Department of Human, Biological and Translational Medical Sciences, School of Medicine, University of Namibia, Windhoek, Namibia.
Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany.
Microbiol Spectr. 2022 Oct 26;10(5):e0158622. doi: 10.1128/spectrum.01586-22. Epub 2022 Sep 27.
Namibia is among 30 countries with a high burden of tuberculosis (TB), with an estimated incidence of 460 per 100,000 population and around 800 new multidrug-resistant (MDR) TB cases per year. Still, data on the transmission and evolution of drug-resistant Mycobacterium tuberculosis complex (Mtbc) strains are not available. Whole-genome sequencing data of 136 rifampicin-resistant (RIFr) Mtbc strains obtained from 2016 to 2018 were used for phylogenetic classification, resistance prediction, and cluster analysis and linked with phenotypic drug susceptibility testing (pDST) data. Roughly 50% of the strains investigated were resistant to all first-line drugs. Furthermore, 13% of the MDR Mtbc strains were already pre-extensively drug resistant (pre-XDR). The cluster rates were high, at 74.6% among MDR and 85% among pre-XDR strains. A significant proportion of strains had borderline resistance-conferring mutations, e.g., promoter mutations or L430P. Accordingly, 25% of the RIFr strains tested susceptible by pDST. Finally, we determined a potentially new bedaquiline resistance mutation (Rv0678 D88G) occurring in two independent clusters. High rates of resistance to first-line drugs in line with emerging pre-XDR and likely bedaquiline resistance linked with the ongoing recent transmission of MDR Mtbc clones underline the urgent need for the implementation of interventions that allow rapid diagnostics to break MDR TB transmission chains in the country. A borderline RIFr mutation in the dominant outbreak strain causing discrepancies between phenotypic and genotypic resistance testing results may require breakpoint adjustments but also may allow individualized regimens with high-dose treatment. The transmission of drug-resistant tuberculosis (TB) is a major problem for global TB control. Using genome sequencing, we showed that 13% of the multidrug-resistant (MDR) M. tuberculosis complex strains from Namibia are already pre-extensively drug resistant (pre-XDR), which is substantial in an African setting. Our data also indicate that the ongoing transmission of MDR and pre-XDR strains contributes significantly to the problem. In contrast to other settings with higher rates of drug resistance, we found a high proportion of strains having so-called borderline low-level resistance mutations, e.g., promoter mutations or L430P. This led to the misclassification of 25% of the rifampicin-resistant strains as susceptible by phenotypic drug susceptibility testing. This observation potentially allows individualized regimens with high-dose treatment as a potential option for patients with few treatment options. We also found a potentially new bedaquiline resistance mutation in .
纳米比亚是结核病（TB）负担沉重的 30 个国家之一，估计发病率为每 10 万人 460 例，每年约有 800 例新的耐多药（MDR）TB 病例。然而，关于耐药结核分枝杆菌复合群（Mtbc）菌株的传播和进化的数据尚不可用。我们使用了 2016 年至 2018 年期间从 136 株利福平耐药（RIFr）结核分枝杆菌中获得的全基因组测序数据进行系统发育分类、耐药预测和聚类分析，并与表型药物敏感性测试（pDST）数据相关联。大约 50%的被调查菌株对所有一线药物均有耐药性。此外，13%的耐多药结核分枝杆菌菌株已经具有预先广泛耐药（pre-XDR）。集群率很高，耐多药和预广泛耐药菌株的集群率分别为 74.6%和 85%。相当一部分菌株具有边界耐药性的突变，例如 启动子突变或 L430P。因此，25%的利福平耐药菌株通过 pDST 测试被认为是敏感的。最后，我们确定了一种潜在的新的贝达喹啉耐药突变（Rv0678 D88G），它发生在两个独立的集群中。与新兴的预广泛耐药和可能的贝达喹啉耐药相关的一线药物高耐药率，以及 MDR Mtbc 克隆的持续传播，突显了迫切需要实施干预措施，以便在该国迅速诊断耐药结核分枝杆菌传播链。引起表型和基因型耐药检测结果差异的优势暴发菌株中的边界利福平耐药突变可能需要调整断点，但也可能允许采用高剂量治疗的个体化方案。 耐多药结核病（TB）的传播是全球结核病控制的一个主要问题。使用基因组测序，我们发现纳米比亚的 13%的耐多药（MDR）结核分枝杆菌复合体菌株已经具有预先广泛耐药（pre-XDR），这在非洲环境中是相当大的。我们的数据还表明，MDR 和预广泛耐药菌株的持续传播是造成这一问题的主要原因。与其他耐药率较高的地区不同，我们发现相当一部分菌株具有所谓的边界低水平耐药突变，例如 启动子突变或 L430P。这导致通过表型药物敏感性测试将 25%的利福平耐药菌株错误分类为敏感。这一观察结果可能为少数治疗选择有限的患者提供个体化高剂量治疗方案。我们还在 中发现了一种潜在的新型贝达喹啉耐药突变。
