lead to pro- 

44

longed respiratory depression following curare-like drugs, such as pancuronium, 

414 succinylcholine or tubocuronium 415 or non-depolarizing relaxants 

such as diallyl-nortroxiferine. 416 

Effect of drug opposed by streptomycin: None identified. 

Thioacetazone 

Discovery. Freund and Schander synthesized benzaldehyde-semicarbazone 

in 1896 and 1902, respectively. 417,418 From this basic compound, derivatives 

with anti-tuberculosis properties were later developed. After investigations 

on sulphonamides had revealed that thiazoles and thiodiazole derivatives 

exerted some activity against mycobacteria, 419 Domagk and 

collaborators at the Bayer Laboratories synthesized a new class of drugs, 

the thiosemicarbazones, of which thioacetazone (figure 25) was shown to 

be active against tubercle bacilli. 420 

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Figure 25. Chemical structure of thioacetazone, synthesized by Domagk and collaborators 

in 1946. 420 

Among the numerous derivatives of semicarbazones, three have found particular 

activity against M. tuberculosis: 421 

p-acetylamino-benzaldehyde-semicarbazone; 

p-methoxy-benzaldehyde-semicarbazone; 

p-ethylsulfone-benzaldehyde-semicarbazone. 

Of these, p-acetylamino-benzaldehyde-semicarbazone, tested under the name 

TB I, now known as thioacetazone, became the most widely used semicarbazone. 

Activity, mechanism of action and resistance. Thiosemicarbazones, including 

thioacetazone, are active only against mycobacteria, and favorable in 

vitro and in vivo results against M. tuberculosis were published in 1949. 419 

The observed in vitro susceptibility of M. tuberculosis varies considerably,

depending on the technique of susceptibility testing and the origin of the 

strain. 422 An observation made in a comparison of tubercle bacilli isolated 

from India and in the United Kingdom showed that Indian strains were 

considerably less susceptible to thioacetazone than strains from the United 

Kingdom. 423 This geographic variation was subsequently confirmed. 424-427 

The susceptibility of strains may vary even within the same country. 428 

The correlation between in vitro and in vivo results is often very poor. 429 

The mode of action of thioacetazone has not been elucidated, 430 although 

it has been shown that thioacetazone forms copper complex salts and it has 

been postulated that these might represent the effective compound. 431 

There is partial cross-resistance between thioacetazone and ethionamide. 

422 

Pharmacokinetics. Thioacetazone is rapidly absorbed and maximum serum 

concentrations are achieved about four hours (range two to six hours) after 

ingestion, 432-434 and is eliminated from serum almost completely within 24 

hours (figure 26). 434 

Dosage. The currently recommended dosage of thioacetazone is 2.5 mg/kg 

body weight per day. 13 Only daily treatment is recommended. 

Adverse drug events (table 7). Thioacetazone frequently causes adverse 

drug events, 435-438 which occur in up to 40% of patients. The most fre- 

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Figure 26. Pharmacokinetics of thioacetazone in healthy volunteers. 434 

46

quent adverse drug events are gastrointestinal (weight loss, nausea, vomiting), 

421 central nervous system, 421 and cutaneous adverse drug events. 435 

An international investigation in 13 countries into adverse drug events due 

to thioacetazone was coordinated by the British Medical Research 

Council. 439 The frequency of adverse drug events in that study was 21% 

compared to eight per cent of patients who were not receiving thioacetazone. 

More than half of the adverse drug events were mild. The study 

confirmed earlier observations that gastrointestinal and neurologic adverse 

drug events (headache, blurred vision, perioral numbness, mental symptoms, 

and peripheral nerve symptoms) were the most frequent, followed by cutaneous 

adverse drug events. Two out of 1,000 patients developed agranulocytosis. 

439 The frequency of adverse cutaneous reactions varied in different 

populations. Differences in nutrition may be a contributor to this 

observation as, for example, consumption of cheese and fish appear to 

increase the risk of cutaneous and neurologic adverse drug events. 440 

It was recognized relatively early that patients with HIV infection 

have increased susceptibility to developing toxic epidermal necrolysis when 

given sulfur-containing medications such as sulfadoxine 441 or sulfamethoxazole. 

442 The causal relationship between the occurrence of cutaneous 

adverse reactions and the use of thioacetazone has been elegantly 

demonstrated (figure 27). 443 Reactions may present as pruritus without 

rash, rash without epidermolysis, and most seriously as toxic epidermal 

necrolysis. 444 The latter has a case fatality rate of 20% to 30%, depending 

on the selection of cases (figure 28). Both reactions and deaths occur 

relatively early in the course of administration, with more than half occur- 

Table 7. Summary of adverse reactions from thioacetazone with estimated frequencies 






Weight loss Toxic epidermal Toxic epidermal Agranulocytosis 

Nausea necrolysis necrolysis 

Vomiting (in HIV) (in non HIV) 

Itching infected patients) infected patients) 

Mental disturbances 

Headache 

Blurred vision 

Perioral numbness 

47

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Figure 27. Demonstration of the causal relation between cutaneous adverse reaction 

and thioacetazone, by HIV status and regimen. 443 

ring within the first three weeks of treatment (figure 29) (Tanzania National 

Tuberculosis / Leprosy Programme, IUATLD, unpublished data). 

Numerous accounts have now been published that confirm the potential 

seriousness of the utilization of thioacetazone in HIV infected tuberculosis 

patients. 445-448 While most adverse reactions are toxic effects, cutaneous 

adverse reactions appear to be largely idiosyncratic, and are not 

influenced by reducing the dosage. 421 

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Figure 28. Adverse cutaneous reactions and deaths associated with the use of 

thioacetazone, by severity of reaction. Tanzania National Tuberculosis / Leprosy 

Programme and IUATLD, unpublished data. 

48

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Because of this strong association, thioacetazone should never be given 

to patients known to be HIV infected. 13 It is also sensible policy to relinquish 

its use in countries where the HIV prevalence among tuberculosis 

patients is known to be high. 449,450 

Interactions. Interactions between thioacetazone and other medications are 

not known. 

Fixed-dose combinations 

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Figure 29. Adverse cutaneous reactions and deaths associated with the use of 

thioacetazone, by duration of thioacetazone intake. Tanzania National Tuberculosis 

/ Leprosy Programme and IUATLD, unpublished data. 

Tuberculosis needs to be treated with multiple drugs. It is thus not surprising 

that efforts have been undertaken to develop so called fixed-dose 

combinations. Fixed-dose combinations simplify treatment, minimize prescription 

errors, and simplify supply management. 191,451 As fixed-dose combinations 

containing rifampicin may be particularly prone to posing difficulties 

in assuring bioavailability, specific requirements have been outlined 

to ensure their quality. 452,453 

The dosages of the individual components in a fixed-dose combination 

are of critical importance to prevent both over- and under-dosage. The 

WHO recommends the dosages per tablet as summarized in table 8. 454,455 

49

Table 8. Fixed-dose combinations (FDC) of antituberculosis drugs and dosages 

of individual drugs as recommended by WHO. 454 

FDC per tablet For daily use (mg drug) For three-times weekly 

use (mg drug) 

{TH} 150 T + 300 H 

50 T + 100 H * – 

{EH} 400 E + 150 H – 

{RH} 300 R + 150 H – 

150 R + 75 H 150 R + 150 H 

60 R + 30 H * 60 R + 60 H 

{RHZ} 150 R + 75 H + 400 Z 150 R + 150 H + 500 Z 

60 R + 30 H + 150 Z * – 

{RHZE} 150 R + 75 H + 400 Z + 275 E – 

* For pediatric use 

Abbreviations: T = thioacetazone; H = isoniazid; E = ethambutol; R = rifampicin; Z = pyrazinamide. 

Fixed-dose combinations will guarantee that drugs cannot be taken separately. 

They thus reduce the potential of acquisition of drug resistance. 

However, prescription errors or selective use of the number of tablets by 

the patient may lead to sub-inhibitory concentrations of all drugs. The 

need for direct observation of drug intake is thus not obviated with their 

introduction into national programs. 

Principal prerequisites 

for an efficacious anti-tuberculosis drug 

It is general practice to define the action of antimicrobial agents as “bacteriostatic” 

or “bactericidal”. This terminology might not be that useful in 

describing the activity of anti-tuberculosis medications. Mitchison has proposed 

the utility of defining three prerequisites for an anti-tuberculosis drug 

(table 9): 456 

• Early bactericidal activity; 

• Sterilizing activity; 

• Ability to prevent emergence of resistance to the companion drug. 

50

Table 9. Grading of activities of anti-tuberculosis drugs. Reproduced from 456 by 

the permission of the publisher Churchill Livingstone. 

Extent of activity Prevention Early Sterilizing 

of resistance bactericidal 

High isoniazid isoniazid rifampicin 

rifampicin pyrazinamide 

ethambutol 

ethambutol rifampicin isoniazid 

streptomycin 

streptomycin streptomycin 

pyrazinamide pyrazinamide thioacetazone 

Low thioacetazone thioacetazone ethambutol 

Early bactericidal activity 

Early bactericidal activity is defined as the ability of the drug to kill tubercle 

bacilli in the first few days of treatment. 24,25,456 In a study measuring 

sputum colony counts in newly diagnosed tuberculosis patients treated with 

a multitude of monotherapy and multidrug therapy regimens during the first 

two weeks of treatment, no other drug or drug combination was superior 

to isoniazid alone in the first two days of treatment (figures 30 and 31). 24,25 

This high early bactericidal activity of isoniazid was subsequently confirmed. 

26,457 It is likely that the rapid reduction in infectiousness seen in 

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Figure 30. Early, two-day bactericidal activity of anti-tuberculosis drugs, measured 

as the reduction in colony-forming units in sputum. 24 

51

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tuberculosis patients once placed on chemotherapy 29,30,458,459 is largely due 

to the use of isoniazid. 

Sterilizing activity 

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Figure 31. Bactericidal activity of isoniazid compared to a four-drug combination 

therapy over the first two weeks of treatment. 25 

Sterilizing activity is defined as the ability to remove so called “persisters”, 

once the large bulk of rapidly growing organisms has been killed. A model 

presented by Grosset clarifies these two major components of chemotherapy 

(figure 32). 460 Inability to destroy rapidly growing bacilli, located 

largely extracellularly, leads to treatment failure, while inability to eradicate 

persisters leads to relapse subsequent to treatment completion. Persisters 

are bacilli that have a lower metabolic activity and thus replicate much 

more slowly than bacilli found in cavity linings. It was postulated that the 

efficacy of rifampicin as a sterilizing agent was due to its activity on special 

populations. 461 This was tested in an experiment reproducing conditions 

appropriate for high and low metabolism of tubercle bacilli, respectively, 

using temperature control as the means. 462 At body temperature, 

there was only slightly higher activity of rifampicin over isoniazid during 

a seven-day period. If pulsed temperature elevation was applied for only 

one hour per day to increase metabolism, rifampicin was considerably more 

active than isoniazid (figure 33). 462 

52

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Ability to prevent emergence of resistance 

to the companion drug 

Prevention of the emergence of drug resistance is defined as the ability of 

a drug to prevent selection of mutants resistant to the companion drug. 

Not every anti-tuberculosis drug has the same ability to prevent emergence 

of resistance against a companion drug in clinical practice (figure 34). 463 

53 

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Figure 32. Schematic presentation demonstrating the mechanisms for treatment 

failure and disease relapse. Reproduced from 460 by the permission of the publisher 

Excerpta Medica. 

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Figure 33. Comparative activity of isoniazid and rifampicin in experiments mimicking 

high and low metabolic activity. Reproduced from 462 by the permission of 

the publisher American Thoracic Society at the American Lung Association.

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Figure 34. Ability of an anti-tuberculosis drug to prevent as a companion drug 

the emergence of isoniazid resistance. 463 

In summary, each anti-tuberculosis medication can be assigned a grading 

scale according to these three properties (table 9). 456 This explains the 

reason for the high efficacy of chemotherapy regimens incorporating isoniazid, 

rifampicin, and pyrazinamide. 

Emergence of anti-tuberculosis drug resistance 

The most convincing evidence for the mechanism of emergence of clinically 

significant drug resistance is effective or functional monotherapy. This 

and related mechanisms are discussed in some detail. 

There are several mechanisms by which tubercle bacilli may acquire 

resistance: 464 

• Effective or functional monotherapy; 

• Monotherapy during sterilization of special populations; 

• Differences in bactericidal activity; 

• Sub-inhibitory concentrations; 

• Differences in post-antibiotic lag phase. 

54

Effective or functional monotherapy 

The first clinical trial in tuberculosis was by necessity limited to the first 

drug developed against tuberculosis, streptomycin. In the trial conducted 

by the British Medical Research Council, a total of 109 patients were admitted 

to the streptomycin arm. 465 Serial susceptibility testing results were 

available among 41 of these patients, 35 of whom acquired streptomycin 

resistance (figure 35). As the testing interval between susceptible and resis- 

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Figure 35. Emergence of streptomycin resistance during monotherapy in the British 

Medical Research Council trial. 465 

tant cultures varied to a considerable extent among individual patients, the 

point in time when resistance emerged cannot be known precisely. For 

this reason, the event was estimated to have occurred at the mid-point 

between the time the last susceptible and the first resistant culture was 

obtained. Resistance had already started to emerge after three weeks of 

treatment. By the time a patient had received two months of streptomycin 

monotherapy, the probability that drug resistance had been acquired exceeded 

60%. 

The explanation for this phenomenon is that among the many susceptible 

bacilli present in cavitary disease, spontaneous mutations occur at a 

given probability for each drug that convey resistance to that drug. The 

bacterial populations found in cavitary lesions obtained from resected lung 

tissue of patients were of the order of 10 7 to 10 9 bacilli, whereas those 

55

found in caseous foci did not exceed 10 2 to 10 4 bacilli. 466 It has been 

experimentally demonstrated that it is selection of these mutants rather than 

adaptation to the medication. 467 In a cavitary lesion containing 10 8 organisms, 

there will be around 10 2 isoniazid resistant mutants (i.e., one in a 

million) with the opportunity to replicate and become the dominant strain 

while the susceptible organisms are being killed off (figure 36). 468,469 

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56 

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Figure 36. Diagrammatic presentation of the emergence of resistance to isoniazid 

during isoniazid monotherapy. Reproduced from 469 by the permission of the 

publisher Churchill Livingstone and the author. 

Monotherapy during sterilization of special populations 

Not all drugs work equally well on all bacillary sub-populations. These 

sub-populations are exemplified in figure 37. 456 None of the drugs works 

on the “dormant” or “latent” 470 sub-population. Other specific sub-populations 

are the target of some drugs, such as pyrazinamide, which is active 

only in an acid environment. If, for instance, a patient with an initially 

isoniazid-resistant strain receives isoniazid, pyrazinamide, and ethambutol, 

the sub-population hypothesis would suggest that the patient’s large bulk 

of rapidly metabolizing organisms is treated with ethambutol monotherapy. 

As there will be effective monotherapy in these special populations, resistant 

mutants should have a survival benefit. 464

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Differences in bactericidal activity 

Isoniazid has the highest early bactericidal activity of all of the anti-tuberculosis 

drugs. Thus, isoniazid-resistant mutants may have a selection advantage 

over a two-day period. This is not usually relevant, as this advantage 

is overcome over the ensuing period. However, should it happen that 

treatment is stopped after two days and subsequently resumed for another 

two-day period, the proportion of isoniazid-resistant mutants will have 

increased at the end of each cycle (figure 38). 464 

Sub-inhibitory concentrations 

Whenever sub-inhibitory concentrations of a drug A are being taken, growth 

of bacilli susceptible to drug A will be mildly suppressed and their natural 

re-growth retarded if it is stopped. This does not apply to mutants resistant 

to drug A. They will not be affected at all by drug A but only by 

other drugs given simultaneously (figure 39). 464 The mutants resistant to 

drug A will thus have a selective advantage. This might not be an uncommon 

scenario as the number of tablets required to be ingested (including 

57 

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Figure 37. Special population hypothesis, indicating those bacterial populations 

at the start which are killed by the various drugs. Reproduced from456 by the permission 

of the publisher Churchill Livingstone.

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Figure 38. Bactericidal effects during two successive initial two-day phases of 

treatment with isoniazid and rifampicin. Reproduced from 464 by the permission of 

the publisher International Union Against Tuberculosis and Lung Disease. 

fixed-dose combination tablets) is large, and during self-administration 

patients might be tempted to take some but not all of the tablets. 

Mitchison 464 points out that this mechanism would be most effective for 

�� 

Figure 39. Sub-inhibitory concentrations of anti-tuberculosis drugs during 

regrowth. Reproduced from 464 by the permission of the publisher International Union 

Against Tuberculosis and Lung Disease.

drugs with a high therapeutic margin such as isoniazid, as the effective 

half-life at sub-inhibitory concentrations would persist longer than that of 

other drugs. 471 The difference in pharmacokinetics of the drugs given 

together (in a combination tablet or in separate preparations) may be such 

that after several hours only one of the drugs is still active, leading to functional 

monotherapy. Sub-inhibitory concentrations of one or more drugs 

may be observed in patients with impaired gastrointestinal absorption. 

Differences in post-antibiotic effect (lag phase) 

When drugs are stopped, the length of time it takes bacilli to restart growth 

(post-antibiotic lag phase) differs for different anti-tuberculosis medications 

(figure 40). 472 Thus, for example, mutants resistant to drug A (with a long 

lag phase) are killed by drug B (with a short lag phase). Mutants resistant 

to drug A will thus start re-growth earlier when both drugs are stopped and 

obtain a selective advantage at the end of the cycle (figure 41). 464 

Clinical trials in the treatment of pulmonary tuberculosis 

Since the discovery of streptomycin, clinical trials with anti-tuberculosis 

medications in various combinations have been carried out throughout the 

world to ascertain the shortest possible and best tolerated efficacious treatment 

regimens. The standard approach for studying a new drug or drug 

Rifampicin 

Ethambutol 

Isoniazid 

0 1 2 3 4 5 6 7 8 9 10 

Lag after 24 hr exposure to drug (days) 

59 

Streptomycin 

Figure 40. Post-antibiotic effects with M. tuberculosis lag periods before recommencement 

of growth after exposure in 7H10 medium. 472

Number of viable bacilli 

Mutants 

resistant 

to A 

Lag due to drug A 

Lag due to 

drug B 

Killing phase Regrowth 

combination is the randomized controlled clinical trial, whereby a group of 

patients is randomly assigned to the new regimen (experimental arm) or to 

the standard regimen (control arm). The element of randomization to reduce 

selection bias was actually first introduced in tuberculosis, with the first 

streptomycin trial of the British Medical Research Council. 465,473,474 

Clinical trials have been conducted all over the world by different organizations 

and institutions. However, there can be little doubt that the leading 

role in the development of modern chemotherapy against tuberculosis 

was taken by the British Medical Research Council and its collaborators 

throughout the world, 122,475 and by the United States Public Health Service 

and the United States Veterans Administration. 476 

While the efficacy of anti-tuberculosis treatment was fully appreciated, 

it is noteworthy that tuberculosis was for a long time not considered to be 

curable; temporary remission and prevention of emergence of resistance 

were the primary objectives for a long time. This is particularly surprising 

as it had been shown already in the 1950s that tuberculosis is curable 

using appropriate combination therapy. 477,478 

In the following, only the highlights leading up to modern chemotherapy 

are summarized. For a more detailed account, the comprehensive 

review by Fox and collaborators from the British Medical Research 

60 

Regrowth starting 

Figure 41. Bacteriopausal effects during regrowth of M. tuberculosis. Reproduced 

from 464 by the permission of the publisher International Union Against Tuberculosis 

and Lung Disease.

Council 122 or the individual trials conducted by the US Public Health 

Service 319,479-491 might be consulted. 

Streptomycin monotherapy 

Shortly after the discovery of streptomycin, clinical trials with streptomycin 

monotherapy were conducted in Great Britain 465 and the United States. 492 

It was noted in these trials that case fatality from tuberculosis was considerably 

reduced. However, it was also seen that patients improved over 

the first few months and subsequently deteriorated, in many cases due to 

acquisition of streptomycin resistance. Among survivors, sputum conversion 

did not much differ between those receiving streptomycin and those 

not (figure 42). 492 The insoluble problem was the selection of resistant 

strains. While toxicity could be reduced by lowering the dosage and spacing 

administration more widely, the problem of bacterial resistance was not 

resolved. 493 The streptomycin trials impacted considerably on research for 

the next 20 years, which largely concentrated on methods of preventing the 

emergence of drug resistance. 

Streptomycin plus para-aminosalicylic acid 

The introduction of para-aminosalicylic acid into the armamentarium allowed 

combination therapy to be used. In a study of the British Medical Research 

Per cent positive 

100 

80 

60 

40 

20 

0 

0 3 6 9 12 

Month of treatment 

61 

Placebo 

Streptomycin 

Figure 42. Sputum culture conversion among patients receiving streptomycin compared 

to placebo. 492

Council, streptomycin monotherapy, para-aminosalicylic acid monotherapy 

and chemotherapy with both drugs combined was carried out. 494,495 It was 

demonstrated unequivocally, and for the first time, that combined chemotherapy 

reduced the risk of acquisition of resistance. Similarly, a clinical trial 

in Denver, Colorado, USA showed that the combination of streptomycin 

and para-aminosalicylic acid overcame the emergence of resistance, in contrast 

to monotherapy with either one (figure 43). 493 

Per cent with resistant strains 

80 

60 

40 

20 

0 

0 28 42 60 75 90 120 

Day of treatment 

62 

Streptomycin 

alone 

PAS 

alone 

Streptomycin 

and PAS 

Figure 43. Emergence of resistance to streptomycin and/or para-aminosalicylic 

acid given alone or in combination. Reproduced from 493 by the permission of the 

publisher American Thoracic Society at the American Lung Association. 

Streptomycin plus para-aminosalicylic acid plus isoniazid 

It appears that the logical step following the introduction of isoniazid, namely 

to compare the efficacy of streptomycin, para-aminosalicylic acid, and isoniazid 

with a control arm of streptomycin plus para-aminosalicylic acid, 

was never subjected to a formal randomized clinical trial, either by the US 

Public Health Service or by the British Medical Research Council. This 

is particularly astonishing, as this triple combination therapy must be 

considered the breakthrough in tuberculosis treatment because it introduced 

the certainty of consistently curing tuberculosis patients with an initially 

fully susceptible strain. 

It is furthermore a curiosity in the history of medicine that the curative 

results of this combination therapy were not even accorded a full-length

article. The experiences in Edinburgh of Sir John Crofton and collaborators 

were relegated to the correspondence section of the American Review 

of Tuberculosis (figure 44). 477 The efficacy of this approach seemed convincing, 

although a randomized trial would surely have been indicated to 

remove any lingering doubts about biased selection and ascertainment. A 

subsequent study of the British Medical Research Council, begun in 1956, 

added a streptomycin supplement until susceptibility to PAS was demon- 


100 

80 

60 

40 

20 

0 

0 2 4 6 8 10 12 

Months of chemotherapy 

Figure 44. Sputum culture conversion in patients with pulmonary tuberculosis due 

to susceptible organsisms, with triple therapy consisting of streptomycin, paraaminosalicylic 

acid, and isoniazid. Reproduced from 477 by the permission of the 


strated. 496 This indicates that the importance of a resistance-preventing 

component in the intensive phase was not yet fully appreciated. In the 

report on US Public Health Service trial 4, it was explicitly stated that there 

was no advantage of using all three drugs in cases of recent origin. 482 In 

US Public Health Service trial 3, a comparison of the combination streptomycin 

plus isoniazid with streptomycin plus PAS was made; it demonstrated 

the superior ability of the isoniazid-containing regimen to induce 

culture conversion (figure 45). 481 However, the difference between a regimen 

of streptomycin plus para-aminosalicylic acid plus isoniazid versus 

streptomycin plus para-aminosalicylic acid was not ascertained. 

Nevertheless, common sense prevailed and by the end of the 1950s, 

the regimen that had been used in Edinburgh became, at least in the United 

63

Per cent culture positive 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

0 4 8 12 16 20 24 28 32 36 40 

Week of treatment 

Figure 45. Sputum culture conversion among patients treated with streptomycin 

and para-aminosalicylic acid compared to streptomycin and isoniazid. 481 

Kingdom, standard practice 497 following a trial by the British Medical 

Research Council demonstrating faster conversion, fewer bacteriologic failures 

and relapses. 496,498 The WHO considered it one of the major regimens 

for low-income countries. 499 It took many years for experts of other 

countries to be convinced of its importance, and that only after an international 

comparative clinical trial. 500 

Isoniazid plus ethambutol 

Because of the frequency of side effects associated with para-aminosalicylic 

acid, ethambutol appeared an attractive alternative. The US Public 

Health Service trial 16 showed that sputum conversion was indistinguishable 

in patients receiving, in addition to isoniazid, ethambutol in lieu of 

para-aminosalicylic acid (figure 46), although there was a marked reduction 

in the occurrence of adverse drug events. 484 

Neither the US Public Health Service nor the British Medical Research 

Council studied a 12-month regimen with isoniazid and ethambutol throughout, 

supplemented by streptomycin in the intensive phase, although this regimen 

has been widely used in low-income countries where thioacetazone 

has been abandoned. 

64 

SM + PAS 

SM + INH


100 

80 

60 

40 

20 

0 

0 4 8 12 16 20 

Isoniazid plus thioacetazone 


In East Africa, a comparison of 12-month regimens was carried out with 

isoniazid plus thioacetazone throughout, one arm containing streptomycin 

during the first two months and another arm without streptomycin. 501 It 

was demonstrated that the two-month supplement of streptomycin contributed 

to a higher cumulative conversion rate (figure 47). 

65 

INH+PAS 

INH+EMB 

Figure 46. Sputum conversion among patients receiving isoniazid and para-aminosalicylic 

acid compared to isoniazid and ethambutol. 484 


100 

80 

60 

40 

20 

0 

12 TH 

2 STH / 10 TH 

0 2 4 6 8 10 12 

Month after start of treatment 

Figure 47. Effect on culture conversion of adding two months of streptomycin to 

a 12-month regimen of isoniazid and thioacetazone. 501

Thioacetazone replaced para-aminosalicylic acid very rapidly throughout 

English-speaking sub-Saharan Africa because of the better tolerance and 

important cost savings. 

Isoniazid plus rifampicin 

With the introduction of rifampicin, a more rapid conversion was demonstrated 

when it replaced streptomycin (figure 48). 487 This was, however, not 

the main progress made with rifampicin-containing chemotherapy. In a trial 

in France, rifampicin-containing regimens were tested in three different dura- 


100 

80 

60 

40 

20 

0 

RMP+INH+EMB 

0 4 8 12 16 20 


66 

SM+INH+EMB 

Figure 48. Effect of replacing streptomycin by rifampicin on culture conversion. 487 

tions of chemotherapy: six, nine, and 12 months. 502,503 It was demonstrated 

that nine months of isoniazid plus rifampicin, supplemented by either ethambutol 

or streptomycin during the first three months, was the optimum duration, 

502 and the relapse rate during a remarkable mean follow-up time of 

101 months with this regimen was only two out of 85 patients. 503 

The use of rifampicin provided curative treatment of less than one 

year’s duration, and the term “short-course chemotherapy” became the brand 

name of this new successful strategy. 504 

Isoniazid plus rifampicin plus pyrazinamide (plus a fourth drug) 

Despite its remarkable efficacy in experimental models, 505,506 pyrazinamide 

was not retained in routine chemotherapy because of its hepatotoxicity.

Based on evidence that the addition of pyrazinamide hastened sputum conversion, 

a series of studies was designed by the British Medical Research 

Council. In 1970, it was demonstrated for the first time that the inclusion 

of rifampicin and pyrazinamide in a regimen of isoniazid and streptomycin 

substantially reduced the subsequent risk of relapse. 122 

A multitude of clinical trials was designed and carried out by the 

British Medical Research Council with regimens containing, as a minimum, 

isoniazid, rifampicin, and pyrazinamide in the intensive phase, virtually 

always supplemented by streptomycin during this period. 122 Two studies 

in East Africa were critical for future research into this combination. 507,508 

In these trials it was observed that regimens containing pyrazinamide but 

not rifampicin were almost as effective as those containing rifampicin. 

Furthermore, there was later evidence that both drugs given in the regimen 

were more effective than one alone. 122 These studies laid the basis for 

modern treatment. 

The consistent finding in these studies was that the four drugs were 

optimally given for a two-month intensive phase, followed either by four 

months of rifampicin plus isoniazid or six months of a combination of drugs 

not containing rifampicin (the continuation phase). 

The role of the fourth drug (streptomycin or ethambutol) is unclear as 

few studies have evaluated it, 491,509 but most likely it has a minor role in 

patients with a strain that is fully susceptible at the outset. 122 A recommendation 

to drop the fourth drug in patients with sputum smear-negative 

tuberculosis seems to have no evidence base. Patients with paucibacillary 

disease may require a shorter duration of treatment (see below); however, 

dropping the fourth drug in the intensive phase may not be justified as it 

may lead to functional monotherapy with rifampicin in lesions with a low 

pH among patients with a strain that is initially resistant to isoniazid (pyrazinamide 

not being active in such lesions). 

Rifampicin-containing continuation phase 

A regimen consisting of a two-month intensive phase with isoniazid, 

rifampicin, pyrazinamide, and streptomycin, followed by a four-month continuation 

phase with isoniazid plus rifampicin, all given daily, was first 

evaluated in Singapore. 510-512 The high efficacy of this regimen was confirmed 

in the United Kingdom, and was equally effective if streptomycin 

was replaced by ethambutol. 513-515 It has become the standard regimen for 

patients with fully susceptible organisms in most industrialized countries. 

Shorter durations have been put on trial, 516,517 but the frequency of relapse 

67

makes it impossible to reduce the minimum duration of six months. In 

the United States, US Public Health Service trial 21 evaluated the same 

regimen, but without the supplement of ethambutol or streptomycin (except 

for those with a high probability of initial resistance) in the intensive phase 

and showed it to be efficacious. 490,491 However, given the possibility of 

drug resistance among new cases of tuberculosis in many locations, the recommendation 

for a four-drug initial treatment is preferred, at least in areas 

where drug resistance is frequent or unknown. In the United Kingdom, a 

four-drug intensive phase is always recommended. 518 The IUATLD and 

WHO also recommend a four-drug intensive phase in new sputum smearpositive 

cases of pulmonary tuberculosis and other severe cases of tuberculosis 

where this regimen is being used. 8,13 

Non-rifampicin-containing continuation phase 

Current options for a non-rifampicin-containing continuation phase are isoniazid 

plus thioacetazone or isoniazid plus ethambutol. 

A four-drug, two-month intensive phase followed by six months of 

isoniazid plus thioacetazone has been found to be highly efficacious in East 

Africa. 519,520 

No critical evaluation of an ethambutol-containing continuation phase 

has been carried out extensively. One trial in India evaluated the effectiveness 

of a fully unsupervised eight-month regimen with isoniazid and 

ethambutol throughout, supplemented by rifampicin and pyrazinamide in the 

two-month intensive phase. 521,522 The entire treatment was self-administered 

and compared to a six-month regimen using rifampicin throughout, given 

twice-weekly, and at least partially supervised. The results during chemotherapy 

were encouraging with the eight-month regimen. Four per cent had an 

unfavorable response during chemotherapy and five per cent relapsed; the 

relapse rate was only half that in the directly observed control arms. 

Intermittent regimens 

To facilitate directly observed therapy, various intermittent regimens have 

been studied extensively. 122,521 In Chennai (formerly Madras), India, all 

parameters were superior in patients receiving twice-weekly isoniazid plus 

para-aminosalicylic acid, supplemented by streptomycin during the intensive 

phase, as compared with patients receiving once-weekly isoniazid plus 

para-aminosalicylic acid for self-administered treatment. 523 This study rep- 

68

esented a major advance in research aiming at improving adherence with 

intermittent regimens. 498 

The majority of the trials have evaluated six-month regimens, with 

rifampicin throughout, each dose given under direct observation. In Denver, 

Colorado, USA, for instance, a regimen with daily treatment given for just 

the first two weeks, followed by twice weekly adminstration for the remainder 

of the course, was highly successful, 524 and similar studies have been 

conducted in Poland. 509,525 

Intermittent regimens have been shown to be as (or almost as) efficacious 

as daily regimens, and greatly facilitate direct observation of drugintake. 

A potential problem with intermittent regimens is that errors resulting 

from missing one dose may have greater impact than missing a single 

dose in a daily regimen. This might be further compounded if the fourth 

drug in the intensive phase is omitted. In a controlled clinical trial in India 

with a twice-weekly regimen, bacteriologic sputum conversion was inferior 

if ethambutol was omitted (figure 49). 521 Twice-weekly regimens might 

also be inferior even if all drugs are being taken in populations where a 

large proportion of patients acetylates isoniazid rapidly, as such patients 

generally have inferior results in widely spaced drug administration. 122 

Thus, while regimens for both twice-weekly and thrice-weekly application 

have been studied, the only intermittent regimens WHO recommends are 

thrice-weekly regimens. 13 


100 

80 

60 

40 

20 

0 

0 1 2 3 4 5 6 

Month after start of treatment 

69 

2 H 2 R 2 Z 2 / 4 H 2 R 2 

2 E 2 H 2 R 2 Z 2 / 4 H 2 R 2 

Figure 49. Effect of adding a fourth drug (ethambutol) during the first two months 

to a rifampicin throughout regimen on culture conversion. 521

Not all drugs are equally suitable for intermittent use. Thioacetazone, 

for example, is not suitable for intermittent use. 526 Furthermore, intermittent 

treatment is indicated only to facilitate directly observed therapy, not 

for self-administered treatment. Thus, unless a rifampicin-containing continuation 

phase is selected, the principal issue is the efficacy of the use of 

intermittent therapy during the intensive phase of treatment. 

Remarkably little is known about the efficacy of intermittent use during 

an intensive phase containing four medications, followed by a selfadministered 

continuation phase that does not contain rifampicin. Concerns 

have been raised that an eight-month regimen with an intermittent intensive 

phase from the outset may be inferior in HIV-infected patients. 527 To 

facilitate directly observed therapy in national programs, these are critical 

issues that need urgent attention. 

Treatment regimens of less than six months’ duration 

Regimens of four months’ duration (containing rifampicin throughout) for 

bacteriologically confirmed pulmonary tuberculosis have been studied in 

Singapore, but yielded unacceptably high relapse rates. 510-512 

A regimen of four and a half months duration for bacteriologically 

(sputum smear and culture) confirmed pulmonary tuberculosis has been 

studied in Agra, India. 516,517 In this trial, four drugs (isoniazid, rifampicin, 

pyrazinamide, and streptomycin) were given for a total of three months, 

followed by one and a half month of isoniazid plus rifampicin, all given 

daily. All but one of the 65 patients enrolled were eligible for and followed 

up for relapse, and only one patient relapsed during the two-year 

follow-up period. 517 Despite the seeming efficacy of this four and a halfmonth 

regimen, confirmatory studies have not become available, the regimen 

has never been accepted by the medical community, and the credibility 

of the result of the study was actually challenged. 528 

Among patients with repeatedly negative sputum smears, shorter regimens 

have been investigated. 122 If the initial culture was negative (but 

radiologically the disease was considered to be active) or positive, relapse 

rates were three per cent or less with a three-month or a four-month regimen, 

respectively. 529 However, in routine practice even countries involved 

in these trials have abandoned the practice of treating patients with newly 

diagnosed (but bacteriologically unconfirmed) pulmonary tuberculosis for 

less than six months. 

Currently, regimens shorter than six months duration are not recommended 

by WHO for bacteriologically unconfirmed tuberculosis. A prin- 

70

cipal consideration is the prevailing uncertainty about the quality of bacteriologic 

examinations (sputum smear microscopy) in many national tuberculosis 

programs. 

Clinical trials in extrapulmonary tuberculosis 

Two forms of extrapulmonary tuberculosis have been studied in welldesigned 

clinical trials: tuberculosis of peripheral lymph nodes and tuberculosis 

of the spine. The treatment of tuberculosis of the central nervous 

system has been subject to numerous investigations, but because of the 

small cases in each study, the certainty about the optimum treatment is limited. 

Tuberculosis of peripheral lymph nodes 

In many populations, tuberculosis of peripheral lymph nodes (particularly 

cervical and axillary) is the most frequent extrapulmonary manifestation of 

tuberculosis. 530 While in the past, in milk-consuming cultures, tuberculosis 

of peripheral lymph nodes may frequently have been caused by M. bovis, 

particularly in children, it is now almost universally caused by M. tuberculosis, 

531 it is found in all age groups, but with a predilection for the 

young 532,533 and for females. 530 

It appears that treatment of lymphatic tuberculosis was long considered 

to be a surgical domain, due to a misunderstanding of it as a localized 

disease process. This concept was demonstrated to be erroneous in a 

retrospective study conducted among cases diagnosed between 1965 and 

1973 in the United Kingdom. 534 

A prospective study of the treatment of tuberculosis of peripheral lymph 

nodes was carried out in the United Kingdom, comparing two 18-month 

regimens, one with isoniazid plus ethambutol, the other with isoniazid plus 

rifampicin throughout, and both supplemented by streptomycin during the 

first two months. 476 No difference in treatment results between the two 

groups was found. 

In a second prospective study, conducted by the British Thoracic Society, 

an 18-month regimen was compared with a nine-month regimen. 535,536 Both 

regimens were based on isoniazid plus rifampicin throughout and supplemented 

by ethambutol during a two-month intensive phase. No difference 

in treatment outcome was identified between the two regimens. 

71

In a third prospective study in the United Kingdom, various regimens 

using isoniazid plus rifampicin throughout were compared. 537 The control 

regimen was the same as the nine-month regimen in the British Thoracic 

Society. One of the experimental regimens had the same duration, but 

ethambutol was replaced by pyrazinamide. The second experimental arm 

received the same regimen as the first, but for only six months. No differences 

among the three regimens were found. 

A review of published materials concludes that a six-month regimen 

similar to that used in pulmonary tuberculosis is also adequate for treatment 

of tuberculosis of peripheral lymph nodes. 538 

It was noted in the British trials that tuberculosis of peripheral lymph 

nodes does not always appear to respond clinically to treatment, and treatment 

may be declared a failure on clinical grounds. Cultures from nodes 

that were newly developing during treatment or from abscesses from newly 

draining nodes subsequent to treatment completion remained bacteriologically 

sterile. It has been postulated that the phenomenon is caused by an 

immunologic response to tuberculo-protein. 535 

Tuberculosis of the spine 

Tuberculosis of the spine is one of the most important extrapulmonary forms 

of tuberculosis both in terms of relative frequency and the substantial potential 

of permanent disability. It has been estimated that more than half of 

all osteoarticular manifestations of tuberculosis in India affect the spine. 539 

Before the advent of anti-tuberculosis chemotherapy, treatment consisted 

of bed-rest, improvement of the patient’s nutritional status, and, in 

some cases, posterior spinal fusion. 540 

In the 1950s and early 1960s, two extreme positions marked the divergence 

of opinions about the appropriate approach to the treatment of tuberculosis 

of the spine. In Nigeria, successful treatment with chemotherapy 

alone was reported. 541,542 In Hong Kong, excellent results were reported 

with anterior spinal fusion. 543-546 

It was against this background that the British Medical Research 

Council planned 539,547,548 and conducted a series of controlled clinical trials, 

resulting in 14 scientific reports. 549-562 

The trials were conducted in Hong Kong, India, Korea, and Zimbabwe. 

All trials evaluated the role of chemotherapy and various operative and nonoperative 

surgical procedures. Chemotherapy lasted from six to 18 months 

at various points in time. The most recent trial established that a regimen 

72

of six months’ duration with isoniazid plus rifampicin throughout was as 

effective as any other regimen. 562 It was concluded that outpatient 

chemotherapy with standard short-course chemotherapy based on isoniazid, 

rifampicin, and pyrazinamide should be the main management of uncomplicated 

spinal tuberculosis. 561 

It is likely, based on the results of these studies, that a regimen that 

is effective for pulmonary tuberculosis should be equally effective for the 

treatment of tuberculosis of the spine. 

Tuberculosis of the central nervous system 

Tuberculous meningitis is the most important central nervous system manifestation 

of tuberculosis. The optimum treatment of tuberculous meningitis 

is not known, and recommendations are based on the pharmacokinetic 

properties of the medications and, to a large extent, on inference and common 

sense. 

The blood-brain barrier poses particular problems for the choice of the 

right drug combinations as penetration into the cerebrospinal fluid and its 

ratio to serum concentrations varies widely among the various anti-tuberculosis 

drugs. 

The key issue is the extent of plasma binding of the drug, as probably 

only the unbound portion penetrates into the central nervous system, 

thus explaining the differences between isoniazid and pyrazinamide on one 

hand, and rifampicin on the other. 

Isoniazid is recognized as a drug with excellent penetration into cerebrospinal 

fluid. 61,563 

Rifampicin, in contrast to isoniazid, has very poor penetration into cerebrospinal 

fluid, 563 but seems to appear in higher concentrations at the beginning 

of treatment, in the phase where the meninges are inflamed. 564,565 

However, because tuberculosis is not a localized disease, the use of 

rifampicin is beneficial for the treatment of lesions other than those in the 

central nervous system that may be simultaneously present. 

Pyrazinamide has excellent penetration into cerebrospinal fluid. 563 

Ethambutol penetrates poorly into normal or uninflamed meninges, but 

penetrates fairly well into inflamed meninges. 565-568 

Streptomycin penetrates relatively poorly into cerebrospinal fluid. 563 

Among the thioamides, ethionamide has been found to have high penetration 

into cerebrospinal fluid. 565,568-570 

73

Based on these pharmacokinetic properties and other considerations, it 

has been recommended that treatment for suspected or confirmed tuberculous 

meningitis should begin with a two-month intensive phase incorporating 

isoniazid, rifampicin, and pyrazinamide plus streptomycin. 571 The optimum 

duration of the continuation phase is not known, but based on limited 

information 572 a continuation phase associating isoniazid and rifampicin for 

a duration of at least seven months has been advocated. 563 This regimen 

may pose problems in patients with an isoniazid-resistant strain because of 

the unpredictable concentrations of rifampicin. Where available, ethionamide 

might provide a less well tolerated alternative in such a case. 570,573 

Influence of HIV infection on the choice of a regimen 

Among tuberculosis patients with HIV infection, two major issues need to 

be addressed. 

The first concerns the initial observations made by clinicians when 

treating HIV-infected patients with anti-tuberculosis drugs: tolerance of the 

medications was poorer than in patients without HIV infection. 

A second issue concerns the efficacy of the regimens usually prescribed. 

Patients with HIV infection may suffer from diarrhea, which may, 

through its lowering of drug serum concentrations, adversely compromise 

the efficacy of the regimen, favoring the emergence of resistance and subsequent 

relapse. 

Adverse drug events 

Adverse drug events occur much more frequently among HIV-infected tuberculosis 

patients. In particular, cutaneous hypersensitivity reactions are frequent. 

These have mostly been attributable to thioacetazone, 443,445,447,574-577 

and to a lesser extent to streptomycin, 575 rifampicin, 215,216,578 and isoniazid. 578 

The frequent and sometimes fatal cutaneous adverse drug events among 

HIV-infected tuberculosis patients due to thioacetazone preclude its use in 

patients known to be HIV-infected. 8,13 It is best replaced with ethambutol. 

An increased frequency of non-cutaneous adverse drug events (hepatotoxicity, 

gastrointestinal disturbances, thrombocytopenia) to isoniazid 578, 579 

and rifampicin has been reported. 578-580 

Anti-retroviral therapy poses particular problems because of interactions 

with rifampicin that preclude simultaneous use of the two regimens. 

74

Treatment efficacy 

As enteropathy is a frequent occurrence in HIV-infected patients, anti-tuberculosis 

medications might be less well absorbed, 581 thus leading to treatment 

failure, relapse 582 or acquisition of drug resistance. 583 Pharmacokinetic 

studies among patients with AIDS in various centers in Puerto Rico and 

the USA have demonstrated that serum peak concentrations, particularly of 

rifampicin and ethambutol, were frequently lower than expected. 334 

However, malabsorption of anti-tuberculosis medications does not seem to 

be a major issue in most HIV-infected patients. 584,585 

Sputum conversion is rapid, and even faster among HIV-positive than 

HIV-negative patients (figure 50). 586 However, concern has been expressed 

�� 

�� 

� 

� 

� 

� 

� 

� 

� 

� 

� 

� 

�� 

� � � �� 

�� 

�� 

75 

�� 

�� 

�� 

�� 

� � � �� 

�� 

Figure 50. Bacteriologic response to chemotherapy among HIV-negative and 

-positive patients, by treatment regimen. 586

that the sputum bacillary load may not reflect the underlying number of bacilli 

a patient harbors, and thus there might be a need for prolonged treatment. 587 

Regimens of six to nine months duration containing rifampicin throughout 

have been highly efficacious in terms of both low frequency of bacteriologic 

failure 576 and relapse. 579,588,589 Eight-month regimens give acceptable 

results in the field. 590 In contrast, 12-month regimens that do not 

incorporate any rifampicin have shown a high frequency of failures 591,592 

and relapse. 591,593,594 

If antiretroviral therapy is given simultaneously with treatment for 

tuberculosis, paradoxical responses have been reported with worsening of 

the clinical presentation, assumed to be an immunologic response. 595 Antiretroviral 

drugs such as protease inhibitors (saquinavir, indinavir, ritonavir, 

and nelfinadvir) and non-nucleoside reverse transcriptase inhibitors (nevirapine, 

delaviridine, and efavirenz) have substantive interactions with 

rifamycins. 596 Rifampicin will reduce the blood concentrations of protease 

inhibitors. The efficacy of the latter will thus be reduced when concommitantly 

administered with rifampicin. The interaction with nucleoside 

reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, 

and lamivudine) is probably not clinically relevant. 596 

The US Public Health Service conducted study 22, comparing the efficacy 

of once-weekly isoniazid plus rifapentine with twice-weekly isoniazid 

plus rifampicin in a four-month continuation phase following a four-drug, 

two-month intensive phase. 597 Among 61 patients with concomitant HIV 

infection, none experienced treatment failure. However, three of the 31 

patients on the rifampicin-containing continuation phase relapsed, all with 

fully susceptible organisms, but five of the 30 patients on the rifapentine 

regimen relapsed, four of whom had acquired rifamycin resistance. 

Obviously, isoniazid as a companion drug in once-weekly treatment is inadequate, 

and patients effectively received rifapentine monotherapy. There 

is indeed cause for concern that, by analogy, HIV-infected patients with 

initial isoniazid resistance may acquire unnoticed (no apparent failure during 

treatment) rifampicin resistance if treated with this drug in the continuation 

phase. 598 Nevertheless, the reasons for acquisition of rifamycin resistance 

in this study have not yet been fully elucidated, and there are 

indications that it is attributable to an inadequate dosage of rifapentine. 

Relapse following cessation of chemotherapy appears to be more frequent 

among HIV-infected compared to HIV-non-infected individuals, 594,599 

and post-treatment preventive chemotherapy with isoniazid appears to reduce 

that risk. 599 

76

Influence of isoniazid resistance on the choice 

of a regimen 

Isoniazid is a key drug in the treatment of tuberculosis and its inclusion in 

every first-line regimen is the standard of care. Pre-existing initial resistance 

to isoniazid might be conducive to the development of additional 

resistance, particularly if treatment organization is poor, as the data from 

the WHO/IUATLD global surveillance project on drug resistance seem to 

suggest (figure 51). 600 

Patients with initial isoniazid resistance who are given a four-drug 

intensive phase for two months, followed by isoniazid and thioacetazone 

in the continuation phase, fail more frequently than patients with fully susceptible 

organisms. 519,601 Such patients can be re-treated effectively with 

a regimen containing rifampicin plus ethambutol throughout, supplemented 

by pyrazinamide during the first three months, and additionally by streptomycin 

during the first two months. 8,13,602-604 

It is not very well known how effective such a re-treatment regimen 

is if there is additional ethambutol resistance. The extent to which such 

functional rifampicin monotherapy in the continuation phase of the re-treat- 

Any rifampicin-resistance (%) 

16 

14 

12 

10 

8 

6 

4 

2 

0 

Weighted regression 

0 2 4 6 8 

Isoniazid mono-resistance (%) 

Figure 51. Correlation between isoniazid mono-resistance and any rifampicin resistance 

among never treated patients. Ecological analysis from the Global Project 

on Surveillance of Anti-tuberculosis Drug Resistance. 600 

77

ment regimen is efficacious and not causing drug resistance in HIV-infected 

patients remains to be seen. 598 

Influence of isoniazid plus rifampicin resistance 

on the choice of a regimen 

Patients with multidrug-resistant tuberculosis (bacilli resistant to at least isoniazid 

and rifampicin) are only rarely expected to be cured solely using the 

six essential drugs. Under program conditions treatment outcome with the 

standard WHO recommended re-treatment regimen is poor if there is multidrug 

resistance. 605 Barring spontaneous remission, such patients are incurable 

and frequently become chronic excretors of bacilli in countries where 

only the essential drugs are available for use. 

Drugs other than the six essential drugs are of lower efficacy, much 

more costly, and in the majority of cases, much less well tolerated. 606-608 

It is also not yet known which treatment strategy is best. Proposals for 

treating multidrug-resistant tuberculosis include the utilization of a standard 

regimen or an individualized approach based on susceptibility testing. 609 

There have been no randomized controlled clinical trials to evaluate these 

regimens and insufficient experience has been accumulated to make firm 

recommendations at this point in time. 

Strategic considerations, indications, 

and recommendations for the choice of treatment 

regimens in a national tuberculosis control program 

The number of possible errors can be minimized by the systematic, country-wide 

use of standard regimens. Recommended standard treatment regimens 

are based on clinical efficacy trials in terms of dosage, mode of 

administration, and duration of treatment. Deviations from standard treatment 

regimens are indicated only in the case of adverse drug events, for 

patients presenting with pre-existing medical conditions that require a modification 

of the regimen, or in the presence of suspected or confirmed resistance 

to one or more drugs. 

Both WHO and the IUATLD recommend standard treatment regimens 

which vary according to the category of the patient. 13 The three categories 

are: 8 

78

• Patients with sputum smear-positive tuberculosis or severe extrapulmonary 

tuberculosis never treated before for as much as one month; 

• Patients with other forms of tuberculosis (sputum smear-negative and 

extrapulmonary) never treated before for as much as one month; 

• Patients with sputum smear-positive tuberculosis treated previously for 

one month or more (return after treatment failure, return after default, 

and relapse). 

No specific recommendations have been made on how to deal with patients 

with continued bacteriologically active disease following a full re-treatment 

course (chronic excretors). 

A primary objective of any tuberculosis control program must be to 

limit to the largest possible extent the emergence of organisms resistant to 

the available medications. This is a guiding principle for any chemotherapy, 

but it is particularly crucial in tuberculosis control, because the armamentarium 

of drugs is limited and the prospects in the near future for new, 

affordable drugs with an efficacy comparable to that of isoniazid, rifampicin 

or pyrazinamide are slim for most low-income countries. 

Choice of first-line regimen 

First-line regimens of six to eight months duration are the most efficacious 

available. All are based on a four-drug initial intensive phase. Whether 

a four-month (with rifampicin) or a six-month continuation phase (without 

rifampicin) is selected depends on the availability of resources for drugs 

and personnel, and considerations about the fall-back (re-treatment) regimen, 

particularly in the case of treatment failure. Twelve-month regimens 

(without rifampicin) have been widely used for bacteriologically unconfirmed 

disease, but their efficacy in HIV-infected patients appears to be 

inferior to the shorter, but more intensive alternatives. 

The continuation phase in the eight-month regimen consists of six 

months of isoniazid plus thioacetazone. A frequently chosen alternative to 

thioacetazone is ethambutol. This change potentially weakens the re-treatment 

regimen (functional rifampicin monotherapy in the continuation 

phase). This increases the risk of development of multidrug resistance. 

The IUATLD therefore recommends the addition of pyrazinamide throughout 

the re-treatment regimen 8 when ethambutol has been used in the continuation 

phase of initial treatment. 

79

Many countries have moved towards a first-line regimen which contains 

rifampicin throughout. Patients truly failing on such a regimen have 

a high probability of initial multidrug resistance (or initial isoniazid resistance 

and acquired rifampicin resistance). The re-treatment regimen recommended 

by the IUATLD and WHO is highly unlikely to cure such a 

patient, and additionally carries the risk of acquisition of ethambutol resistance. 

It is not clear whether re-treatment incorporating both ethambutol 

and pyrazinamide in the continuation phase will overcome this problem. 

Given the relative weakness of these two drugs, there is a risk of losing 

both. This has been termed the “amplifier effect” (a new term for an old 

phenomenon, successive acquisition of additional drug resistance) and has 

been observed to occur in an outbreak in urban Peru. 610,611 It has not been 

observed in other settings where a non-rifampicin-containing continuation 

phase is routine in the first-line regimen. 612 

8-month regimens 

The eight-month regimen evaluated in East Africa (a directly observed fourdrug, 

two-month intensive phase followed by six months of self-administered 

isoniazid plus thioacetazone) has become the principal treatment regimen 

for previously untreated smear-positive pulmonary tuberculosis in 

IUATLD collaborative programs. 8,604 Programs basing their chemotherapy 

on this regimen are using a highly cost-effective intervention. 613 

Replacement of streptomycin by ethambutol in the intensive phase did 

not adversely affect adherence to directly observed therapy in a study conducted 

in large urban settings in Tanzania, 614 and gave similar treatment 

outcome under routine conditions in Madagascar, although the proportion 

of failures was somewhat higher than in the streptomycin group. 615 It also 

yielded good results in Benin. 616 

It is likely that replacement of thioacetazone by ethambutol is equally 

effective, as demonstrated in a clinical trial in India in a patient population 

with a low prevalence of HIV infection. 521,522 When thioacetazone cannot 

be used because of a high prevalence of HIV infection, its replacement by 

ethambutol is therefore often recommended. 8 


The shortest treatment regimen of proven efficacy for bacteriologically confirmed 

tuberculosis consists of six months of isoniazid plus rifampicin, supplemented 

by pyrazinamide plus either streptomycin or ethambutol during 

the first two months. This has been convincingly demonstrated where all 

80

medications were taken daily throughout the course of treatment. 122 In 

Poland, a study with this regimen, with the continuation phase given twice 

weekly, led to neither failures nor relapses. 525 Similar good results were 

obtained with the same regimen in Singapore, with the continuation given 

thrice weekly. 617 

Most industrialized countries have adopted this regimen, given daily 

in the intensive phase and daily or intermittent in the continuation phase, 

as their regimen of choice for patients without a history of prior treatment. 


The best documented 12-month regimen currently used in low-income countries 

consists of 12 months of isoniazid plus thioacetazone, supplemented 

by streptomycin during the first two months. 122 This regimen has been 

widely used in IUATLD collaborative programs in patients without a prior 

history of treatment. Amongst these, it is given for cases with positive 

sputum smears who cannot receive a directly observed rifampicin-containing 

intensive phase and for the majority of patients whose sputum smears 

are negative or who have extrapulmonary tuberculosis which is not lifethreatening. 

In Uganda, the frequency of adverse drug events and survival as the 

main outcomes of interest were compared for the above 12-month regimen 

and a nine-month, rifampicin-throughout regimen (supplemented by pyrazinamide 

during the first two months) among HIV-infected patients. 618 As expected, 

adverse drug events were much more common in the former than the 

latter regimen, but survival over a two-year follow-up period was identical. 

In Malawi, HIV-infected patients with sputum smear-negative tuberculosis 

who were treated with a 12-month regimen (12 months of isoniazid 

plus thioacetazone or ethambutol, supplemented with streptomycin during 

the first month), had a very high relapse rate approaching 20% (compared 

to seven per cent among HIV-negative patients). 590 These findings critically 

challenge the continued use of such a regimen in countries where the 

prevalence of HIV infection among tuberculosis patients is high. 

Choice of re-treatment regimen 

Treatment regimens for a national tuberculosis control program should be 

designed to allow curative treatment of patients requiring a re-treatment 

regimen, because it is the patient’s last chance to get cured. The need for 

a re-treatment regimen is based on the increased probability of resistance 

81

to the medications used in patients who have received prior treatment. That 

this is the case has been amply demonstrated. 619 An efficacious re-treatment 

regimen must encompass at all times, throughout treatment, at least 

two drugs to which the organism is still likely to be susceptible. Countries 

which do not have access to medications other than the six essential drugs 

for patients who might require them must choose a re-treatment regimen 

based on these six drugs. 

Because isoniazid is always given in the first-line regimen, a patient 

failing to respond to the treatment regimen will have a high probability of 

already having isoniazid resistance at the outset of treatment. To adhere 

to the principle of a re-treatment regimen incorporating at least two efficacious 

drugs, neither rifampicin nor ethambutol should have been used as 

the sole companion drug with isoniazid at the point of failure (defined as 

sputum smear-positive at five months or later), if either of these drugs is 

to be effective in a re-treatment regimen. Their use as a sole companion 

drug with isoniazid constitutes functional monotherapy in such a patient 

and presents a risk that resistance will have developed to the companion 

drug (in this case, either rifampicin or ethambutol). This has been the 

rationale behind the recommendation of the IUATLD to utilize isoniazid 

plus thioacetazone in the continuation phase. Should bacilli resistant to 

thioacetazone emerge, re-treatment is still likely to be successful. 

This re-treatment regimen proposed by WHO and the IUATLD consists 

of eight months of isoniazid, rifampicin, and ethambutol, supplemented 

by pyrazinamide during the first three, and streptomycin during the first 

two months. This regimen uses the full range of available drugs except 

thioacetazone. Such a regimen has a high probability of curing any patient 

who does not commence treatment with organisms already resistant to both 

isoniazid and rifampicin. Patients with multidrug-resistant strains have, 

after taking the re-treatment regimen, an outcome that is not appreciably 

better than reported outcomes in the pre-chemotherapy era. 620 

Treatment of patients with organisms resistant to isoniazid 

and rifampicin 

Patients who fail on directly observed treatment containing isoniazid and 

rifampicin throughout, i.e., patients failing on a six-month first-line regimen 

or the above-mentioned eight-month re-treatment regimen, are more 

likely to harbor organisms resistant to both isoniazid and rifampicin (multidrug-resistant 

organisms). In most low-income countries such patients are 

designated “chronic excretors” whose fate has to be left to the natural course 

82

of the disease, as alternative drugs (other than the six essential drugs) are 

not usually available in sufficient quantity. 

The emergence of multidrug-resistant tuberculosis has been documented 

in an increasing number of countries and has, in some countries, reached 

levels that seriously threaten tuberculosis control. 621,622 

The WHO has addressed this issue in both a formal publication 606 and 

workshop proceedings. 608,609 

Curative treatment of multidrug-resistant tuberculosis poses a multitude 

of problems. Amongst these are: 

• the high cost of the necessary drugs (currently up to 100 times as 

expensive per course as a first-line regimen); 609 

• the relative weak activity of most of these drugs against M. tuberculosis; 

• the high frequency of adverse reactions requiring specialist expertise; 

• the prolonged duration (21 months has been proposed as a minimum); 606 

• the logistic difficulties anticipated in implementing such regimens in a 

national tuberculosis program; 

• difficulties in implementing standardized laboratory facilities to correctly 

identify susceptibility patterns; 623 

• gaps in knowledge as to what approach to treatment (individualized or 

standardized) is most appropriate. 624 

As there is an increasing demand to utilize such alternative medications, 

and technical knowledge is generally poor about their proper usage in most 

countries where the problem has emerged or is emerging, the danger of 

uncontrolled usage is great. Resistance to these drugs is likely to emerge 

quickly in unprepared settings. 625 It is hoped that the agenda set forth by 

WHO 608 will generate sufficient information in an ordered and timely fashion 

and appropriate technical expertise will accompany implementation of 

any such project to ensure continued curability of tuberculosis in such settings. 

Unfortunately, multidrug-resistant tuberculosis has emerged precisely 

in areas of the world that have demonstrated poor tuberculosis control in 

the first place, and whether a deterioration of the situation in such settings 

can be prevented with the introduction of drugs potentially able to cure 

multidrug-resistant tuberculosis remains to be seen. 

83

Case holding 

Prescription of an adequate course of treatment is not sufficient; it must be 

ensured that the prescribed medications are also actually taken until the 

successful, curative completion of therapy. 

Directly observed therapy 

Ensuring regularity of treatment is the key to timely completion of therapy 

and the prevention of acquisition of drug resistance. The problems with 

self-administered chemotherapy in ensuring regular adherence have long 

been recognized, 279 and to ascertain the efficacy of regimens in clinical trials, 

direct observation of drug intake during part or the entire course of 

treatment has thus been standard in many investigations. 122 

Directly observed therapy refers to treatment where a qualified person 

(usually, but not always, 626 a health care worker) ensures that the prescribed 

medications are taken by observing the patient ingesting them. 627 Directly 

observed ambulatory therapy has its evidence base in studies in Chennai 

(formerly Madras) and Hong Kong, 628 and the recognition of the need for 

alternatives to costly hospitalization. 

Directly observed therapy might be conceived of as a coercive procedure, 

but it may also help to strengthen the relationship between patient 

and health care worker. 629 If this does not occur, then directly observed 

therapy may not achieve an increase in the proportion of patients completing 

therapy. 630 

The major effects of directly observed therapy that might be expected 

are a reduction in the risk of acquiring drug resistance and in the frequency 

of relapse following completion of chemotherapy, as convincingly demonstrated 

in a study in the United States (figure 52). 631 

Can emergence of drug resistance be outpaced 

in a national tuberculosis program? 

Strains resistant to isoniazid should have a comparative advantage, as patients 

harboring such a strain will, on average, be transmitters for a longer period 

of time than patients with a fully susceptible strain. Thus, one would expect 

an increase in the prevalence of primary resistance to isoniazid. This is, 

however, not the case in well-managed programs. 632,633 Some studies sug- 

84

Number of cases per 100,000 population 

1.2 

0.8 

0.4 

0.0 

1.2 

0.8 

0.4 

0.0 

1.2 

0.8 

0.4 

0.0 

1980 1982 1984 1986 1988 1990 1992 

Year of notification 

gest that the transmissibility is the same for isoniazid-susceptible and isoniazid-resistant 

strains, 634,635 while others indicate that transmissibility of 

isoniazid-resistant strains is reduced; 122 thus the question of transmissibility 

has not been fully resolved. However, strains which are resistant because 

of katG gene deletion have lower virulence in experimental animal models, 

636,637 while mutation of the inhA gene has no effect on virulence. 636 

Thus, a fraction of isoniazid-resistant strains may have a comparative selection 

disadvantage. In an effective tuberculosis program with a directly 

observed intensive phase utilizing the four most potent drugs, followed by 

a self-administered, non-rifampicin-containing continuation phase, no significant 

multidrug resistance (resistance to at least isoniazid and rifampicin) 

has emerged over 12 years of usage. 632 This could indicate that a qualitatively 

good program may outpace the rate of emergence of drug resistance. 

However, a study from The Netherlands indicates that some specific 

mutations of the katG gene lead to high-level resistance and as great 

a probability of producing secondary cases as isoniazid-susceptible strains. 638 

85 

Multidrug-resistant relapse 

Primary resistance 

Acquired resistance 

Figure 52. Effect of directly observed therapy on relapse, primary resistance, and 

acquired resistance, in Tarrant County, Texas, United States. Arrow indicates point 

in time of introduction of universal directly observed therapy. Reproduced from 631 

by the permission of the publisher Massachusetts Medical Society.

Strains resistant to isoniazid alone can virtually always be killed when 

regimens containing both rifampicin and pyrazinamide are used and 

rifampicin is given throughout. 603 The introduction of the short-course regimens 

in countries such as Algeria and Korea was accompanied by a clear 

decline in resistance to isoniazid and chronic excretors for this reason. 639,640 

However, in the case of Algeria, the introduction of short-course regimens 

was associated with the appearance of and slow increase in cases with multidrug 

resistance among previously treated patients, possibly related to the 

fact that directly-observed treatment was not the policy. The rate of decline 

in cases of tuberculosis (and particularly of re-treatment cases) in that community 

was greater than the rate of appearance of multidrug resistance, thus 

outpacing the drug resistance. However, if this community had experienced 

a rise in the numbers of cases, rather than a decline (as would have 

occurred if the community was affected heavily by HIV infection), this 

might not have been the case. 

This is one of the main reasons why the IUATLD has preserved a 

very conservative policy with respect to treatment regimens, in order to 

preserve the usefulness of rifampicin as an efficacious agent in the overall 

scheme of treatment policy. 

The approach to management of adverse drug events 

The major clinical presentations of adverse drug events that may occur in 

a patient treated with the essential drugs and the approach to managing 

them will be discussed here. Adverse drug events from second-line drugs 

should always be dealt with by a specialist in the field. The discussion is 

limited to the major clinical syndromes occurring in the routine management 

of tuberculosis in clinical practice. 

In any patient who takes prolonged treatment, episodes of ill health 

may occur which may be ascribed by the patient or the health care provider 

to adverse effects of the treatment given. This is not necessarily the case. 

In the large clinical trials of preventive chemotherapy carried out by the 

US Public Health Service among household contacts of tuberculosis patients, 

one group of patients was assigned to the treatment arm and another to a 

placebo in which identical tablets were given which contained no active 

medication. 641 Neither the patient nor the care provider knew the type of 

pills that individual patients were taking. The events that occurred during 

treatment were thus observed without knowledge of the treatment. In a 

86

number of cases, the health care provider, based on the assumption that the 

treatment was causing adverse drug events, discontinued the treatment. 

When the code indicating what the patient was taking was broken and 

the results analyzed, it became apparent that 20% of all episodes considered 

to have been adverse drug events to the “medication” were, in fact, 

“placebo” effects. 641 This indicates that the “adverse events” were, indeed, 

intercurrent illnesses or events unrelated to the treatment itself, although 

they had every appearance of having been due to the medications. 

This has important implications for the evaluation of “adverse events” 

in patients on treatment for tuberculosis. If one or other of the essential 

medications used in the treatment of tuberculosis (such as isoniazid or 

rifampicin) is stopped due to what is (incorrectly) perceived as an adverse 

drug event, the outcome of the treatment can be seriously affected. 

Discontinuation of an essential medication in the treatment of a tuberculosis 

patient for what is perceived as an adverse drug event must be carefully 

considered and correctly undertaken if the patient’s chances of successful 

treatment are not to be seriously affected. 

The patient with hepatitis 

Clinical hepatitis is to be suspected in a patient presenting with a syndrome 

of malaise, nausea, vomiting, anorexia, fever, abdominal pain, hepatomegaly, 

jaundice or dark urine. 642 

Hepatic disease during anti-tuberculosis chemotherapy is not necessarily 

caused by the drugs, but may be attributable to other causes, such 

as alcohol abuse, cirrhosis, infectious hepatitis or indeed the tuberculosis 

itself. Nevertheless, appropriate management of the patient requires an 

approach as if one or more of the drugs were responsible. 

The key suspect drugs are isoniazid, pyrazinamide, and rifampicin, if 

the patient is on any of these. In that case, such as in the intensive phase 

of chemotherapy, all three drugs should be stopped immediately if the symptoms 

are severe and/or if there is jaundice. The patient should temporarily 

be placed on ethambutol plus streptomycin in such a case. This combination 

is unlikely to be hepatotoxic and, while a relatively weak combination, 

still ensures temporary adequate treatment without a high risk of emerging 

drug resistance. In the presence of malaise and nausea only (without 

jaundice), rifampicin might in addition be kept in the regimen as it is rarely 

a cause of hepatitis. 

87

The patient is maintained on these two drugs until the acute symptoms 

subside, which usually occurs within one or two weeks. 

Isoniazid might then be added in a dosage of 50 mg per day. If there 

is no clinical deterioration, the dose of isoniazid may then be increased to 

100 mg on day 4, to 200 mg on day 7 and to the full dose on day 14. 642 

Following the patient for another seven days, rifampicin might then be reintroduced, 

and if well tolerated, pyrazinamide might finally be added if 

rifampicin plus isoniazid has been well tolerated for seven days, and if it 

has been given for less than two months prior to the onset of hepatitis. 

This schedule can be expected to be successful in over 90% of cases. 642 

Some clinicians prefer to re-introduce isoniazid at the full dose when 

liver enzymes (where available) have normalized, or if liver enzyme tests 

are not available after two weeks (Schraufnagel DE, personal written communication, 

April 3, 2001; O’Brien RJ, personal written communication, 

April 19, 2001). 

The patient with gastrointestinal symptoms 

Gastrointestinal symptoms such as nausea, pain and vomiting might be prodromal 

symptoms of hepatitis, and close clinical observation is mandatory. 

In addition to isoniazid, rifampicin, and pyrazinamide, thioacetazone frequently 

causes gastrointestinal symptoms. In a patient on isoniazid and 

thioacetazone, the latter is probably the cause. Such reactions can often 

be dealt with easily by taking the medications with a meal or before going 

to bed. Monitoring of the response is important. If the symptoms do not 

subside, the isoniazid plus thioacetazone combination should be replaced 

by isoniazid plus ethambutol. Should the symptoms persist despite the 

change, isoniazid and the possibility of liver toxicity must be suspected and 

the patient be placed on streptomycin plus ethambutol until symptoms subside. 

Isoniazid might be re-introduced subsequently, as described above. 

The patient with impaired vision 

The most frequent drug-related cause of impaired vision among the medications 

used for treating tuberculosis is ethambutol. Optic toxicity is not 

detectable fundoscopically. If ethambutol is suspected, it must be withdrawn 

immediately and never be given again. If the event occurs in the 

intensive phase where ethambutol is given as a fourth companion drug, no 

replacement is necessary (although streptomycin might be used if deemed 

88

necessary). If the event occurs in the continuation phase when the patient 

is on isoniazid plus ethambutol, the latter should be replaced by thioacetazone 

or rifampicin. 

The patient with vestibulo-cochlear toxicity 

Vestibulo-cochlear toxicity is virtually always due to streptomycin. It is 

often, but not always, dose-dependent. Thus, it should first be checked 

whether the dosage given is appropriate to weight and age (toxicity increases 

with both). If the dose cannot be reduced or if dose reduction fails to 

improve the symptomatology, streptomycin should be stopped and not be 

given again (unless the drug resistance pattern makes its use imperative). 

As streptomycin is usually given only in the intensive phase as a fourth 

companion drug, it can be stopped without replacement. Streptomycin 

should never be given to pregnant women because of the potential risk of 

causing deafness in the unborn child. 

The patient with neurologic symptoms 

A distinction should be made between peripheral and central nervous system 

toxicity from anti-tuberculosis medications. 

Peripheral neuropathy, presenting as paresthesia, such as tingling and 

numbness, starting at the feet with proximal spread is the usual manifestation. 

408 Myalgias, weakness, and ataxia may accompany these symptoms. 

Peripheral neuropathy is usually due to isoniazid, is rare and occurs usually 

only in malnourished or alcohol-dependent patients. Pyridoxine is 

effective in treating this condition, but the dosage for treatment should not 

exceed 50 mg per day, as there might be antagonism with isoniazid, 108 

although the clinical relevance of this antagonism is not clear. 

Infrequently, toxic psychosis and epileptic convulsions may occur with 

isoniazid, and very rarely, in patients with signs of malnutrition or malabsorption, 

a pellagroid syndrome (with dermatitis, diarrhea, and dementia) 

has been reported. Pyridoxine is usually effective for treating such cases. 

The patient with hypersensitivity reactions 

or muco-cutaneous signs and symptoms of toxicity 

Cutaneous adverse drug events, ranging from pruritus, to rashes, and most 

severely to toxic epidermal necrolysis, sometimes accompanied by fever, 

may be caused by thioacetazone, isoniazid, rifampicin, streptomycin, or 

89

pyrazinamide. Cutaneous adverse drug events are much more frequent 

among patients with HIV infection than among non-HIV-infected patients. 

If the patient is on thioacetazone, it is by far the most likely cause. It 

should be stopped immediately, and never be given again. 

In all instances of rash with or without fever, all drugs should be 

stopped. When the symptoms subside, usually within a day or two, the 

drug least likely to be the cause should be re-introduced in a test dose. 

This drug is usually isoniazid and is given at a dose of 150 mg. If the 

patient was hypersensitive to isoniazid, a rise in temperature, pruritus, or 

rash will develop within two to three hours. 499 If there is no reaction to 

the test dose, the next test dose might be tried. Over the following days, 

the full dose is gradually introduced. Subsequently, rifampicin might be 

similarly re-introduced, starting with a test dose of 75 mg (or less), and so 

on. Under strict observation, it might be possible to desensitize with 

rifampicin much more rapidly, i.e., within two days. 643 If there is pruritus 

or rash only, desensitization to isoniazid might not be necessary, as 

symptoms often subside spontaneously. 

Very often desensitization is successful, and the full range of medications 

can be reintroduced within one to two weeks. It should be reiterated 

that such desensitization should never be attempted with thioacetazone. 

The patient with hematologic abnormalities 

Blood dyscrasias comprise only 10% of the total number of drug-induced 

adverse events but account for approximately 40% of fatal reactions related 

to drug administration. 93 They occur with all six essential anti-tuberculosis 

medications. In symptomatic patients, the offending drug should be 

withdrawn and never be given again. 

Relative leukopenia and hemolytic anemia due to isoniazid require permanent 

withdrawal of the drug and often treatment with corticosteroids to 

reverse hemolysis. Sideroblastic anemia due to isoniazid is usually responsive 

to treatment with pyridoxine. Rarely, other neutropenia, eosinophilia, 

and thrombocytopenia may occur, which will respond to withdrawal of isoniazid. 

Similarly, the rare pure red cell aplasia responds to withdrawal of 

isoniazid. Complete recovery from agranulocytosis usually occurs following 

withdrawal of isoniazid. 

With the exception of thioacetazone, blood dyscrasias due to anti-tuberculosis 

drugs are rare events. It is probably exceedingly difficult to identify 

the offending drug in the field. 

90

The patient with acute renal toxicity 

Acute renal toxicity may be the result of a hemolytic anemia, glomerulonephritis 

and interstitial nephritis. The most likely cause of this rare 

adverse drug event is rifampicin. The drug should be withdrawn and never 

be given again. If renal insufficiency has developed, the dosages of ethambutol 

and streptomycin must be reduced according to the remaining function 

as these drugs are almost entirely excreted through the kidneys. 

The patient with osteo-articular pain 

Arthralgia is a frequent adverse drug event resulting from accumulation of 

uric acid due to pyrazinamide. In many instances, the dosage of pyrazinamide 

is higher than that recommended in patients who have such reactions 

and, if so, should be reduced to within the recommended limits. It 

often occurs towards the end of the intensive phase, when pyrazinamide 

can be withdrawn without replacement. Alternatively, acetyl salicylic acid 

commonly alleviates the symptoms. Intermittent administration of pyrazinamide 

will also reduce the effect of uric acid retention. Allopurinol is 

ineffective. 

The approach to the patient 

with pre-existing medical conditions 

Patients may present not only with tuberculosis but also other medical conditions 

that require modifications of the standard treatment. In this chapter, 

some of the major medical conditions that require such adjustments are 

discussed. 

The patient with liver injury 

Patients with mild and clinically unrecognizable liver injury, including those 

who abuse alcohol, may be treated with the standard treatment, which needs 

to be adjusted only if clinical signs of hepatitis occur as discussed in the 

previous chapter. 

Patients presenting with clinical signs of hepatitis should not be given 

the drugs with the greatest potential for hepatotoxic reactions. These include 

isoniazid, rifampicin, and pyrazinamide. Such a patient might be treated 

91

with ethambutol plus streptomycin until the acute signs of hepatitis subside. 

Subsequently, isoniazid and / or rifampicin might be re-introduced 

under close observation. Depending on the feasibility of introducing the 

latter, treatment duration will need to be adjusted. If neither rifampicin 

nor isoniazid can be given, treatment should probably be given for 

18 months. The continuation phase with streptomycin and ethambutol 

should not be given more frequently than three times per week to reduce 

the cumulative toxicity of streptomycin. 

The patient with renal failure 

Streptomycin and ethambutol are excreted mainly through the kidneys and 

are thus safe only if appropriate dose adjustments can be made in patients 

with renal insufficiency. This is not usually possible without access to 

monitoring of blood levels or measurement of creatinine clearance, a service 

not usually available in low-income countries. Such a patient is thus 

best treated with isoniazid, rifampicin, and pyrazinamide in the intensive 

phase. In the continuation phase, isoniazid plus thioacetazone or isoniazid 

plus rifampicin can be given. Treatment duration is not affected. 

The patient with impaired hearing or impaired balance 

Patients with pre-existing vestibulo-cochlear impairment should not be given 

streptomycin. Streptomycin may be replaced by ethambutol. 

The patient with impaired vision 

Patients with impaired vision other than due to myopia, hyperopia or presbyopia, 

should not be given ethambutol. Ethambutol may be replaced by 

streptomycin in such cases. 

The patient with gastrointestinal malabsorption 

Patients recognized or suspected to have gastrointestinal malabsorption may 

pose serious problems for adequate chemotherapy, as shown in a study on 

risk factors for acquisition of rifampicin monoresistance. 644 On the other 

hand, a study among HIV-infected patients in Nairobi has not demonstrated 

important differences in pharmacokinetic profiles of isoniazid, rifampicin, 

and ethambutol between patients with and patients without HIV infection, 

92

and no association with diarrhea. 584 Similarly, studies in South Africa have 

shown that malabsorption in asymptomatic HIV-infected patients is not a 

major issue and no important pharmacokinetic differences have been seen 

in a series of AIDS patients. 585 Thus, malabsorption of anti-tuberculosis 

medications in HIV-infected patients may not be that serious a problem. 

Nevertheless, it is probably reasonable to always include the parenteral 

streptomycin in patients suspected of having malabsorption. 

The pregnant patient 

Pregnant women with tuberculosis do not pose particular problems for treatment. 

Dose adjustment is probably indicated with increasing body weight 

as the volume of distribution increases. Because of the potential of 

vestibulo-cochlear toxicity to the fetus, streptomycin should not be given 

in pregnancy. Isoniazid, rifampicin, ethambutol, pyrazinamide, and thioacetazone 

are safe in pregnancy, and are not reported to have teratogenic or 

other adverse effects on the fetus. 

Second-line drugs that should be avoided in pregnancy include other 

aminoglycosides, polypeptides, thioamides, and quinolones. 

93

2. Prophylactic treatment 

In this monograph, prophylactic treatment is defined as treatment to prevent 

acquisition of infection with M. tuberculosis in a person exposed to 

tubercle bacilli. Its aim is to minimize the risk of acquiring latent infection. 

Little evidence is available to document the efficacy of such prophylactic 

treatment. The little that is known is summarized here. 

Rationale and experiences 

with prophylactic treatment 

In the early 1950s, Zorini reported experiments with prophylactic treatment 

in guinea pigs, using various dosages of isoniazid. 645,646 Briefly, guinea 

pigs were given isoniazid or placebo in their drinking water for one month 

and then challenged with an endoperitoneal injection of M. tuberculosis. 

The results were unequivocal in that a considerably larger proportion of 

placebo-treated animals developed tuberculosis in comparison to those receiving 

isoniazid. 

Among humans, the effect of isoniazid compared to placebo in preventing 

tuberculin skin test conversion has been ascertained within the context 

of clinical trials on preventive chemotherapy. 641 A tuberculin skin test 

was given before random allocation to either isoniazid or placebo for one 

year. At the end of treatment, the rate of conversion among persons who 

were initially tuberculin skin test negative was compared in the two groups. 

These four US Public Health Service studies were conducted among various 

groups of patients (patients in a mental institution, contacts of known 

cases, school children, and contacts of newly diagnosed tuberculosis 

patients). The protection afforded against conversion from a negative to a 

positive tuberculin skin test after one year of treatment with isoniazid in 

these studies is summarized in figure 53. 641 It shows that the confidence 

intervals are wide (small numbers eligible for assessment), and thus that 

the extent of protection is uncertain. 

95

Schools 

Contacts of 

new cases 

Contacts of 

known cases 

Mental patients 

- 50 0 20 40 50 

Protection (%) (log scale) 

Figure 53. Protection from prophylactic treatment in the prevention of acquisition 

of tuberculous infection in four clinical trials conducted by the US Public Health 

Service. 641 

Indications and recommendations for the use 

of prophylactic treatment 

Prophylactic treatment is, for all practical purposes, rarely indicated. Even 

if the evidence is scant, however, it makes sense to provide it to a newborn 

child with a potentially infectious parent, especially the mother. This 

is recommended in industrialized countries, 356 but should most likely be a 

universal indication. 

It is not clear what the appropriate duration of prophylactic treatment 

should be. It is probably indicated, however, to continue it for perhaps up 

to three months after relevant exposure has ended. 

Children under the age of five years are also at high risk of acquiring 

tuberculous infection from a person with sputum smear-positive tuberculosis 

living in the same household and, if they become infected, are at 

high risk of progression to clinically manifest tuberculosis. The IUATLD 

has thus recommended systematic treatment with isoniazid of asymptomatic 

children in such a situation. 8 Some of these children will not yet have 

been infected (the infected being the primary target group) and will thus 

receive true prophylactic treatment. 

96

Early vaccine development 

3. Vaccination 

Vaccination with Mycobacterium tuberculosis 

Early in the twentieth century, von Behring attempted vaccination (or as 

he called it, “Jennerization”) of cattle by utilizing increasing doses of living 

M. tuberculosis. 647,648 Similar to these attempts, Webb in the United 

States tried to make experimental animals resistant to re-challenge with 

increasing doses of virulent M. tuberculosis, and a few children were also 

“vaccinated” with this approach, apparently with no adverse outcome. 649 

While this approach seemed indeed to provide some protection against a 

subsequent challenge in cattle and other experimental animals compared to 

controls, protection was incomplete in the case of von Behring’s “bovovaccination” 

and in the guinea pig. Furthermore, with “Jennerization” in 

cattle there was the potential that the microorganism would appear in 

milk. 650 Theobald Smith also pointed out that the unknown duration of 

the incubation period carried great dangers, even if the immediate effect 

seemed to be innocuous. 650 This approach was therefore only short-lived. 

However, more recently, the idea of attenuating M. tuberculosis and 

using such an attenuated strain as a vaccine has been picked up again, and 

it is expected that the vaccine properties of such mutants will be tested at 

least experimentally in the near future. 651 

Vaccination with Mycobacterium chelonae 

Early in the twentieth century, Friedmann proposed vaccination with M. chelonae, 

a mycobacterium recovered from the turtle. 652 Because the argument 

of vaccination was largely based on the hypothesis that persons ill 

with tuberculosis could develop increased resistance in suppressing progression 

from morbidity to death, this method was mainly used in the treatment 

of clinically manifest tuberculosis. 653 There was probably no effect 

at all if judged by current standards. Only a very small study was published 

reporting the results of M. chelonae vaccination in children exposed 

to tuberculosis but without clinical signs of the disease. 654 The study was 

97

too small to allow a meaningful interpretation of the efficacy of this vaccination. 

The method never gained much attention beyond Germany, and 

fell into oblivion as vaccination with BCG drew increasing attention in the 

immediately succeeding years. 

Vaccination with BCG 

Vaccine development 

A virulent strain of M. bovis, isolated by Nocard in 1902, from milk obtained 

from a cow with tuberculous mastitis 655 was inoculated for the first time 

on January 8, 1908, by Albert Calmette (1863-1933) and Camille Guérin 

(1872-1961) 656 at the Pasteur Institute in Lille, France 657 onto a medium 

consisting of cooked potato and glycerinated bile. 

The strain, to become known as Bacille Calmette-Guérin (BCG), was 

sub-cultured in 230 passages on bile potato medium until 1921 when it no 

longer changed its characteristics. 

After thirty passages the strain ceased to kill guinea pigs; after sixty 

it was still slightly virulent for rabbits and horses, but avirulent for guineapigs, 

monkeys, and calves. 655 From 1912 onwards, experiments were conducted 

among calves, demonstrating their resistance to subsequent infection 

with virulent bacilli. 655 It may be noted that the main objective in the 

development of this vaccine was to obtain an effective vaccine against tuberculosis 

in goats 658 and cattle. 658,659 It is now clear that it was not the glycerinated 

bile medium that was the reason for the loss of virulence. 660,661 

By sub-culturing four bovine strains on Calmette’s bile-potato medium over 

six years, Griffith failed to reproduce Calmette’s finding and to induce stable 

attenuation. 662 The reasons for the loss of virulence of M. bovis BCG 

remain unclear until today. 

On July 1, 1921, Weill-Hallé, a pediatrician, requested the vaccine for 

use in an infant born to a mother who had died of tuberculosis shortly after 

delivery. The child was to be brought up by a grandmother who was herself 

suffering from tuberculosis. 663 The child was given 6 mg of BCG 

orally and developed normally over the next six months without any sign 

of illness, either from the vaccine or from tuberculosis. 655,663 Over the next 

three years, 317 infants (67 of whom were born into, and brought up by 

families with tuberculosis patients) were vaccinated with 30 mg oral BCG 

vaccine, given in three portions at 48-hour intervals. 

98

Following these early experiments in humans, BCG was distributed to 

a large number of laboratories, largely in Europe, and given to hundreds 

of thousands of children within a decade after its introduction. 664-667 Trials 

to evaluate its impact began in Europe 668-670 and North America. 671,672 

Controlled assessment of the vaccine’s efficacy was conspicuously 

absent, and one of its most violent opponents was Petroff in the USA, who 

doubted both the vaccine’s innocuousness and efficacy. 673,674 Despite the 

justified concerns about the quality of the data on efficacy given all the 

methodological problems (such as selection bias), it seemed apparent that 

BCG reduced case fatality from tuberculosis among exposed children in a 

variety of settings (figure 54). 666 It also seemed to protect adult student 

nurses heavily exposed to tuberculosis both from death and disease (figure 

55). 668-670,675 

Deaths per 100 infants 

(log scale) 

35 

20 

10 

5 

3 

Not vaccinated Vaccinated 

Figure 54. Early, non-controlled comparisons in crude infant mortality before and 

after introduction of BCG vaccination in 16 countries, reported up to 1932. 666 

The assumption of the safety of BCG vaccination was severely challenged 

when 72 of 251 children who were presumably vaccinated with BCG 

between December 10, 1929, and April 30, 1930, died from tuberculosis 

in Lübeck, Germany. 676-678 While not all circumstances surrounding this 

disaster have ever become public, 679 it soon became apparent that BCG was 

not the cause. The preliminary epidemiologic analysis in July 1930 already 

showed large differences in case fatality by week of vaccination (figure 56), 

indicating that strains with different virulence had been mixed. 680 This was 

bacteriologically confirmed by demonstrating that virulent tubercle bacilli, 

but not BCG, were consistently isolated on autopsy. 676 The epidemiologic 

99

Cases per 1,000 

140 

120 

100 

80 

60 

40 

20 

0 

TBN + 

BCG - 

TBN - 

BCG - 

Tuberculosis 

cases 

TBN - 

BCG + 

and bacteriologic investigations demonstrated conclusively that batches containing 

both BCG and M. tuberculosis in varying proportions had been fed 

to the infants during the epidemic. 676,678,681,682 Among the 53 fatal cases 

ascertained by mid-July 1930, the interval between vaccination and death 

ranged from 34 to 129 days with a median of 79 days. 

100 

Tuberculosis deaths 

TBN + 

BCG - TBN - 

BCG - 

TBN - 

BCG + 

Figure 55. Results from a non-randomized, self-selection evaluation of the effect 

of BCG vaccination on tuberculosis cases and deaths among student nurses in 

Norway. 670 

Number of cases 

30 

20 

10 

0 

Healthy 

TB 

TB death 

February March April June 

Weekly vaccinations with critical strain 

Figure 56. Curve of the tuberculosis epidemic following an accidental mix of BCG 

vaccine strain with a virulent strain of Mycobacterium tuberculosis in Lübeck, 

Germany, 1930. 676

Petroff’s concerns about a reversion to virulence of BCG have never 

been confirmed, and his observation of different colony morphology with 

virulent and avirulent colonies 673 have not been confirmed elsewhere. 676 

The BCG strain family 

Until the introduction of freeze-drying in Japan in 1943, 683 the only means 

of maintaining a viable strain was through sub-culturing. With the distribution 

of the vaccine strain to multiple laboratories in the world, each using 

slightly different techniques for strain maintenance, it is not surprising that 

the BCG family shows large diversity. 660 The first freeze-dried French 

strain (1949) from the Pasteur Institute in Paris was strain 1173-P2 , from 

which the Glaxo and Danish strains descended. 684 

Recent work based on molecular characterization of the various substrains 

points to various mutations that have occurred at different points in 

time (figure 57), 685-687 and indicates that the various BCG sub-strains are 

morphologically and genetically different from each other. 

Safety record of BCG vaccination 

A large review has shown BCG to be one of the safest vaccines. 688,689 The 

demarcation between a normal reaction and an adverse reaction is not always 

clear. 690 The normal reaction is a red indurated area measuring five to 

15 mm. A crust is formed around this induration, which is soft at the center 

for three to four weeks. At six to ten weeks, the crust falls off, leaving 

a flat scar measuring three to seven millimeters. 690 Regional lymphadenopathy 

in the absence of erythema or vesicle formation should also 

be considered a normal reaction to the vaccine. 691 Complications include 

cutaneous lesions and regional suppurative lymphadenitis; more severe localized 

or multiple lesions (such as musculo-skeletal lesions); 692-694 and nonfatal 

and fatal complications resulting from hypersensitivity reactions or 

mycobacterial dissemination. 688,689,695-702 The risk of complications varies 

with the type of vaccine and with the age at vaccination. The risk of 

osteomyelitis ranged from 0.01 to 50 per 1 million vaccinations, that of 

multiple or generalized lesions from 0.01 to 2 and that of fatal cases from 

0.01 to 1 per million vaccinated individuals. 688,689 The lowest complication 

rates were reported with the Tokyo strain, and the highest with the 

Gothenburg strain produced in Denmark. 692,703 

101

Pasteur, 1921 

Moreau, 1924 

Tokyo, 1925 

Gothenburg, 1926 

Pasteur, 1927 

Danish, 1931 

102 

Tice, 1934 

Montreal, 1937 

Connaught, 1948 

Glaxo, 1954 

Pasteur, 1961 

Pasteur Merieux, 1989 

Figure 57. Proposed genealogical tree of BCG vaccine substrains since isolation at the Institut Pasteur in 1921. Reproduced 

from686 by the permission of the publisher Churchill Livingstone.

In a prospective study in South Africa among 10,000 neonates receiving 

the Copenhagen strain intradermally at birth, at six weeks post vaccination 

the vaccination scar had healed in more than 95% of children, 1.5% 

had no vaccination scar, and in 3% adverse events were noted. 704 All 

adverse events were local (oozing, abscesses, rarely combined with lymphadenopathy). 

Because BCG is a live vaccine, concerns were raised early on about 

the safety of its use in persons infected with HIV, 705-707 and several case 

reports about disseminated mycobacteriosis 708-714 and mycobacterial meningitis 

due to BCG 708,710,715 have been published. A study among motherchild 

pairs with and without HIV infection has shown that children of mothers 

with HIV infection who also had HIV infection themselves had a slightly 

increased risk of suppurative lymphadenitis, but the manifestations were 

mild and easily manageable (figure 58). 716 Apparently, living BCG can 

persist for decades and cause localized 717 or disseminated 718 complications 

after acquisition of immunosuppression. Nevertheless, most of these case 

reports appear to be isolated events, although it has been argued that disseminated 

disease attributable to BCG vaccination in HIV-infected children 

might be exceedingly difficult to diagnose. 719 However, a study in Zambia 

among HIV-symptomatic children with a median age of 15 months, showed 

that mycobacteremia due to BCG must be exceedingly rare. 720 A recom- 

Relative risk 

(log scale) 

7 

3 

1 

0.7 

Referent 

Mother neg 

Child neg 

103 

Mother pos 

Child neg 

Mother pos 

Child pos 

Figure 58. Relative risk of a complication following BCG vaccination among children 

born to an HIV-infected mother. 716

mendation by WHO states that no principal changes in BCG vaccine policy 

are warranted unless children present with symptomatic HIV infection, 721 

a statement that has not been challenged. 722,723 

Management of adverse reactions due to BCG vaccination 

Children with lymphadenitis due to BCG were randomly allocated to receive 

either isoniazid or no treatment. 724 There was no difference in the duration 

of lymphadenitis between the two groups, nor did isoniazid prevent 

the occurrence of suppuration. Similarly, children with abscess formation 

were randomly assigned to receive either isoniazid or erythromycin (serving 

as placebo). 725 The response in each treatment group was the same. 

In another study, comparing excision, excision plus isoniazid, and isoniazid 

alone compared to a control group without intervention, no significant differences 

were observed between the various interventions, and in particular, 

isoniazid offered no advantage. 726 Non-suppurative lymphadenitis is a 

normal reaction, and is best left without antibiotic treatment. 690,727 

Patients with suppurative lymphadenitis following BCG vaccination 

were randomly assigned to treatment with simple needle aspiration, introducing 

the needle subcutaneously two to three centimeters distant from the 

node, versus no treatment. 728 Regression was significantly faster in the 

treated than in the non-treated group, and spontaneous drainage was less 

frequent. 

For osteoarticular mycobacteriosis due to BCG, combination therapy 

is indicated, but results were not always favorable (both in terms of sequelae 

and relapses) in a case series from Sweden. 729 

A standard course of treatment (as for clinically manifest tuberculosis) 

is also indicated in disseminated mycobacteriosis due to BCG. As this 

is a rare complication, however, treatment regimens have not been amenable 

to formal study. In treatment, it should be kept in mind that BCG is, like 

its parent organism, M. bovis, naturally resistant to pyrazinamide. 

Efficacy and effectiveness of BCG vaccination 

Efficacy is the extent to which an intervention produces a beneficial result 

under ideal conditions. The best setting to address efficacy is thus prospectively, 

in a controlled clinical trial. In contrast, effectiveness takes the various 

constraints that are found in the field into account in the actual routine 

delivery of the intervention. 730 Effectiveness is often ascertained 

104

etrospectively, such as in case-control studies. Efficacy (in clinical trials) 

and effectiveness (in case-control studies) have been ascertained in various 

settings. The principle underlying the design of prospective and retrospective 

studies is summarized in table 10. These trials were supplemented 

by community trials and contact studies. The variation in estimates of protection 

ranged widely, from harm (more cases among the vaccinated than 

among controls) to a high level of protection. 

The efficacy of BCG vaccination is best ascertained in a prospective 

clinical trial, while an estimate of its effectiveness in routine application 

might be obtained through retrospective studies, such as case-control, contact, 

or case-population studies, although possible confounding effects cannot 

be controlled so easily. 

Briefly, clinical trials are a prospective ascertainment of cases occurring 

among the exposed. Clinical trials thus start with looking at the exposure 

(BCG vaccination given or not) and then ascertain the outcome (tuberculosis) 

in a group of individuals, preferably randomly assigned to exposure 

(table 10). 731 These are population-based studies and the denominator is 

Table 10. Study design of clinical trials and case-control studies. 

Design of a clinical trial 

Outcome 

Exposure Characteristic Characteristic Person-time 

present absent of observation 

Exposure present A – E 

Exposure absent C – F 

Total A+C – E+F 

Incidence rate among the exposed: A / E 

Incidence rate among the unexposed: C / F 

Relative risk: (A / E) / (C / F). 

Design of a case-control study 

Exposure Case 

Outcome 

Control Total 

Exposure present a b a+b 

Exposure absent c d c+d 

Total 

Odds among the exposed: a / b 

Odds among the unexposed: c / d 

Relative odds: (a / b) / (c / d). 

a+c b+d N=a+b+c+d 

105

the number of person-years of observation. The measures are incidence 

rates among the exposed and unexposed and the summary measure is the 

relative risk (the risk among the exposed divided by the risk among the 

unexposed). Vaccine efficacy (in per cent) is calculated as (1 – relative 

risk) × 100. 732 The 95% confidence intervals were calculated (or recalculated, 

where appropriate) using the formula proposed by Orenstein in his 

review on assessment of vaccine efficacy, 732 unless adjusted or stratified 

summary estimates were provided by the authors. 

To defray the costs incurred in clinical trials and to obtain results more 

quickly, it was proposed to ascertain the effectiveness of BCG vaccination 

by means of (retrospective) case-control studies. 733 Briefly, case-control 

studies start with looking at the outcome (tuberculosis) and then ascertain 

exposure (BCG vaccination given or not) in a group of patients with the 

outcome, compared to an appropriately selected control group of persons 

without the outcome (table 10). 734 A relative risk cannot be calculated as 

this measurement is confined to population-based studies. The measurement 

of risk in a case-control study is the odds ratio (or relative odds). For 

rare diseases the odds ratio approximates the relative risk in a clinical trial. 

The advantages and disadvantages in the use of the case-control approach 

are linked to its being observational, having subjects selected on the basis 

of disease status, and using controls from the population from which the 

cases emanated. 735 The advantages of case-control studies include avoidance 

of ethical problems arising in situations where there is already evidence 

that the vaccine is better than placebo; allowing much faster conduct than 

randomized trials; and requiring a much smaller number of subjects. They 

are thus substantially cheaper to conduct than randomized clinical trials. 735 

The most challenging difficulty in the design of case-control studies 

is the selection of appropriate controls in that they have to be selected in 

such a way that they are comparable to cases in every respect except for 

the outcome. Selection bias resulting from a failure to ensure this comparability 

may thus invalidate any findings. 

The results of some of these case-control studies are summarized 

below. Vaccine effectiveness (in per cent) from a case-control study is 

estimated as (1 – odds ratio) × 100. 732 For unmatched case-control studies, 

the 95% confidence intervals were calculated (or recalculated where 

appropriate) using Woolf’s method. 734 For matched and adjusted analyses, 

the confidence interval published by the authors of the study was chosen. 

If not stated for matched studies, the confidence interval around the crude 

odds ratio was calculated as above. 

106

Prospective and retrospective studies on BCG vaccination 

In one of the first clinical trials with a methodologically fairly acceptable 

design (systematic alternate allocation), BCG was given to children exposed 

to a parent with tuberculosis and compared to a similar group who did not 

receive the vaccine. 736 The impact on fatality was dramatic, with an 82% 

reduction in the risk (figure 59). Nevertheless, suspicion about the efficacy 

of BCG vaccination persisted, particularly in the United States, 737 but 

also in the United Kingdom, 679 largely because the design of many studies 

was dubious at best. 

One of the most conspicuous differences observed in the protection 

afforded by BCG reveals that age at vaccination is important. Of further 

crucial importance is the type of tuberculosis that is targeted for protection 

by vaccination. 

In the following summary of the best-known studies in the English literature, 

the studies are identified as being prospective or retrospective. For 

each of these two study types five classes were examined: 

• protection against disseminated and meningeal tuberculosis, and against 

death from tuberculosis; 

• protection afforded to children by vaccination of newborns or infants; 

• protection afforded by vaccinating children beyond the age of one year; 

Per cent with fatal outcome 

12 

10 

8 

6 

4 

2 

0 

10 of 84 

All due to 

miliary TB 

107 

1 of 41 

Pulmonary 

tuberculosis 

Controls Vaccinated 

Reduction: 81.5% 

Figure 59. Comparative case fatality from tuberculosis among newborns vaccinated 

and not vaccinated with BCG in a clinical trial with systematic assignment to 

the experimental or control arm. 736

• protection afforded by vaccinating adolescents or adults; 

• protection afforded by vaccinating people of various ages. 

Protection conferred by BCG vaccination against disseminated 

and meningeal tuberculosis, and against death from tuberculosis 

Five major prospective studies have looked into the protection afforded 

by BCG vaccination against death from tuberculosis (figure 60). 736,738-744 

All of these studies were conducted before the advent of curative 

chemotherapy. Four of the studies showed a point estimate of the protective 

efficacy of 80% and above, and one afforded no protection. The 

confidence interval was wide in all studies, because the number of events 

was small. 

Several retrospective studies (including two using two different control 

groups) examined the protection against disseminated and meningeal 

tuberculosis (figure 61). 745-747,747-753 The protective effectiveness was usually 

in excess of 80% and in no case did the 95% confidence interval 

include zero. 

N. Am. Indians 

Chicago 

Philadelphia 

Saskatchewan 

New York City 

-400 -100 0 30 50 80 90 95 

Per cent protection 

108 

Death 

Death 

Death 

Death 

Death 

Figure 60. Results from five controlled clinical trials to evaluate the efficacy of 

BCG vaccination against death from tuberculosis. 736,741-744

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109 

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Figure 61. Results from retrospective studies on the effectiveness of BCG vaccination 

against death from meningeal, other extrapulmonary, or disseminated tuberculosis. 

745-747,747-753 

It may be concluded from these studies that BCG affords very good 

protection against death from tuberculosis, and against disseminated and 

meningeal tuberculosis. 

Protection conferred by BCG vaccination of newborns and infants 

Three prospective studies looked into the protective efficacy of BCG given 

to newborns or infants against all forms of tuberculosis or morbidity 

(figure 62). 742,743,754 The point estimate of the efficacy was between 50% 

and 80%. 

Several retrospective studies examined the effectiveness of newborn or 

infant vaccination (figure 63). 747,748,753,755-762 The level of protection in these 

studies varies widely, but frequently above 50%. Noteworthy is the study 

from Zambia, which stratified effectiveness estimates by HIV status, 760 

showing that HIV-infected children had no protection as compared to 60% 

protection among HIV-negative children.

Saskatchewan 

Saskatchewan 

Chicago 

Chicago 

Chicago 

Bangkok 

Bangkok 

Saudi Arabia 

Bangui 

Birmingham 

Canadian Indians 

Lusaka 

Asians, UK 

Papua New Guinea 

-400 -100 0 30 50 80 90 95 

Buenos Aires 

Rangoon 

Sri Lanka 

Lusaka 

-400 -100 0 30 50 80 90 95 


110 

Infants, any form 

Infants, morbidity 



Infants, morbidity 


Figure 62. Results from prospective studies on the efficacy of BCG vaccination 

against tuberculosis in newborns and infants. 742,743,754 

Laboratory 

confirmed 

All forms 






HIV negative 





HIV positive 


against tuberculosis in newborns and infants. 747,748,753,755-762

Protection conferred by BCG vaccination of children over one year of age 

Only three protective studies of BCG vaccination of older children are available 

(figure 64). 763-768 All three showed a very low level of protection, of 

less than 30%. In Chingleput, south India, where BCG gave little or no 

protection, there was a tendency to provide some protection in children 

below the age of 15 years, but a similar tendency towards harm (more cases 

in the vaccinated than the non-vaccinated) in older persons (figure 65). 765 

Puerto Rico 

Chingleput 

Madanapelle 

-400 -100 0 30 50 80 90 95 


111 

Children, any form 

Children, pulmonary 

culture confirmed 



against tuberculosis in children other than infants. 763-768 

Harm / protection (%) 

20 

0 

-20 

Protection 

Harm 

0 5 15 25 35 45 

Age group (years) 

Figure 65. Protection from BCG vaccination by age, Chingleput, India. 765

Three retrospective studies among children also showed very variable 

levels of protection, from 16% to 74% (figure 66). 750,769,770 

These studies seem to show that vaccination of older children does not 

offer protection against tuberculosis that is as reliable as vaccination at an 

earlier age. 

Protection conferred by BCG vaccination among adolescents and adults 

Six prospective studies have examined the protection of BCG vaccination 

against tuberculosis among adolescents or adults (figure 67). 668,670,763-765,767, 

768,771-778 The study in Ulleval, Norway, was the first ever conducted prospective 

study. 668,670 It does, however, not live up to current requirements for 

a controlled trial, as student nurses with a negative tuberculin skin test at 

entry could choose whether to be vaccinated or not. In this context, the 

study conducted in England (where M. microti, not BCG was used) remains 

the only study of high standard that has shown a very high level of protection, 

of close to 80%, in this age group. 771-776 The other studies show 

little or no protection, with a tendency to reveal a potentially harmful effect 

in India. 763-765,777 In England, protection appeared to last for about 10 years 

before dropping rapidly (figure 68). 776 In contrast, in Chingleput, where 

there was no overall protection, vaccination appeared to confer harm (more 

cases than in the control group) in the first five years and minimal protection 

subsequently (figure 69). 765 

Bangkok 

Edinburgh 

Cali 

-400 -100 0 30 50 80 90 95 


112 


Case-control 


Case-control 

Children, pulmonary 

Contact study 


against tuberculosis in children other than infants. 750,769,770

Ulleval 

England 

South Africa 

Madanapelle 

Chingleput 

Karonga District 

-400 -100 0 30 50 80 90 95 


113 

Nurses 

Adolescents 

Mine workers 

Adults 

Adults, Pulmonary 

Culture confirmed 

Adults, first or 

second vaccination 


against tuberculosis in adults. 668,670,763-765,767,768,771-778 

The two retrospective studies show a protective effectiveness of 10% 779 

and close to 60%, 780 respectively (figure 70). 

These studies seem to indicate that vaccination of adolescents or adults 

is rarely a useful intervention. 

Protection (%) 

100 

80 

60 

40 

20 

0 

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 

Year of follow-up 

Figure 68. Protection from BCG vaccination among British school children during 

follow-up. 776

Harm / protection (%) 

20 

0 

-20 

-40 

-60 

-80 

-100 

-120 

-140 

Protection 

Harm 

0.0 2.5 5.0 7.5 10.0 12.5 15.0 


Figure 69. Protection from BCG vaccination in Chingleput, India during followup. 

765 

Canadian Indians 

Chile 


Protection conferred by BCG vaccination across various age groups 

Of the seven clinical trials studying protective efficacy across a wide range 

of age groups, with a preponderance of persons other than infants, two 

showed a high level of protection, of around 80%, while all of the others 

showed little or no protection (figure 71). 738,763-765,767,768,781-787 

These observations reconfirm that utilization of BCG vaccination in 

age groups other than infants is rarely an effective intervention. 

One retrospective study from the Gambia reported that 35 patients 

among 200 without a BCG scar died during chemotherapy, while none of 

114 

Any age 

Case-control 

Adults 

Case-control 

-400 -100 0 30 50 80 90 95 

Figure 70. Results from retrospective studies on the efficacy of BCG vaccination 

against tuberculosis in adults. 779,780

Haiti 

N. Am. Indians 

Madanapelle 

Muscogee / Russell 

Muscogee 

Chingleput 

Illinois 

Muscogee 

85 with a BCG scar did so. 788 While considerable attention was paid to 

adjustment for potential confounding factors (yet the effect remained), the 

authors were still cautious in concluding that BCG vaccination reduces case 

fatality from pulmonary tuberculosis. 

Hypotheses about the variation in the efficacy of BCG 

vaccination 

While the overall evidence is quite clearly in favor of a protective effect 

of BCG vaccination, the observed variations are large in both prospective 

and retrospective studies. A number of hypotheses have been formulated 

to address these discrepancies. Smith 789 and Smith and Fine 790 have comprehensively 

reviewed the evidence, and the following outline is guided by, 

and draws heavily on, their assessment. 

The principal hypotheses to explain the variations observed in the protection 

offered by BCG include: 

• Differences in methodological stringency; 

• Differences in vaccine strains; 

• Differences in vaccine dose; 

-400 -100 0 30 50 80 90 95 


115 





All forms, 5-28 yr, 

10-yr follow-up 

Pulmonary, 

Culture confirmed 

Mental institutions 

All forms, 5-28 yr, 

10-yr follow-up 


against tuberculosis in all ages. 738,763-765,767,768,781-787

• Differences in virulence of M. tuberculosis strains; 

• Differences in risk attributable to exogenous reinfection tuberculosis; 

• Differences in genetic make-up of vaccinees; 

• Differences in nutritional status of vaccinees; 

• Differences in prevalence of infection with environmental mycobacteria; 

• Other factors. 

Differences in methodological stringency 

Quite obviously, not every study can be methodologically as rigorously conducted 

as ideal standards of study design and conduct call for. 731,734 Among 

the clinical trials, several have been excluded from major reviews and metaanalyses 

such as those conducted by Colditz and collaborators. 791,792 These 

authors found that study validity score explained 66% of the variation in 

prospective clinical trials and 36% in retrospective case-control studies, 791 

and only 15% in case-control studies on BCG protection against infant 

tuberculosis. 792 Nevertheless, perhaps the most relevant trial showing no 

protection against bacteriologically confirmed tuberculosis, conducted in 

Chingleput, India, was judged to be of high scientific quality by a WHO 

expert committee specifically charged to ascertain the trial’s validity. 793 

It must be kept in mind that the range of protection cannot be taken 

at face value, but must also be seen in the context of what the study in 

question sought to address. BCG trials (be they prospective or retrospective) 

ascertained protection against various outcomes such as morbid state 

(tuberculosis or death from tuberculosis) and site of disease, e.g., pulmonary, 

extrapulmonary single site, and disseminated tuberculosis, taking into account 

such things as bacteriologic certainty of the case, age of the patients, and 

time elapsed since vaccination. What seems apparent from the studies is 

the tendency of BCG to provide its greatest protection within the few years 

following vaccination, against death from tuberculosis, disseminated disease 

manifestations, and bacteriologically unconfirmed tuberculosis. In summarizing 

these effects, BCG is generally most effective against serious forms 

of tuberculosis occurring shortly after infection acquired at an early age. 

Thus, any evaluation of the protective efficacy of BCG vaccination should 

be stratified according to these variables. 

116

Differences in vaccine strains 

The available BCG vaccine strains differ widely in phenotype and genotype. 

660,661,685,686 It has been proposed 794 that differences in vaccine strains 

may account for observed variations in vaccine efficacy. In the rabbit 

model, not all BCG (and M. microti) strains provided the same level of 

protection. 795 However, the most powerful argument against this hypothesis 

arises from the Chingleput study, where two vaccine strains were 

used 763-765 that had documented high efficacy in other settings but were not 

shown to be efficacious in Chingleput. Furthermore, one of the studies (a 

case-control study from Indonesia) cited for evidence of differential effectiveness 

of strains, examined successive vaccination policies, and was thus 

by necessity a non-concurrent study which additionally failed to adjust for 

time elapsed since vaccination. 796 

Differences in vaccine dose 

BCG has been administered through various routes, initially orally, then 

parenterally. The latter administration may have been given intradermally 

or transdermally via multipuncture devices. The dosage reaching the target 

thus may well have varied. Nevertheless, the following observations 

seem to contradict the argument of an influence of differential dosage effect. 

Three controlled clinical trials with low efficacy used multipuncture administration, 

768,785,786 and one with high efficacy did so too. 742 Furthermore, 

the trial in Chingleput specifically considered in its design the possibility 

of deterioration of vaccine potency in the field, and allocated vaccinees also 

to two arms receiving a ten-fold difference in dose, with no difference in 

effect. 763-765 

Differences in virulence of M. tuberculosis strains 

That not all tubercle bacilli are equally virulent has been demonstrated 

repeatedly both for M. bovis BCG 797 and M. tuberculosis in general, 798,799 

and for isoniazid-resistant strains in particular. 38,800-802 

The hypothesis that the relative frequency of more or less virulent 

tubercle bacilli affects the observed protective efficacy of BCG vaccination 

is based on the argument that tubercle bacilli of lower virulence might also 

cause tuberculin skin test reactions of smaller size. Such persons then 

might be classified as “non-reactors”, i.e., persons not infected with tubercle 

bacilli, thus becoming eligible for vaccination. Vaccination of actually 

117

infected persons may thus mask any protective effect of BCG vaccination, 

as vaccination is not expected to provide protection against those who are 

already infected. 803 

The argument fails to account for the fact that BCG provided no protection 

at all in some trials. Depending on the proportion of individuals 

who had escaped infection with environmental mycobacteria at the point 

of BCG vaccination, masking of protection by BCG vaccination would be 

expected to be incomplete. 

Differences in risk attributable to exogenous re-infection tuberculosis 

BCG vaccination is expected to provide protection against tuberculosis 

resulting from infection acquired subsequent to vaccination. It is not 

expected to provide greater protection than a naturally acquired primary 

infection. Protection conferred by a primary infection against disease from 

re-infection is incomplete. 804-811 Thus, the protective efficacy of BCG might 

be increasingly masked as the contributory fraction of cases attributable to 

re-infection increases. 812,813 Thus, following this argument, the protection 

afforded by BCG is expected to be lower where the risk of infection with 

M. tuberculosis (and thus re-infection) is high. 

This is not borne out by observations. The annual risk of infection 

in the United Kingdom decreased considerably over time, 814 yet the level 

of protection afforded by BCG remained high and virtually unchanged. 761 

Differences in genetic make-up of vaccinees 

Because differences in protection from BCG among males and females were 

observed in at least one study, 766 other genetic factors may also play a role 

in the differential protection conferred by BCG. Nevertheless, the finding 

that BCG gave virtually no protection to children in Chingleput, 765 but high 

protection in children from the Indian sub-continent living in the United 

Kingdom 758,761 would tend to disfavor this hypothesis. 

Differences in nutritional status of vaccinees 

As nutritional status affects the functioning of the cellular immune system, 

it might be expected that poor nutritional status would adversely affect the 

protective efficacy of BCG vaccination. However, BCG provided very high 

protection against tuberculosis death among poorly nourished North American 

Indian children, even somewhat higher than among well-nourished British 

adolescents, 776 a finding that would tend to contradict this hypothesis. 

118

Differences in prevalence of infection with environmental mycobacteria 

BCG vaccination has been used not only for protection against tuberculosis, 

but also against leprosy, 815-821 often with more success than in the prevention 

of tuberculosis. 777,822,823 It is thus apparent that different mycobacterial 

species (in this case M. tuberculosis, M. bovis BCG, M. microti, and 

M. leprae) exert a modification of the immunologic response to infection 

with another mycobacterial species. 824 It is thus postulated that infection 

with one species of mycobacterium triggers a cellular immune response prepared 

to act more swiftly in the killing of mycobacteria of another species 

acquired during a subsequent infection. This is most apparent from the 

(limited) protection provided by infection with M. tuberculosis against superinfection 

with tubercle bacilli, 810 and the apparently similar effect of M. bovis 

BCG under certain circumstances. That BCG can also afford protection 

against leprosy would indicate that cross-protection is not limited to closely 

related mycobacterial species. 

It has been postulated that different mycobacterial species induce different 

immunologic responses, some beneficially increasing protection against 

super-infection with another mycobacterial infection, while others may 

increase susceptibility to progression to clinically overt disease. 825 In experimental 

models, protection afforded by vaccination with M. bovis BCG, 

M. fortuitum, M. avium, M. kansasii, and M. scrofulaceum (then called Gause 

strain) against M. tuberculosis was examined in the guinea pig. 826 All environmental 

mycobacteria used in this study provided some protection, but 

with a wide variation, yet none provided as high a level of protection as 

BCG vaccination. It has therefore been postulated that the low protection 

afforded by BCG in Georgia as compared to the high protection observed 

in Britain may be attributable to a differential prevalence of infection with 

environmental mycobacteria. 826 Edwards and colleagues demonstrated similar 

protection by vaccinating with M. avium complex against M. tuberculosis 

isolated in Chingleput as with the Danish BCG strain. 827 Orme and 

Collins demonstrated that airborne infection with M. avium in mice was as 

effective as intravenous BCG in protection against a challenge with virulent 

tubercle bacilli. 828 Brown and colleagues administered M. vaccae in 

drinking water to mice, subsequently challenged them with BCG and measured 

the proliferative response of spleen cells. 829 The results showed that, 

depending on the timing of the exposure of the mice to M. vaccae before 

BCG vaccination, M. vaccae could enhance, mask or interfere with the 

expression of sensitization by BCG. 

119

If environmental mycobacteria do indeed provide protection against 

M. tuberculosis, and infection with them occurs before the administration 

of BCG, then the effect of the latter will be at least partially masked. 813 

This may explain the larger protection conferred by BCG given earlier in 

life than if given later as demonstrated in Chingleput. 765 

Furthermore, the risk of tuberculosis would be expected to be greater 

in initially tuberculin negative persons than in individuals with small tuberculin 

skin test reaction sizes (more likely attributable to infection with environmental 

than tubercle bacilli). 

In Puerto Rico, protection from BCG was lower in rural areas, where 

non-specific sensitivity was higher than in urban areas, where protection 

from BCG was higher. 830 However, in Chingleput, the rate of tuberculosis 

among persons with a reaction size of more than nine millimeters to a 

sensitin produced from M. avium complex (PPD-B) was identical to that 

among those with zero to nine millimeters reaction sizes. 765 

In the United Kingdom, the risk of tuberculosis was higher among initially 

tuberculin skin test negative adolescents than among those reacting 

to 100 tuberculin units only, but the risk decreased over time (figure 72). 776 

The protection afforded against tuberculosis by a tuberculin skin test reaction 

that can be elicited only by this large dose of tuberculin is remarkably 

similar (but smaller) to that imparted by BCG vaccination (figure 73). 

In the Karonga, Malawi, trial the risk of tuberculosis during followup 

was lowest among those with an initial tuberculin skin test reaction size 

of six to 10 mm (figure 74). 831 After adjustment for age and sex, the risk 

was also lower among those with reactions of one to five millimeters than 

among non-reactors. 832 

That different species of mycobacteria seem to act on the immune system 

has also been demonstrated by observations from Sweden. After the 

cessation of mass BCG vaccination, there was a large increase in peripheral 

lymphadenitis due to environmental mycobacteria (figure 75) ( 703,833,834 

and Romanus V, personal written communication, Feb 18, 2000). Similarly, 

in the Czech Republic, the incidence of lymphadenitis among children due 

to M. avium following cessation of BCG vaccination was 3.6, compared to 

0.2 per 100,000 person-years among children vaccinated on the insistence 

of their parents, 835 suggesting a protection of 95% (95% confidence interval 

88% to 98%) from BCG against lymphadenits due to M. avium. 

While not all findings are consistent with the hypothesis that environmental 

mycobacteria may mask the protection that BCG can confer in 

their absence, 832 it may explain to a considerable extent certain variations 

in observed efficacy. 

120

Incidence per 10,000 

70 

60 

50 

40 

30 

20 

10 

0 

Other factors 

Reacting to 

100 TU only 

Tuberculin 

negative 

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 


Figure 72. Risk of tuberculosis during follow-up of British school children, by initial 

tuberculin skin test reaction size, among placebo recipients, BCG trial, Great 

Britain. 776 

Incidence per 10,000 

80 

70 

50 

0 

-100 

Reacting to 

100 TU only 

BCG vaccinated 

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 


Figure 73. Comparative protection from BCG vaccination and presumed infection 

with environmental mycobacteria among British school children during follow-up. 776 

It has been suggested that infestation with parasites, in particular with 

helminths, may affect the human T cell immune responses to mycobacterial 

antigens. 836 Treatment of helminths resulted in significant improvement 

121

Relative risk (log scale) 

10 

3 

1 

0.5 

0.2 

Ref 

0 

1 - 5 6 - 10 11 - 15 16 - 20 20 + 

Induration (mm) 

Figure 74. Risk of tuberculosis during follow-up by size of initial tuberculin skin 

test reaction, Karonga District, Malawi. Reproduced from 831 by the permission of 

the publisher Elsevier Science. 

of T cell proliferation and interferon-gamma production. This could explain 

to some extent the reduced efficacy of BCG in countries in the world where 

helminthic infestation is common. 836 

Number of reported cases 

80 

60 

40 

20 

0 

Discontinuation of mass 

BCG vaccination 

70 75 80 85 90 

Year of report 

Figure 75. Reported cases of mycobacteriosis due to M. avium complex, Sweden, 

1969-1993. Data courtesy Victoria Romanus, Swedish Institute for Infectious Diseases. 

122

BCG re-vaccination 

It is or has been the policy in many countries to re-vaccinate with BCG at 

school entry or later in life. There is no evidence that this increases protection 

against tuberculosis, 723,837,838 but in northern Malawi it has been 

shown to considerably increase protection against leprosy. 777 Re-vaccination 

schemes often fall into the lowest tuberculosis risk period in life (age 

five to 14 years) and target a population where protection from BCG vaccination 

is dubious or variable at best. 

Effects of BCG other than those directed 

against tuberculosis 

BCG has been shown to be protective against leprosy in some situations 

815-818,839 while not in others. 819 It has also shown to be effective against 

M. ulcerans, albeit with an apparently very short-lived protection. 840 

The best known indications for BCG against other than mycobacterial 

diseases are its use as an immunotherapeutic agent in the treatment of superficial 

bladder cancer 841-850 and, to a lesser extent, malignant melanoma. 851 

It has also been suggested that BCG reduces the risk of atopy and asthma, 

852-854 and reductions in the risk of intestinal nematodes in children 855 and 

HIV-infected patients have been reported. 856,857 


of BCG vaccination 

Approximately 100 million children now receive BCG every year. 723 The 

number of doses produced in the year 2000, in descending order, were the 

Copenhagen 1331 strain, D2PB302, Tokyo 172, Sofia SL 222, Pasteur 1173, 

Glaxo 1077, and the Russian strain. 723 

While there have been wide variations in the protection afforded by 

BCG vaccination in different trials, the evidence is overwhelming that BCG 

provides protection against tuberculosis, especially against tuberculous meningitis 

and death from disseminated tuberculosis in children. Where it worked, 

its protective effect waned over time, to disappear after 15 to 20 years. 

The evidence for protection against bacteriologically confirmed tuberculosis 

in adults has been less consistent. 

123

Because BCG vaccination is given early in life, the protection afforded 

is limited in time, and its effect on bacteriologically confirmed tuberculosis 

in adults is inconsistent, it cannot be expected to have a great impact 

on the epidemiology of tuberculosis. 858,859 

It seems inappropriate to conclude from meta-analyses that BCG provides 

some average protection. 791,792 The observed range in protection is 

real and remains largely unexplained. 

In light of the evidence, WHO recommends its use in newborn children 

or as early in life as possible. 793,860 This is still sound policy for those 

countries in the world where tuberculosis is highly prevalent, and tuberculous 

meningitis is a frequent, disabling or fatal occurrence. It fails to 

address the role of BCG where tuberculosis in children has become a rare 

occurrence. 

The IUATLD has developed recommendations on criteria for the discontinuation 

of mass BCG vaccination. 861 Three key issues enter into the 

decision making process on the discontinuation of BCG vaccination. 

The first is the extent of protection BCG actually imparts in a given 

location. In the USA, the low efficacy of BCG vaccination in Georgia, 

Georgia-Alabama, and Puerto Rico had an important impact on the decision 

not to routinely utilize BCG vaccination. As such prospective studies 

are usually beyond the realm of resource availability, effectiveness 

might alternatively be studied utilizing the case-control or contact study 

approach. 

The second is the frequency of serious forms of tuberculosis in children 

(meningitis, disseminated forms) weighted against the frequency of 

adverse reactions from the vaccine itself. This has been best studied in 

Sweden where the frequency of serious adverse reactions from BCG vaccination 

(osteoarticular and disseminated mycobacteriosis due to BCG) outweighed 

the incidence of cases that the vaccine was intended to prevent 

(figure 76). 703 Similarly, BCG vaccination may become non-cost-effective 

as the frequency of childhood tuberculosis decreases, so that an increasing 

number of children need to be vaccinated to prevent one case. 

The third consideration is the value attached to the preservation of the 

utility of the interpretation of tuberculin skin test results. BCG vaccination 

induces tuberculin sensitivity and complicates the interpretation of tuberculin 

skin testing results. In industrialized countries with an elimination 

strategy in mind, the tuberculin skin test is an important means of identifying 

persons with tuberculous infection at a high risk of progression to 

tuberculosis who would benefit from preventive chemotherapy. 

124

Number of cases 

30 

20 

10 

0 

Gothenburg strain produced in: Cessation of mass 

Sweden Denmark BCG vaccination 

1950 1955 1960 1965 1970 1975 1980 1985 1990 

Year of report 

WHO discourages re-vaccination because there is no evidence of its 

usefulness. 862 Lack of evidence is, however, not synonymous with lack of 

efficacy. Re-vaccination at school entry is likely to be inefficient (even if 

it were efficacious), because it falls into the period in life when the risk 

of tuberculosis is lowest. 

Finally, concerning HIV infection, the WHO has concluded after careful 

review of available data, that BCG vaccination schemes do not need to 

be altered unless HIV infection is symptomatic (AIDS). 721 This, too, seems 

to be a reasonable recommendation given the lack of evidence of an 

increased frequency of serious adverse events in BCG-vaccinated children 

who also have acquired HIV infection from their mother. However, it 

appears that HIV infection lowers the protective effect against extrapulmonary 

tuberculosis. 863 In industrialized countries, where the need for BCG 

vaccination is generally lower, it is usually recommended not to give BCG 

vaccination to individuals known to have HIV infection. 864 

The freeze-dried vaccine should be kept refrigerated and protected from 

light, and diluted only immediately before vaccination. In most countries, 

BCG vaccine is given by the intradermal route, generally by injection with 

a 25 or 26 gauge needle, in the deltoid insertion region of the upper arm. 865 

Most manufacturers (including all those who provide vaccine for UNICEF, 

125 

BCG osteitis 

Childhood 

tuberculosis 

Figure 76. Osteitis due to BCG vaccination and incidence of pulmonary tuberculosis 

among Swedish-born children, Sweden 1949-1993. 703

the largest purchaser in the world) recommend a 0.05 mL dose for infants, 

and the double dose for children. 

Difficulties have arisen for decision makers about the value of vaccinating 

health care workers at increased risk of infection with M. tuberculosis, 

particularly in settings where multidrug-resistant tuberculosis is common. 

The uncertainty stems from the scarcity of data on protection against 

tuberculosis among adults, and the generally low level of protection (or 

none at all) among adults in clinical trials. While decision analyses appear 

to favor the use of BCG vaccination in such settings, 866 such a conclusion 

has been disputed, largely based on the argument that it deprives those vaccinated 

from ever learning whether they have acquired tuberculous infection 

or not (loss of specificity of the tuberculin test). 867 Nevertheless, in 

areas where BCG has been demonstrated to provide appreciable protection 

against tuberculosis among adults, where there is a high risk for health care 

workers of becoming infected, and where multidrug-resistant tuberculosis 

is common, a BCG vaccination policy for health care workers might deserve 

consideration. Where these conditions are not met, non-vaccination of 

health care workers might be more appropriate. 

In summary, barring a better alternative, BCG vaccination remains a 

useful adjunct for the individual protection against disabling and lethal forms 

of childhood tuberculosis in most parts of the world where tuberculosis 

remains highly prevalent. It cannot be expected, however, to have great 

impact on the epidemiologic situation of tuberculosis. 858,859 

126

4. Preventive chemotherapy 

In the early 1950s Lincoln described her observations with chemotherapy 

and its effect on case fatality from primary tuberculosis. 868 In particular, 

fatality from tuberculous meningitis fell from 100% to 17% with streptomycin 

and para-aminosalicylic acid, and to 12% with the introduction of 

isoniazid. None of the patients with miliary tuberculosis treated with isoniazid 

alone or in combination with other drugs developed tuberculous 

meningitis. She concluded that: 

“...the use of isoniazid will have to be considered for every child with 

active primary tuberculosis and probably also for children with known recent 

conversion of tuberculin tests even if chest roentgenograms are normal. The 

duration of therapy would most likely be for a year in order to cover the 

period during which meningitis would be most likely to develop...” 868 

While credit for the idea of preventive chemotherapy might be shared 

by various investigators, 641 this is almost certainly one of the earliest 

accounts to spell out so clearly the research agenda on which the US Public 

Health Service, and subsequently other bodies, would engage. 

It is noteworthy that two issues are raised here. The first is the prevention 

of complications from clinically manifest tuberculosis; the second 

is the notion of prevention of disease from recently acquired asymptomatic 

infection. In this monograph the term preventive chemotherapy is defined 

as treatment of latent, asymptomatic tuberculous infection with the intent 

to reduce the risk of progression to clinically manifest disease, and not what 

is essentially chemotherapy of active tuberculosis. Nevertheless, the first 

US Public Health Service controlled trial dealt precisely with that, and provided 

evidence of a 70% protection with isoniazid monotherapy against 

development of complications from primary tuberculosis. 641,869,870 Similarly, 

a controlled trial conducted in India among patients with minimal radiographic 

lesions, not certain to be active or inactive, offered evidence for 

a 68% protection against bacteriologically confirmed pulmonary tuberculosis. 

871 This type of investigation will not be dealt with further at this point. 

Numerous clinical trials of preventive chemotherapy (in the stricter 

sense of the definition used here) have been conducted. They encompassed 

a range of variables, including persons at varying risk of tuberculosis, choice 

of anti-tuberculosis agent, and duration of therapy. While no attempt is 

127

made here to provide a comprehensive list of all of the trials, the best 

known have been selected to review the efficacy that preventive chemotherapy 

has offered in randomized controlled clinical trials in various settings. 

In order to provide comparable results, Wald 95% confidence intervals 

731 were calculated for all trial efficacy estimates, unless (in some recent 

publications) the authors provided adjusted risk ratios or provided insufficient 

data to recalculate confidence intervals. In this case, the confidence 

intervals provided by the authors were used. 

Prevention of disease in tuberculin skin test reactors 

Persons who react to tuberculin, but whose acquisition of tuberculous infection 

lies in the remote past, have a relatively small annual risk of progression 

to clinically active tuberculosis compared with persons who have 

recently acquired infection. 1 While the exact point of acquisition of infection 

is rarely known for an individual, several studies have been conducted 

among patients whose tuberculous infection has been unlikely, to have been 

of recent origin on average (wide spread of acquisition points in time). 

The first point of interest is the efficacy of preventive chemotherapy in providing 

protection against progression to tuberculosis during, and only during, 

the length of treatment. Three of the four trials for which such information 

is available used isoniazid for twelve months 641,872-874 , and in one it 

was given for nine months. 875 The results obtained by the end of the treatment 

period are summarized in figure 77. 

Mental patients 

Contacts of 

known cases 

Alaskan villagers 

Greenland villagers 

0 50 70 90 


Figure 77. Protection from isoniazid preventive therapy against tuberculosis among 

tuberculin skin test reactors during the year of treatment. 641,872-875 

128

Tuberculosis was much more frequent among mentally ill patients in 

institutions than in the general population in the United States, and it was 

natural to consider this group for preventive chemotherapy to reduce the 

risk of endogenous reactivation disease. 872 People of all ages were included, 

but older patients made up the bulk of participants, with an average age of 

around 50 years. After exclusion of those participants known to have had 

a negative tuberculin skin test at intake, the protection afforded by isoniazid 

during the treatment year was 81%. 

Persons in contact with notified tuberculosis patients for various lengths 

of time were included in another US Public Health Service clinical trial. 874 

Some of the index cases had long since been cured of active disease, while 

others were still on treatment. Contacts who had already developed tuberculosis 

at the time of enrolment were excluded from the trial. Over half 

of the enrolled were initially tuberculin negative and stratification by initial 

tuberculin skin test result was not provided. The risk of tuberculosis 

during the treatment year was very low and the confidence interval around 

the observed point estimate of protection of 69% was thus very wide. 

However, eight of the nine observed cases in the placebo group had occurred 

among those with an initially positive tuberculin skin test. 

In Alaska, a community preventive chemotherapy trial was started when 

the annual infection rate was almost 100 times greater than in the continental 

United States. 641,873 In the Bethel Hospital service area where the 

trial was conducted, the annual risk of infection was 25%, a rate far exceeding 

any reported risk elsewhere in the world. 876 By the time of starting 

the trial the risk of infection had already substantially decreased. Because 

of the adverse climatic and transport conditions it was not feasible to test 

all persons with tuberculin. Approximately one third of those tested had 

a tuberculin skin test diameter of less than five millimeters. During the 

treatment year the protection from isoniazid was 66%. Protection was 

demonstrated at all levels of adherence (amount of isoniazid taken), with 

an indication that six months of isoniazid might have sufficed. 876 

In Greenland it had been realized, by the mid-1950s, that the majority 

of tuberculosis cases developed in the years immediately after primary 

infection. A trial was thus undertaken to study the efficacy of isoniazid 

preventive chemotherapy at the community level. 875,877 Children below the 

age of 15 years were excluded from the trial. Placebo or isoniazid were 

given weekly for a total duration of nine months. Half of the participants 

received all dosages and over 80% received at least three quarters of the 

intended dosages. The crude protection afforded by isoniazid during the 

129

year following commencement of treatment was 22%. For reasons that are 

not understood, there was no protection observed in those aged less than 

25 years, in contrast to 56% protection in those aged 25 to 34 years, and 

intermediate protection in the other age groups. 

Prevention of disease in persons with risk factors 

The risk of tuberculosis among persons with long-standing tuberculous infection 

(those studied in the above presented trials) is fairly small, thus the 

effectiveness of a preventive chemotherapy scheme is relatively modest. 

Conversely, it is of special interest to study the efficacy of isoniazid preventive 

chemotherapy in persons with a recognized increased risk of tuberculosis, 

because the attributable fraction of cases that can be prevented is 

relatively large if the prevalence of the risk factor is also high. 

Recently acquired infection 

Recently acquired tuberculous infection is not only associated with an 

increased risk of progression to tuberculosis, but it is also a frequent event. 

Four studies of preventive chemotherapy among contacts of newly diagnosed 

index cases of tuberculosis are selected here to illustrate the point 

(figure 78). 878-881 

In April 1960, a patient with pulmonary tuberculosis in a marine camp 

of the Royal Netherlands Navy infected a large number of his mates in a 

Netherlands Navy 

Kenya 

USA 

Japan 

- 50 0 50 70 90 95 



contacts of tuberculosis patients. 878-881 

130

arracks. 878 On entering service in January, 59 of the men sharing the barracks 

had a negative tuberculin skin test, while by the beginning of April, 

56 of them had become converters. In the entire camp 305 conversions 

were registered among 1,105 initially negative men. A double-blind controlled 

trial was carried out among the 261 converters who were not excluded 

due to departure or because they had already contracted tuberculosis at the 

time of starting the trial. After one year, nine cases had developed tuberculosis 

in the placebo group compared to only one in the isoniazid group. 

During follow-up for a total observation period of four years, three additional 

cases developed, all in the placebo group, indicating an overall protection 

of 93%. 

In Nairobi, Kenya, contacts of newly diagnosed tuberculosis cases were 

randomly assigned to receive isoniazid or placebo for one year. 880 During 

the treatment year and the two-year follow-up period, preventive chemotherapy 

provided 85% protection against culture-confirmed pulmonary tuberculosis. 

A large trial was conducted by the US Public Health Service among 

contacts of newly identified cases of tuberculosis. 879 Contacts found to 

have tuberculosis during the initial examination were excluded from the 

trial. Over 25,000 contacts were eligible for enrolment. Of these, 48% 

had tuberculin skin test reaction sizes of five or more millimeters of induration. 

Approximately two thirds of contacts were less than 20 years old. 

About two thirds of study participants were estimated to have taken all of 

their medications, and about 80% three quarters or more. Among those 

who could be reexamined at the end of the 12-month period of medication, 

isoniazid gave 77% protection against tuberculosis. 

In Japan, contacts of new cases of tuberculosis were randomly assigned 

to receive placebo or isoniazid. 881 The protection afforded was only 30%, 

with confidence intervals including zero. 

Infection with the human immunodeficiency virus 

Infection with HIV is the strongest yet identified risk factor for progression 

from tuberculous infection to tuberculosis. Because HIV alters the 

biological response to M. tuberculosis so fundamentally, it could not be 

taken for granted that isoniazid preventive chemotherapy would work as 

well as in immunocompetent patients. 

Tuberculosis is accompanied by an increase in tumor necrosis factor 

alpha (TNF-α). TNF-α also increases in vitro replication of HIV. 882 It 

131

might be expected, therefore, that prevention of development of tuberculosis 

would also delay onset of AIDS among HIV infected patients (figure 

79). There is, however, as yet little epidemiological evidence that this 

is the case. 883 

A series of controlled clinical trials has been undertaken in various 

settings to evaluate the efficacy of isoniazid (and other compounds) compared 

to placebo in protecting HIV-infected individuals against tuberculosis 

(figure 80). 

The first study of this kind was conducted in Port-au-Prince, Haiti. 884 

The efficacy of 12 months of isoniazid compared to placebo was ascertained. 

The protection among persons with five or more millimeters of 

induration to a tuberculin skin test was 83%. The population was small, 

however, and the confidence intervals were consequently wide. An additional 

finding was a significant delay in onset of HIV disease in the isoniazid 

group compared to those receiving placebo. Survival analysis also 

demonstrated significant protection against AIDS-defining illnesses and 

AIDS-attributable death among tuberculin-positive, but not among tuberculin-negative, 

patients. 

In Lusaka, Zambia, HIV-positive individuals were randomly assigned 

to receive twice-weekly isoniazid for six months or placebo and a third arm 

Infection 

with M. tbc 

Preventive 

therapy 

Tuberculosis TNF - � 

HIV replication 

Increased 

immunosuppression 

132 

AIDS 

Granuloma 

formation 

Figure 79. Schematic presentation of the impact of tuberculosis on TNF-α production 

and HIV replication, and prevention of the chain of events with preventive 

therapy.

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HIV-infected persons. 884-888 

with a rifampicin plus pyrazinamide containing regimen. 885 They were followed 

up for a median of 1.8 years. The main outcome measures were 

incidence of tuberculosis and death. Among those with a tuberculin skin 

test reaction of five or more millimeters of induration, the point estimate 

of protection from isoniazid was 74%, yet because of the small number, 

the confidence intervals were wide and included zero. There was no difference 

in mortality between preventive chemotherapy and placebo groups. 

An important observation was that the effect of preventive chemotherapy 

declined following cessation of treatment so that by 18 months after the 

completion of therapy incidence rates in treated and non-treated groups were 

the same. 

In Kampala, Uganda, HIV-infected patients were enrolled in a randomized 

trial to receive one of four arms: placebo, isoniazid for six months, 

or two rifampicin-containing regimens (one with, the other without pyrazinamide). 

Among patients with a tuberculin skin test reaction of five or 

more millimeters of induration, isoniazid reduced the risk of tuberculosis 

over a mean follow-up time of 15 months by 67%. 886 Survival did not 

differ between the groups. 

Collaborating centers in New York City and elsewhere conducted a 

randomized trial to assess the efficacy of isoniazid in patients with HIV 

infection who were anergic. 887 Anergy was defined as reacting with more 

than five millimeters of induration to tuberculin and less than two millimeters 

to both mumps antigen and tetanus toxoid. Patients were addi- 

133

tionally considered to belong to groups at risk of tuberculous infection. 

Only nine cases of tuberculosis occurred in the entire cohort of more than 

500 patients during a follow-up period of 30 months following cessation 

of treatment with six months of either placebo or isoniazid: three in the 

isoniazid group and six in the placebo group. This corresponds to an overall 

protection of 52%, yet with 95% cent confidence intervals including 

zero. 

In Nairobi, Kenya, HIV-positive patients were randomly assigned to 

receive either daily isoniazid for six months or placebo (irrespective of the 

tuberculin skin test result). 888 Outcome measures were incidence of tuberculosis 

and death. The follow-up period from enrolment onwards was a 

median of 1.8 years. The protection among persons with positive tuberculin 

skin test reactions (not further defined) was 40%, yet with confidence 

intervals overlapping zero. There was a slight, statistically significant reduction 

in risk of death among tuberculin-positive isoniazid recipients compared 

to the controls. 

Spontaneously healed tuberculosis with fibrotic residuals 

Patients with tuberculosis that has healed spontaneously with fibrotic lesions 

are frequently found, and remain an important source of reactivation tuberculosis, 

particularly in countries where the tuberculosis risk has been rapidly 

declining and most cases are the result of endogenous reactivation. Three 

such studies are shown here (figure 81). 

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patients with fibrotic lesions, hemodialysis, or silicosis. 123,641,891-893 

134

A large trial was conducted in Europe by the International Union 

Against Tuberculosis Committee on Prophylaxis among patients with fibrotic 

lesions. 123,889 Patients were randomly assigned to four groups, each consisting 

of close to 7,000 patients. A control group received placebo, and 

three groups received three, six or twelve months, respectively, of isoniazid. 

They were followed up to five years following intake. Among persons 

completing twelve months of, and adhering to, the prescribed course 

of chemotherapy the protection afforded by isoniazid was 93%. The effect 

was greater among those with larger than among those with smaller radiographic 

lesions. 

Similarly, the US Public Health Service conducted a trial among patients 

with inactive lesions and followed them up for five years following enrolment 

into a randomized trial of twelve months isoniazid versus placebo. 641 

The protection afforded by isoniazid was 60%. 

In New York City, another study with two years of isoniazid was conducted 

among patients with inactive lesions. 890,891 The number of patients 

enrolled was small, and the protection afforded was 43% over a period of 

six years from enrolment. 

Silicosis 

Silicosis is a well-recognized risk factor for tuberculosis and is highly prevalent 

in countries where mining industries and other environments (granite 

quarry workers) offer poor protection against silica dust inhalation. In a 

study jointly organized by the Hong Kong Chest Service, the Tuberculosis 

Research Centre, Madras, and the British Medical Research Council, patients 

in Hong Kong were enrolled into a double-blind randomized trial with six 

months of isoniazid (and two rifampicin-containing arms) compared to a 

placebo group. 892 During the five-year follow-up period, isoniazid offered 

a protection of 34%, but the 95% interval included zero (figure 81). 

Renal failure 

A relatively small study with 184 patients on renal dialysis or after renal 

transplant were randomly assigned to receive either one year isoniazid or 

placebo. They were followed up for one year following cessation of therapy. 

Among those who completed therapy, the protection afforded by isoniazid 

was 41%, but the confidence interval overlapped zero (figure 81). 893 

135

Prevention of disease following cessation 

of preventive chemotherapy 

One consideration has been the duration of efficacy of isoniazid preventive 

chemotherapy. In the three studies shown here, the protection remained 

unaltered over four to five years following cessation of preventive 

chemotherapy (figure 82). 123,875,876 Similar maintenance of efficacy over 

even longer periods was shown in other studies. 641 In the longest followup 

reported, from the Bethel, Alaska area, protection persisted for more 

than 19 years. 894 

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Figure 82. Long-term efficacy of preventive chemotherapy with isoniazid. 123,641,876 

Nevertheless, in areas where the risk of infection is high and a large 

proportion of cases is emanating from recently infected persons, protection 

might be expected to decline over time. However, once the tubercle bacilli 

have been eliminated from the body, one might expect some protection to 

be afforded against super-infection leading to disease, similar to that expected 

from BCG vaccination. 

Prevention of disease with different durations 

of treatment 

The duration necessary to provide optimum protection from isoniazid has 

not been satisfactorily determined. In fact, the only study seeking direct

evidence was the trial of the International Union Against Tuberculosis 

Committee on Prophylaxis (figure 83). 123 Among “completer-compliers” 

the answer is quite clear-cut. Most benefit was obtained with twelve months 

chemotherapy with 93% protection, while six months offered 69% protection, 

and three months 32%. 

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Figure 83. Impact of duration of intake of isoniazid preventive therapy on protective 

efficacy. 123 

However, if all patients were analyzed (and not only “completer-compliers”), 

the differences between six months and twelve months became 

much smaller, as adherence dropped with increasing length of treatment. 

For this reason and considering the cumulative risk of adverse drug events 

and personnel costs, it has been suggested that six months of preventive 

chemotherapy with isoniazid was more cost-effective than twelve 

months. 895 

However, the primary decision that has to be taken in the selection 

of a regimen (curative or preventive) is efficacy; the second is effectiveness. 

In consideration of these findings, recommendations have been made 

for preventive chemotherapy to be given for six to twelve months, with 

every effort made to ensure adherence for six months. 356 The isoniazid 

preventive chemotherapy trials in the United States showed that the optimum 

duration might lie somewhere around nine months (figure 84). 896 The 

American Thoracic Society and the US Centers for Disease Control now 

recommend nine months of isoniazid treatment. 897 The British Thoracic 

Society recommends six to twelve months for preventive chemotherapy, the 

longer duration recommended for HIV-positive patients. 898,899 

137

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Figure 84. Tuberculosis risk and duration of intake of isoniazid preventive therapy 

in the Bethel, Alaska, preventive chemotherapy studies. Reproduced from 896 

by the permission of the publisher International Union Against Tuberculosis and Lung 

Disease. 

Prevention of disease with alternatives to isoniazid 

Rifampicin has been remarkably effective in shortening the required duration 

of chemotherapy of tuberculosis. 122,504 It is postulated to act particularly 

well on mycobacterial sub-populations with only short bursts of metabolic 

activity. 456 Such a situation probably exists in the case of latent 

tuberculous infection and it is thus appealing to hypothesize that rifampicin 

might be effective in preventive chemotherapy and may also reduce the 

duration of the required treatment period compared to isoniazid. 

In a mouse model, Lecoeur and collaborators tested the efficacy of 

rifampicin with or without other drugs in combination as a preventive 

chemotherapy tool in comparison with isoniazid. 900 

Latent, sub-clinical infection was produced by vaccination with BCG 

and subsequent challenge with M. tuberculosis. After an initial increase in 

viable tubercle bacilli, this produced a stable count of bacilli in the spleen, 

indicating that the relatively limited population was no longer actively multiplying 

in the spleen when drug treatment was given. In a first experi- 

138

ment, mice were assigned to five groups: 1) no treatment, 2) isoniazid for 

six months, 3) rifampicin for two months, 4) rifampicin plus isoniazid for 

two months, and 5) rifampicin plus isoniazid plus pyrazinamide for two 

months (figure 85). From this experiment, it was shown that two months 

of rifampicin-containing preventive chemotherapy was as effective as six 

months of isoniazid. 900 

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139 

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Figure 85. Mouse model of latent tuberculous infection and efficacy of various 

durations and combinations of preventive therapy on spleen bacillary count. 

Reproduced from 900 by the permission of the publisher American Thoracic Society 

at the American Lung Association. 

In a second experiment, in comparison to isoniazid the relative efficacy 

of various combinations with rifampicin of different durations was 

evaluated. Mice received 1) six months of isoniazid, 2) three months of 

rifampicin plus isoniazid plus pyrazinamide, 3) three months of rifampicin, 

or 4) two months of rifampicin plus pyrazinamide. The experiment was 

calibrated in such a way as to ensure that viable bacilli remained at cessation 

of therapy to allow their culture from spleen at cessation and after 

a follow-up of a six-month period without treatment. All rifampicin 

combinations proved superior to isoniazid treatment for six months 

(figure 86). 900 The best combination was rifampicin plus pyrazinamide 

(without isoniazid). Rifampicin alone for three months was also very 

effective.

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Two types of studies are available to test the hypothesis in human subjects 

that rifampicin with or without isoniazid is first, efficacious, and second, 

equivalent or better than isoniazid alone, even if given for shorter 

durations. The first type consists of comparisons of rifampicin and 

rifampicin combinations with placebo, the second comparisons of rifampicin 

and rifampicin combinations with isoniazid (equivalence studies). The 

hypothesis and sample size requirements differ in the two approaches. 

Rifampicin and rifampicin combinations in comparison 

to placebo 

Studies comparing rifampicin (and combinations) with placebo have been 

carried out among patients with silicosis and patients with HIV infection 

(figure 87). 885,886,892 

In Kampala, Uganda, two arms had rifampicin-containing regimens. 

Compared to placebo, daily rifampicin plus isoniazid for three months gave 

60% protection among tuberculin-positive patients with HIV infection. 

Rifampicin plus isoniazid plus pyrazinamide given daily for three months 

offered 49% protection. 886 

140 

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Figure 86. Mouse model of latent tuberculous infection and efficacy of various 

rifampicin combinations of preventive therapy on spleen bacillary count. Reproduced 

from 900 by the permission of the publisher American Thoracic Society at the American 

Lung Association.

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Figure 87. Protection against tuberculosis with rifampicin containing preventive 

therapy among persons with HIV infection or silicosis. 885,886,892 

In the study on patients with silicosis in Hong Kong presented above, 

in addition to the isoniazid (for six months) and placebo arms, two additional 

arms contained rifampicin. One of these consisted of twelve weeks 

of rifampicin alone and the second of twelve weeks of rifampicin plus isoniazid. 

892 All drugs were given daily. Rifampicin alone for twelve weeks 

gave 46% protection. Rifampicin plus isoniazid for the same duration 

offered 29% protection, with the confidence interval including zero. 

In Lusaka, Zambia, a twice-weekly regimen of rifampicin plus pyrazinamide 

given for three months gave 19% protection (the confidence intervals 

overlapping zero) against confirmed tuberculosis in HIV-infected 

patients. 885 

Rifampicin and rifampicin combinations in comparison 

to isoniazid 

A few studies have provided information on the equivalence of rifampicincontaining 

preventive chemotherapy with isoniazid preventive chemotherapy 

(figure 88). 885,892,901,902 Again, these studies were carried out among 

patients with risk factors (silicosis and HIV infection). 

In Hong Kong, twelve weeks of rifampicin provided 44% protection 

compared to six months of isoniazid, a statistically significant superiority, 

while the 25% comparative effect of twelve weeks with rifampicin plus 

isoniazid was not statistically different from the protection offered by isoniazid. 

892 Thus, the overall protection against tuberculosis with preventive 

chemotherapy among silicosis patients was relatively poor, and rifampicin 

alone appeared to be superior to rifampicin plus isoniazid. 

141

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In Cité Soleil and Petit Place Cazeau, Haiti, patients with HIV infection 

and a tuberculin skin test induration of five or more millimeters were 

randomly assigned to receive either isoniazid for 24 weeks or rifampicin 

plus pyrazinamide for eight weeks. 901 All drugs were given twice weekly, 

the first weekly dose directly observed, the second self-administered. The 

overall protection afforded by the rifampicin-containing regimen was minus 

30%, with confidence intervals overlapping zero. During the first ten 

months after entry, the risk among isoniazid recipients was significantly 

lower than among rifampicin recipients. 

Similarly, in Lusaka, Zambia, isoniazid for six months gave better protection 

than rifampicin plus pyrazinamide for three months, but the confidence 

intervals were wide, the difference was not statistically significant, 

and the protective effect from both arms was lost after two to three years. 885 

The long-term evaluation showed that protection lasted for about two and 

a half years and none of the regimens appeared to have an effect on HIV 

progression or mortality. 903 

In a multi-center study involving 53 treatment units in Brazil, Haiti, 

Mexico, and the United States, a total of 1,583 HIV-infected patients were 

randomized to receive either isoniazid for twelve months (control arm) or 

rifampicin plus pyrazinamide for two months (experimental arm). 902 Among 

the inclusion criteria were the presence of a tuberculin skin test reaction of 

five or more millimeters of induration. For bacteriologically confirmed 

cases, the relative protection of the two-month regimen was 33% for bacteriologically 

confirmed, and five per cent for confirmed and probable cases. 

The 95% confidence interval was reasonably narrow, overlapped zero, and 

142 

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Figure 88. Protection against tuberculosis with rifampicin containing preventive 

therapy compared to isoniazid preventive therapy (equivalence studies) among persons 

with HIV infection or silicosis. 885,892,901,902

thus suggested equivalence (the hypothesis of the study) between the two 

regimens. Completion of therapy was superior in the experimental compared 

to the control arm. 

In the United States, preventive chemotherapy regimens using rifampicin 

(plus pyrazinamide) of two to four months’ duration have been recommended. 

897 However, recent reports on fatal and severe hepatitis associated 

with preventive therapy using rifampicin plus pyrazinamide 904 have 

led to a change of the recommendation and advising great caution in the 

use of this combination. 904 

Effectiveness of preventive chemotherapy 

There can be little doubt about the efficacy of preventive chemotherapy, at 

least with isoniazid if given for twelve months to persons with tuberculous 

infection without additional risk factors. There are indications that a regimen 

of nine months’ duration might still be similarly efficacious in reducing 

the risk of tuberculosis. The efficacy of isoniazid in patients with risk 

factors is much less well established, and many studies dealing with HIVinfected 

patients suffer from inadequate sample sizes. It also seems that 

rifampicin-containing regimens of shorter duration can afford similar protection, 

but the optimal duration and the role of companion drugs have not 

been sufficiently well established. A short-coming of most preventive 

chemotherapy trials has been the self-administration of medications, thus 

portraying more the effectiveness than the potential efficacy of the regimen 

in question. 

All studies that have evaluated that component have clearly demonstrated 

the adverse effect of non-adherence on the regimen’s efficacy, as 

would be expected. This has been the case even in the setting of clinical 

trials where adherence might be better than under daily operations within 

the context of a national program. 

Several studies have also demonstrated that the type of patients who 

are selected for preventive chemotherapy is important, and that large numbers 

may have to be treated to prevent a single case if the persons selected 

have a low risk of tuberculosis. 

In a simplified form, operational effectiveness can thus be summarized 

as the product of tuberculosis risk given the presence of tuberculous infection, 

the efficacy of the regimen, and adherence to the prescribed medications. 

In a few examples, table 11 summarizes different situations and the 

143

Table 11. Preventive therapy – effectiveness. Effectiveness of preventive therapy 

in dependence of risk of tuberculosis, efficacy of treatment regimen, and adherence 

to the regimen. All parameters are shown as fractions. Risk of tuberculosis 

is allowed to vary from 0.05 (estimated cumulative risk subsequent to the first five 

years following infection) to 0.30 (estimated cumulative risk of a person dually infected 

with M. tuberculosis and HIV). 

Risk Efficacy Adherence Overall Number to treat 

of tuberculosis of regimen to treatment effectiveness to prevent 1 case 

0.05 0.60 0.30 0.009 111 

0.10 0.60 0.30 0.018 56 

0.30 0.60 0.30 0.054 19 

0.30 0.90 0.30 0.081 12 

0.30 0.90 0.50 0.135 7 

0.30 0.90 0.80 0.216 5 

impact on overall operational effectiveness. The risks of tuberculosis shown 

here are for persons with long-standing tuberculous infection, recently 

acquired tuberculous infection and concomitant HIV infection (0.05, 0.10, 

and 0.30 for the respective risks of tuberculosis). Efficacy examples have 

been taken from isoniazid-preventive chemotherapy ranges, and adherence 

has been made up to vary as might be expected among different patients 

with a condition that is not symptomatic. The overall effectiveness is the 

product of these three variables and the number of patients that must be 

treated to prevent one case is the reciprocal value of effectiveness. The 

example shows that effectiveness will greatly vary depending on the selection 

of patients, the type of regimen and the extent to which patients adhere 

to treatment. Although reality is not quite as straightforward as in this 

example (it assumes that each component proportionally reduces effectiveness), 

it may help in deciding under which circumstances preventive 

chemotherapy is to be recommended. The specific indication will depend 

on the availability of resources, as the overall effectiveness is, under any 

circumstance, relatively modest. Not accounted for in this model is the 

probability of tuberculous infection actually being present when a “positive” 

tuberculin skin test is recorded. 

A study in Kampala, Uganda, ascertained the operational feasibility 

and effectiveness of preventive chemotherapy in a high-risk population, 

apparently motivated to attend voluntary testing sites for HIV. 905 Among 

patients who were found to be HIV-positive, only about 60% returned to 

obtain their result and to receive counseling (figure 89) and of these only 

144

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a small fraction was actually referred for evaluation of eligibility for preventive 

chemotherapy. Quite obviously, the collaboration was poor despite 

the study setting. Additional patients were lost for tuberculin testing and 

reading, only a fraction of these were actually eligible for preventive 

chemotherapy, and not all of those who were eligible were actually adherent. 

Only three per cent of the initial cohort completed preventive 

chemotherapy, and the efficacy was never assessed. 


of preventive chemotherapy 

It is apparent that the place preventive chemotherapy will have within the 

context of a national tuberculosis control program will depend foremost on 

the epidemiologic situation and on the availability of resources. Rapid 

improvement in the epidemiologic situation and sufficient resources often 

go together, while the reverse is also the case. 906 

In industrialized countries embarking on strategies to eliminate tuberculosis, 

preventive chemotherapy will play an important role, yet the situation 

is rather different in countries with a high or even increasing tuberculosis 

burden where resources are very tight even to secure the treatment 

of all known cases of bacteriologically confirmed tuberculosis. 

Within the context of resource availability, it should be considered that 

the costs for isoniazid are probably of least concern in most settings. 

145 

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Figure 89. Operational feasibility of preventive therapy usage in a voluntary counseling 

and testing site for HIV infection. 905

Logistical problems may, however, impose substantial impediments in some 

settings in low-income countries. Of critical importance is the capability 

to exclude the presence of active tuberculosis. This is particularly the case 

in adults, where the bacterial load of unrecognized tuberculosis might be 

sufficiently high to favor selection of isoniazid-resistant mutants if monotherapy 

is being given. In the Uganda study, 905 a sizeable portion of HIVinfected 

patients who were examined had active pulmonary tuberculosis, 

and not all had positive sputum smears on direct microscopic examination. 

For good reasons, WHO has thus recommended that both sputum smear 

microscopy and chest radiography are mandatory in HIV-infected patients 

before commencing preventive chemotherapy. 907 

The IUATLD limits the recommendations for preventive chemotherapy 

in low-income countries to asymptomatic children under the age of five 

years who live in the same household as a newly discovered sputum smearpositive 

case. 8 This is a group of persons with a high risk of becoming 

infected because of the closeness of contact. Preventive chemotherapy (or 

prophylactic treatment in the portion of children who have escaped infection) 

can be administered without prior investigation except for a clinical 

assessment of health. Even in the presence of an asymptomatic primary 

complex, the bacillary load will be too small in such children to pose the 

problem of selecting isoniazid-resistant bacilli. The drug of choice is isoniazid 

(5 mg/kg body weight), as it is the least expensive and the drug with 

which there is most experience. The duration of treatment might be pragmatically 

adjusted to the length of the tuberculosis treatment regimen prescribed 

for the index person, i.e., between six and twelve months. 

For national programs wishing to expand their preventive chemotherapy 

program to other risk groups, the above measures to exclude active 

tuberculosis before initiating preventive chemotherapy should be strictly 

enforced. 

146

Appendix 1 

Adjunctive treatment 

Adjunctive therapy with corticosteroids 

The role of corticosteroids in the treatment of tuberculosis is not precisely 

known and the opinion concerning their use in different clinical situations 

is often somewhat controversial. The available evidence for and against 

their use is reviewed here, following the extensive review by Dooley et 

al., 908 supplemented by additional reports. 

Pulmonary tuberculosis 

The value of corticosteroids in the treatment of pulmonary tuberculosis has 

been evaluated in several controlled trials. 909-920 

Sputum conversion was not affected by corticosteroid therapy in any 

of these studies; early sputum conversion was faster in the control group 

in one study and faster in the corticosteroid group in another. 

On the other hand, clinical and radiologic improvement was generally 

more rapid in the corticosteroid treated group, particularly among the more 

seriously ill patients. In the United States Public Health Service trial, prednisolone 

produced more frequent and more rapid radiologic clearing of the 

infiltrate in black patients, but was of no benefit in white patients. 918 

In the five-year follow up of the United States Veterans Administration 

study, patients treated with corticosteroids were less likely to have died due 

to relapse of their tuberculosis, or due to respiratory illnesses such as bronchitis, 

respiratory insufficiency, or pneumonia. 917 

A controlled clinical trial from India 920 is significant in two ways. 

First, it is the only study using corticosteroids as adjunct therapy together 

with rifampicin-containing regimens. Second, it revealed that patients treated 

with corticosteroids who had strains initially resistant to isoniazid and streptomycin 

had a poorer bacteriologic response than those not treated with 

steroids. The deleterious effect of steroids in patients with sub-optimal 

chemotherapy had been observed earlier. 921 This had previously been shown 

in animal models as well, 922,923 and is not unexpected. 

147

In an uncontrolled study in Zambia, HIV-infected patients treated for 

tuberculosis who had adjunct therapy with corticosteroids developed herpes 

zoster and Kaposi’s sarcoma significantly more often, while generalized 

lymphadenopathy improved. 924 

The routine use of corticosteroids as adjunct therapy for pulmonary 

tuberculosis cannot, therefore, be recommended. In addition to the multitude 

of known adverse effects directly related to steroid use, in tropical 

countries parasitic infestation is common and corticosteroids in such patients 

may precipitate dissemination 925 and abscesses. 926 

The indication for the use of corticosteroids in pulmonary tuberculosis 

should be restricted to patients so seriously ill that their prognosis is judged 

to be very poor and thus the steroids are potentially life-saving. 7,927 

Extrapulmonary tuberculosis 

Tuberculosis of serous membranes 

Pleural tuberculosis 

A number of studies have been reported evaluating the use of corticosteroids 

in pleural tuberculosis. 928-937 Not all of the studies were conducted 

with the same rigor and only eight provide sufficient information for an 

adequate evaluation. 928-933,936,937 

Most studies showed a more rapid resolution of effusions in those 

given corticosteroids. In the studies that evaluated residual pleural thickening 

as the crucial endpoint, three found less thickening in the steroid 

treated group 930-932 and two found no difference between placebo and steroid 

treated groups. 936,937 

From these studies it would appear that the value of corticosteroids in 

the treatment of pleural effusion is doubtful. Weighted against the possible 

adverse effects, steroids should probably not be routinely used in tuberculous 

pleural effusion. 

Pericardial tuberculosis 

The efficacy of corticosteroid therapy for tuberculous pericarditis may differ 

for the different physiological stages of the disease (effusive, effusiveconstrictive, 

and constrictive). 908 Several retrospective studies fail to address 

these points and lack well-defined endpoints. 938,939 In a retrospective study 

addressing the critical issue of stage of disease, patients on corticosteroids 

148

had a more rapid decrease in pericardial effusion as compared to those not 

given corticosteroids. 940 

Prospective studies evaluating the use of corticosteroids in the treatment 

of tuberculous pericarditis were conducted in the Transkei area of 

South Africa. 941-944 These studies showed that fewer patients with acute 

effusive pericarditis on corticosteroids required repeated drainage, 941 and 

patients with effusive-constrictive pericarditis had faster improvement. 942 

In neither study were there differences in constriction, but among patients 

with acute effusive pericarditis, corticosteroid recipients had a lower risk 

of death. Among HIV-infected patients in Harare, Zimbabwe, corticosteroids 

significantly reduced case fatality. 945 

From these studies it would seem that adjuvant treatment with corticosteroids 

is indicated in patients with pericardial tuberculosis. 

Peritoneal tuberculosis 

Because of the similarity in the pathogenesis of peritoneal and pericardial 

tuberculosis, both involving serous membranes, a beneficial effect of corticosteroid 

use in peritoneal tuberculosis similar to that in pericardial tuberculosis 

might be expected. 946 Alternatively one may argue that tuberculous 

peritonitis is more similar to tuberculous pleurisy. In a retrospective study 

from Saudi Arabia, the frequency of recurrent abdominal pain and emergency 

department visits were used as endpoints to compare the usefulness 

of corticosteroid adjunctive therapy. 947 Corticosteroids appeared to have an 

effect in reducing the frequency of these events. However, as the study 

was a retrospective evaluation of a case series comparing patients who were 

given corticosteroid therapy with patients who had not received corticosteroids, 

it is not possible to draw firm conclusions. A prospective trial, allocating 

patients to a three-month course with either prednisone or placebo, 

was carried out with death and intestinal obstruction evaluated as endpoints. 

948 Corticosteroid-treated patients fared better, but the small sample 

size did not detect a significant difference in the frequency of these events. 

The evidence for the usefulness of corticosteroid treatment as adjunctive 

treatment in peritoneal tuberculosis is sufficiently convincing to recommend 

its routine use. 

Meningeal tuberculosis 

Adjunctive treatment with corticosteroids in meningeal tuberculosis has been 

widely reported. 949-964 However, not all of the published reports were 

prospective, controlled trials. 

149

In none of the nine prospective trials was treatment outcome worse in 

the group treated with corticosteroids, as compared to the control group. Survival 

in the corticosteroid treated group was improved in four, 957,960,961,964 

tended to be better in one, 963 and was not better in four. 955,956,959,964 

Fewer sequelae in the corticosteroid-treated group were found in four studies. 

959,960,963,964 

Studies that looked at the stage of disease and the effects of corticosteroids 

found a lack of effect in mild and terminal disease stages (assessed 

by the degree of neurologic impairment), but a significant benefit for patients 

with intermediate disease stage. 954,957,960 One of these studies 957 determined 

that there was no difference in treatment outcome between doses of 1 mg 

and 10 mg of dexamethasone. The duration of corticosteroid treatment in 

this study was one month. 

There is sufficient evidence to recommend the use of corticosteroids 

in moderate to severe meningeal and cerebral tuberculosis to improve survival, 

although not all patients will benefit from adjunctive corticosteroid 

treatment. 

Corticosteroid treatment in other forms of tuberculosis 

Corticosteroids have been given for other forms of tuberculosis. 

In the treatment of endobronchial tuberculosis, adjunctive therapy with 

corticosteroids has been shown to be beneficial. 965,966 In children with 

bronchial obstruction due to hilar lymphadenopathy, resolution of symptoms 

was faster and complications less frequent in corticosteroid-treated 

children compared to controls. 967 

Patients with peripheral lymphatic tuberculosis are known to frequently 

develop new nodes and draining abscesses during chemotherapy which are 

bacteriologically sterile and thought to represent an immunologic reaction. 535 

It would be desirable to evaluate the potential usefulness of adjunctive corticosteroid 

treatment, yet no controlled trial has investigated this issue. 

The use of corticosteroids in the treatment of genitourinary tuberculosis 

has been reported, 968,969 but the design of the studies was insufficient to 

draw conclusion on their efficacy in reducing ureteral strictures. 

The role of surgery in the chemotherapy era 

Surgery has played a major role in the history of treatment of tuberculosis, 

and thoracic surgery was actually largely developed around the treat- 

150

ment of pulmonary tuberculosis. 679,970,971 Efficacious chemotherapy has 

removed the need for surgical intervention in the routine treatment of 

patients. 

The usual indications for surgery in the treatment of tuberculosis are 

for the treatment of complications. This is true for pyopneumothorax, respiratory 

distress due to massive pleural effusion, extensive restrictive pleural 

thickening, restrictive pericarditis, obstructive hydrocephalus, long-tract neurological 

signs in tuberculous spondylitis, and ureteral obstruction. There 

are, with the exception of extensive drug resistance, virtually no indications 

for surgery for primary treatment of tuberculosis. The guidelines for such 

surgery follow those for any other cause of such complications. 

In industrialized countries, surgery has also been used with some success 

as an adjunct in patients with strains resistant to all or virtually all 

medications. 972-976 Such services are not usually available in national tuberculosis 

control programs of low-income countries, and are fortunately still 

rarely needed in most countries. 

What will be summarized here are indications that are frequent and 

do not require sophisticated surgical procedures. 

Surgical treatment in respiratory tract tuberculosis 

Tuberculous pyopneumothorax 

The development of an empyema or, more precisely, a tuberculous pyopneumothorax 

is a well-recognized complication in patients with cavitary 

tuberculosis whose cavities are located near the pleura. 977,978 In such 

patients, penetration of anti-tuberculosis medications into the pleural space 

and the empyema might be sub-optimal and may even lead to acquisition 

of drug resistance. 979 Furthermore, in contrast to pleural effusions, resorption 

of an empyema is less likely to occur, thus draining of the pus is usually 

indicated. 

In the field, the most simple and effective approach is insertion of a 

drain, laid in such a way that it leads over two or three ribs before penetrating 

into the pleural space. The drain should be sutured to the skin. 

The patient is offered a bed that is about one meter above the floor, and 

the drainage is led into a bottle filled with water serving as a water lock. 

In patients whose entire lung is collapsed, full expansion of the lung can 

be expected, often leaving pleural thickening, however. As decortication 

151

is not usually an option, this is the best possible result that might be expected 

in such cases. 

Pleural tuberculosis 

Massive pleural effusions often require draining to relieve the patient from 

respiratory distress. Care should be taken not to drain more than about 

one liter in a single session to prevent cardiovascular and electrolyte disturbances. 

Accompanied by adequate chemotherapy, resolution of the accumulated 

fluid is usually prompt. Some authorities recommend complete 

draining of the effusion, 937 but it is uncertain whether this is really required. 

Surgical treatment in tuberculosis of the spine 

As previously shown (Chapter 1), chemotherapy alone of tuberculosis of 

the spine yields excellent results. Only the “radical Hong Kong operation” 

improves the results of chemotherapy somewhat, but not importantly so. 562 

Because of the sophistication required, this procedure is beyond the capacity 

in the periphery of national programs where adequate chemotherapy 

alone is the key to success. 

Superficial abscess might be drained by needle aspiration, but might 

also recur after the procedure. 980 

152

Numerous drugs other than the first-line anti-tuberculosis drugs discussed 

in Chapter 1, and often called “second-line drugs”, have shown activity 

against M. tuberculosis. Generally, these medications are less efficacious, 

associated with a higher frequency of adverse drug events, and are more 

expensive. In most low-income countries, these drugs are not routinely 

available in national programs. Where they are, their use is best limited 

to specialists with experience in dealing with adverse drug events. 

Nevertheless, the global emergence of multidrug resistance (resistance 

to at least isoniazid and rifampicin) has brought up the discussion about 

their use on a wider scale. 605,607-609,611,981-983 For this reason, brief summaries 

of these drugs are presented here. 

Aminoglycosides (other than streptomycin) 

Amikacin 

Appendix 2 

Active agents other 

than essential drugs and drug classes 

(second-line drugs) 

Amikacin is a semi-synthetic aminoglycoside, synthesized by Kawaguchi 

and collaborators through acetylation of the 1-aminogroup of the 2-desoxistreptamine 

moiety of kanamycin A at the Bristol-Banyu research laboratories 

in Japan, 984 and reported in 1972. 985 

Amikacin has broad activity, particularly against gram-negative bacteria 

986 and is active against M. tuberculosis. 987 Some researchers have found 

it to be usually more active against M. tuberculosis than other aminoglycosides. 

224,283 Cross-resistance with other aminoglycosides may occur, 283 

and is particularly frequent with kanamycin, and incomplete with the 

polypeptide capreomycin. 988 Amikacin is frequently active against streptomycin-resistant 

strains of M. tuberculosis. 989 However, it appears to have 

little early bactericidal activity. 990 Like other aminoglycosides, amikacin 

is not absorbed orally and the usual route of administration is intramuscular 

or intravenous, at a dose of 7.5 mg/kg to 15 mg/kg (depending on the 

dosage interval). 

153

Like other aminoglycosides, amikacin affects the neuromuscular junction 

and may lead to neuromuscular blockade, 409,410,991 an effect that may 

be reduced by lithium, 992 but not reversed by neostigmine. 

Indomethacin may interact with amikacin in newborns by increasing 

serum levels to toxic concentrations. 993 Neurotoxicity might be increased 

by muscle relaxants such as tubocourarine, succinylcholine or decamethonium. 

Kanamycin 

Kanamycin was isolated from Streptomyces kanamyceticus by Umezawa 

and collaborators in 1957. 994 It is a mixture of kanamycin A, B, and C. 995-997 

Kanamycin is active against a range of gram-negative bacteria and 

mycobacteria including M. tuberculosis. 998 

Kanamycin is not absorbed orally, but intramuscular administration 

leads to peak serum levels within an hour and the serum half-life is about 

four to six hours. 998 It is mainly excreted through the kidneys and thus, 

as with all aminoglycosides, dose adjustments are warranted in patients with 

renal failure. 998 

The usual dosage of kanamycin is 0.5 g to 1 g per day. 998 

Similar to other aminoglycosides, eighth cranial nerve toxicity is the 

most important. Auditory toxicity is more pronounced than vestibular toxicity 

998 and is very frequent, affecting up to 20% of patients after three 

months, and up to 60% if treatment lasts for six months. 999 Like other 

aminoglycosides, kanamycin may cause neuromuscular blockade. 409 Other 

adverse drug events include renal toxicity and, rarely, allergies. 998 

As with other aminoglycosides, resistance is thought to be acquired 

through a single extrachromosomal plasmid factor with multi-step selection. 

1000 Capreomycin resistant strains are not usually resistant to 

kanamycin. 476 The inverse seems to be the case for low, but not for high 

kanamycin resistance. 476 

Capreomycin 

Capreomycin, a polypeptide antibiotic, was isolated from Streptomyces capreolus 

by Herr and collaborators at the Lilly Research Laboratories in 1959. 1001 

Capreomycin is active against various species of mycobacteria, including 

M. tuberculosis. 1002,1003 

154

Similar to aminoglycosides, capreomycin causes auditory, vestibular, 

and renal toxicity. 1004 Also like aminoglycosides, it is not orally absorbed 

and the usual administration is intramuscular. Rare adverse drug events 

include hypokalemia. 1004 

Cross-resistance between kanamycin and capreomycin is incomplete. 1005 

Cycloserine 

Cycloserine (originally called orientomycin) was first isolated in 1952 from 

a Streptomyces strain, designated strain K-300 by Kurosawa. 1006 The identity 

with the compound discovered two years later in the United States was 

elucidated by Shoji, 1007 and Mitui and Imaizumi in 1957, 1008 but not before 

Lederle Laboratories also isolated the compound and recognized its identity 

with oxamycin, isolated by the Merck Laboratories, 1009-1011 and the Pfizer 

Laboratories which also isolated the compound. 1012 Cycloserine can be isolated 

from Streptomyces orchidaceus, S. garyphalus, or S. lavendulae. 

Cycloserine is active against M. tuberculosis and several species of 

gram-positive bacteria. 1006 

Cycloserine inhibits cell wall synthesis 1013,1014 by inhibiting the synthesis 

of peptidoglycan by blocking action of D-alanine racemase and Dalanine:alanine 

synthase. 46 

Cycloserine is rapidly absorbed after oral administration, with a peak 

serum level of 10 to 50 mg/L following administration of 0.75 g to 1 g 

after 0.5 to 4 hours. 

The usual dosage is two to three times daily (250 mg/day), 1015 but it 

is often given as a single dose. 

The main adverse drug events due to cycloserine are neurologic and 

psychiatric, 159,1016-1022 although it has also been used in the treatment of mentally 

ill tuberculosis patients without observation of major mental toxicity. 

1023 In a summary of several reports, cycloserine toxic adverse drug 

events were reported in over 20%. 1006 Most frequently reported or observed 

were vertigo and disorientation. Neuropsychiatric changes including drowsiness, 

slurred speech, psychoses, epileptiform reactions, 1016 as well as electroencephalographic 

changes and coma, were frequently noted. These effects 

of cycloserine are probably due to an interaction with the action of some 

monoamine oxidase inhibitors, as shown in experimental animals. 1024 

Cardiac depression, pareses, paresthesias and headache, pruritic rashes, 

drug fever, liver enzyme elevations, and gastrointestinal disturbances were less 

frequently reported adverse drug events. Smaller doses, and administration 

155

twice rather than once per day, reduce the frequency of adverse drug events. 

Stevens-Johnson syndrome has been reported in an HIV-infected patient. 1025 

Cycloserine appears to interact with alcohol, increasing the toxic effects 

of alcohol. 1026 

Determination of resistance to cycloserine is difficult, and the correspondence 

of laboratory results with clinical data is poor (figure 90). 466 

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Figure 90. Proportion of strains of M. tuberculosis from resected lungs, in vitro 

resistant to anti-tuberculosis drugs, as a function of duration of treatment, the strain 

containing no susceptible organisms. Reproduced from 466 by the permission of the 


Para-aminosalicylic acid 

In 1940, Bernheim demonstrated that salicylic acid and benzoic acid 

increased the oxygen consumption and carbon dioxide production of 

M. tuberculosis. 1027 Based on these observations, Lehmann investigated 

more than 50 derivatives of benzoic acid with the purpose of finding a substance 

possessing activities against M. tuberculosis. The most active compound 

he identified in the experiments was para-aminosalicylic acid, first 

published as preliminary results in the Lancet in 1946. 1028 Soon thereafter 

the first reports appeared, demonstrating its considerable anti-tuberculosis

activity in experimental models. 256 The use of para-aminosalicylic acid 

became a core component in early combination therapy until its replacement 

by the better tolerated ethambutol. 122 

It is likely that para-aminosalicylic acid, and not streptomycin, was the 

first anti-tuberculosis drug tested specifically against M. tuberculosis, as suggested 

in an editorial 1029 and correspondence of Lehman (reproduced with 

the permission of the South African Medical Journal): 1030,1031 

“Dear Dr Dubovsky, 

Your letter to the Director of the Central Laboratory at Sahlgrens 

Hospital was forwarded to me. It was the most remarkable letter I 

have received for many years. You are the first outside Sweden who 

has paid attention to the fact that PAS was in clinical use before streptomycin, 

eight months before ... Perhaps you wonder why I published 

the first paper on PAS so long after it was taken in clinical use. The 

reason was that as Ferrosan, a small company, had not taken out a 

patent on PAS, I didn’t dare to publish the formula on PAS as other 

greater companies could take over the production of PAS ...” 

The MIC of M. tuberculosis is 1 mg/L. 1032 

In analogy with the observation that benzoic acid inhibits the respiration 

of tubercle bacilli, 1027 para-aminosalicylic acid might be built into coenzyme 

F of the bacterium instead of para-aminobenzoic acid, and thereby 

inhibit growth. 430 

Maximum serum concentrations with twice 4 g granular para-aminosalicylic 

acid are achieved within five to eight hours and remain above the 

minimum inhibitory concentration over the entire dosing interval. 1032 

The granular form of para-aminosalicylic acid is better tolerated than 

the previously used tablet form. A dosage of 4 g twice daily of the granular 

form produces serum concentrations above the minimum inhibitory 

concentration over the entire dosing interval. 1032 Good experiences with 

infusion therapy have also been reported. 1033 

Para-aminosalicylic acid has been an unpleasant drug to take because 

of the bulk required and the frequency of adverse drug events, 1034 which 

include gastrointestinal and cutaneous adverse drug events. 1035 Para-aminosalicylic 

acid may cause hypothyroidism, 1036,1037 and intestinal malabsorption. 

1038,1039 Among hematologic changes are thrombocytopenia in 

adults 1040,1041 and children. 1042 

Para-aminosalicylic acid has been reported to increase isoniazid blood 

levels. 1043-1045 It may cause hypoglycemia in diabetics. 1046 

157

Quinolones 

Quinolones have a potential in the treatment of susceptible and drug-resistant 

tuberculosis. Quinolones that have been considered include 

ciprofloxacin, 1047-1056 clinafloxacin, 1051 difloxacin, 1055 enoxacin, 1055 fleroxacin, 

1057 gatifloxacin, 1058 levofloxacin, 1051,1058-1060 lomefloxacin, 1061,1062 moxifloxacin, 

1061,1063 norfloxacin, 1055 ofloxacin, 1051,1053-1055,1064-1068 sitafloxacin, 1058 

sparfloxacin, 1051 temafloxacin, 1051 and tosufloxacin. 1051 Most clinical experience 

has been accumulated with ofloxacin and ciprofloxacin. Some of 

the quinolones have little or no activity against M. tuberculosis, while the 

potential of others is far greater. 1069 

Fluoroquinolones inhibit DNA gyrase of M. tuberculosis. 176 

The MICs of ciprofloxacin and ofloxacin are well below levels that 

can be achieved in serum. 1054 The early bactericidal activity of ciprofloxacin 

is, however, not as pronounced as that of isoniazid, 1056 and is inferior to 

that of ofloxacin. 27 Clinically, there is anecdotal evidence that even prolonged 

ciprofloxacin may not prevent reactivation of tuberculosis. 1047 

Ciprofloxacin levels in bronchial biopsy specimens exceed those in the 

serum, indicating an accumulation of the compound in the lung 

parenchyma. 1052 

A dosage of 600 mg to 800 mg ofloxacin per day has been used successfully. 

1067 

In animals, quinolones induce changes in immature articular cartilage 

of weight-bearing joints, but these concerns have not been substantiated in 

children and adolescents. 1070 However, cases of arthropathy from ofloxacin 

among adults have been reported. 1071 

Antacids appear to lower serum concentrations of quinolones. 1072 

Resistance to fluoroquinolones arises rapidly, and cross-resistance 

between quinolones is the rule. 1073 The most common cause of resistance 

results from mutations in the gyrA gene encoding the DNA gyrase, 1073 an 

enzyme required for replication and gene transcription. 1074 Quinolones should 

be used in combination with at least two other anti-tuberculosis drugs, as 

resistance might develop rapidly in a large proportion of patients. 1075 

Rifamycins other than rifampicin 

Rifabutin 

Rifabutin is a semi-synthetic spiropiperidyl derivative of rifamycin S, 1076 

which was synthesized in the research laboratories of Farmitalia Carlo Erba 

by Marsili et al.; its synthesis was announced in 1981. 1077 

158

Rifabutin is active against a wide range of microorganisms, including 

gram-negative and gram-positive bacteria, and mycobacteria. 1078,1079 In particular, 

among mycobacteria, it is more active against environmental species 

that are naturally resistant to rifampicin, 1080,1081 including M. avium complex. 

1081-1085 While there is considerable cross-resistance with rifampicin, 

it is also active against a relative small subset of M. tuberculosis strains 

that have low resistance to rifampicin. 1083 However, this proportion is too 

small to make it a generally useful drug in rifampicin-resistant disease. 1086 

Treatment results among patients with drug-susceptible organisms are similar 

to those obtained with rifampicin. 1087-1089 However, studies on early 

bactericidal activity suggest that it is less active on extracellular bacilli than 

rifampicin. 1090 

Rifabutin is more lipid soluble than rifampicin, thus tissue penetration 

is superior. 1091 It has a longer terminal half-life, and is extensively metabolized. 

1091 

The daily (and twice-weekly) recommended dosage of rifabutin is 

5 mg/kg body weight. 897 

Adverse drug events reported with rifabutin treatment are similar to 

those with rifampicin treatment and include rash, hepatitis, fever, thrombocytopenia, 

orange-colored body fluids, arthralgia, uveitis, and leukopenia. 

897,1076 Some of these reactions may be potentiated through the interaction 

with anti-retroviral protease inhibitors. 

Rifabutin induces hepatic metabolism, but not as markedly as 

rifampicin. 1091 It does not affect the pharmacokinetics of antiretroviral drugs 

that are excreted in the urine. 1091 A number of results from interaction studies 

show that rifabutin is a less potent inducer of the cytochrome P-450 family, 

and thus causes fewer clinically significant interactions than rifampicin, 1092 

or they are less pronounced. 281 In particular, interactions with protease 

inhibitors are generally less than with rifampicin, 897,1093 and it is the rifamycin 

of choice for patients receiving highly active anti-retroviral therapy. 

Resistance in sub-inhibitory concentrations is less rapidly acquired than 

with rifampicin. 1094 Similar to rifampicin, acquisition of resistance is frequently 

accompanied by mutations in the rpoB gene. 1095 However, up to 

20% of rifampicin-resistant mutants with mutations in the rpoB gene are 

susceptible to rifabutin. 1096 This difference is not due to additional mechanisms 

of resistance, it is just that some of the mutations selected by 

rifampicin do not sufficiently modify the rpoB structure as to render this 

protein resistant to rifabutin (Telenti A, personal written communication, 

March 15, 2001). 

159

Rifapentine 

Rifapentine (cyclopentyl rifamycin SV) is a semisynthetic derivative of 

rifampicin, synthesized at the Lepetit laboratories in Italy. Its properties 

were first described in a publication in 1981. 1097 

Rifapentine is comparable in its spectrum of activity to that of 

rifampicin. 1098,1099 It is active in the experimental mouse model both against 

latent infection with M. tuberculosis 1100 and clinical active disease. 1101 

Rifapentine is an RNA synthesis inhibitor like rifampicin. 1099 

The most conspicuous property of rifapentine is shown in a comparison 

of its pharmacokinetics with rifampicin. The serum elimination halflife 

is much longer in rifapentine 176 than rifampicin (figure 91). 181 The 

serum elimination half-life tβ 1/2 is 14 to 18 hours, 1102,1103 and is similar in 

adults and adolescents. 1104 Intrapulmonary concentrations of rifapentine are 

below those in serum. 1105 In contrast to rifampicin, higher peak levels are 

achieved following food intake than after fasting. 1102 Pharmacokinetics are 

not influenced by HIV status. 1102 A key issue that needs to be addressed 

is its high degree of plasma binding, which might require higher dosages 

than used so far. 

The usual dosage is currently 600 mg twice-weekly. 1099 However, 

higher doses are now being studied. 

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160 

�� 

�� 

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Figure 91. Comparative pharmacokinetics of rifampicin and rifapentine. 

Reproduced from 181,1102 by the permission of the publisher ASM Press.

Adverse drug events similar to those associated with the use of 

rifampicin have been reported. 1099 

Interactions that are expected most likely resemble those with 

rifampicin. 

The pattern and mechanism of resistance to rifapentine is identical to 

that of rifampicin. 

Thioamides 

Following on from the discovery of the pyridine-containing isoniazid, numerous 

pyridine derivatives were tested, and the activity of thio-isonicotinamide 

against M. tuberculosis was found by several groups, 1106,1107 ethionamide, 

one of these thioamides, was introduced by the group of Liberman, Rist, 

and Grumbach. 1106-1108 

Thioamides are active against M. tuberculosis and to a lesser extent 

against other mycobacteria. 1109 

The mechanism of action of ethionamide is, like isoniazid, at the level 

of synthesis of mycolic acids. 46 

Prothionamide is rapidly absorbed and rapidly excreted. 1110 Therefore, 

the daily dosage is usually divided into two doses. Ethionamide has excellent 

penetration into cerebrospinal fluid. 570 

The usual dosage of both ethionamide and prothionamide is 500 to 

1,000 mg per day, divided into two doses. 1111 

The most important adverse drug event from thioamides are gastrointestinal 

disturbances and hepatotoxicity. 1112-1119 It also appears to potentiate 

the hypothyroid effect of para-aminosalicylic acid. Comparisons between 

ethionamide and prothionamide seem to indicate that the latter might be less 

toxic than the former, 1111,1120 though the difference might not be important. 

Although isoniazid and thioamide have the same parent compound, 

isonicotinic acid, isoniazid-resistant bacilli are often susceptible to ethionamide. 

1108 

Drugs and drug classes with potential activity against 

M. tuberculosis under investigation and development 

There can be little doubt about the necessity for the development of new 

anti-tuberculosis medications, given the limited amount of available 

choices. 1121 The Global Alliance for Tuberculosis Drug Development has 

161

published a scientific blueprint for drug development that should assist in 

overcoming some of the barriers that impede the development, testing, and 

marketing of new compounds. 1069 

Among the currently most promising candidates are long-acting 

rifamycins and fluoroquinolones (discussed above), oxazolidinone compounds, 

and nitroimidazopyrans. These and some other compounds under 

investigation are briefly summarized here. 

Acetamides 

Acetamides belong to a new class of compounds designed to inhibit the βketoacyl 

synthase reaction of fatty acid synthesis in mycobacteria. 1122 

Because of their specific target, they exhibit virtually no activity against 

microorganisms other than mycobacteria. The MICs of the most potent 

compounds compare to those obtained with the most efficacious first-line 

drugs. 1122 

Amoxicillin plus clavulanic acid 

M. tuberculosis possesses a beta-lactamase that might be responsible for its 

natural resistance to beta-lactam antibiotics. 1123-1125 Thus, beta-lactam antibiotics 

are essentially inactive against tubercle bacilli. Clavulanic acid is a 

beta-lactamase blocker and, if given simultaneously with amoxicillin, makes 

the latter active against beta-lactam producing microorganisms. This combination 

has also been proposed and used in the treatment of drug-resistant 

tuberculosis. 1126,1127 

Amoxicillin was synthesized in the Beecham Research Laboratories, 

patented in 1964, and described for the first time in 1970/71. 1128,1129 

The addition of clavulanic acid to amoxicillin has shown in vitro activity 

against M. tuberculosis. 1130-1133 Since then, several reports have appeared 

demonstrating successes in the treatment of patients with multidrug-resistant 

tuberculosis who also received amoxicillin plus clavulanic acid. 1134-1137 

The daily dosage might be 2 g of the combination. 402 

The most important adverse drug event seen with beta-lactam antibiotics 

are hypersensitivity reactions, which might be immediate (urticaria, 

laryngeal edema, bronchospasm, hypotension, or local swelling), late (morbilliform 

rashes, serum sickness, or urticaria), or other than late reactions 

(toxic epidermal necrolysis, interstitial nephritis, pulmonary infiltration, vasculitis, 

hemolytic anemia, neutropenia, or thrombocytopenia). 1138 

162

Clarithromycin 

Erythromycin, the prototype of the macrolide antibiotics, was first used to 

treat infections in 1952. 1139 

Clarithromycin is a macrolide that differs from erythromycin by the 

methylation of the hydroxyl group at position 6 on the lactone ring. 1140 

Clarithromycin has a wide anti-bacterial spectrum that includes 

mycobacteria. 1132,1139,1141-1147 Most frequently it has been used as prophylactic 

agent or against disease caused by M. avium complex. 1147-1154 While 

it shows in vitro activity against M. tuberculosis complex in human 

macrophages, 1145 the concentrations needed to inhibit growth appear to 

exceed those achievable in the serum and lung tissue of humans. 1155 It has 

therefore not been widely used in the treatment of tuberculosis. 

Clarithromycin is usually rapidly absorbed and reaches C max after two 

to three hours. 1140 Its serum elimination half life tβ 1/2 is 2.5 to 5 hours. 

It undergoes extensive hepatic metabolism. Because of its predominant 

renal excretion, dose adjustment might be necessary in patients with severe 

renal impairment. 1140 

Twice-daily 500 mg clarithromycin in AIDS patients was well tolerated, 

prevented M. avium complex disease and reduced mortality. 1148 In 

the treatment of M. avium complex disease, a dosage of twice daily 1,000 mg 

has been given. 1149,1156 

Fullerene derivatives 

Fullerenes show an absolute lack of solubility in any polar solvent, and 

covalent attachment of solubilizing chains was therefore developed, resulting 

in the formation of water-soluble fulleropyrrolidines. 1157 Certain such 

ionic fullerene derivatives have shown equally good activity against both 

susceptible and multidrug-resistant isolates of M. tuberculosis. 

Nitroimidazopyrans 

A series of nitroimidazopyrans, originally investigated as radiosensitizers 

for use in cancer chemotherapy, 1158 were shown to have in vitro and in 

vivo activity against M. tuberculosis. 1141,1159 However, the original compounds 

were shown to be mutagenic. 1160 Newer derivatives showed substantial 

activity against M. tuberculosis and lacked the mutagenicity shown 

previously with bicyclic nitroimidazoles. 1161 There is considerable in vivo 

activity in the mouse model against M. tuberculosis, which is comparable 

163

to that of isoniazid. 1162 It appears that the action is on both protein and 

lipid synthesis, 1161 inhibiting fatty acid and mycolic acid synthesis. 1163 

Similar to the nitroimidazoles (to which metronidazole belongs), nitrofurans 

show substantial in vitro bactericidal activity against bacilli held in 

a hypoxic stationary phase. 1164 

Because the recently synthesized nitroimidazopyran compound acts 

against multidrug-resistant tubercle bacilli, 1161 it might prove a valuable 

agent in the future. 

Oxazolidinones 

Oxazolidinones are a class of protein synthesis inhibitors and include linezolid 

and eperezolid. 1165,1166 

Oxazolidinones have promising activity against a range of microorganisms 

including, and other than, M. tuberculosis. 1166 

Oxazolidinones appear to inhibit a step in the protein synthesis. 1167 It 

has been proposed that they inhibit protein synthesis by binding to the 50S 

ribosomal subunit. 1168 

In experimental animals, oxazlidinones appear to be rapidly absorbed. 1166 

Paromomycin 

Paromomycin is an aminocyclosidic antibiotic complex, isolated from S. 

rimosus forma paromomycinus in 1959 in the Parke-Davies laboratories 1169 

in the same year as aminosidin was isolated from S. chrestomyceticus in 

the Farmitalia laboratories. It is also identical to catenulin, which was isolated 

from S. catenulae in 1952 in the Pfizer laboratories. Paromomycin 

is an antibiotic complex consisting of at least six antibiotics, and belongs 

to the neomycin family. 1170 

Its potential in the treatment of tuberculosis lies with the advantage 

that there is little cross-resistance with either streptomycin or with amikacin/ 

kanamycin. Its early bactericidal activity indicates that it is at least as 

effective as amikacin. 1171 Its toxicity (similar to that of neomycin) may, 

however, preclude its prolonged parenteral use. 

Phenothiazines 

Phenothiazines are derivatives of methylene blue and are used in the management 

of psychosis. Originally, Paul Ehrlich had reported that methylene 

blue immobilized bacteria, and their evaluation as potential antimicro- 

164

ial agents was thus only natural. 1172-1174 However, the concentrations 

needed to exert activity by far exceed what is achievable within the nontoxic 

range. The argument for considering phenothiazines for the treatment 

of tuberculosis stems from the fact that pulmonary macrophages concentrate 

chlorpromazine (the first phenothiazine developed) 100-fold above 

what is found in plasma, concentrations that are active against mycobacteria 

in vitro 1172 and in vivo. 1175 Thioridazine, a well tolerated phenothiazine, 

has been shown to be active against both susceptible and resistant tubercle 

bacilli. 1176-1178 Chlorpromazine has a titrable ability to slow the growth of 

intracellular tubercle bacilli in vitro. 1179 Phenothiazines have not yet been 

tested for their activity against tuberculosis in humans. 

Tuberactinomycin 

Tuberactinomycin, a polypeptide, was isolated in the Toyo Jozo research 

laboratories in Japan from Streptomyces griseoverticullatus var. tuberacticus 

in 1966. 1180 and was shown to be active against both kanamycin-susceptible 

and -resistant strains. 1181,1182 Tuberactinomycin-N was semisynthetically 

derived from this compound and found to have stronger 

antimycobacterial activity and to be associated with less ototoxicity. 1183,1184 

Its use has been largely limited to East Asia, where it was found to be a 

useful alternative to capreomycin in the treatment of multidrug-resistant, 

aminoglycoside-resistant tuberculosis. 

165

Appendix 3 

Current vaccine development strategies 

The incomplete protection that BCG provides against tuberculosis and its 

dismally disappointing effects in some areas have challenged researchers to 

develop a vaccine with better and more consistent performance. It is uncertain 

whether a much better vaccine can be developed in the near future, as 

the development of vaccines against bacteria that do not exert their pathogenicity 

through toxins has been fraught with difficulties. Vaccine development 

strategies currently being pursued include: 1185-1188 

• Immunotherapy; 

• Vaccination with saprophytic (environmental) mycobacteria; 

• Auxotrophs; 

• DNA vaccines; 

• Recombinants; 

• Subunits. 

Immunotherapy with M. vaccae 

M. vaccae is an environmental mycobacterium not known to cause disease 

in humans. A killed suspension of M. vaccae has been proposed, not to 

vaccinate against future tuberculosis, but to increase therapeutic response 

in the treatment of clinically manifest tuberculosis. 1189 

Numerous anecdotes have been published to illustrate its putative 

effects, but a clinical trial utilizing rigorous scientific standards has not 

shown any beneficial effect in addition to chemotherapy alone. 1190 Another 

controlled clinical trial indicates that immunotherapy with M. vaccae may 

be effective. In that trial, sputum culture conversion at one month (but 

not at two months) was significantly higher among persons receiving M. vaccae 

compared to controls. In addition, radiographic improvement was 

swifter. 1191 In yet another trial, no relevant differences during treatment 

and a four-year follow-up were found. 1192 

167

However, an effect is difficult to demonstrate in the case of fully drugsusceptible 

tuberculosis, which responds superbly to chemotherapy. What 

is perhaps needed is to study its value in the treatment of multiple drugresistant 

tuberculosis, where the unequivocal outcome of death is a frequent 

enough event to permit a more definitive evaluation of the claims for 

improved immunologic response. 

Vaccination with saprophytic (environmental) mycobacteria 

The experiments by Palmer and Long have shown that various species of 

environmental mycobacteria provide some protection against experimental 

tuberculosis, but to different degrees and never exceeding that of BCG. 826 

As mentioned above, the trial in the United Kingdom and the observations 

in Malawi have lent further credibility to the hypothesis that certain environmental 

species might offer some protection against tuberculosis. This 

line of experimentation has been further pursued and evidence accumulated 

that animals vaccinated with environmental mycobacteria have an increased 

resistance to a subsequent challenge with virulent tubercle bacilli compared 

to non-vaccinated animals. 828 So far, none of these vaccinations have been 

superior to BCG vaccination. 

Auxotrophs 

Another approach has been the development of so-called auxotrophic vaccines, 

where BCG and M. tuberculosis have been used to generate selected 

auxotrophs by insertional mutagenesis. 1185 The advantage of such a vaccine 

might be that it would gradually die in the host (an advantage in 

immunocompromised hosts) and that a weakened auxotrophic M. tuberculosis 

might be more immunogenic than BCG. 1185 However, survival time 

of the vaccine might be critical and has not yet been characterized sufficiently 

well to demonstrate superiority over BCG vaccination in experimental 

models, 1193 but certain mutations in genes involved in amino-acid 

biosynthesis have been promising in experimental models. 1194 

DNA vaccines 

Most efforts currently being undertaken are in the development of a DNA 

vaccine, 1195-1204 but none of the experimental models has yet shown superiority 

to BCG vaccine. There is, however, some experimental evidence that 

168

this type of vaccine may not only protect against subsequent infection with 

M. tuberculosis, but may stimulate the immune response even among experimental 

animals with active disease. 1205 There are indications that the combination 

of priming with a DNA vaccine followed by a booster with BCG 

might induce higher protective efficacy in mice than BCG vaccination 

alone. 1206 

Recombinants 

Recombinant vaccines use existing microorganisms, e.g., vaccinia viruses 1207 

or BCG, 1208,1209 which are genetically modified to produce additional antigens 

thought to enhance the immune response. 1185 This approach is fairly 

recent and needs further research, which will most likely be aided by the 

deciphering of the entire sequence of the M. tuberculosis genome. 1210 In 

vitro, BCG engineered to secrete recombinant human interferon-alpha was 

substantially more active than unaltered BCG in inducing interferon gamma 

in human peripheral blood mononuclear cells 1209 In a guinea pig model, 

such a recombinant vaccine was superior than two BCG strains in preventing 

gross lesions and dissemination. 1211 

Subunits 

Particular components (subunits) of M. tuberculosis may be better suited to 

inducing protective immunity than an entire organism. Recent research is 

thus evaluating the protective efficacy of such subunits. 1212 Preliminary 

experimental studies appear to be promising, providing protection similar 

to that obtained with BCG vaccination. 1213,1214 Subunits are potentially specific 

and safe. A disadvantage of subunit vaccines is their limited persistence 

and thus potentially reduced duration of immune response. 1215 In 

experimental mice models, re-challenge with a mycloyl transferase protein 

significantly boosted the protection against challenge with M. tuberculosis 

in animals whose immune protection had waned following BCG vaccination 

at birth. 1216 

169

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IMPRESSION, BROCHAGE 

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