Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Antimicrobial Pharmacodynamics and Therapeutics, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Antimicrob Agents Chemother. 2020 Aug 20;64(9). doi: 10.1128/AAC.00860-20.
In 2019, the WHO tuberculosis (TB) treatment guidelines were updated to recommend only limited use of streptomycin, in favor of newer agents or amikacin as the preferred aminoglycoside for drug-resistant However, the emergence of resistance to newer drugs, such as bedaquiline, has prompted a reanalysis of antitubercular drugs in search of untapped potential. Using 211 clinical isolates of from South Africa, we performed phenotypic drug susceptibility testing (DST) to aminoglycosides by both critical concentration and MIC determination in parallel with whole-genome sequencing to identify known genotypic resistance elements. Isolates with low-level streptomycin resistance mediated by were frequently misclassified with respect to streptomycin resistance when using the WHO-recommended critical concentration of 2 μg/ml. We identified 29 isolates from South Africa with low-level streptomycin resistance concomitant with high-level amikacin resistance, conferred by and 1400, respectively. Using a large global data set of genomes, we observed 95 examples of this corresponding resistance genotype ( 1400), including identification in 81/257 (31.5%) of extensively drug resistant (XDR) isolates. In a phylogenetic analysis, we observed repeated evolution of low-level streptomycin and high-level amikacin resistance in multiple countries. Our findings suggest that current critical concentration methods and the design of molecular diagnostics need to be revisited to provide more accurate assessments of streptomycin resistance for -containing isolates. For patients harboring isolates of with high-level amikacin resistance conferred by 1400, and for whom newer agents are not available, treatment with streptomycin may still prove useful, even in the face of low-level resistance conferred by .
2019 年，世卫组织结核病（TB）治疗指南进行了更新，建议仅有限使用链霉素，转而推荐新型药物或阿米卡星作为治疗耐药性结核病的首选氨基糖苷类药物。然而，新型药物（如贝达喹啉）耐药性的出现促使人们重新分析抗结核药物，以寻找未开发的潜力。我们使用来自南非的 211 株临床分离株，通过临界浓度和 MIC 测定平行进行表型药物敏感性试验（DST）来检测氨基糖苷类药物，同时进行全基因组测序以鉴定已知的基因型耐药元件。由 引起的低水平链霉素耐药的分离株，在使用世卫组织推荐的 2μg/ml 临界浓度时，常常被错误分类为链霉素耐药。我们从南非鉴定出 29 株具有低水平链霉素耐药性的分离株，同时对高水平阿米卡星耐药，分别由 和 1400 介导。使用大型全球基因组数据集，我们观察到 95 个具有这种对应耐药基因型（ 1400）的例子，包括在 257 个广泛耐药（XDR）分离株中的 81 个（31.5%）。在系统发育分析中，我们观察到低水平链霉素和高水平阿米卡星耐药性在多个国家中反复进化。我们的研究结果表明，当前的临界浓度方法和分子诊断设计需要重新考虑，以更准确地评估含 的分离株的链霉素耐药性。对于携带高水平阿米卡星耐药性（由 1400 介导）的 分离株的患者，并且新型药物不可用，即使由 赋予的低水平耐药性，使用链霉素治疗仍可能证明是有用的。
