Drug-Resistant Tuberculosis
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Drugs 2000 Feb; 59 (2): 171-179 0012-6667/00/0002-0171/$25.00/0 © Adis International Limited. All rights reserved.
Drug-Resistant Tuberculosis What Do We Do Now? Amalio Telenti1 and Michael Iseman2 1 Division of Infectious Diseases and Institute of Microbiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland 2 National Jewish Medical and Research Center, Denver, Colorado, USA
Abstract
Drug-resistant tuberculosis (TB) represents a threat to TB control programmes. Erratic and inappropriate use of currently available medications, HIV-TB coinfection, and concern about transmission of drug-resistant strains in the general population all contribute to a worrying picture. What do we do now? In the last few years, there has been considerable progress in the understanding of mechanisms of action and resistance to antituberculosis agents, and in establishing the value of directly observed therapy in preventing treatment failure. However, a limited effort has been devoted to the development of new active compounds or of rapid diagnostic tests, and their relevance to global tuberculosis control has been questioned.
The emergence of multidrug-resistant tuberculosis (MDR-TB) has been recently defined as resistance to at least isoniazid and rifampicin (rifampin). Because of the strongly deleterious effects of multidrug resistance on treatment, it has generated concern for the future of tuberculosis control.[1,2] Available data suggest that multidrug-resistance may represent a public health threat in areas with a high prevalence of tuberculosis, suboptimal tuberculosis control programmes, and/or HIV.[1,2] In this review, we address several issues on drugresistant tuberculosis: mechanisms of resistance, diagnosis of resistance, pathogenicity of drug-resistant strains, current recommendations for treatment and prophylaxis, progress in the development of new drugs, as well as public health and institutional measures of control. 1. Mechanisms of Resistance and Drug Targets in Mycobacterium tuberculosis Mycobacteria are characterised by a highly hydrophobic cell envelope acting as an effective per-
meability barrier to many compounds[3] and well developed drug-efflux systems (e.g. 14 members of the major facilitator family and numerous ABC transporters).[4] In addition, mycobacteria produce hydrolytic or drug-modifying enzymes (eg. βlactamases, aminoglycoside acetyl transferases).[4-6] These are among the factors cited to explain the natural resistance of many species of mycobacteria to frequently used antibacterials. There are, therefore, a limited number of compounds used to treat tuberculosis: isoniazid, rifampicin, streptomycin, ethambutol and pyrazinamide being the main agents. Correct management of patients using well defined combinations of these agents during prolonged periods (6 to 9 months) leads to a >95% cure rate. Unfortunately, physician error and poor patient adherence to treatment may result in treatment failure due to resistance. Resistance is defined as ‘primary or initial’ when identified in an
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