The impact of duration of antibiotic exposure on bacterial resistance predictions using in vitro dynamic models

Abstract

Objectives: To explore whether the duration of in vitro simulated antibiotic exposure influences bacterial resistance, time-dependent amplification of resistant subpopulations of Staphylococcus aureus was studied in 10 day simulations in a dynamic model with daptomycin as a prototypic agent. Methods: S. aureus ATCC 43300 was exposed to once-daily dosing of daptomycin at subtherapeutic ratios of 24 h area under the curve (AUC24) to the MIC (32 and 64 h). To provide an integral presentation of the time course of mutants grown on agar plates containing 2 × and 4 × the MIC of daptomycin, areas under the bacterial mutant kinetic curves (AUBCMs) were calculated. Results: Daptomycin-resistant S. aureus mutants were enriched graduallyover the entire treatment duration, with systematic increases in AUBCM and concomitant decreases in susceptibility. AUBCM analyses were also applied to resistance data reported from other studies with S. aureus exposed to daptomycin and garenoxacin over a wide range of AUC24/MIC ratios. Although the maximal AUBCMs were greater with longer than with shorter exposures, the treatment or observation durations did not influence the predicted anti-mutant AUC24/MIC ratios. Conclusions: These findings suggest that the duration of in vitro simulated antibiotic exposure is important for estimates of the maximal enrichment of resistant mutants but not for the prediction of the anti-mutant AUC24/MIC ratio. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.