Pharmacokinetics/pharmacodynamics of antofloxacin hydrochloride in a neutropenic murine thigh model of Staphylococcus aureus infection
Abstract
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 Emax dose-response model was used to estimate the daily dose and AUC24 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 AUC24 h/MIC ratio was the PK/PD parameter that best correlated with efficacy (R2=92.3%, 90.8% for the two organisms, compared with Cmax/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 AUC24 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 (R2>90%), and a total AUC24 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.
Keywords:
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 Emax dose-response model was used to estimate the daily dose and AUC24 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 AUC24 h/MIC ratio was the PK/PD parameter that best correlated with efficacy (R2=92.3%, 90.8% for the two organisms, compared with Cmax/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 AUC24 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 (R2>90%), and a total AUC24 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.