Abstract

Anti-tuberculosis drugs are a two-edged sword. While they destroy pathogenic M. tuberculosis they also select for drug resistant bacteria against which those drugs are then ineffective. Global surveillance has shown that drug resistant Tuberculosis is widespread and is now a threat to tuberculosis control programs in many countries. Application of molecular methods during the last decade has greatly changed our understanding of drug resistance in tuberculosis. Application of molecular epidemiological methods was also central to the description of outbreaks of drug resistance in Tuberculosis. This review describes recommendations for Tuberculosis treatment according to the WHO guidelines, the drug resistance problem in the world, mechanisms of resistance to first line and second line drugs and applications of molecular methods to detect resistance causing gene mutations. It is envisaged that molecular techniques may be important adjuncts to traditional culture based procedures to rapidly screen for drug resistance. Prospective analysis and intervention to prevent transmission may be particularly helpful in areas with ongoing transmission of drug resistant strains as recent mathematical modeling indicate that the burden of MDR-TB cannot be contained in the absence of specific efforts to limit transmission.

Highlights

  • Drug resistance and global surveillance: history Shortly after the first anti-tuberculosis (TB) drugs were introduced, streptomycin (STR), para-aminosalicylic acid (PAS), isoniazid (INH) resistance to these drugs was observed in clinical isolates of Mycobacterium tuberculosis (Crofton and Mitchison, 1948)

  • The report showed that drug resistance was present globally, and that MDR-TB ranged from 0% to 14% in new cases and 0% to 54% in previously treated cases

  • This report confirmed that drug resistant TB was a sufficient problem since MDRTB ranged from 0–16% among new cases and from 0% to 48% in previously treated cases

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Summary

Introduction

Drug resistance and global surveillance: history Shortly after the first anti-tuberculosis (TB) drugs were introduced, streptomycin (STR), para-aminosalicylic acid (PAS), isoniazid (INH) resistance to these drugs was observed in clinical isolates of Mycobacterium tuberculosis (Crofton and Mitchison, 1948). Resistance to first line anti-TB drugs has been linked to mutations in at least 10 genes; katG, inhA, ahpC, kasA and ndh for INH resistance; rpoB for RIF resistance, embB for EMB resistance, pncA for PZA resistance and rpsL and rrs for STR resistance. Various studies have identified five mutations in codon 306 [(ATG-GTG), (ATG-CTG), (ATG-ATA), (ATG-ATC) and (ATG-ATT)] which result in three different amino acid substitutions (Val, Leu and Ile) in EMB-resistant isolates (Lee et al, 2002; Sreevatsan et al, 1997c; Mokrousov et al, 2002b; Ramaswamy et al, 2000).

Methods for genotypic detection of resistance
Findings
16 S rRNA inhA ethA ethR alr ddl rrs

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