Pharmacokinetics/pharmacodynamics of antofloxacin hydrochloride in a neutropenic murine thigh model of Staphylococcus aureus infection

Aim: Antofloxacin hydrochloride is a new fluoroquinolone antibiotic with broad‐spectrum in vitro activity. Using the neutropenic murine thigh infection model, we defined the pharmacodynamic profile and property of antofloxacin hydrochloride against Staphylococcus aureus . Methods: Single‐dose pharmacokinetic studies of antofloxacin hydrochloride were carried out in thigh infected mice. Therapy was initiated at 2 h postinoculation with 5–640 mg/kg per d fractionated for different dosing regimens. The thighs were removed for bacterial measurement after 24 h of therapy, the best pharmacokinetic/pharmacodynamic (PK/PD) index correlated with the efficacy was determined by nonlinear regression analysis. A sigmoid E max dose‐response model was used to estimate the daily dose and AUC 24 h /MIC (minimal inhibitory concentration) required to achieve a static effect. Results: The PK was linear with similar elimination half‐life over the dose range studied. The AUC 24 h /MIC ratio was the PK/PD parameter that best correlated with efficacy ( R 2 =923%, 90.8% for the two organisms, compared with C max /MIC and T>MIC [%], respectively). The 24 h static dose ranged from 34.3 to 153.7 mg/kg per d for all S aureus strains, the total AUC 24 h /MIC ratio to achieve bacteriostatic effect varied from 31.7 to 122.5 (mean, 65.7±30.6). Conclusion: Antofloxacin hydrochloride showed powerful antibacterial activity against the S aureus isolates used in our neutropenicinfected mice model. Our data suggested that the AUC/MIC ratio appeared to be most closely linked to the bacterial outcome ( R 2 >90%), and a total AUC 24 h /MIC ratio of 65.7 appears to be the target value to achieve a net bactericidal activity against S aureus , similar to the results of other fluoroquinolones.