鉴定异烟肼耐药标志物，以指导将高剂量异烟肼纳入结核病治疗方案。
Identifying isoniazid resistance markers to guide inclusion of high-dose isoniazid in tuberculosis treatment regimens.
机构信息
Family Medicine and Population Health (FAMPOP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
Family Medicine and Population Health (FAMPOP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
出版信息
Clin Microbiol Infect. 2020 Oct;26(10):1332-1337. doi: 10.1016/j.cmi.2020.07.004. Epub 2020 Jul 9.
OBJECTIVES
Effective use of antibiotics is critical to control the global tuberculosis pandemic. High-dose isoniazid (INH) can be effective in the presence of low-level resistance. We performed a systematic literature review to improve our understanding of the differential impact of genomic Mycobacterium tuberculosis (Mtb) variants on the level of INH resistance. The following online databases were searched: PubMed, Web of Science and Embase. Articles reporting on clinical Mtb isolates with linked genotypic and phenotypic data and reporting INH resistance levels were eligible for inclusion.
METHODS
All genomic regions reported in the eligible studies were included in the analysis, including: katG, inhA, ahpC, oxyR-ahpC, furA, fabG1, kasA, rv1592c, iniA, iniB, iniC, rv0340, rv2242 and nat. The level of INH resistance was determined by MIC: low-level resistance was defined as 0.1-0.4 μg/mL on liquid and 0.2-1.0 μg/mL on solid media, high-level resistance as >0.4μg/mL on liquid and >1.0 μg/mL on solid media.
RESULTS
A total of 1212 records were retrieved of which 46 were included. These 46 studies reported 1697 isolates of which 21% (n = 362) were INH susceptible, 17% (n = 287) had low-level, and 62% (n = 1048) high-level INH resistance. Overall, 24% (n = 402) of isolates were reported as wild type and 76% (n = 1295) had ≥1 relevant genetic variant. Among 1295 isolates with ≥1 variant, 78% (n = 1011) had a mutation in the katG gene. Of the 867 isolates with a katG mutation in codon 315, 93% (n = 810) had high-level INH resistance. In contrast, only 50% (n = 72) of the 144 isolates with a katG variant not in the 315-position had high-level resistance. Of the 284 isolates with ≥1 relevant genetic variant and wild type katG gene, 40% (n = 114) had high-level INH resistance.
CONCLUSIONS
Presence of a variant in the katG gene is a good marker of high-level INH resistance only if located in codon 315.
目的
有效使用抗生素对于控制全球结核病大流行至关重要。在存在低水平耐药的情况下，高剂量异烟肼（INH）可能有效。我们进行了系统的文献回顾，以提高我们对基因组结核分枝杆菌（Mtb）变异体对 INH 耐药水平的差异影响的理解。以下在线数据库进行了搜索：PubMed、Web of Science 和 Embase。符合条件的文章报告了具有相关基因型和表型数据的临床 Mtb 分离株，并报告了 INH 耐药水平。
方法
对合格研究报告的所有基因组区域进行了分析，包括：katG、inhA、ahpC、oxyR-ahpC、furA、fabG1、kasA、rv1592c、iniA、iniB、iniC、rv2242 和 nat。通过 MIC 确定 INH 耐药水平：低水平耐药定义为液体中 0.1-0.4μg/mL，固体中 0.2-1.0μg/mL；高水平耐药定义为液体中>0.4μg/mL，固体中>1.0μg/mL。
结果
共检索到 1212 条记录，其中 46 条被纳入。这 46 项研究报告了 1697 株分离株，其中 21%（n=362）对 INH 敏感，17%（n=287）为低水平耐药，62%（n=1048）为高水平耐药。总体而言，24%（n=402）的分离株为野生型，76%（n=1295）有≥1 个相关遗传变异。在 1295 株有≥1 个变异的分离株中，78%（n=1011）katG 基因有突变。在 867 株 katG 基因 315 位密码子突变的分离株中，93%（n=810）有高水平 INH 耐药性。相比之下，只有 50%（n=72）的 144 株不在 315 位的 katG 变异株有高水平耐药性。在 284 株有≥1 个相关遗传变异和野生型 katG 基因的分离株中，40%（n=114）有高水平 INH 耐药性。
结论
只有位于密码子 315 时，katG 基因的变异才是高水平 INH 耐药的良好标志物。
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