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: Binh An Diep, Anna Afasizheva, Hoan N Le, Osamu Kajikawa, Gustavo Matute-Bello, Christine Tkaczyk, Bret Sellman, Cedric Badiou, Gerard Lina, Henry F Chambers
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 208 Issue 1 Pg. 75-82 (Jul 2013) ISSN: 1537-6613 [Electronic] United States
• PMID: 23532096 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Anti-Bacterial Agents
• Bacterial Toxins
• Chemokine CCL2
• Exotoxins
• Hemolysin Proteins
• Interleukin-8
• Leukocidins
• Oxazolidinones
• Panton-Valentine leukocidin
• staphylococcal alpha-toxin
• Vancomycin
• Linezolid

Topics

• Acetamides (therapeutic use)
• Animals
• Anti-Bacterial Agents (therapeutic use)
• Bacterial Load (drug effects)
• Bacterial Toxins (analysis, antagonists & inhibitors, biosynthesis)
• Chemokine CCL2 (analysis)
• Disease Models, Animal
• Exotoxins (analysis)
• Hemolysin Proteins (analysis)
• Interleukin-8 (analysis)
• Leukocidins (analysis)
• Linezolid
• Lung (chemistry)
• Methicillin-Resistant Staphylococcus aureus (drug effects)
• Oxazolidinones (therapeutic use)
• Pneumonia, Staphylococcal (drug therapy, microbiology, mortality)
• Rabbits
• Vancomycin (therapeutic use)