Abstract
To study the hypothesis of the mutant selection window (MSW) in a pharmacodynamic context, the susceptibility of a clinical isolate of methicillin-resistant Stap. hylococcus aureus exposed to moxifloxacin (MOX), levofloxacin (LEV) and ciprofloxacin (CIP) was tested daily 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) and LEV (half-life 6.8 h) and twicedaily administration of CIP (half-life 4 h) provided peak concentrations (Cmax) that equaled the MIC, fell between the MIC and the mutant prevention concentration (MPC), i.e., inside the MSW, or that exceeded the MPC. The respective ratios of Cmax to MIC varied from 1.3 to 24. With all three quinolones, the greatest increases in MIC were observed at Cmax/MICs of 2–6, that corresponded to quinolone concentrations within the MSW over most of the dosing interval.No changes in MIC were observed with the smallest Cmax/MICs (<1.5) and at the highest Cmax/MICs (18–24) where quinolone concentrations exceeded the MPC over most of the dosing interval. These «protective» Cmax/MIC ratios correspond to 66% of the usual clinical dose of MOX, 220% – of LEV and 640% of – CIP.Thus, MOX may protect against resistance development at sub-therapeutic doses whereas LEV and CIP provide a similar effect only at doses that exceed their usual clinical doses.These data support the MSW concept.
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