Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) remains the dominant cause of death from a bacterial infectious disease.1 Sustained global efforts to meet the ambitious elimination targets of WHO’s END-TB strategy have had a limited impact so far. This reflects the complex and multifaceted challenge posed, with multidrug resistant (MDR)-TB representing a significant and growing problem. In 2021, there were an estimated 450 000 new cases of MDR-TB, a 3.1% increase from 2020.1 Furthermore, only 36% of this population accessed treatment, due in part to the challenges of recognising drug resistance. While culture-based methods have historically provided the gold standard for drug susceptibility testing, they are limited by the prolonged turnaround time which can extend from weeks to months due to dependence on the slow growth rate of MTB. In patients with unrecognised drug-resistant TB, antituberculous therapy may therefore be ineffective or suboptimal, worsening morbidity and prognosis and promoting the development of further drug resistance. Technological advances over the past 15 years have led to a steady transition towards more rapid diagnostic molecular methods that focus on identifying the presence of gene mutations associated with resistance. These include automated platforms for targeted PCR that provide screening at scale, coupled with whole genome sequencing (WGS) for coverage at depth and scope to identify emerging mutations of clinical significance. In 2017, the UK became the first country to systematically implement WGS into the routine diagnostic workflow of mycobacterial infection, achieving clinically impactful improvements in the reporting time of genotypic drug-resistance mutations.2 As data accumulate globally, our understanding of genotypic correlates of phenotypic resistance3 is evolving, supporting wider WGS adoption. However, this transition carries potential risks and …

中文翻译：

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结核病的异质耐药性：我们是否遗漏了隐藏在视线中的耐药细菌？

由结核分枝杆菌 (MTB) 引起的结核病 (TB) 仍然是细菌性传染病死亡的主要原因。1 全球为实现世卫组织终结结核病战略雄心勃勃的消除目标而做出的持续努力迄今为止所产生的影响有限。这反映了所面临的复杂和多方面的挑战，其中耐多药（MDR）结核病是一个重大且日益严重的问题。 2021 年，估计有 45 万耐多药结核新发病例，比 2020 年增加 3.1%。1 此外，这一人群中只有 36% 接受了治疗，部分原因是认识耐药性的挑战。虽然基于培养的方法历来为药物敏感性测试提供了黄金标准，但它们受到周转时间延长的限制，由于依赖于 MTB 的缓慢生长速度，周转时间可能从数周延长至数月。因此，对于未识别的耐药结核病患者，抗结核治疗可能无效或不理想，导致发病率和预后恶化，并促进进一步耐药性的发展。过去 15 年的技术进步导致了向更快速诊断分子方法的稳步过渡，这些方法专注于识别与耐药性相关的基因突变的存在。其中包括提供大规模筛查的靶向 PCR 自动化平台，以及可深度和广度覆盖的全基因组测序 (WGS)，以识别具有临床意义的新兴突变。 2017 年，英国成为第一个将 WGS 系统地纳入分枝杆菌感染常规诊断工作流程的国家，在基因型耐药突变的报告时间方面实现了具有临床影响的改进。2随着全球数据的积累，我们对表型的基因型相关性的理解逐渐加深。阻力3正在不断发展，支持更广泛的WGS采用。然而，这种转变带来了潜在的风险……