Valafar Siavash J
Department of Biology, University of California, Irvine, Irvine, California, USA
Antimicrob Agents Chemother. 2021 Feb 17;65(3). doi: 10.1128/AAC.02091-20.
Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes , , and , and the intergenic region '- were considered in this review. Fifty-two articles were included that described 9,306 clinical isolates (5,804 INH resistant [INH] and 3,502 INH susceptible [INH]) from 31 countries. The three most frequently mutated loci continue to be locus 315 of (315; = 4,271), locus -15 of (-15; = 787), and locus -8 of (-8; 106). However, the diagnostic value of -8 is far lower than previously thought, as it only appears in 25 (0.4%) of the INH isolates lacking the first two mutations. I catalogued 45 new loci (29 , nine , and seven ) 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 the case of INH monoresistance, likely to convert to multidrug-resistant TB (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 whole-genome sequencing (WGS) for diagnostics. Finally, I provide five recommendations for future diagnostic platforms.
分子检测正迅速成为全球结核病（TB）防控的一个不可或缺的组成部分。耐药的罕见机制逃避了这些检测平台的检测，削弱了我们控制疫情的能力。本文是对2013年9月至2019年12月间报道的赋予异烟肼（INH）耐药性突变的已发表文章的系统综述。本综述考虑了基因、和，以及基因间区域‘-’。纳入了52篇文章，这些文章描述了来自31个国家的9306株临床分离株（5804株对INH耐药[INH]和3502株对INH敏感[INH]）。三个最常发生突变的位点仍然是基因的315位点（315；=4271）、基因的-15位点（-15；=787）和基因的-8位点（-8；106）。然而，-8位点的诊断价值远低于先前的认识，因为它仅出现在25株（0.4%）缺乏前两个突变的INH分离株中。我整理了45个与INH耐药相关的新位点（29个基因、9个基因和7个基因），并确定了59个位点（本综述和先前综述共有的）作为分子诊断的可靠基础。纳入所有观察到的突变后的累积敏感性为85.6%。在14.4%的耐药分离株中，未检测到耐药机制，这使得它们可能逃避分子检测，而对于单一INH耐药的情况，可能会转变为耐多药结核病（MDR-TB）。将本研究整理的信息整合到当前的诊断工具中对于对抗MDR-TB的出现至关重要，而排除这些信息可能会导致对常见机制的意外选择和多样化进化。观察到许多低频耐药性赋予突变表明全基因组测序（WGS）在诊断方面具有优势。最后，我为未来的诊断平台提供了五条建议。
