Are ciprofloxacin dosage regimens adequate for antimicrobial efficacy and prevention of resistance? Pseudomonas aeruginosa bloodstream infection in elderly patients as a simulation case study.

The aim of this work was to define the optimal dosage (OD) of ciprofloxacin in order to prevent the emergence of bacterial resistance of Pseudomonas aeruginosa in a geriatric population with a bloodstream infection. A thousand pharmacokinetic profiles were simulated with a ciprofloxacin pharmacokinetic model from the literature. Three dosing regimens were tested for five days: once daily (QD), twice daily (BID), and thrice daily (TID). First of all, effective dosages (ED) of ciprofloxacin were defined as those achieving a target AUC24 /MIC ≥ 125. Then, these ED were simulated in order to calculate the percentage of time spent within the mutant selection window (TMSW ) and to select optimal dosage (OD) defined as those achieving TMSW ≤ 20%. Based on the AUC24 /MIC, for low MICs (0.125 μg/mL), all dosing regimens recommended by French guidelines were effective. For intermediate MICs (0.25 and 0.5 μg/mL), simulated doses higher than those recommended were needed to achieve the efficacy target. About prevention of resistance for low MICs, dosages recommended were only effective in patients with creatinine clearance (CLCR ) ≥ 60 mL/min. For intermediate MICs, dosages higher than recommended were needed to achieve the optimality target. This study shows that current ciprofloxacin dosing guidelines have not been optimized to prevent the emergence of bacterial resistance, especially in geriatric patients with mild to severe renal impairment. To achieve both efficacy and prevention of resistance, ciprofloxacin dosages greater than those recommended would be needed. Tolerance of such higher doses needs to be evaluated in clinical studies.