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

作　　者：Xiu-mei XIAO Yong-hong XIAO 

机构地区：[1]Department of Laboratory, Medicine, Peking University Third Hospital, Beijing 100083 [2]Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100083, China

出　　处：《Acta Pharmacologica Sinica》2008年第10期1253-1260,共8页中国药理学报（英文版）

摘　　要：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 AUC24h/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 （R^2=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 Saureus 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 neutropenic infected 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 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.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 AUC24h/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 （R^2=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 Saureus 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 neutropenic infected 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 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.

关 键 词：antofloxacin hydrochloride PK/PD murine thigh infection model Staphylococcus aureus AUC24h/MIC 

分 类 号：R37[医药卫生—病原生物学]