Multidrug-resistant Tuberculosis

Resurgent and Emerging Infectious Diseases Volume 1

Multidrug-resistant Tuberculosis Edited by

Ivan Bastian Mycobacterium Reference Laboratory, Institute of Medical & Veterinary Science, Adelaide, Australia

and

Franchise Portaels Mycobacteriology Unit, Institute of Tropical Medicine, Antwerp, Belgium

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SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.

A C L P . Catalogue record for this book is available from the Library of Congress.

I S B N 978-94-010-5794-3 I S B N 978-94-011-4084-3 (eBook) DOI 10.1007/978-94-011-4084-3

Printed on acid-free paper

A l l Rights Reserved © 2000 Springer Science+Business Media Dordrecht Originally published by Kluwer Academic Publishers in 2000 No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner.

This book is dedicated to all those suffering from tuberculosis, who battle with body and spirit against the disease. Among these are the patients,

particularly those in penitentiary hospitals in Siberia, who watch helplessly as their illness is rendered more severe, and often fatal, under the weight of

multidrug-resistance.

This book also recognises the players in the fight against tuberculosis: the doctors and nurses, health professionals, researchers, and laboratory

personnel.

Lastly, IB would like to thank Stephanie, who left home for two years though she didn't know why,

and Carmela, who knew why but still came.

During the preparation of this book, Ivan Bastian was supported by a Neil Hamilton Fairley Fellowship (987069) from the National Health and Medical Research Council of Australia.

Many of the contributors to this book participated in a Colloquium entitled "Tuberculosis, the real millennium bug: addressing the threat in developing and industrialised countries", which was held in Antwerp between 14-17 December 1999 through the auspices of the Institute of Tropical Medicine.

The word of a woman seems simple enough But nothing is ordinary Upon reflection, we see that it is sacred It radiates the joy of the world

Most things in life are sacred Many people kneel before the Gods I wish for you a simple happiness And that your dreams come true often

The sun comes and goes Thank you for your aid You see, we are given but one life

The entire world is shroud in a thick smoke It is a bad omen But we must believe in the forces of good If we are to protect our house

From so far away You came to our side You saved us from death And we kneel before you F or life is a precious gift from God

Written by a tuberculosis patient in a penitentiary hospital in Siberia

Translatedfrom Russian by A Disu and B Antoine

Table of Contents

Chapter 1 - Introduction 1 1. Bastian and F. Portaels 1. Historical perspective 1 2. The Definition ofMRTB 4

2.1 Rationale for the current definition ofMDRTB 5 2.2 Importance of a strict definition for MDRTB 6

3. Virulence and other questions about MDRTB 7 4. MDRTB in the present and future 9 5. "The perfect expression of our imperfect civilization" 11

References 12

Chapter 2 - The epidemiology of multidrug-resistant tuberculosis 17 in the United States and other established market economies

M. Moore, E. McCray and 1. M. Onorato 1. Introduction 17 2. Emergence ofMDRTB in the United States 18 3. Trends in TB in the United States, 1992-1998 19 4. MDRTB in the United States, 1993-1998 21 5. MDRTB in other established market economies 24 6. Lessons learned 24

References 26

Chapter 3 - Epidemiology of multidrug-resistant tuberculosis in 29 low- and middle-income countries

M. A. Espinal 1. Introduction 29 2. Transmission dynamics ofMDRTB 30 3. Assessment ofMDRTB prevalcence 32 4. Magnitude ofMDRTB problem 33

4.1 Africa 33 4.2 Latin America 35 4.3 Asia 36 4.4 Eastern Europe 37

5. Concluding remarks 40 Acknowledgments 40 References 40

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Chapter 4 - The interaction of human immunodeficiency virus and 45 multidrug-resistant Mycobacterium tuberculosis

E. McCray and 1. M. Onorato 1. Introduction 45 2. Trends in MDRTB and HIV co-infection, 46

and characteristics ofMDRTB patients with HIV infection in the United States, 1993-1997

3. Outbreaks ofMDRTB involving HIV-infected patients 48 4. Association of HI V and TB co-infection with acquired 50

drug resistance 5. Summary and conclusions 52

References 52

Chapter 5 - Clinical mismanagement and other factors producing 59 antituberculosis drug resistance

A. Pablos-Mendez and K. Lessnau 1. The genesis of anti-tuberculosis drug resistance 59 2. Clinical mismanagement producing drug resistance 61

2.1 Delayed diagnosis and isolation 62 2.2 Inappropriate drug regimens 63

2.2.1 Inadequate initial therapy 63 2.2.2 Premature cessation of treatment 64 2.2.3 Inappropriate treatment modifications when 65

complications arise 2.2.4 Adding a single drug to a failing regimen 65 2.2.5 Failure to adjust preventive therapy 65

2.3 Poor treatment adherence and incomplete follow-up 66 3. Programmatic factors associated with drug resistance 67

3.1 Use of treatment regimens other than standardized 68 short-course chemotherapy (SCC)

3.2 Failure to employ direct observation of treatment 68 3 .3 Availability of antituberculosis drugs over the counter 69

and in fixed dose combinations 3.4 Failure to isolate MDRTB patients 70

4. Conclusions 70 References 71

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Chapter 6 - The molecular mechanisms of drug resistance in 77 Mycobacterium tuberculosis

H. E. Takiff 1. Introduction 77 2. Isoniazid resistance 79

2.1 The catalase/peroxidase, KatG 79 2.2 InhA, KasA, and AcpM 80 2.3 OxyR and regulators of the peroxide response 82

3. Pyrazinamide 84 4. Ethambutol 86 5. Rifampicin 87 6. Streptomycin 90 7. Fluoroquinolones 92 8. Kanamycin and amikacin, viomycin and capreomycin 96 9. Cycloserine 98 10. Conclusion 99

Acknowledgments 100 References 100

Chapter 7 - DOTS and multidrug-resistant tuberculosis 115 M. C. Raviglione 1. Introduction 115 2. DOTS: Current Status of tuberculosis control 116

achievements world-wide 3. The drug resistance situation world-wide 4. Evidence that DOTS prevents MDRTB 5. Can MDRTB be eliminated as a public health

problem by DOTS? 6. Elimination ofMDRTB 7. Adapting DOTS to high MDRTB burden settings:

research issues 8. Conclusion

Acknowledgments References

118 119 121

125 127

128 129 129

Chapter 8 - Conventional methods for antimicrobial susceptibility 133 testing of Mycobacterium tuberculosis

L. Heifets 1. Introduction 2. General principles of a drug susceptibility test

133 134

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3. Drug susceptibility tests using egg-based medium 135 3.1 The original proportion method (simplified variant) 135 3.2 The resistance ratio (RR) method 136 3.3 The absolute concentration method 137

4. Direct and indirect tests using 7HI017Hll Agar 138 4.1 Original CDC version 138 4.2 Disc version of the proportion method 139 4.3 National Jewish modification of the proportion method 139

5. Indirect test in liquid medium (BACTEC® method) 139 6. Conclusions 141

References 142

Chapter 9 - Novel rapid antimicrobial susceptibility tests for 145 Mycobacterium tuberculosis

1. C. Palomino 1. Introduction 145 2. Novel genotypic techniques 146

2.1 Automated DNA sequencing 146 2.2 PCR-single strand conformation polymorphism 147

(PCR-SSC) 2.3 PCR-heteroduplex formation (PCR-HDF) 147 2.4 Solid phase hybridization assay 148 2.5 Emerging new technologies for rapid detection 149

ofMDRTB 2.5.1 DNA microarrays 149 2.5.2 Reporter systems 149 2.5.3 Miscellaneous genotypic techniques 150

3. Novel phenotypic techniques 151 3.1 Myobacteria growth indicator tube (MGIT) 151 3.2 The PhaB assay 152 3.3 E-test 152 3.4 Rapid metabolic tests 153 3.5 Microcolony detection method 154 3.6 Miscellaneous phenotypic procedures 154

4. Conclusions 155 References 156

Chapter 10 - Pharmacology of the second-line antituberculosis 163 drugs

C. A. Peloquin and B. Auclair 1. Introduction 163 2. Aminoglycosides and polypeptides 163

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3. Clofazimine 165 4. Cycloserine 166 5. Ethionamide 167 6. Fluoroquinolones 168 7. Para-aminosalicylic acid 170 8. Other drugs 171 9. Therapeutic drug monitoring 172 10. Summary 172

References 172

Chapter 11 - Treatment of multidrug-resistant tuberculosis 175 M D. Iseman and G. A. Huitt 1. Introduction 175 2. Inadequate treatment programs and acquired 176

drug resistance 3. Biologic mechanisms of resistance 176 4. Current epidemiology of resistance 177 5. Effects of drug resistance on treatment outcome 178

5.1 HIV -negative immunocompetent patients 178 5.2 Patients with HIV-infectioniAIDS/Immunosuppression 179

6. Implications of multi drug resistance for initial therapy 179 7. Treatment of patients with multidrug-resistant tuberculosis 180

7.1 Initiation of retreatment for MDRTB 181 7.2 Drugs used in retreatment regimens 182 7.3 Monitoring re-treatment 183 7.4 The role of resectional surgery 184 7.5 What to do in cases of ultimate treatment failure? 185

8. Prevention of tuberculosis in the contacts ofMDRTB 185 patients

9. Summary 186 References 187

Chapter 12 - Treatment of multidrug-resistant tuberculosis in 191 developing countries

1. Crofton and A. Van Deun 1. Introduction 191 2. Causes ofMDRTB in developing countries 191 3. The extent ofMDRTB in developing countries 192 4. Misdiagnosis ofMDRTB 193 5. Particular problems in developing countries 193 6. Potential approaches to the problem 194

6.1 The individualised approach 194 6.2 The standardised approach 195

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7. Appropriate contexts for MDRTB treatment programmes 198 7.1 Countries with successful DOTS programmes and low 198

MDRTBrates 7.2 Countries with recently-introduced, effective DOTS 199

programmes 7.3 The former Soviet Union 200 7.4 Countries with high MDRTB rates and no DOTS 200

programme 8. Surgery for MDRTB cases 201 9. Conclusions 201

References 201

Chapter 13 - Treatment of outcome of multidrug-resistant 205 tuberculosis

E. E. Telzak 1. Introduction 205 2. HIV -negative patients 206 3. HIV-positive patients 208 4. Recommendations for empiric treatment 209 5. Conclusion 210

References 210

Chapter 14 - Chemoprophylaxis and BCG in contacts of multidrug- 213 resistant tuberculosis

R. A. Stapledon, R. Lumb and 1. S. Lim 1. Introduction 2. Prevention and control of tuberculosis 3. Chemoprophylaxis

3.1 Rationale 3.2 Treatment of drug susceptible TB infection 3.3 HIV and TB co-infection 3.4 Chemoprophylaxis for drug-resistant TB 3.5 Drug options 3.6 Limitations

4. Bacille Calmette Guerin 5. Summary

Acknowledgment References

213 214 214 214 215 215 216 217 218 218 221 221 221

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Chapter 15 - Multidrug-resistant tuberculosis and the health care 225 worker

D. M. Weinstock and K. A. Sepkowitz 1. Introduction 225 2. Outbreaks of nosocomial MDRTB involving 226

HCWs: what is known 3. Preventing active MDRTB among HCWs: BCG 230

versus TST screening and prophylactic therapy 4. Managing the HCW after exposure to MDRTB 232 5. Prophylaxis of the HCW exposed to MDRTB 232 6. Furloughing the HCW with active MDRTB 233 7. Addressing HCW concerns over MDRTB 234 8. Conclusions 235

References 235

Chapter 16 - The development of new chemotherapeutics for 241 multidrug-resistant tuberculosis

C. E. Barry 1. Introduction 241 2. The near end of the pipeline: semisynthetic derivatives 242

of rifamycin for the treatment of multidrug-resistant tuberculosis

3. Targeting latent organisms-metronidazole and beyond 243 4. The trouble with prodrugs 244 5. The deep end of the dream pool; a new paradigm for 246

drug development 6. Conclusion 248

References 249

Chapter 17 - Population dynamics and control of multidrug- 253 resistant tuberculosis

C. Dye and B. G. Williams 1. Introduction 253 2. A mathematical model for MDR 254 3. Dynamics and control ofMDR 258 4. Conclusions 264

Acknowledgements 266 References 266

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Chapter 18 - Administrative, engineering, and personal protective 269 measures for controlling Mycobacterium tuberculosis

C. Richards and W R. Jarvis 1. Introduction 269 2. Health care facility risk assessment 270 3. Administrative measures 270

3.1 Infection control plan 271 3.2 Early identification and diagnosis 271

3.2.1 Specimen collection 272 3.2.2 Ambulatory settings 272

3.3 Patient isolation 274 3.4 Healthcare worker education and training 274 3.5 Health care worker counselling and screening 275 3.6 Cough induction 275 3.7 Discharge planning 275 3.8 Program evaluation 276

4. Engineering controls 276 4.1 Ventilation 276

4.1.1 Local exhaust ventilation 276 4.1.2 General ventilation 277

4.2 HEP A filtration 278 4.3 Ultraviolet germicidal irradiation 278

5. Personal respiratory protective devices 279 5.1 Respirator's performance criteria 279 5.2 Specific respirators 279 5.3 Effectiveness 279

6. Effectiveness and adoption of TB control practices 280 7. Costs of TB control practices 281 8. Special challenges in limited resource regions 282

and countries 282 9. Summary and conclusions 282

References 283

Chapter 19 - Making DOTS-Plus work 285 P. E. Farmer, S. S. Shin, J. Bayona, J. Y. Kim, J. J. Furin and J. G. Brenner 1. Introduction 285 2. What is DOTS-plus? 286 3. Political commitment 288

3.1 The additional costs of treating MDRTB 289 3.2 Strict control of second-line drugs 289 3.3 Expansion ofTB control initiatives 290

4. The role of reference laboratories 4.1 Drug resistance surveillance

5. Procurement of second-line antituberculous drugs 5.1 Inclusion of second-line drugs on the WHO

Essential Drugs List 5.2 Pooled procurement of second-line drugs

6. The importance of directly observed therapy 7. Evaluating DOTS-plus efforts 8. Conclusions: from DOTS to DOTS-plus and back again

References

Index

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290 291 294 295

296 297 298 301 302

307