Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
BMJ Glob Health. 2024 Mar 28;9(3):e013532. doi: 10.1136/bmjgh-2023-013532.
Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance () whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction.
We curated and quality-controlled WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling. Validation leveraged a national DR survey conducted in South Africa.
isolates from 29 countries (n=19 149) met sequence quality criteria. Global marginal genotypic resistance among mono-resistant TB estimates overlapped with the South African DR survey, except for isoniazid, ethionamide and second-line injectables, which were underestimated (n=3134). Among multidrug resistant (MDR) TB (n=268), estimates overlapped for the fluoroquinolones but overestimated other drugs. Globally pooled mono-resistance to isoniazid was 10.9% (95% CI: 10.2-11.7%, n=14 012). Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% (0.1-11%), n=111 and India 2.8% (0.08-9.4%), n=114). Given the recent interest in drugs enhancing ethionamide activity and their expected activity against isolates with resistance discordance between isoniazid and ethionamide, we measured this rate and found it to be high at 74.4% (IQR: 64.5-79.7%) of isoniazid-resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3964).
This is the first attempt at global antibiogram estimation. DR prevalence in can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics, but public WGS data demonstrates oversampling of isolates with higher resistance levels than MDR. Nevertheless, our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug-susceptible TB in South Asia and indicate underutilisation of ethionamide in MDR treatment.
全球结核病（TB）耐药性（DR）监测主要关注利福平。我们研究了公共和监测全基因组测序（WGS）数据的潜力，通过基于计算机的耐药性预测，生成扩展的国家耐药率估计值（药敏谱）。
我们整理和质量控制了 WGS 数据。我们使用经过验证的随机森林模型来预测 12 种药物的表型耐药性，并针对模型性能、暴发采样和利福平耐药性过采样进行了偏倚校正。验证利用了南非进行的一项全国性 DR 调查。
来自 29 个国家（n=19149）的分离株符合序列质量标准。单耐药结核病全球估计的边缘基因耐药性与南非 DR 调查结果重叠，除异烟肼、乙胺丁醇和二线注射剂外，这些药物的耐药性估计值较低（n=3134）。在耐多药结核病（MDR）（n=268）中，氟喹诺酮类药物的耐药性估计值重叠，但其他药物的耐药性估计值过高。全球单耐异烟肼率为 10.9%（95%CI：10.2-11.7%，n=14012）。南亚的单左氧氟沙星耐药率最高（巴基斯坦 3.4%（0.1-11%），n=111 和印度 2.8%（0.08-9.4%），n=114）。鉴于最近对增强乙胺丁醇活性的药物和预计对异烟肼和乙胺丁醇耐药性不一致的分离株具有活性的药物的兴趣，我们测量了这种耐药率，发现预测对乙胺丁醇敏感的异烟肼耐药分离株中有 74.4%（IQR：64.5-79.7%）为高。MDR 中对吡嗪酰胺和左氧氟沙星的全球敏感性率为 15.1%（95%CI：10.2-19.9%，n=3964）。
这是首次尝试进行全球药敏谱估计。可以使用公共 WGS 和关键抗生素的表型耐药性预测可靠地估计 的耐药流行率，但公共 WGS 数据显示，与 MDR 相比，具有更高耐药水平的分离株被过度采样。尽管如此，我们的结果引起了对南亚经验性使用短程氟喹诺酮方案治疗耐药物理结核病的关注，并表明在 MDR 治疗中乙胺丁醇的利用不足。
