title: Ceftobiprole efficacy in vitro against Panton-Valentine leukocidin production and in vivo against community-associated methicillin-resistant Staphylococcus aureus osteomyelitis in rabbits.
abstract: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected. In vitro sub-MIC antibiotic effects on growth and PVL production by 11 PVL(+) MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL(+) methicillin-susceptible S. aureus (MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 10(7) CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days. In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log(10)-CFU-count decrease. In vivo, the mean log(10) CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P = 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P = 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P = 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.
authors.affiliation: Département de Médecine Aiguë Spécialisée, Hôpital Universitaire Raymond Poincaré, Assistance Publique-Hôpitaux de Paris, France.
authors.forename: Azzam
authors.initials: A
authors.lastname: Saleh-Mghir
authors.forename: Oana
authors.initials: O
authors.lastname: Dumitrescu
authors.forename: Aurélien
authors.initials: A
authors.lastname: Dinh
authors.forename: Yassine
authors.initials: Y
authors.lastname: Boutrad
authors.forename: Laurent
authors.initials: L
authors.lastname: Massias
authors.forename: Emilie
authors.initials: E
authors.lastname: Martin
authors.forename: François
authors.initials: F
authors.lastname: Vandenesch
authors.forename: Jérôme
authors.initials: J
authors.lastname: Etienne
authors.forename: Gérard
authors.initials: G
authors.lastname: Lina
authors.forename: Anne Claude
authors.initials: AC
authors.lastname: Crémieux
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000096:biosynthesis*; D002511:Cephalosporins / Q000494:pharmacology*; D015169:Colony Count, Microbial; D017714:Community-Acquired Infections / Q000382:microbiology*; D005098:Exotoxins / Q000096:biosynthesis*; D005260:Female; D007956:Leukocidins / Q000096:biosynthesis*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010019:Osteomyelitis / Q000382:microbiology*; D011817:Rabbits; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D002511:Cephalosporins; D005098:Exotoxins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; C443755:ceftobiprole; D012293:Rifampin