Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion

Abstract

Enrichment of resistant mutants at antibiotic concentrations above the minimum inhibitory concentration (MIC) but below the mutant prevention concentration (MPC), i.e. within the mutant selection window (MSW), might be dependent on the shape of the pharmacokinetic profile. To address this issue, two strains of Staphylococcus aureus were exposed to fluctuating (bolus administration) and constant (continuous infusion) concentrations of ciprofloxacin. Staphylococcus aureus ATCC 43300 and ATCC 6538 exhibiting different MPC/MIC ratios (4 and 16, respectively) were exposed to ciprofloxacin twice daily by bolus administration and continuous infusion for 3 days. With each organism and mode of administration, a series of pharmacokinetic profiles was simulated to have the same 24-h area under the concentration-time curve (AUC24) to MIC ratio. The simulated AUC24/MIC ratios were designed to provide ciprofloxacin concentrations within the MSW over most of the dosing interval (bolus administration) or over the entire dosing interval (continuous infusion). In all simulations, ciprofloxacin-resistant staphylococci were enriched in a concentration-dependent manner, i.e. the higher the AUC24/MIC, the later the onset of mutant selection and the smaller the area under the bacterial mutant curve (AUBC M). The relationships between AUC24/MIC and AUBC M were independent of the shape of the simulated pharmacokinetic profiles that corresponded to the different modes of ciprofloxacin administration. For mutants resistant to > or = 4 x MIC of ciprofloxacin, the AUC24/MIC was less predictive of the AUBC M than the AUC24/MPC ratio. This study indicates the mode of ciprofloxacin administration does not influence selection of resistant staphylococci, which is better predicted by AUC24/MPC than by AUC24/MIC.