Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
Antimicrob Agents Chemother. 2012 Jun;56(6):3047-53. doi: 10.1128/AAC.06460-11. Epub 2012 Apr 2.
Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter -15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P < 0.0001). Lineage 1 was associated with inhA promoter -15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P < 0.0001). In conclusion, M. tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance.
细菌因素可能导致全球耐多药结核病（TB）的出现和传播。只有少数研究报告了不同细菌因素之间的相互作用。我们研究了 2000 年至 2008 年在瑞士进行的全国性研究中分离的耐多药结核分枝杆菌。我们通过 Bactec MGIT-960 确定了一线药物的定量耐药水平，并通过测序相关基因的热点区域确定了耐药基因型。我们通过分子方法确定了近期传播，并收集了临床数据。总的来说，我们分析了 158 株对异烟肼、利福平或乙胺丁醇耐药的分离株，其中 48 株（30.4%）为耐多药。在 154 株异烟肼耐药株中，katG 突变与高水平耐药相关，inhA 启动子突变与低水平耐药相关。只有 katG(S315T)（所有异烟肼耐药株的 65.6%）和 inhA 启动子-15C/T（22.7%）在分子群中发现。结核分枝杆菌谱系 2（包括北京基因型）与任何耐药性相关（调整后的比值比[OR]，3.0；95%置信区间[CI]，1.7 至 5.6；P < 0.0001）。谱系 1 与 inhA 启动子-15C/T 突变相关（OR，6.4；95% CI，2.0 至 20.7；P = 0.002）。我们发现遗传株背景影响特定突变所传递的异烟肼耐药水平（所有谱系的耐药突变相互作用测试；P < 0.0001）。总之，结核分枝杆菌耐药突变与不同水平的耐药性和传播有关，结核分枝杆菌谱系与特定的耐药性赋予突变和表型耐药性相关。我们的研究还支持不同耐药突变与菌株遗传背景之间的上位性相互作用在结核分枝杆菌耐药性中的作用。
