Emergence of bedaquiline, pretomanid and linezolid resistance after implementation of new drug-resistant tuberculosis regimens in South Africa

项目总结 耐药(DR)结核病(TB)有可能破坏在全球控制结核病和 爱滋病毒。在全球每年新增的近50万耐多药结核病病例中，只有一半被治愈 而那些广泛耐药(XDR)结核病患者的预后甚至更差。新的和改变用途的药物 对结核病的治疗带来了MDR/XDR结核病治疗的革命性变化，从而提高了治愈率，并缩短了完全口服时间 养生法。贝达奎林(Bdq)和前列托马尼德(PA)是第一批新的结核病药物类别中的药物 从1968年开始。与重新调整用途的药物利奈唑胺(LZD)相结合，这些新药提供了 存活率和治愈率大幅提高。出现广泛的BDQ、PA或LZD耐药性 可能会削弱这些药物的潜力。耐药的自然历史被概念化为进化。 从药物引入后不久的零星耐药突变株和低水平耐药突变株，到少数高度耐药突变株 适应的可传播菌株，在成熟的耐药结核病疫情中在人群中传播耐药性。如图所示 在耐多药/广泛耐药结核病中，只有在耐药性广泛传播后，才会出现人群水平的耐药性 菌株的出现，而不是通过结核病治疗中获得性耐药性的孤立实例。在建议的 研究，我们将检查在南非出现的Bdq、PA和LZD耐药性，作为这些治疗的 新药扩大到所有耐药结核病病例。在目标1中，我们将前瞻性地描述 应用全基因组测序技术检测沙门氏菌Bdq、Pa和Lzd基因突变 三个省的病人。在目标2中，我们将检查最低抑菌浓度(MIC)以评估 在研究过程中，对Bdq、Pa和LZD的耐药性水平发生了有意义的变化。在《目标3》中，我们将 使用WGS、之前的治疗暴露和地理空间分析来确定增加的传播率和 Bdq、Pa和Lzd抗性的地理传播。拟议的研究将提供以下重要信息： 可以为这些关键的新结核病药物的新的快速诊断分析的开发提供信息。此外，我们的 表型分析将为是否有必要在现有治疗基础上增加药物提供决策依据 养生或增加特定药物的剂量。最后，我们对遗传克隆和基因克隆的分析 地理传播将为结核病控制项目提供早期预警信号，说明可能会广泛传播 传递的阻力。南非是结核病出现和传播的领头羊。这是一个 高负担国家，引领全球推广包含BDQ、LZD和 现在，爸爸，对于所有的抗药性患者。建议的研究的最佳时机是前瞻性地研究 BDQ、PA和LZD耐药性的出现、演变和扩散 全球结核病DR治疗。

PROJECT SUMMARY Drug-resistant (DR) tuberculosis (TB) threatens to derail the progress made in global control of TB and HIV. Of the nearly 500,000 new cases of multidrug-resistant (MDR) TB worldwide annually, only half are cured and those with extensively drug-resistant (XDR) TB have even poorer outcomes. New and repurposed drugs for TB have revolutionized MDR/XDR TB treatment, resulting in improved cure rates and shorter, fully-oral regimens. Bedaquiline (Bdq) and pretomanid (Pa) are medications from the first novel TB drug classes created since 1968. Combined with a repurposed medication, linezolid (Lzd), these new drugs have provided substantial improvements in survival and cure rates. The emergence of widespread Bdq, Pa or Lzd resistance could undermine these drugs’ potential. The natural history of drug resistance is conceptualized as evolving from sporadic drug-resistant mutants with low-level resistance soon after the drug is introduced, to a few highly adapted transmissible strains that spread resistance across a population in a mature DR TB epidemic. As seen in MDR/XDR TB, population-level drug resistance appears only after widespread transmission of drug-resistant strains occurs, rather than through isolated instances of acquired resistance on TB treatment. In the proposed study, we will examine the emergence of Bdq, Pa, and Lzd resistance in South Africa as treatment with these new drugs is expanded to all drug-resistant TB cases. In Aim 1, we will prospectively characterize changes in resistance-conferring mutations for Bdq, Pa and Lzd using whole genome sequencing (WGS) on isolates from patients in three provinces. In Aim 2, we will examine minimum inhibitory concentrations (MIC) to assess for meaningful shifts in the level of resistance to Bdq, Pa, and Lzd over the course of the study. In Aim 3, we will use WGS, prior treatment exposure, and geospatial analysis to identify increased transmissibility and geographic spread of Bdq, Pa, and Lzd resistance. The proposed study will provide essential information that can inform the development of new rapid diagnostic assays for these critical new TB drugs. Further, our phenotypic analyses will inform decisions on whether it is necessary to add drugs to existing treatment regimens or increase the dose of a specific medication. Finally, our analyses of genetic clonality and geographic spread will provide early warning signs to TB control programs about the potential for widespread transmitted resistance. South Africa serves as a bellwether for the emergence and spread of DR TB. It is a high-burden country that is leading the global scale up of new treatment regimens containing Bdq, Lzd, and now Pa, for all drug-resistant patients. The proposed study is optimally timed to prospectively study the emergence, evolution and dispersal of drug resistance to Bdq, Pa and Lzd as they are being scaled up for the DR TB treatment worldwide.