title: Comparative efficacy of daptomycin, vancomycin, and cloxacillin for the treatment of Staphylococcus aureus endocarditis in rats and role of test conditions in this determination.
abstract: The in vivo efficacy of daptomycin, a new cell wall-active anti-gram-positive-bacterial agent, was compared to those of cloxacillin and vancomycin in a rat model of Staphylococcus aureus endocarditis. Both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains were used. When therapy was initiated early (8 h) after infection, at the time when valvular bacterial counts were relatively low (approximately 10(6) CFU/g of vegetation), 3 days of therapy was found to be effective against the MSSA strains whatever the antibiotic regimen. In contrast, when the onset of therapy was delayed up to 15 h after infection, so that higher bacterial counts could develop on the valves (approximately 10(9) CFU/g of vegetation), a longer period of treatment (6 days) was required to cure infection. Under these conditions after 3 days of therapy, daptomycin was more effective than cloxacillin and vancomycin against the MSSA strains. Similarly, daptomycin showed a greater activity than vancomycin against the MRSA strain after 3 days of treatment, but after 6 days both antibiotics were equally effective. Decreasing doses of daptomycin showed decreasing activity: 10 mg/kg of body weight every 12 h (q12h) was better than 5 mg/kg q12h, whereas 5 mg/kg q24h (providing drug levels in blood detectable only during the first 12 h) failed to cure infection. In vitro, daptomycin was highly bactericidal at high concentrations (25 and 60 micrograms/ml, corresponding to peak levels in serum after doses of 5 and 10 mg/kg, respectively) and bacteriostatic at lower concentrations (0.5 to 2.5 micrograms/ml, corresponding to trough levels in serum). In conclusion, against low-bacterial-count S. aureus endocarditis, daptomycin showed an efficacy similar to those of vancomycin and cloxacillin. Against high-bacterial-count S. aureus endocarditis, daptomycin showed a higher bactericidal activity than cloxacillin (against the MSSA strains) and vancomycin (against both the MSSA and MRSA strains).
authors.affiliation: Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Cantoni
authors.forename: M P
authors.initials: MP
authors.lastname: Glauser
authors.forename: J
authors.initials: J
authors.lastname: Bille
mesh_terms: D000818:Animals; D003023:Cloxacillin / Q000097:blood / Q000627:therapeutic use*; D017576:Daptomycin; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000097:blood / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D014640:Vancomycin / Q000097:blood / Q000627:therapeutic use*
chemical_list: D010455:Peptides; D014640:Vancomycin; D017576:Daptomycin; D003023:Cloxacillin