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

项目摘要 耐药结核病（DR）威胁着全球结核病控制取得的进展， 艾滋病。在全世界每年近50万例新的耐多药（MDR）结核病病例中，只有一半被治愈 而广泛耐药结核病（XDR）患者的预后更差。新药和再利用药物 彻底改变了MDR/XDR结核病治疗，提高了治愈率，缩短了全口服 养生法贝达喹啉（Bdq）和pretomanid（Pa）是第一批新型结核病药物类别中的药物 从1968年开始结合重新使用的药物利奈唑胺（Lzd），这些新药提供了 生存率和治愈率的显著提高。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性的自然史被概念化为进化 从药物引入后不久具有低水平抗性的零星耐药突变体，到一些高度耐药突变体， 在成熟的耐药结核病流行中，适应性传播菌株在人群中传播耐药性。看到 在耐多药/广泛耐药结核病中，只有在耐药结核病广泛传播后， 结核病的发生不是通过对结核病治疗的获得性耐药性的孤立实例。拟议 在这项研究中，我们将研究南非出现的Bdq，Pa和Lzd耐药性，作为这些药物的治疗方法。 新的药物被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 使用全基因组测序（WGS）对来自 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的抗性水平发生有意义的变化。在目标3中，我们 使用WGS、治疗前暴露和地理空间分析来识别增加的传播性， Bdq、Pa和Lzd抗性的地理分布。拟议的研究将提供必要的信息， 可以为这些关键的新型结核病药物的新的快速诊断测定的开发提供信息。此外，我们的 表型分析将决定是否有必要在现有治疗中增加药物 方案或增加特定药物的剂量。最后，我们对遗传克隆性和 地理传播将为结核病控制项目提供有关结核病广泛传播的可能性的早期预警信号。 传递阻力南非是耐药结核病出现和传播的领头羊。这是一个 高负担国家，引领全球扩大含Bdq、Lzd和 现在，爸爸，所有耐药患者。拟议研究的最佳时机是前瞻性研究 对Bdq、Pa和Lzd的耐药性的出现、演变和扩散，因为它们正在扩大规模， 全球DR TB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.