Department of Global Health, School of Public Health, Peking University, Beijing, China; National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China; National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Chinese Center for Disease Control and Prevention, Beijing, China.
National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
Lancet Microbe. 2024 Nov;5(11):100899. doi: 10.1016/S2666-5247(24)00131-9. Epub 2024 Sep 28.
WHO issued the first edition catalogue of Mycobacterium tuberculosis complex (MTBC) mutations associated with drug resistance in 2021. However, country-specific issues might lead to arising complex and additional drug-resistant mutations. We aimed to fully reflect the characteristics of drug resistance mutations in China.
We analysed MTBC isolates from the nationwide drug-resistant tuberculosis surveillance with 70 counties in 31 provinces, municipalities, and autonomous regions in China. Three types of MYCOTB plates were used to perform drug susceptibility testing for 12 antibiotics (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, amikacin, kanamycin, ethionamide, clofazimine, linezolid, delamanid, and bedaquiline). Mutations were divided into five groups according to their odds ratios, positive predictive values, false discovery rate-corrected p values, and 95% CIs: (1) associated with resistance; (2) associated with resistance-interim; (3) uncertain significance; (4) not associated with resistance-interim; and (5) not associated with resistance. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to quantify the association between mutations and minimum inhibitory concentrations (MICs). Our dataset was compared with the first edition of the WHO catalogue.
We analysed 10 146 MTBC isolates, of which 9071 (89·4%) isolates were included in the final analysis. 744 (8·2%) isolates were resistant to rifampicin and 1339 (14·8%) to isoniazid. 208 (1·9%) of 11 065 mutations were classified as associated with resistance or associated with resistance-interim. 33 (97·1%) of 34 mutations in group 1 and 92 (52·9%) of 174 in group 2 also appeared in groups 1 or 2 of the WHO catalogue. Of 81 indel mutations in group 2, 15 (18·5%) were in the WHO catalogue. The newly discovered mutation gyrA_Ala288Asp was associated with levofloxacin resistance. MIC values for rifampicin, isoniazid, moxifloxacin, and levofloxacin corresponding to resistance mutations in group 1 were significantly different (p<0·0001), and 12 high-level resistance mutations were detected. 61 mutations in group 3 occurred as solo in at least five phenotypically susceptible isolates, but with MIC values moderately higher than other susceptible isolates. Among 945 phenotypically resistant but genotypically susceptible isolates, 433 (45·8%) were mutated for at least one efflux pump gene.
Our analysis reflects the complexity of drug resistance mutations in China and suggests that indel mutations, efflux pump genes, protein structure, and MICs should be fully considered in the WHO catalogue, especially in countries with a high tuberculosis burden.
National Key Research and Development Program of China and the Science and Technology Major Project of Tibetan Autonomous Region of China.
世界卫生组织于 2021 年发布了第一版与结核分枝杆菌复合群（MTBC）耐药相关的突变目录。然而，特定于国家的问题可能会导致出现复杂和额外的耐药突变。我们旨在充分反映中国耐药突变的特征。
我们分析了来自中国 31 个省、自治区和直辖市的 70 个县的全国耐药结核病监测中的 MTBC 分离株。使用三种类型的 MYCOTB 板对 12 种抗生素（利福平、异烟肼、乙胺丁醇、左氧氟沙星、莫西沙星、阿米卡星、卡那霉素、乙硫异烟胺、氯法齐明、利奈唑胺、德拉马尼和贝达喹啉）进行药敏试验。突变根据其比值比、阳性预测值、错误发现率校正 p 值和 95%CI 分为五类：（1）与耐药相关；（2）与耐药性中间相关；（3）不确定意义；（4）与耐药性中间无关；（5）与耐药性无关。使用 Wilcoxon 秩和检验和 Kruskal-Wallis 检验来量化突变与最小抑菌浓度（MIC）之间的关系。我们的数据与世界卫生组织第一版目录进行了比较。
我们分析了 10146 株 MTBC 分离株，其中 9071 株（89.4%）分离株纳入最终分析。744 株（8.2%）对利福平耐药，1339 株（14.8%）对异烟肼耐药。11065 个突变中的 208 个（1.9%）被归类为与耐药或耐药性中间相关。组 1 中的 33 个（97.1%）和组 2 中的 92 个（52.9%）突变也出现在世界卫生组织目录的组 1 或组 2 中。组 2 中的 81 个插入缺失突变中，有 15 个（18.5%）在世界卫生组织目录中。新发现的突变 gyrA_Ala288Asp 与左氧氟沙星耐药相关。组 1 中耐药突变对应的利福平、异烟肼、莫西沙星和左氧氟沙星的 MIC 值有显著差异（p<0.0001），并检测到 12 种高水平耐药突变。组 3 中的 61 个突变在至少 5 个表型敏感的分离株中单独出现，但 MIC 值略高于其他敏感分离株。在 945 个表型耐药但基因表型敏感的分离株中，有 433 个（45.8%）至少有一个外排泵基因发生突变。
我们的分析反映了中国耐药突变的复杂性，并表明插入缺失突变、外排泵基因、蛋白质结构和 MIC 值应在世界卫生组织目录中得到充分考虑，特别是在结核病负担较高的国家。
中国国家重点研发计划和西藏自治区科技重大专项。
