In Vitro Pharmacodynamic Evaluation of the Mutant Selection Window Hypothesis Using Four Fluoroquinolones against Staphylococcus aureus
Abstract
To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant Staphylococcus aureus exposed to moxifloxacin (MOX), gatifloxacin (GAT), levofloxacin (LEV), and ciprofloxacin (CIP) was tested daily by using an in vitro dynamic model that simulates human pharmacokinetics. A series of monoexponential pharmacokinetic profiles that mimic once-daily administration of MOX (half-life, 12 h), GAT (half-life, 7 h), and LEV (half-life, 6.8 h) and twice-daily administration of CIP (half-life, 4 h) provided peak concentrations (C(max)) that either equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC) (i.e., within or "inside" the MSW), or exceeded the MPC. The respective ratios of the area under the curve (AUC) over a 24-h dosing interval (AUC(24)) to the MIC varied from 13 to 244 h, and the starting inoculum was 10(8) CFU/ml (6 x 10(9) CFU per 60-ml central compartment). With all four quinolones, the greatest increases in MIC were observed at those AUC(24)/MIC values (from 24 to 62 h) that corresponded to quinolone concentrations within the MSW over most of the dosing interval (>20%). Less-pronounced increases in MIC were associated with the smallest simulated AUC(24)/MIC values (15 to 16 h) of GAT and CIP, whose C(max) exceeded the MICs. No such increases were observed with the smallest AUC(24)/MIC values (13 to 17 h) of MOX and LEV, whose C(max) were close to the…
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