Please go to the Table of Contents page to access the entire publication.

World Health Organization

Geneva 2004

ANTI-TUBERCULOSIS
DRUG RESISTANCE
IN THE WORLD
Third Global Report

The WHO/IUATLD Global Project on Anti-tuberculosis

Drug Resistance Surveillance
1999-2002
WHO Library Cataloguing-in-Publication Data

WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance.

Anti-tuberculosis drug resistance in the world: third global report/
the WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance
Surveillance, 1999-2002.

1.Tuberculosis, Multidrug-resistant - epidemiology 2.Drug resistance, Bacterial - statistics

3.Bacteriological techniques 4.Data collection - methods
5.Cross-sectional studies I.Title.

ISBN 92 4 156285 4 (NLM classification: WF 360) WHO/HTM/TB/2004.343

© World Health Organization 2004

All rights reserved. Publications of the World Health Organization can be obtained from Marketing
and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland
(tel: +41 22 791 2476; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission
to reproduce or translate WHO publications – whether for sale or for noncommercial distribution
– should be addressed to Marketing and Dissemination, at the above address (fax: +41 22 791 4806;
email: permissions@who.int).

The designations employed and the presentation of the material in this publication do not imply
the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the delimi-
tation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for
which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that
they are endorsed or recommended by the World Health Organization in preference to others of
a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary
products are distinguished by initial capital letters.

All reasonable precautions have been taken by WHO to verify the information contained in this pu-
blication. However, the published material is being distributed without warranty of any kind, either
express or implied. The responsibility for the interpretation and use of the material lies with the
reader. In no event shall the World Health Organization be liable for damages arising from its use.

Designed and typeset in Italy

Printed in Singapore
WRITING COMMITTEE

Written by:
• Mohamed Abdel Aziz, M.D., M.P.H., M.B.T.Sc.,World Health Organization, Geneva,
Switzerland
• Abigail Wright, M.P.H., World Health Organization, Geneva, Switzerland
• Aimé De Muynck, Ph.D., M.D., M.P.H., M.Sc., Consultant, World Health
Organization, Geneva, Switzerland
• Adalbert Laszlo, Ph.D., World Health Organization, Geneva, Switzerland

With the contribution of:

• Françoise Portaels, Ph.D., Prince Léopold Tropical Institute Antwerp, Belgium
• Hans L. Rieder, M.D., M.P.H., International Union Against Tuberculosis and Lung
Disease (The UNION), Kirchlindach, Switzerland
• Andrea Infuso, M.D., EuroTB, Institut de Veille Sanitaire, Saint-Maurice, France
• Armand Van Deun, M.D., Prince Léopold Tropical Institute, Antwerp, Belgium
• Andrea Luna, M.D., M.P.H., Instituto de Salud Pública de Chile, Santiago, Chile
• Sabine Rüesch-Gerdes, Ph.D., National Reference Centre for Mycobacteria, Borstel,
Germany
• Karin Weyer, DSc., Medical Research Council, Pretoria, South Africa
• Francis Drobniewski, Ph.D. Health Protection Agency, Mycobacterium Reference
Unit, London, UK
• Rose Liefooghe, M.Sc. Consultant, World Health Organization, Geneva, Switzerland
• Charles Wells, M.D., Division of TB Elimination, Centers for Disease Control and
Prevention (CDC), Atlanta, GA, USA
• Brian Williams, Ph.D., World Health Organization, Geneva, Switzerland
• Kitty Lambregts, M.D., Ph.D., World Health Organization, Geneva, Switzerland
• Malgorzata Grzemska, M.D., Ph.D., World Health Organization, Geneva,
Switzerland
• Paul Nunn, M.D., World Health Organization, Geneva, Switzerland
• Marcos Espinal, M.D., Dr.P.H., M.P.H., World Health Organization, Geneva,
Switzerland
• Leopold Blanc, M.D., M.P.H., World Health Organization, Geneva, Switzerland
• Christopher Dye, DPhil, World Health Organization, Geneva, Switzerland
• Mario Raviglione, M.D., World Health Organization, Geneva, Switzerland
GLOBAL NETWORK OF SUPRANATIONAL REFERENCE LABORATORIES

• Département de Microbiologie, Unité de Mycobactériologie, Institut de Médicine

Tropicale Prince Léopold, Antwerp, Belgium (Professor Françoise Portaels) (Coordinating
Centre, 1999-2004)
• Laboratoire de la Tuberculose, Institut Pasteur d’Algérie-Alger, Algiers, Algeria
(Dr Fadila Boulahbal)
• Queensland Mycobacterium Reference Laboratory, Chermside, Australia (Dr Chris Gilpin)
• National Institute of Public Health, Prague, Czech Republic (Dr Marta Havelkova)
• Instituto de Salud Pública de Chile, Santiago, Chile (Dr Andrea Luna)
• Centre national de Référence des Mycobacteries, Institut Pasteur, Paris, France
(Dr Véronique Vincent)
• National Reference Centre for Mycobacteria, Forschungszentrum, Borstel, Germany,
(Dr Sabine Rüesch-Gerdes)
• Kuratorium Tuberkulose in der Welt e.V., Gauting, Germany (Professor Knut Feldmann)
• Tuberculosis Research Centre (TRC), Indian Council of Medical Research, Chennai, India
(Dr Chinnambedu N. Paramasivan)
• Laboratory of Bacteriology, Istituto Superiore de Sanità, Rome, Italy (Dr Graziella Orefici)
• Japan Anti-Tuberculosis Association, Tokyo, Japan (Dr Satoshi Mitarai)
• Instituto Nacional de Saúde, Porto Codex, Portugal (Dr Maria Filomena Rodrigues)
• Korean Institute of Tuberculosis, Seoul, Republic of Korea (Dr Gill-han Bai/ Dr Sang Jae Kim)
• Unit for Tuberculosis Operational and Policy Research, Medical Research Council,
Pretoria, South Africa (Dr Karin Weyer)
• Servicio de Microbiologia, Hospital Universitari Vall d’Hebron, Autonomous University,
Barcelona, Spain (Dr Nuria Martin-Casabona)
• Swedish Institute for Infectious Disease Control, Solna, Sweden (Dr Sven Hoffner)
• National Institute of Public Health and the Environment (RIVM), Bilthoven, The
Netherlands (Dr Dick van Soolingen)
• Health Protection Agency, Mycobacterium Reference Laboratory Unit, King’s College
Hospital (Dulwich), London,United Kingdom (Dr Francis Drobniewski)
• Mycobacteriology / Tuberculosis Laboratory, Centers for Disease Control and Prevention
(CDC) Atlanta, GA, United States of America (Dr Beverly Metchock)
• Department of Public Health, Massachusetts State Laboratory Institute, Boston, MA,
United States of America (Dr Alexander Sloutsky)
CONTRIBUTING MEMBERS OF THE WORKING GROUP

•Algeria: Professor Fadila Boulahbal •Andorra: Dr Margarida Coll Armangue •Argentina:

Dr Lucia Barrera, Omar Latini •Australia: Dr Richard Lumb •Austria: Dr John-Paul Klein
•Belgium: Dr Maryse Wanlin, Dr An Aerts •Bosnia and Herzegonia: Dr Biljana Stefanovic,
Professor Zehra Dizdarevic •Botswana: Dr Lisa J Nelson, Mr Gasekgale Moalosi, Mr Michael
Mwasekaga •Cambodia: Dr Onazaki, Dr Kouske Okada •Canada: Melissa Phypers,
Dr Edward Ellis •Chile: Dr Andrea Luna Heine, Dr Rosario Lepe •China: Dr Wu Xongrong,
Dr Kai Man Kam, Dr Su Ya, Dr Du Changmei, Dr Daniel Chin •Colombia: Dr Clara Inés Léon
Franco, Dr Martha Inírida Guerrero, Dr Claudia Sierra, Dr Nancy Naranjo, Dr Maria Consuelo
Garzón •Croatia: Dr Ira Gjenero Margan •Cuba: Dr Ernesto Montoro, Dr Mária J. Llanes,
Lic. Dihadenys Lemus •Czech Republic: Dr Vlasta Mazánková, Mr Jiri Holub •Democratic
Republic of Congo: Professor Francoise Portaels, Dr Henrietta Wembanyama •Ecuador:
Dr Judith Vaca, Dr Dolores Kuffo •Egypt: Dr Essam Elmoghazy •El Savador: Dr Julio Garay
Ramos •Estonia: Dr Vahur Hollo •Finland: Dr Petri Ruutu •France: Dr Bénédicte Decludt,
Jerome Robert •Georgia: Professor George Khechinashvili •Germany: Dr Walter Haas,
Dr Michael Forßbohm •Honduras: Dr Noemi Paz de Zavala, Dr Hilda Membreño •Iceland:
Dr Blöndal Thorsteinn •India: Dr Chinnambedu Paramasivan, Dr Lakhbir Singh Chauhan,
Dr Reuben Granich •Ireland: Dr Joan O’Donnell •Israel: Dr Daniel Chemtob, Dr Zohar Mor
•Italy: Dr Dina Caraffa de Stefano, Dr GB Migliori •Japan: Dr Chyoji Abe •Kazakhstan:
Dr Rimma Agzamova, Dr Galemzhan Borankulovich Rakishev •Latvia: Dr Janis
Leimans •Lithuania: Dr Edith Davidaciené, Dr Anaida Sosnovskaja, Dr Puneet Dewan
•Luxembourg: Dr Pierrette Huberty-Krau, Dr Nobert Charlé •Malta: Dr Malcolm P Micallef
•Mongolia: Dr Gombagaram Tsogt, Dr Naranbat Nymadawa •Nepal: Dr Dirgh Singh Bam,
Dr Christian Gunnenburg •Netherlands: Dr Paul van Gerven, Dr Nico Kalisvaart •New
Zealand: Dr Helen Heffernan •Norway: Dr Einar Heldal, Dr Brita Winje Askeland •Oman:
Dr Suleiman Al-Busaidy •Poland: Dr Maria Korzeniewska-Kosela •Puerto Rico: Dr Ada
Martinez •Qatar: Dr Zubaida Daham F. Al-Suwaidi •Russian Federation (Orel): Dr Paul
Arguin, Dr Evgenia Nemtsova, Dr Boris Kazzeony, Helen Kiryanova •Russian Federation
(Tomsk): Dr Irena Gelmananova, Dr Donna Barry, Professor Mikhail I. Perelman, Olga
Sirotkina, Vera Pavlova •San Marino: Dr Antonella Sorcinelli •Serbia and Montenegro:
Professor Dusan Popovac, Dr Radmila Curcic •Singapore: Dr Cynthia Chee •Slovakia:
Dr Eva Rajecova, Dr Ivan Solovic •Slovenia: Professor Jurij Sorli •South Africa: Dr Karin
Weyer •Spain (Barcelona): Dr Nuria Martin-Casabona •Spain (Galicia): Dr Elena Cruz
Ferro, Dr Emma Fernández Nogueira, Dr María Luisa Pérez del Molino Bernal •Sweden:
Dr Victoria Romanus •Switzerland: Dr Peter Helbling, Dr Ekkehardt Altpeter •Thailand:
Dr Dhanida Rienthong •The Gambia: Dr Richard Adegbola, Dr Francis Drobniewski
•Turkmenistan: Dr Babakuli Jumaev MSF, Dr Ashir Ovezov •United Kingdom (England,
Wales and Northern Ireland): Dr John Watson, Dr Alistair Story, Dr Delphine Antoine
•Scotland: Dr Jim McMenamin, Dr Fiona Johnston •United States of America: Dr Marisa
Moore •Uruguay: Dr Valentin Cuesta, Dr Jorge Rodriguez •Uzbekistan: Dr Helen Cox,
Dr Gulnoz Tulkunovna Uzakova, Dr Roy Male •Venezuela: Dr Raimond Armengol,
Dr Albina Vasquez •Zambia: Dr Vincent Tihon •WHO Regional Offices: •Africa: Dr Daniel
Kibuga, Dr Eugene Nyarko •The Americas: Dr Rodolfo Rodriguez Cruz, Dr Pilar Ramon-
Pardo •Eastern Mediterranean: Dr Akihiro Seita, Dr Samiha Baghdadi •Europe: Dr Richard
Zaleskis, Mr Jerod Scholten •South-East Asia: Dr Jai P. Narain, Dr Nani Nair •Western
Pacific: Dr Dongil Ahn, Dr Marcus Hodge
 ACKNOWLEDGEMENTS

This project was in part financially supported by the United States Agency for International
Development. The Tuberculosis Coalition for Technical Assistance (TBCTA) funded labo-
ratory training activities associated with this project. We are grateful to EuroTB for their
participation and contribution of European drug resistance surveillance data. This project
could not have succeeded without the support of national authorities and the institutions
hosting each of the national and international laboratories. A special acknowledgement is
due to Dan Bleed and Mehran Hosseini for technical support of data management.
Please click on the different underlined parts for access to the PDF files.

ANTI -TB DRUG RESISTANCE IN THE WORLD

C ONTENTS

FOREWORD ...............................................................................................................................................13
SUMMARY ..................................................................................................................................................15
1. BACKGROUND AND METHODS ...............................................................................................15
2. RESULTS .............................................................................................................................................15
2.1 Magnitude and trends of anti-TB drug resistance ....................................................15
New cases ................................................................................................................................15
Previously treated cases .......................................................................................................16
Association of drug resistance with the quality of TB control ...................................16
2.2 MDR-TB ........................................................................................................................................16
2.3 Patterns and amplification 1994–2002 .........................................................................17
3. CONCLUSIONS ................................................................................................................................17
3.1 Scale of the epidemic of drug-resistant TB ..................................................................17
4. RECOMMENDATIONS...................................................................................................................18
4.1 Management of TB control .................................................................................................18
4.2 Surveillance of drug resistance .........................................................................................19

1. INTRODUCTION ...............................................................................................................................21
2. BACKGROUND ..................................................................................................................................23
2.1 ANTIMICROBIAL RESISTANCE AND PUBLIC HEALTH ....................................................23
2.2 MECHANISMS OF ANTI-TB DRUG RESISTANCE AND FACTORS
ASSOCIATED WITH ITS EMERGENCE.....................................................................................23
2.3 THE THREAT OF DRUG RESISTANCE FOR TB CONTROL ...............................................24
2.3.1 Increased access to drugs ...............................................................................................24
2.3.2 HIV .............................................................................................................................................25
2.3.3 Private sector ........................................................................................................................25

3. MATERIALS AND METHODS .................................................................................................27

3.1 METHODOLOGICAL FRAMEWORK ........................................................................................27
3.2 DEFINITIONS OF DRUG RESISTANCE ....................................................................................27
3.2.1 Drug resistance among new cases .............................................................................27
3.2.2 Drug resistance among previously treated cases.................................................27
3.2.3 Combined prevalence of drug resistance ................................................................27
3.3 SURVEY AREAS AND SAMPLING STRATEGIES .................................................................28
3.3.1 Surveillance terminology and target survey areas ..............................................29
3.3.2 Sample size and sampling strategies .........................................................................29
3.4 BACTERIOLOGICAL METHODS ................................................................................................30
3.5 COLLECTION OF DATA .................................................................................................................31

9
 ANTI -TB DRUG RESISTANCE IN THE WORLD

3.5.1 Patient eligibility and registration ..............................................................................31

3.5.2 Accuracy of information on prior TB treatment ....................................................31
3.5.3 Data management in individual countries ..............................................................31
3.6 STATISTICAL PROCEDURES – DATA ENTRY, CHECKING AND CLEANING..............32
3.7 STATISTICAL ANALYSIS ...............................................................................................................32
3.7.1 Phase 3 of the Global Project (most recent data) ................................................32
3.7.2 Dynamics of resistance over time................................................................................32
3.7.3 Determinants of drug resistance (ecological analysis).......................................33
3.7.3.1 Sources of information ...........................................................................................33
3.7.3.2 Statistical analysis of the aggregate data ........................................................33
3.7.4 MDR projections .................................................................................................................34
3.7.5 Patterns of resistance........................................................................................................34
3.7.6 Resistance to RMP: a good surrogate marker for MDR?.....................................34
3.8 VALIDITY OF THE FINDINGS ......................................................................................................35
3.8.1 Selection bias .......................................................................................................................35
3.8.2 Observation and information bias ..............................................................................35
Test bias....................................................................................................................................35
Representativeness of rates ................................................................................................35
Analysis of trends...................................................................................................................36
Ecological fallacy ...................................................................................................................36
The estimation of the MDR burden ..................................................................................36
Patterns ....................................................................................................................................36
CONTENTS

4. RESULTS .................................................................................................................................................43
4.1 PREVALENCE OF DRUG RESISTANCE ....................................................................................43
4.1.1 Drug resistance among new cases of tuberculosis ..............................................43
Any resistance among new cases .....................................................................................44
MDR among new cases........................................................................................................46
Resistance among new cases according to number of drugs ...................................46
Any resistance among new cases by individual drug..................................................48
New cases resistant to INH but susceptible to RMP......................................................49
4.1.2 Drug resistance among previously treated cases.................................................49
Any resistance among previously treated cases ...........................................................50
MDR among previously treated cases .............................................................................52
Resistance among previously treated cases according to number of drugs ........52
Resistance among previously treated cases by individual drug...............................54
4.1.3 Combined prevalence of drug resistance ................................................................54
Any resistance among combined cases ..........................................................................54
MDR among combined cases ............................................................................................55
Resistance among combined cases according to number of drugs .......................56
Any resistance among combined cases by individual drug ......................................56
4.2 PREVALENCE OF DRUG RESISTANCE BY REGION ............................................................57
4.2.1 Drug resistance among new cases ..............................................................................57
4.2.2 Drug resistance among previously treated cases.................................................58
4.2.3 A closer look at the European Region ........................................................................60
4.3 DYNAMICS OF DRUG RESISTANCE PREVALENCE OVER TIME (1994-2002) ........61
4.3.1 Dynamics of drug resistance among new cases....................................................62
Dynamics in settings reporting two data points ..........................................................62
Trends in settings reporting three or more data points ..............................................64

10
ANTI -TB DRUG RESISTANCE IN THE WORLD

4.3.2 Dynamics of drug resistance among previously treated cases ......................65

Dynamics in settings reporting two data points ..........................................................66
Trends in settings reporting three or more data points ..............................................67
4.3.3 Dynamics of drug resistance among combined cases .......................................67
Dynamics in settings reporting two data points ..........................................................68
4.4 POTENTIAL DETERMINANTS OF DRUG RESISTANCE ....................................................70
4.4.1 Variables included in the ecological analysis .........................................................70
4.4.2 Bivariate analysis ................................................................................................................72
4.4.3 Multivariate analysis .........................................................................................................72
4.5 MAGNITUDE OF THE MDR-TB PROBLEM .............................................................................73
4.5.1 MDR-TB “hot spots”............................................................................................................73
Dynamics of the hot spots (1994–2002) .........................................................................74
4.5.2 Burden of MDR-TB ..............................................................................................................76
4.5.3 Resistance to RMP: a good surrogate marker for MDR?.....................................76
4.6 DRUG RESISTANCE PATTERNS
(relationships between new and previously treated cases, amplification,
and major pathways of drug resistance creation) ...............................................................78
4.7 PROFICIENCY TESTING IN THE SUPRANATIONAL LABORATORY
NETWORK, 1994-2002 ................................................................................................................82

5. DISCUSSION .......................................................................................................................................83
5.1 MAGNITUDE OF RESISTANCE BY REGION ........................................................................84
African region ..................................................................................................................................84

CONTENTS
Region of the Americas................................................................................................................85
Eastern Mediterranean region..................................................................................................86
European region .............................................................................................................................87
South-east Asian region ..............................................................................................................89
Western Pacific region..................................................................................................................90
5.2 ECOLOGICAL ANALYSIS .............................................................................................................91
5.3 BURDEN OF MDR ...........................................................................................................................91
5.4 SRLN ....................................................................................................................................................92
5.5 DRUG RESISTANCE PATTERNS ...............................................................................................93
Increase in drug resistance rate .........................................................................................93
Amplification of drug resistance proportions ...............................................................94
Major drug resistance pathways.......................................................................................94
Implications ............................................................................................................................94

ANNEXES ....................................................................................................................................................95
REFERENCES.......................................................................................................................................... 133
COUNTRY PROFILES ....................................................................................................................... 141

11