Antituberculosis Chemotherapy
Progress in Respiratory Research Vol. 40 Series Editor Chris T. Bolliger Cape Town
Antituberculosis Chemotherapy Volume Editors Peter R. Donald Tygerberg Paul D. van Helden Tygerberg 53 figures, 2 in color, 50 tables, 2011 Basel Freiburg Paris London New York New Delhi Bangkok Beijing Tokyo Kuala Lumpur Singapore Sydney
Prof. Dr. Peter R. Donald Desmond Tutu Tuberculosis Centre Department of Paediatrics and Child Health Faculty of Health Sciences Stellenbosch University PO Box 19063 Tygerberg 7505 (South Africa) Prof. Dr. Paul D. van Helden Director DST/NRF Centre for Excellence for Biomedical Tuberculosis Research MRC Centre for Molecular and Cellular Biology Division of Molecular Biology and Human Genetics Faculty of Health Sciences Stellenbosch University PO Box 19063 Tygerberg 7505 (South Africa) Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents. Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 2011 by S. Karger AG, P.O. Box, CH 4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel ISSN 1422 2140 ISBN 978 3 8055 9627 5 e-isbn 978 3 8055 9628 2
Contents Foreword Preface VII VIII Retrospectoscope Chapter 1 History of Drug Discovery: Early Evaluation Studies and Lessons Learnt from Them 2 Ahmad, Z. (Baltimore, Md./Srinagar); Makaya, N.H.; Grosset, J. (Baltimore, Md.) Chapter 2 Tuberculosis Treatment Trials Past and Present: Old and New Challenges 10 Nunn, A. (London) Present Treatment Chapter 3 The Rifamycins: Renewed Interest in an Old Drug Class 18 Burman, W. (Denver, Colo.); Dooley, K.E.; Nuermberger, E.L. (Baltimore, Md.) Chapter 4 Isoniazid Pharmacokinetics and Efficacy in Adults and Children 25 Donald, P.R.; Schaaf, H.S. (Tygerberg) Chapter 5 Recent Developments in the Study of Pyrazinamide: An Update 32 Mitchison, D.A. (London); Zhang, Y. (Baltimore, Md.) Chapter 6 Experience with Phase III Clinical Trials of Antituberculosis Drugs and Regimens: Conclusions and Lessons for the Future 44 Jindani, A. (London) Chapter 7 Fluoroquinolones in the Management of Tuberculosis 51 Singh, K.P. (London); Gillespie, S.H. (St. Andrews) Chapter 8 Current Standard Treatment 61 Vernon, A.A. (Atlanta, Ga.) Chapter 9 Tuberculosis Recurrence: Exogenous or Endogenous? 73 Williams, M.; Müller, B.; Uys, P.; Victor, T.C.; Warren, R.M.; Gey van Pittius, N.C. (Tygerberg) Chapter 10 Second-Line Antituberculosis Drugs: Current Knowledge, Recent Research Findings and Controversies 81 Schaaf, H.S. (Tygerberg); Seddon, J.A. (Tygerberg/London); Caminero, J.A. (Las Palmas/Paris) V
Chapter 11 Acquisition, Transmission and Amplification of Drug-Resistant Tuberculosis 96 Müller, B.; Warren, R.M.; Williams, M. (Tygerberg); Böttger, E.C. (Zürich); Gey van Pittius, N.C.; Victor, T.C. ( Tygerberg) Chapter 12 The Treatment of Tuberculosis in Children 105 Cruz, A.T.; Starke, J.R. (Houston, Tex.) The Future Chapter 13 Issues and Challenges in the Development of Novel Tuberculosis Drug Regimens 118 Erondu, N.; Ginsberg, A. (New York, N.Y.) Chapter 14 Drug Resistance in Mycobacterium tuberculosis: Molecular Mechanisms and Laboratory Susceptibility Testing 128 Böttger, E.C. (Zürich) Chapter 15 The Role of the Mouse Model in the Evaluation of New Antituberculosis Drugs 145 Nuermberger, E.L. (Baltimore, Md.) Chapter 16 Current Issues in Tuberculosis Pharmacokinetics 153 Egelund, E.F.; Peloquin, C.A. (Gainesville, Fla.) Chapter 17 Pharmacological Considerations of Antitubercular Agents in Children 161 Goldman, J.L.; Kearns, G.L.; Abdel-Rahman, S.M. (Kansas City, Mo.) Chapter 18 Pharmacogenetics of Antituberculosis Drugs 176 Aarnoutse, R. (Nijmegen) Chapter 19 Interactions between Antituberculosis and Antiretroviral Agents 191 McIlleron, H. (Cape Town); Khoo, S.H. (Liverpool) Chapter 20 Diabetes Mellitus and Tuberculosis Treatment 203 Ruslami, R. (Bandung); van Crevel, R. (Nijmegen) Chapter 21 Early Bactericidal Activity of Antituberculosis Agents 213 Diacon, A.H.; Maritz, J.S.; Donald, P.R. (Cape Town) Chapter 22 Assessment of Whole-Blood Bactericidal Activity in the Evaluation of New Antituberculosis Drugs 220 Wallis, R.S. (Groton, Conn.) Chapter 23 Serial Sputum Colony Counting in Drug Development 227 Sloan, D.; Davies, G. (Liverpool) Chapter 24 The Evaluation of New Antituberculosis Drugs in Children 235 McNeeley, D.F. (Arlington, Va.); Raoof, A. (Beerse); Lin, J. (Titusville, N.J.); Marais, B.J. (Tygerberg) Chapter 25 A New Era in Tuberculosis Treatment: What Does the Future Hold? 243 Duncan, K. (Seattle, Wash.) Author Index 247 Subject Index 248 VI Contents
Foreword As series editor of Progress in Respiratory Research, it has always been my aim to cover the complete field of diseases of the chest which involve the lung. Up to now we have had many different topics but there has been one big gap concerning infectious diseases. Practising in Cape Town for more than a decade, I enjoy many fantastic aspects of the mother city of South Africa, but sadly I am also acutely aware that Cape Town is also known as the tuberculosis capital of the world. Tuberculosis together with HIV is one of the top medical priorities of South Africa, but this is also true for many developing countries, a fact which is often ignored in first- world set- ups. In the modern, extremely mobile world, it is however of great importance to follow global trends in communicable diseases closely, as air travel can spread highly infectious agents quickly or change the approach to treatment drastically, as recently shown with the emergence of multidrug resistance or even extremely resistant tuberculous strains. Luckily we have many leading researchers in the field of tuberculosis in South Africa, and the team at the Faculty of Health Sciences, University of Stellenbosch, is arguably one of the leading tuberculosis research set- ups on a global level. This is true for clinical as well as for basic science. It was therefore a logical choice for me to ask two eminent senior researchers from my own faculty to compile a volume for the blue series on drug therapy of tuberculosis. Professors Peter Donald and Paul van Helden assembled some of the best- known specialists in the field and were instrumental to cover all aspects of modern antituberculous chemotherapy, as they explain in their preface following this foreword. Once again the main people responsible at the publishing house S. Karger AG, Basel, were Linda Haas and Stefan Sessler, who helped processing the various chapters, but also reminded some authors of delayed submissions to speed up delivery. Their input greatly facilitated the volume editors and my task to come up with the finished product on time. The final product is a must for all involved in the treatment of tuberculosis irrespective of whether one lives in highly industrialized or emerging countries: tuberculosis is of importance to all. C.T. Bolliger, Cape Town VII
Preface Drugs for the treatment of tuberculosis have been available for nearly 60 years, and yet tuberculosis remains one of the major infectious diseases of mankind causing immeasurable suffering and mortality, and placing an enormous financial burden on countries and individuals. Since approximately 1980, short- course 6- month treatment regimens based on the use of isoniazid, rifampicin and pyrazinamide have been available and used extensively throughout the world to successfully treat millions of tuberculosis patients. Nonetheless, despite this long usage, it is clear that our understanding of these drugs and their optimal use is deficient in many respects. Part of the reason for this is the lack of interest in tuberculosis as a rewarding and stimulating research subject that followed the successful introduction of these drugs and the resulting lack of younger researchers entering the tuberculosis field. Under the influence of HIV and its devastating interaction with tuberculosis, this has changed over the last 2 decades with increasing interest in tuberculosis research and the development of a number of promising new candidate antituberculosis drugs. It used to be remarked that knowledge of syphilis would lead one into knowledge of every important aspect of medicine; perhaps this role is now being fulfilled by tuberculosis? Within the field of tuberculosis almost every aspect of the medical sciences is covered from sociology and human behaviour to the very foundations of the immune response. This volume reviews one aspect of tuberculosis and is devoted to the field of tuberculosis chemotherapy with the emphasis on new developments regarding our existing drugs and the prospects for the introduction of new drugs and their evaluation. However, there is also still much to be learnt from experience with our existing drugs, and in compiling this volume we have not hesitated to look over our shoulders at experience with the evaluation and clinical use of existing drugs in the past. The most appropriate pathway to evaluate new antituberculosis drugs and regimens remains uncertain so that several of the methodologies currently in use are reviewed, and we hope that this will generate more discussion of these important subjects. Our current essential drugs isoniazid, rifampicin and pyrazinamide are likely to remain in use for the foreseeable future, and aspects of their optimal use are discussed. Drug resistance remains an everpresent threat to patients and tuberculosis control programmes. As this volume demonstrates, the discovery, development and evaluation of antituberculosis drugs make a lengthy process, and we cannot allow our new drugs to follow the same path to resistance that has befallen our current drugs in many parts of the world. Several papers thus address the problems associated with drug resistance, its spread and diagnosis. Lastly childhood tuberculosis has recently been recognized as an important, but neglected, part of the tuberculosis problem; the pharmacokinetics and toxicity of antituberculosis agents in children can differ significantly from that in adults and may require adjustments in dosages to ensure an optimal safe and effective therapy in children with tuberculosis. Some of these issues and the evaluation of antituberculosis drugs in children are discussed by experts in the field of paediatric pharmacokinetics. As editors we must offer our sincere thanks to our colleagues who have contributed so generously of their time VIII
Peter R. Donald Paul D. van Helden and expertise in helping compile this volume; as academics we are only too aware of the pressures of time and the time it takes to write a paper. Finally we appreciate the willingness of the publishers to accept our proposal of antituberculosis chemotherapy as a suitable subject to review in the belief that this can increase the dissemination of new knowledge about this important subject and so contribute to the better management of tuberculosis throughout the world. Peter R. Donald, Paul D. van Helden, Tygerberg Preface IX