Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus

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Abstract
The therapeutic activity of ceftobiprole medocaril, the water-soluble prodrug of ceftobiprole, was compared to that of vancomycin in a rat tissue cage model of chronic methicillin-resistant Staphylococcus aureus (MRSA) foreign-body infection. The MICs and MBCs of ceftobiprole and vancomycin in Mueller-Hinton broth for strain MRGR3 were 1 and 4 and 1 and 2 μg/ml, respectively. In vitro elimination rates of strain MRGR3 of 4 and 8 μg/ml of ceftobiprole or vancomycin were equivalent. After 2 weeks of infection, mean ± standard error of the mean viable counts of strain MRGR3 were 6.83 ± 0.11 log CFU/ml of tissue cage fluid ( n = 87). High-dose regimens of ceftobiprole medocaril (equivalent to 150 mg/kg of ceftobiprole) or 50 mg/kg vancomycin produced nearly identical average peak and trough levels of ceftobiprole and vancomycin in tissue cage fluid, which exceeded the MBC of either antibiotic towards strain MRGR3 for ≥75% of each dosing interval. After 7 days of therapy with ceftobiprole medocaril or vancomycin, average counts of MRGR3 decreased significantly ( P < 0.02) by 0.68 ± 0.28 ( n = 29) and 0.88 ± 0.22 ( n = 28) log CFU/ml of tissue cage fluid, respectively, compared with cages of untreated animals, but were not significantly different from each other. No resistant mutants were detected on ceftobiprole-supplemented agar following therapy with this cephalosporin. The in vivo activity of ceftobiprole medocaril against chronic MRSA foreign-body infections was equivalent to that of vancomycin and did not lead to the emergence of resistant subpopulations.

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