Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Staphylococcus aureus Infection
ABSTRACTCefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity againstStaphylococcus aureus. The objective of our study was to examine thein vivoactivity of cefquinome againstS. aureusstrains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).In vivopostantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected withS. aureusstrain ATCC 29213. The animals were treated by subcutaneous injection of cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and producedin vivoPAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additionalS. aureusisolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %Tthat the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10CFU reduction from baseline, and a 1-log10CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make cefquinome an attractive option for the treatment of infections caused byS. aureus.