Pharmacokinetics/pharmacodynamics of antofloxacin hydrochloride in a neutropenic murine thigh model of Staphylococcus aureus infection.
OBJECTIVE
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)=92.3%, 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).


CONCLUSIONS
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 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.
Xiao
Xiu-mei
XM
Department of Laboratory Medicine, Peking University Third Hospital, Beijing 100083, China.
Xiao
Yong-hong
YH
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications*; D015242:Ofloxacin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013848:Thigh / Q000382:microbiology
D000900:Anti-Bacterial Agents; C522674:antofloxacin; D015242:Ofloxacin