TB resistance emergence

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 the treatment. This can contribute to improved rational selection of candidate drug combinations for evaluation in clinical trials and to a mechanistic evaluation of early bactericidal activity in Phase II clinical studies. To that end we also investigated the impact of in-vivo mimicking pharmacokinetic profiles at a range of dose scenarios. Using static kill curve experiments, embedded in two evolution cycles, it was demonstrated that rifampicin resistance was solely phenotypic but part of isoniazid phenotypic resistance could be accounted for by genotype, which was concentration dependent. Using a Hollow Fibre Infection Model it was subsequently 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.