Concentration dependency of phenotypic and genotypic isoniazid-rifampicin resistance emergence was investigated to obtain a mechanistic understanding on how anti-mycobacterial drugs facilitate the emergence of bacterial populations that survive throughout treatment. Using static kill curve experiments, observing two evolution cycles, it was demonstrated that rifampicin resistance was the result of non-specific mechanisms and not associated with accumulation of drug resistance encoding SNPs. Whereas, part of isoniazid resistance could be accounted for by accumulation of specific SNPs, which was concentration dependent. Using a Hollow Fibre Infection Model it was demonstrated that emergence of genotypic resistance only occurs when antibiotic levels fall below MIC although MICs are typically maintained following clinical dosing provided that adherence to the regimen is good. This study showed that disentangling and quantifying concentration dependent emergence of resistance provides improved rational for drug and dose selection although further work on understanding underlying mechanisms is needed to improve the drug development pipeline.

中文翻译：

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了解抗分枝杆菌剂量依赖性耐药性的出现

研究了表型和基因型异烟肼-利福平耐药性出现的浓度依赖性，以获得关于抗分枝杆菌药物如何促进在整个治疗过程中存活的细菌种群出现的机制理解。使用静态杀伤曲线实验，观察两个进化周期，证明利福平耐药是非特异性机制的结果，与编码 SNP 的耐药性的积累无关。然而，部分异烟肼抗性可以通过特定 SNP 的积累来解释，这取决于浓度。使用中空纤维感染模型证明，仅当抗生素水平低于 MIC 时才会出现基因型耐药性，尽管只要对方案的依从性良好，通常在临床给药后维持 MIC。这项研究表明，解开和量化浓度依赖性的耐药性出现为药物和剂量选择提供了更好的合理性，尽管需要进一步了解潜在机制以改善药物开发流程。