A Systematic Review of Mutations Associated with Isoniazid Resistance Points to Continuing Evolution and Subsequent Evasion of Molecular Detection, and Potential for Emergence of Multidrug Resistance in Clinical Strains of Mycobacterium tuberculosis.

This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes katG, inhA, fabG1, and the intergenic region oxyR'-ahpC were considered in this review. Fifty-two articles were included describing 9,306 clinical isolates (5,804 INHR, 3,502 INHS) from 31 countries. The three most frequently mutated loci continue to be katG315 (4,271), inhA-15 (787), and inhA-8 (106). However, the diagnostic value of inhA-8 is far lower than previously thought, only appearing in 25 (0.4%) INHR isolates lacking the first two mutations. We catalogued 45 new loci (29 katG, nine inhA, seven ahpC) associated with INH resistance and identified 59 loci (common to this and previous reviews) as a reliable basis for molecular diagnostics. Including all observed mutations provides a cumulative sensitivity of 85.6%. In 14.4% of resistant isolates no mechanism of resistance was detected, making them likely to escape molecular detection, and in case of mono INH resistance likely to convert to MDR-TB. Integrating the information cataloged in this study into current diagnostic tools is essential for combating the emergence of MDR-TB, and its exclusion can lead to an unintended selection against common mechanisms and to diversifying evolution. Observation of many low-frequency resistance-conferring mutations points to an advantage of WGS for diagnostics. Finally, we provide five recommendations for future ...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research