title: Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia.
abstract: The protective efficacy of tedizolid phosphate, a novel oxazolidinone that potently inhibits bacterial protein synthesis, was compared to those of linezolid, vancomycin, and saline in a rabbit model ofStaphylococcus aureusnecrotizing pneumonia. Tedizolid phosphate was administered to rabbits at 6 mg/kg of body weight intravenously twice daily, which yielded values of the 24-h area under the concentration-time curve approximating those found in humans. The overall survival rate was 83% for rabbits treated with 6 mg/kg tedizolid phosphate twice daily and 83% for those treated with 50 mg/kg linezolid thrice daily (P= 0.66 by the log-rank test versus the results obtained with tedizolid phosphate). These survival rates were significantly greater than the survival rates of 17% for rabbits treated with 30 mg/kg vancomycin twice daily (P= 0.003) and 17% for rabbits treated with saline (P= 0.002). The bacterial count in the lungs of rabbits treated with tedizolid phosphate was significantly decreased compared to that in the lungs of rabbits treated with saline, although it was not significantly different from that in the lungs of rabbits treated with vancomycin or linezolid. Thein vivobacterial production of alpha-toxin and Panton-Valentine leukocidin, two keyS. aureus-secreted toxins that play critical roles in the pathogenesis of necrotizing pneumonia, in the lungs of rabbits treated with tedizolid phosphate and linezolid was significantly inhibited compared to that in the lungs of rabbits treated with vancomycin or saline. Taken together, these results indicate that tedizolid phosphate is superior to vancomycin for the treatment ofS. aureusnecrotizing pneumonia because it inhibits the bacterial production of lung-damaging toxins at the site of infection.
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Vien T M
authors.initials: VT
authors.lastname: Le
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Hoan N
authors.initials: HN
authors.lastname: Le
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Marcos Gabriel
authors.initials: MG
authors.lastname: Pinheiro
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Hahn
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Dinh
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Kajal B
authors.initials: KB
authors.lastname: Larson
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey, USA.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Flanagan
authors.affiliation: INSERM U1111, Université Lyon 1, CNRS UMR5308, ENS Lyon, Lyon, France.|Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Bron, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Badiou
authors.affiliation: INSERM U1111, Université Lyon 1, CNRS UMR5308, ENS Lyon, Lyon, France.|Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Bron, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lina
authors.affiliation: Department of Infectious Diseases, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.affiliation: Department of Infectious Diseases, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
authors.affiliation: Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, University of California, San Francisco, California, USA binh.diep@ucsf.edu.
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000069349:Linezolid / Q000627:therapeutic use; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010755:Organophosphates / Q000627:therapeutic use*; D010080:Oxazoles / Q000627:therapeutic use*; D000071067:Pneumonia, Necrotizing / Q000188:drug therapy* / Q000382:microbiology; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy* / Q000382:microbiology; D011817:Rabbits; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D010755:Organophosphates; D010080:Oxazoles; D014640:Vancomycin; D000069349:Linezolid; C515040:tedizolid phosphate
keywords: PVL; alpha-toxin; linezolid; pneumonia; rabbit model; tedizolid; vancomycin