title: Effects of linezolid on suppressing in vivo production of staphylococcal toxins and improving survival outcomes in a rabbit model of methicillin-resistant Staphylococcus aureus necrotizing pneumonia.
abstract: BACKGROUND
  Linezolid is recommended for treatment of pneumonia and other invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). The premise underlying this recommendation is that linezolid inhibits in vivo production of potent staphylococcal exotoxins, including Panton-Valentine leukocidin (PVL) and α-hemolysin (Hla), although supporting evidence is lacking.
  
  
  METHODS
  A rabbit model of necrotizing pneumonia using MRSA clone USA300 was used to compare therapeutic effects of linezolid (50 mg/kg 3 times/day) and vancomycin (30 mg/kg 2 times/day) administered 1.5, 4, and 9 hours after infection on host survival outcomes and in vivo bacterial toxin production.
  
  
  RESULTS
  Mortality rates were 100% for untreated rabbits and 83%-100% for vancomycin-treated rabbits. In contrast, mortality rates were 25%, 50%, and 100% for rabbits treated with linezolid 1.5, 4, and 9 hours after infection, respectively. Compared with untreated and vancomycin-treated rabbits, improved survival of rabbits treated 1.5 hours after infection with linezolid was associated with a significant decrease in bacterial counts, suppressed bacterial production of PVL and Hla, and reduced production of the neutrophil-chemoattractant interleukin 8 in the lungs.
  
  
  CONCLUSIONS
  Across the study interval, only early treatment with linezolid resulted in significant suppression of exotoxin synthesis and improved survival outcomes in a rabbit model of MRSA necrotizing pneumonia.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California-San Francisco, 1001 Potrero Ave, San Francisco, CA 94110, USA. bdiep@medsfgh.ucsf.edu
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
authors.forename: Anna
authors.initials: A
authors.lastname: Afasizheva
authors.forename: Hoan N
authors.initials: HN
authors.lastname: Le
authors.forename: Osamu
authors.initials: O
authors.lastname: Kajikawa
authors.forename: Gustavo
authors.initials: G
authors.lastname: Matute-Bello
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.forename: Bret
authors.initials: B
authors.lastname: Sellman
authors.forename: Cedric
authors.initials: C
authors.lastname: Badiou
authors.forename: Gerard
authors.initials: G
authors.lastname: Lina
authors.forename: Henry F
authors.initials: HF
authors.lastname: Chambers
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D058491:Bacterial Load / Q000187:drug effects; D001427:Bacterial Toxins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018932:Chemokine CCL2 / Q000032:analysis; D004195:Disease Models, Animal; D005098:Exotoxins / Q000032:analysis; D006460:Hemolysin Proteins / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D007956:Leukocidins / Q000032:analysis; D000069349:Linezolid; D008168:Lung / Q000737:chemistry; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D023303:Oxazolidinones / Q000627:therapeutic use*; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D011817:Rabbits; D014640:Vancomycin / Q000627:therapeutic use
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D018932:Chemokine CCL2; D005098:Exotoxins; D006460:Hemolysin Proteins; D016209:Interleukin-8; D007956:Leukocidins; D023303:Oxazolidinones; C078284:Panton-Valentine leukocidin; C021091:staphylococcal alpha-toxin; D014640:Vancomycin; D000069349:Linezolid
keywords: MRSA; Panton-Valentine leukocidin; Staphylococcus aureus; alpha-hemolysin; linezolid; pneumonia; protein synthesis inhibitor; rabbit model; treatment; vancomycin