Comparative efficacies of tedizolid phosphate, vancomycin, and daptomycin in a rabbit model of methicillin-resistant Staphylococcus aureus endocarditis

• Published in: Antimicrobial agents and chemotherapy 2015-06, Vol.59 (6), p.3252-3256
• Main Authors: Chan, Liana C, Basuino, Li, Dip, Etyene C, Chambers, Henry F
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - therapeutic use; Daptomycin; Daptomycin - therapeutic use; Drug Administration Schedule; Endocarditis; Endocarditis - drug therapy; Endocarditis - microbiology; Experimental Therapeutics; Methicillin-Resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - pathogenicity; Microbial Sensitivity Tests; Organophosphates; Organophosphates - therapeutic use; Oxazoles; Oxazoles - therapeutic use; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin; Vancomycin - therapeutic use
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.04376-14

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.