Abstract
According to the mutant selection window (MSW) hypothesis resistant mutants are selected at antibiotic concentrations above the MIC but below the mutant prevention concentration (MPC). There are contradictory reports on the relationships between MIC- and MPCrelated pharmacokinetic indices and the enrichment of resistant mutants. To compare the AUC/MIC and AUC/ MPC ratios as predictors of bacterial resistance, two methicillin-resistant strains of Staphylococcus aureus, ATCC 43300 and ATCC 6538, exhibiting different MPC/ MIC ratios (4 and 16, respectively) were exposed to twicedaily ciprofloxacin for 3 consecutive days using an in vitro dynamic model. Simulated ratios of 24-hour AUC (AUC24) to MIC were designed to provide ciprofloxacin concentrations within the MSWs over most of the dosing interval. Ciprofloxacin-resistant mutants of S. aureus ATCC 6538 (AUC24/MICs 48, 140 and 260 h; the time inside the MSW (TMSW) 75–100% of the dosing interval) and S. aureus ATCC 43300 (AUC24/MICs 30, 72 and 100 h; TMSW 56–63%) were enriched during the treatments. With each organism, this enrichment was concentrationdependent: the higher the AUC24/MIC, the later the onset of mutant selection and the smaller the area under the bacterial mutant curve (AUBCM). Although both AUC24/ MIC and AUC24/MPC were predictive of resistance of the individual organisms, only AUC24/MPC was a bacterial strain-independent predictor. With combined data on S. aureus ATCC 6538 and ATCC 43300, there were tight correlations between the AUBCM and log AUC24/ MPC for mutants of resistant to 2×, 4×, 8×MIC of ciprofloxacin (r2 0.88, 0.96 and 0.97, respectively). Weaker correlations were established between the AUBCM and log AUC24/MIC (r2 0.33–0.49). This study suggests that selection of resistant staphylococci is better predicted by AUC24/MPC than AUC24/MIC.
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