title: Comparative efficacies of tedizolid phosphate, vancomycin, and daptomycin in a rabbit model of methicillin-resistant Staphylococcus aureus endocarditis.
abstract: Tedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid against Staphylococcus aureus in vitro. The in vivo efficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistant S. aureus strain COL (infection inoculum of 10(7) CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P = 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P = 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (10(8) CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0-24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0-24 for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.
authors: Division of Infectious Diseases, San Francisco General Hospital, San Francisco, California, USA Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA lchan@labiomed.org.
authors: Liana C
authors: LC
authors: Chan
authors: Division of Infectious Diseases, San Francisco General Hospital, San Francisco, California, USA.
authors: Li
authors: L
authors: Basuino
authors: Division of Infectious Diseases, San Francisco General Hospital, San Francisco, California, USA.
authors: Etyene C
authors: EC
authors: Dip
authors: Division of Infectious Diseases, San Francisco General Hospital, San Francisco, California, USA.
authors: Henry F
authors: HF
authors: Chambers
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017576:Daptomycin / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004696:Endocarditis / Q000188:drug therapy* / Q000382:microbiology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity*; D008826:Microbial Sensitivity Tests; D010755:Organophosphates / Q000627:therapeutic use*; D010080:Oxazoles / Q000627:therapeutic use*; D011817:Rabbits; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D014640:Vancomycin / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D014640:Vancomycin; D017576:Daptomycin; C515040:tedizolid phosphate