Pharmacodynamic Characterization of Ceftobiprole in Experimental Pneumonia Caused by Phenotypically Diverse Staphylococcus aureus Strains

Abstract

ABSTRACT Ceftobiprole (BPR) is an investigational cephalosporin with activity against Staphylococcus aureus , including methicillin-resistant S. aureus (MRSA) strains. The pharmacodynamic (PD) profile of BPR against S. aureus strains with a variety of susceptibility phenotypes in an immunocompromised murine pneumonia model was characterized. The BPR MICs of the test isolates ranged from 0.25 to 2 μg/ml. Pharmacokinetic (PK) studies were conducted with infected neutropenic BALB/c mice; and the BPR concentrations were measured in plasma, epithelial lining fluid (ELF), and lung tissue. PD studies with these mice were undertaken with eight S. aureus isolates (two methicillin-susceptible S. aureus strains, three hospital-acquired MRSA strains, and three community-acquired MRSA strains). Subcutaneous BPR doses of 2 to 125 mg/kg of body weight/day were administered, and the change in the number of log 10 CFU/ml in lungs was evaluated after 24 h of therapy. The PD profile was characterized by using the free drug exposures ( f ) determined from the following parameters: the percentage of time that the concentration was greater than the MIC ( T > MIC), the maximum concentration in serum/MIC, and the area under the concentration-time curve/MIC. The BPR PK parameters were linear over the dose range studied in plasma, and the ELF concentrations ranged from 60 to 94% of the free plasma concentration. fT > MIC was the parameter that best correlated with efficacy against a diverse array of S. aureus isolates in this murine pneumonia model. The 80% effective dose (ED 80 ), ED 50 , and stasis exposures appeared to be similar among the isolates studied. BPR exerted maximal antibacterial effects when fT > MIC ranged from 6 to 22%, regardless of the phenotypic profile of resistance to β-lactam, fluoroquinolone, erythromycin, clindamycin, or tetracycline antibiotics.