Cefquinome is a
cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such as Escherichia coli. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of
cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of
therapy. Serum
drug levels following 4-fold-escalating single doses of
cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of
cefquinome were linear over a dose range of 10 to 640 mg/kg of
body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (fT>MIC) was the PK-PD index that best correlated with efficacy (R(2) = 73% for E. coli, compared with 13% for the maximum concentration of the free
drug in serum [fCmax]/MIC and 45% for the free-
drug area under the concentration-time curve from 0 to 24 h [fAUC0-24]/MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total
cefquinome doses administered every 4 h to treat animals infected with four additional E. coli isolates. A sigmoid maximum-effect (Emax) model was used to estimate the magnitudes of the %fT>MIC associated with net bacterial stasis, a 1-log10 CFU reduction from baseline, and a 2-log10 CFU reduction from baseline; the corresponding values were 28.01% ± 2.27%, 37.23% ± 4.05%, and 51.69% ± 9.72%. The potent bactericidal activity makes
cefquinome an attractive option for the treatment of
infections caused by E. coli.