title: Intensive therapy with ceftobiprole medocaril of experimental foreign-body infection by methicillin-resistant Staphylococcus aureus.
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 microg/ml, respectively. In vitro elimination rates of strain MRGR3 of 4 and 8 microg/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 > or =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.
authors.affiliation: Service of Infectious Diseases, University Hospitals of Geneva, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. Pierre.Vaudaux@hcuge.ch
authors.forename: Pierre
authors.initials: P
authors.lastname: Vaudaux
authors.forename: Asllan
authors.initials: A
authors.lastname: Gjinovci
authors.forename: Manuela
authors.initials: M
authors.lastname: Bento
authors.forename: Dongmei
authors.initials: D
authors.lastname: Li
authors.forename: Jacques
authors.initials: J
authors.lastname: Schrenzel
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Lew
mesh_terms: D000818:Animals; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005547:Foreign Bodies / Q000150:complications*; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000209:etiology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: D002511:Cephalosporins; C443755:ceftobiprole; D014640:Vancomycin; C505439:ceftobiprole medocaril