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WHO/TB/ WHO/CDS/CSR/RMD/ GUIDELINES for SURVEILLANCE of DRUG RESISTANCE in TUBERCULOSIS WORLD HEALTH ORGANIZATION GENEVA WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance WHO/CDS/TB/ WHO/CDS/CSR/RMD/ GUIDELINES FOR SURVEILLANCE OF DRUG RESISTANCE IN TUBERCULOSIS SECOND EDITION Edited by: MOHAMED ABDEL AZIZ ADALBERT LASZLO MARIO RAVIGLIONE HANS RIEDER MARCOS ESPINAL ABIGAIL WRIGHT Cover photograph: JED DAVENPORT PERU, 1997 World Health Organization Geneva 2003 WHO Library Cataloguing-in-Publication Data Guidelines for surveillance of drug resistance in tuberculosis / edited by Mohamed Abdel Aziz... [et al.] -- 2nd ed. 1. Tuberculosis, Multidrug-resistant - epidemiology 2.Drug resistance 3. Antitubercular agents - pharmacology 4.Epidemiologic surveillance - methods 5. Guidelines I.Abdel Aziz, Mohamed II.Title. ISBN (NLM classification: WF 360) WHO/CDS/TB/ WHO/CDS/CSR/RMD/ World Health Organization 2003 All rights reserved. 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 delimitation 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. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use. Printed in Italy Design and printing: Jotto Associati s.a.s. - Biella - Italy CONTENTS ACKNOWLEDGEMENTS 5 INTRODUCTION 7 Causes of anti-tuberculosis drug resistance... 7 Establishing a drug resistance surveillance system... 8 Choice of drugs... 9 DEFINITIONS OF RESISTANCE 11 Acquired resistance to anti-tuberculosis drugs...11 Primary resistance to anti-tuberculosis drugs...12 Importance of distinguishing patients who have been previously treated from those not previously treated...13 LABORATORIES AND DIAGNOSTIC CENTRES 15 National Reference Laboratory...15 Diagnostic centres...15 SAMPLE SIZE AND SAMPLING STRATEGIES 17 Sample size...17 Sampling strategies...17 ORGANIZATION AND SURVEY OUTLINE 21 Suitable survey areas...21 National coordination team...21 Preparatory phase...21 Quality control of the survey INTAKE OF PATIENTS 25 Inclusion criteria Sputum collection...25 Registration...25 Collection and transport of sputum samples...26 NATIONAL REFERENCE LABORATORY 29 Decontamination Cultures...29 Identification...30 Susceptibility testing Quality assurance...32 Supranational Reference Laboratory...32 DATA MANAGEMENT AND ANALYSIS 35 Data collection Data management...35 Data analysis...35 Interpretation of results...36 REFERENCES 39 ANNEXES 1 Drug resistance survey protocol checklist Weighted cluster sampling Safe shipment of infectious material Preparation of media Proportion method Sputum shipment - form Clinical information - form Results of bacteriological examination - form Anti-TB drug resistance results Proficiency testing report form Supranational laboratory list GUIDELINES FOR SURVEILLANCE OF DRUG RESISTANCE IN TUBERCULOSIS ACKNOWLEDGEMENTS The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance wishes to thank for their contribution to the development of these guidelines all the following participating colleagues in the WHO/IUATLD Global Project: the supranational laboratory network since 1994, the supranational coordinating laboratories, the directors of national reference laboratories and national TB control programmes in participating countries, and international TB experts. 5 INTRODUCTION One of the aims of ensuring effective management of tuberculosis (TB) is to minimize the development of drug resistance. Surveillance of anti-tb drug resistance is therefore an essential tool for monitoring the effectiveness of TB control programmes and improving national and global TB control efforts. The use of drug sensitivity tests for monitoring and guiding TB treatment programmes was recommended many years ago (1-3), and information available at the time suggested that there could be high and increasing levels of drug resistance in many parts of the world (4-8). In 1994, the World Health Organization (WHO) joined forces with the International Union Against Tuberculosis and Lung Disease (IUATLD) and launched the Global Project on Antituberculosis Drug Resistance Surveillance. The aims of the Global Project are to measure the prevalence and monitor the trend of anti-tb drug resistance worldwide using a standardized methodology, and to study the correlation between the level of drug resistance and treatment policies in the different countries. The overall goal of the Project is to improve the performance of national TB control programmes (NTPs) through policy recommendations on drug management (9-12). These guidelines have been developed to assist NTPs in adopting country-specific anti-tb drug resistance surveillance systems measure susceptibility to the first-line drugs. The standardization of quality assurance and proficiency testing methods, through various centres worldwide that function as Supranational Reference Laboratories (SRLs) (3) will ensure that the results are comparable both within and between participating countries. As the decisions on treatment regimens and programme management can be made only at the country level, prevalence of drug resistance should be monitored primarily at that level. These guidelines update the 1997 (13) edition that was agreed upon in a meeting bringing together world experts in mycobacteriology and TB control. This revision, requested at the IUATLD meeting in Madrid 1999, is based on the lessons learned by the Global Project since CAUSES OF ANTI-TUBERCULOSIS DRUG RESISTANCE Resistance of Mycobacterium tuberculosis to anti-tb drugs is a man-made problem. Wild strains of M. tuberculosis that have never been exposed to anti-tb drugs are almost never clinically resistant (5). Exposure to a single drug - as a result of poor adherence to treatment, inappropriate prescription, irregular drug supply, and/or poor drug quality - suppresses the growth of bacilli susceptible to that drug but permits the multiplication of pre-existing drug-resistant organisms. This phenomenon is called acquired resistance. Subsequent transmission of such resistant bacilli to other persons may lead to disease that is drug-resistant from the outset, a phenomenon known as primary resistance. The emergence of drug-resistant M. tuberculosis has been associated with a variety of management, health provider and patient-related factors. In some countries, management 7 INTRODUCTION factors may include the lack of availability of a standardized therapeutic regimen, or poor implementation compounded by frequent or prolonged shortages of drug supply in areas with inadequate resources or political instability. Use of anti-tb drugs of unproven quality is an additional concern, as is the sale of such medications over the counter and on the black market. Moreover, incorrect management of individual cases, difficulties in selecting the appropriate chemotherapeutic regimen with the right dosage, and patients non-adherence to prescribed treatment contribute to the development of drug resistance. In summary, anti-tb drug resistance results from the absence of a system properly organized to ensure prompt diagnosis and effective treatment within a well implemented TB control strategy. Data presented in the first and second Global Reports suggest that HIV infection is not an independent risk factor for drug resistance (9, 10). However, in settings with high HIV prevalence, the number of TB cases is increasing dramatically. It is therefore important to take TB/HIV co-infection into consideration when anti-tb drug resistance surveillance (DRS) protocols are being developed and implemented. ESTABLISHING A DRUG RESISTANCE SURVEILLANCE SYSTEM Since 1994, several countries have established national anti-tb DRS projects. Those projects adopted a standardized methodology for susceptibility testing with the assistance of the SRLs. Establishing surveillance of drug resistance at the country level requires strict adherence to the following three principles: 1. The sample of specimens should be representative of the TB patients in the country/geographical setting under study and the sample size should be determined to permit standard epidemiological analysis. It is recommended that anti-tb drug resistance surveillance covers the whole country/geographical area and that the sample size is derived from the total number of new sputum-positive cases in this country. 2. The patient's history should be carefully obtained and available medical records reviewed to clearly determine whether the patient has previously received anti-tb drugs. This is essential to distinguish between drug resistance among newly diagnosed cases and drug resistance among previously treated cases. 3. The laboratory methods for anti-tb drug susceptibility testing (DST) should be selected from among those that are internationally recommended. Four DST methods have been standardized and are widely used throughout the world (15): - proportion method and its economic and standard variants - resistance ratio method - absolute concentration method - BACTEC 460 radiometric method. Comparability of data resulting from any of the above four methods is assured by the quality assurance (QA) and proficiency testing performed by the SRL network. 8 GUIDELINES FOR SURVEILLANCE OF DRUG RESISTANCE IN TUBERCULOSIS INTRODUCTION CHOICE OF DRUGS Four of the six anti-tb drugs used in first-line treatment - isoniazid (H), rifampicin (R), streptomycin (S), and ethambutol (E) - should be tested by all countries adopting these guidelines. These drugs were chosen because they have been, and continue to be, widely used throughout the world, and resistance can be reliably measured by standardized techniques and has been studied for many years. Given the difficulties in standardizing susceptibility testing for pyrazinamide, this drug should not be routinely included in the panel of anti-tb drugs to be tested for surveillance purposes. Guidelines for DST for second line anti-tb drugs are detailed elsewhere (16). 9 DEFINITIONS OF RESISTANCE Resistance to each of the four anti-tb drugs routinely tested is defined according to the results of bacteriological testing (see Susceptibility testing, page 30). Multidrug resistance (MDR) is defined as resistance to both isoniazid and rifampicin, with or without resistance to other agents. ACQUIRED RESISTANCE TO ANTI-TUBERCULOSIS DRUGS Patients diagnosed with TB who start anti-tb treatment and acquire resistance to one or more of the drugs used during the treatment are said to have developed acquired drug resistance. This can be ascertained only if the drug susceptibility pattern is determined before the start of treatment, as well as at a later point in treatment or at the end of treatment. Acquired drug resistance is thus a sensitive indicator of combined physician and patient adherence to internationally recommended treatment regimens. Such an approach is only possible in countries with the resources to perform serial susceptibility testing. In most of the world, systematic evaluation is not usually feasible and an alternative approach to estimating acquired resistance needs to be practical. Proxy for acquired drug resistance: resistance among previously treated patients Because acquired drug resistance is intimately linked to the use of anti-tb drugs, patients with a history of previous anti-tb treatment lasting at least 1 month should be grouped as previously treated patients. This group includes patients in any of the four following categories, which should be reported separately whenever feasible: Treatment failure patients failing anti-tb treatment, i.e. patients who begin treatment for smear-positive pulmonary TB and who remain smear-positive, or become smear-positive again, at 5 months or later during the course of treatment. Relapse patients who become smear-positive again after having been treated for TB and declared cured after the completion of their treatment. Return after default patients who interrupt their treatment for more than 2 months after having received a total of at least 1 month of anti-tb treatment and who then return with bacteriologically confirmed tuberculosis (return after default) Chronic patients who continue to be smear-positive after the completion of a re-treatment regimen. 11 DEFINITIONS OF RESISTANCE Definition Previously treated case For the purpose of surveillance, resistance in a previously treated patient is defined as the presence of resistant strains of M. tuberculosis in a patient who, in response to direct questioning, admits having been treated for tuberculosis for 1 month or more, or, in countries where adequate documentation is available, in a patient for whom there is evidence of such history. PRIMARY RESISTANCE TO ANTI-TUBERCULOSIS DRUGS Patients who are diagnosed with TB and who harbour organisms resistant to one or more anti-tb drugs, but have never been previously treated for TB or have been treated for less than one month, are said to have primary resistance. Primary drug resistance is a theoretical concept, as history of prior anti-tb treatment can never be entirely accurate. Initial drug resistance has thus been proposed in reference to patients presenting with an organism resistant to any anti-tb drug before the start of therapy. However, the systematic use of this term may discourage thorough investigation of prior anti-tb treatment history. Given the importance of distinguishing between primary and acquired resistance an approach to assessing primary drug resistance has to be as feasible and as accurate as possible. Proxy for the prevalence of primary drug resistance: resistance among new cases Patients should be interviewed in a standardized manner to exclude prior history of up to 1 month of anti-tb treatment. Patients who claim never to have received such treatment (which should be verified by checking TB registers) are said not to have been previously treated. Definition New case For the purpose of surveillance, resistance among new cases is defined as the presence of resistant strains of M. tuberculosis in a patient who, in response to direct questioning, denies having had any prior anti-tb treatment (for more than 1 month), and, in countries where adequate documentation is available, for whom there is no evidence of such history. 12 GUIDELINES FOR SURVEILLANCE OF DRUG RESISTANCE IN TUBERCULOSIS DEFINITIONS OF RESISTANCE IMPORTANCE OF DISTINGUISHING PATIENTS WHO HAVE BEEN PREVIOUSLY TREATED FROM THOSE NOT PREVIOUSLY TREATED Distinguishing between patients with and without history of at least 1 month of anti-tb treatment not only has implications for classification for the purpose of surveillance of drug resistance, but also has programmatic relevance for decisions on the type of treatment a patient is to receive. In general, it is expected to detect higher prevalence of resistance among previously treated cases than among new cases. Inaccurate classification of patients and/or combining drug resistance data from both categories will be misleading and will make the interpretation of data more difficult. 13 LABORATORIES AND DIAGNOSTIC CENTRES NATIONAL REFERENCE LABORATORY The National Reference Laboratory (NRL), which should be the reference institution in the country, prepares cultures from the sputum samples and undertakes the identification of M. tuberculosis strains as well as drug susceptibility testing (DST). Basic laboratory equipment and materials must be available and functional in the NRL before the implementation of the surveillance. If there are peripheral culture laboratories, mycobacterial strains, rather than sputum samples, can be sent to the NRL for testing. One of the main tasks of the NRL is to ensure the quality of culture and of DST performed by regional or peripheral units by establishing a regular on-site supervision programme for those units, and by providing training in, and quality assurance systems for, the laboratory procedures. External quality assurance programmes, organized by the SRL, will validate the results of susceptibility tests done by the NRL. One NRL should be responsible for the surveillance of not more than million people. In countries with larger populations, it is recommended that capacity for cultures and DST at the regional/provincial level be strengthened or that additional NRLs be established. DIAGNOSTIC CENTRES Diagnostic centres include all institutions where decisions on the diagnosis are taken and patients suspected of having TB are registered. Most diagnostic centres in control programmes with limited means are small, non-specialized health centres and clinics or outpatient departments of hospitals, operated by the government or by nongovernmental organizations. Private sector institutions and general practitioners are not included unless their activities are based on some agreement with the NTP and they are following national guidelines for diagnosis and treatment. 15 SAMPLE SIZE AND SAMPLING STRATEGIES SAMPLE SIZE The sampling universe for a survey on the prevalence of anti-tb drug resistance should include all newly registered sputum smear-positive TB patients in the country. The calculation of an appropriate sample size should be based on the following (17): the total number of new sputum smear-positive cases detected in the previous year in the country or in the geographical setting to be studied; expected prevalence of resistance to rifampicin from available data (in the absence of available data, the best guess of investigators should be used); precision should be between 1-2%, while ensuring that obtaining the calculated sample is logistically feasible; a confidence interval of 95% should be used for estimated prevalence. If the cluster sampling method is adopted, the cluster design effect needs to be taken into account, and the calculated sample size therefore needs to be multiplied by 2 (13). Finally, the calculated sample size needs to be increased by 5-20% to account for expected losses. These include patients diagnosed as smear-positive who do not return to the diagnostic centres and from whom it is not possible to obtain two sputum samples; patients whose culture is contaminated or does not grow; and patients whose susceptibility testing does not give interpretable results (unreadable or too few colonies). SAMPLING STRATEGIES Different sampling strategies can be adopted to select a representative sample of TB patients. In order to select a representative group of newly registered patients, a randomization step is essential (14, 18). Simple random sampling of individual patients is not practical in TB diagnostic centres, mainly because routines usually identical for most patients would be disrupted and compliance of staff and patients would consequently be low and the quality of data poor. Involving all diagnostic centres can also give rise to logistic problems and high costs. Randomization can take place at the level either of diagnostic centres or possibly of health districts. In this way, routines would be slightly changed for some diagnostic centres, but remain identical for all newly registered smearpositive patients in a particular centre. In countries with significant logistic problems, sentinel site surveill
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