Efficacy of Human Simulated Exposures of Ceftaroline against Phenotypically Diverse Enterobacteriaceae Isolates

Ceftaroline fosamil, a new broad-spectrum cephalosporin, exhibits potent bactericidal activity against common Gram-negative pathogens, including Enterobacteriaceae, and Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The purpose of this study was to evaluate the efficacy of a human simulated dose of ceftaroline fosamil against clinical Enterobacteriaceae in both neutropenic and immunocompetent mouse thigh infection models. Thirty-five Enterobacteriaceae isolates with ceftaroline MICs ranging from 0.25 to 32g/ml were selected for the neu-tropenic model, and five Escherichia coli isolates were also tested in the immunocompetent model. Two hours after inoculation, the ceftaroline fosamil human simulated regimen of 600 mg intravenously (i.v.) every 12 h was administered. The change in log10 CFU after 24 h was compared to that in 0 h controls. The human simulated regimen produced predictable efficacy against 18 of 20 isolates with aMIC of<1g/ml. Similar efficacy was seen in the immunocompetent model against isolates with aMIC of<2 g/ml, and enhanced efficacy was observed against the isolate with aMIC of 4g/ml. Human simulated exposures to ceftaroline fosamil at 600 mg every 12 h provided predictable efficacy against EnterobacteriaceaewithMICs of<1g/ml and enhanced effi-cacy within the immunocompetent model, supporting the clinical utility of ceftaroline fosamil against these organisms. Enterobacteriaceae, including Escherichia coli andKlebsiella spp.,are potential pathogens in community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs). In recent surveillance studies, E. coli an