AAC Accepts, published online ahead of print on 2 November 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00642-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

In Vivo Activity of Ceftobiprole in Murine Skin Infections Due to Staphylococcus aureus and Pseudomonas aeruginosa

Jeffrey Fernandez^*, Jamese J. Hilliard, Darren Abbanat, Wenyan Zhang, John L. Melton, Colleen M. Santoro, Robert K. Flamm, and Karen Bush

Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Raritan, New Jersey

^* To whom correspondence should be addressed. Email: jfernan5{at}its.jnj.com.

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (30), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (MSSA), S. aureus OC 8525 (MRSA), P. aeruginosa OC 4351 (inducible AmpC -lactamase), and P. aeruginosa OC 4354 (overproducing AmpC -lactamase). In the MSSA and MRSA infection models, ceftobiprole, dosed as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% smaller than cefazolin, vancomycin, or linezolid treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% smaller than with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8 and 32-fold lower MICs for meropenem; both treatments were more effective than cefepime (P < 0.001) against the inducible and overproducing AmpC -lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.