Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis 2013 International Union Against Tuberculosis and Lung Disease Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis 2013 José A. Caminero, editor with contributions from Armand Van Deun Paula I. Fujiwara Ignacio Monedero Chen-Yuan Chiang Hans L. Rieder Anthony D. Harries Einar Heldal Arnaud Trébucq Edith Alarcón Raimond Armengol Cécile Macé Christophe Perrin Riitta A. Dlodlo Gilles Cesari Donald A. Enarson International Union Against Tuberculosis and Lung Disease This publication was made possible thanks to the support of MISEREOR and the U.S. Centers for Disease Control and Prevention’s Coordinating Offi ce for Global Health and National Center for HIV, Viral Hepatitis, STDs and TB Prevention Editor International Union Against Tuberculosis and Lung Disease (The Union) 68 boulevard St Michel, 75006 Paris, France Suggested citation Caminero JA, ed. Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis. Paris, France: International Union Against Tuberculosis and Lung Disease, 2013. First published online 22 March 2013; revised 6 May 2013. © International Union Against Tuberculosis and Lung Disease (The Union) 68 boulevard St Michel, 75006 Paris, France March 2013 All rights reserved. No part of this publication may be reproduced without the permission of the authors and publisher. ISBN: 979-10-91287-03-6 Contents Abbreviations ix 1 Justifi cation for the Guidelines 1 Justifi cation for the Guidelines: drug-resistant tuberculosis can be cured 1 The challenge of a new epidemic and the lack of anti-tuberculosis medicines 2 Lack of evidence in drug-resistant tuberculosis clinical and operational management 4 Objectives of the Guidelines 4 References 5 2 Historical background and global epidemiology of Mycobacterium tuberculosis resistance 7 Historical background of anti-tuberculosis drug resistance 7 Surveillance of anti-tuberculosis drug resistance 9 Distribution and determinants of anti-tuberculosis drug resistance 10 References 11 3 Basic concepts and defi nitions of drug resistance in tuberculosis 13 Biological characteristics of Mycobacterium tuberculosis 14 Basic concepts of resistance 15 Defi nitions of drug resistance in tuberculosis 16 Emerging drug resistance in Mycobacterium tuberculosis 19 Genetic markers of resistance to anti-tuberculosis drugs 21 Transmissibility and reproductive fi tness of resistant Mycobacterium tuberculosis 23 References 24 4 Building a tuberculosis programme that addresses drug resistance 27 Minimum requirements for the diagnosis of drug-resistant tuberculosis 28 Minimum requirements for the treatment of patients with drug-resistant tuberculosis 30 iv CONTENTS Cost of services and how to budget for them 32 Training and supervision in drug-resistant tuberculosis patient management 34 Framework for effective drug-resistant tuberculosis control: the Green Light Committee and other international alliances 36 References 37 5 How drug resistance affects tuberculosis treatment outcome and monitoring parameters 39 Effect of drug resistance on treatment outcome 39 Effect on treatment monitoring parameters 42 References 45 6 High-risk groups for drug-resistant tuberculosis 47 Case fi nding and prioritisation of interventions 47 Failures, bacteriological relapses, defaulters and the dangers of poor adherence 51 References 52 7 Laboratory diagnosis and treatment monitoring of drug-resistant tuberculosis 55 Diagnosis 56 Treatment monitoring 66 References 69 8 Principles of treatment for susceptible and drug-resistant tuberculosis 71 Introduction: brief historical review of anti-tuberculosis chemotherapy 72 Bacteriological bases for the treatment of tuberculosis, including drug-resistant tuberculosis 73 Core versus companion drugs in the intensive and continuation phases 79 Rationale for an ideal initial treatment regimen 80 Rationale for an ideal drug-resistant tuberculosis treatment regimen 84 Conclusions 96 References 98 9 Anti-tuberculosis drugs: mechanisms of action and rationale for use 99 Introduction 100 Anti-tuberculosis drugs: mechanisms of action 101 CONTENTS v Role of fi rst-line oral anti-tuberculosis drugs in the management of drug-resistant tuberculosis 101 Fluoroquinolones: mechanism of action and role in the treatment of drug-resistant tuberculosis 107 Injectable anti-tuberculosis drugs: mechanism of action and role in the treatment of drug-resistant tuberculosis 109 Group 4—thioamides, cycloserine/terizidone and p-aminosalicylate: mechanism of action and ideal sequence of introduction in a drug-resistant tuberculosis regimen 111 Most effective drugs in Group 5 and recommended sequence of use 113 Cross-resistance among anti-tuberculosis drugs 116 Potential new drugs for drug-resistant tuberculosis treatment 116 New drugs from already known families 118 Conclusions 119 References 119 10 Adverse reactions to anti-tuberculosis drugs: practical approaches and appropriate management 121 Introduction 121 Adverse reactions to fi rst-line anti-tuberculosis drugs 122 Adverse reactions to second-line anti-tuberculosis drugs 124 Initiation of multidrug-resistant tuberculosis treatment 127 Monitoring of adverse drug reactions 128 Management of adverse drug reactions 129 References 130 11 Drug-resistant tuberculosis and human immunodefi ciency virus: update and management 133 Drug-resistant tuberculosis and HIV: reasons for and consequences of association of the two diseases 133 Drug-resistant tuberculosis and HIV: clinical facts and typical and atypical tuberculosis presentation 134 Diagnosing tuberculosis and drug-resistant tuberculosis in persons living with HIV 135 Management of HIV-positive patients with drug-resistant tuberculosis 136 Problems with co-treatment 138 Collaborative TB/HIV activities 143 References 145 12 Management of drug-resistant tuberculosis in special situations 147 Drug-resistant tuberculosis management during pregnancy 147 Drug-resistant tuberculosis management in diabetes mellitus patients 154 vi CONTENTS Drug-resistant tuberculosis management: other frequent co-morbidities 156 References 159 13 An optimised cascade of treatment regimens 161 Defi nitions 161 Rationale for a cascade of treatment regimens 162 Principles for the choice of fi rst-line drug regimens 163 Daily versus intermittent treatment 164 Special situations in the treatment of tuberculosis 164 Second-line treatment regimens 166 Third-line treatment regimens for multidrug-resistant tuberculosis 168 Remaining issues 171 References 173 14 Tuberculosis infection control: minimal requirements given limited resources 177 Introduction 177 Basic concepts regarding the propagation of Mycobacterium tuberculosis 179 Administrative control measures 181 Environmental control measures 184 Respiratory protection and personal protection measures 186 Monitoring and evaluation of infection control activities 187 Monitoring of latent tuberculosis infection and tuberculosis disease among health-care workers 187 References 188 15 Treatment delivery and adherence: organising ambulatory directly observed treatment and social support 191 Introduction 191 What is directly observed treatment and why is it important? 192 What are the modalities of directly observed treatment? 193 What knowledge must the directly observed treatment support person have? 194 What factors affect adherence to treatment? 195 What interventions can improve adherence? 196 Organisation of supervised treatment 198 Factors that favour adherence to treatment 200 Infection control in the drug-resistant tuberculosis patient’s home 200 Strategies to improve adherence 201 Indicators used to assess treatment adherence 202 References 202 CONTENTS vii 16 Monitoring and evaluation of drug-resistant tuberculosis management 205 Introduction and objectives 206 Indicators 207 Defi nitions 207 What records are necessary for multidrug-resistant tuberculosis patient management? 210 How are results reported? 213 How are data tabulated, assessed and used to facilitate and improve management of multidrug-resistant tuberculosis in the future? 215 References 225 17 Management of second-line medicines for tuberculosis treatment 227 Introduction 227 Selection of medicines to treat drug-resistant tuberculosis patients 227 Quantifi cation 228 Procurement of drug-resistant tuberculosis medicines 229 Quality assurance of drug-resistant tuberculosis medicines purchased 229 Prices of drug-resistant tuberculosis medicines 230 Importation of drug-resistant tuberculosis medicines 231 Storage and distribution in-country 231 Rational use 231 References 232 Appendices 233 Abbreviations 2LI second-line injectable drug AFB acid-fast bacillus Am amikacin Amx/Clv amoxicillin/clavulanate ART antiretroviral therapy ARV antiretroviral (drug) ATS American Thoracic Society AUC24 area under the concentration-time curve from 0 to 24 h BTS British Thoracic Society CD4 cells CD4+T lymphocytes Cf clofazimine Cfx ciprofl oxacin Cm capreomycin CPC cetylpyridinium chloride Cs cycloserine DALY disability-adjusted years of life DM diabetes mellitus DOT directly observed treatment DOTS originally an acronym for directly observed treatment, short course, DOTS became the term used to describe the tuberculosis control strategy recommended by the WHO DR-TB drug-resistant tuberculosis DST drug susceptibility testing E ethambutol EBA early bactericidal activity Eth ethionamide FDA fl uorescein diacetate used for vital staining FDC fi xed-dose combination FLD fi rst-line drug FQ fl uoroquinolone GDF Global