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 (AUC(24)) to the MIC (32 and 64 h). To provide an integral presentation of the time course of mutants grown on agar plates containing 2x and 4x the MIC of daptomycin, areas under the bacterial mutant kinetic curves (AUBC(M)s) were calculated.
Results: Daptomycin-resistant S. aureus mutants were enriched gradually over the entire treatment duration, with systematic increases in AUBC(M) and concomitant decreases in susceptibility. AUBC(M) analyses were also applied to resistance data reported from other studies with S. aureus exposed to daptomycin and garenoxacin over a wide range of AUC(24)/MIC ratios. Although the maximal AUBC(M)s were greater with longer than with shorter exposures, the treatment or observation durations did not influence the predicted anti-mutant AUC(24)/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 AUC(24)/MIC ratio.