title: Pharmacodynamics of a simulated single 1,200-milligram dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant staphylococcus aureus infection.
abstract: The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once-daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC(0-24)), 48 h (AUBKC(0-48)), and 72 h (AUBKC(0-72)). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC(0-24)s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC(0-48) and AUBKC(0-72) against one MRSA strain and a lower AUBKC(0-48) for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC(0-48) and AUBKC(0-72) for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC(0-24)s for two of the MRSA strains (P < 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections.
authors.affiliation: The Medicines Company, Quebec, Canada. adam.belley@themedco.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Belley
authors.forename: Francis F
authors.initials: FF
authors.lastname: Arhin
authors.forename: Ingrid
authors.initials: I
authors.lastname: Sarmiento
authors.forename: Hong
authors.initials: H
authors.lastname: Deng
authors.forename: Warren
authors.initials: W
authors.lastname: Rose
authors.forename: Greg
authors.initials: G
authors.lastname: Moeck
mesh_terms: D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D017326:Clinical Trials, Phase III as Topic; D015169:Colony Count, Microbial; D003470:Culture Media; D017576:Daptomycin / Q000494:pharmacology*; D054796:Drug Dosage Calculations; D006020:Glycopeptides / Q000494:pharmacology*; D006801:Humans; D007260:Infusion Pumps; D000077427:Lipoglycopeptides; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D014640:Vancomycin / Q000494:pharmacology* / Q000031:analogs & derivatives
chemical_list: D000900:Anti-Bacterial Agents; D003470:Culture Media; D006020:Glycopeptides; D000077427:Lipoglycopeptides; D014640:Vancomycin; D017576:Daptomycin; C100708:oritavancin