In Vivo Activity of Ceftobiprole in a Staphylococcal Murine Skin Infection Model (original) (raw)

2006

Abstract

ABSTRACT Background: Ceftobiprole medocaril, the prodrug of ceftobiprole (BPR), an investigational broad-spectrum cephalosporin with anti-MRSA activity, was compared to cefazolin (CFZ), vancomycin (VAN), and linezolid (LZD) in a murine skin and soft-tissue infection model. Methods: Female Skh-1 mice were infected subcutaneously (sc) with S. aureus Smith (MSSA), or methicillin-resistant S. aureus OC 8525 (MRSA) suspended in brain heart infusion media with 0.1% dextran beads, and dosed sc 1, 3, 25 and 27 h post-infection. Forty-eight hours after infection, the animals were euthanized, skin lesions measured and the number CFU in each lesion was determined. Results: In MSSA, BPR achieved a >1.7 log reduction in CFU/g skin tissue compared to the initial inoculum at doses of 1.6 to 100 mg/kg/day. This reduction was only achieved with CFZ at doses of 25 and 100 mg/kg/day and VAN at 100 mg/kg/day. At doses lower than 100 mg/kg/day, no reduction in bacterial burden was noted with VAN or LZD. In MRSA infections, BPR showed similar or improved reduction in bacterial load at doses of 1.6 to 100 mg/kg/day over CFZ, VAN, and LZD. BPR was also more effective in reducing the lesion volume at the infection site compared to CFZ, LZD, and VAN in MSSA and MRSA infections with the exception of the 100 mg/kg/day dose of VAN. Δ Log CFU/g Skin (from infecting inoculum) MSSA MSSA MSSA MSSA MRSA MRSA MRSA MRSA Dose (mg/kg/day) BPR CFZ VAN LZD BPR CFZ VAN LZD 0 1.6 1.6 1.6 1.6 0.8 0.8 0.8 0.8 1.6 -1.0 0.9 1.5 1.4 0.3 0.8 1.5 0.4 6.2 -1.7 -0.6 1.6 0.6 -0.8 0.6 1.2 0 25 -2.0 -1.7 0.2 0.1 -1.3 -0.3 -0.7 -0.4 100 -1.7 -1.9 -3.1 -0.4 -1.4 -0.9 -1.4 -0.4 Conclusion: In a murine skin and soft-tissue infection model against MRSA, equivalent doses of BPR compared to CFZ, LZD, or VAN resulted in equal or greater killing activity. In this MSSA infection model, BPR at low doses was more effective than CFZ, LZD, or VAN.

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