title: Does linezolid modulate lung innate immunity in a murine model of methicillin-resistant Staphylococcus aureus pneumonia?
abstract: OBJECTIVE
  Methicillin-resistant Staphylococcus aureus is an important cause of mortality among nosocomial infections. Recent investigations suggest that linezolid is superior to vancomycin in achieving clinical cure in patients with nosocomial pneumonia. We hypothesized that linezolid may exhibit anti-inflammatory properties in vivo model of pneumonia.
  
  
  METHODS
  Prospective interventional study.
  
  
  METHODS
  University affiliated laboratory.
  
  
  METHODS
  BALB/c mice.
  
  
  METHODS
  Three groups of BALB/c mice were inoculated with methicillin-resistant S. aureus American Type Culture Collection 33,591 to induce pneumonia. Each group (n = 6) underwent bronchoalveolar lavage at 24 hrs, 48 hrs, and 72 hrs after inoculation after treatment with vancomycin, linezolid, or no antibiotic. Bronchoalveolar lavage fluid levels of monocyte chemotactic protein-5 and interleukin-6 were quantified using cytometric bead array. Metalloproteinase-9 was detected by enzyme-linked immunosorbent assay and gelatin zymography. Neutrophil apoptosis in bronchoalveolar lavage was assessed by annexin V and 7-aminoactinomycin D staining. Neutrophil activity was determined by myeloperoxidase enzyme activity. Phagocytosis of apoptotic neutrophils by linezolid- vs. vancomycin treated-alveolar macrophages was examined in vitro.
  
  
  RESULTS
  Infected mice had a significant reduction in lung bacterial titers compared with controls (p < .05) after treatment with linezolid or vancomycin. There was no difference in bronchoalveolar lavage levels of monocyte chemotactic protein-5 or interleukin-6 between vancomycin- and linezolid-treated groups. Both antimicrobials were comparable in modulating the expression of matrix metalloproteinase-9 in bronchoalveolar lavage. Neutrophil apoptosis was comparable in both vancomycin- and linezolid-treated groups at all three time points. Vancomycin showed lower myeloperoxidase activity compared with linezolid in the first 24 hrs after inoculation (p = .03), but the difference was undetectable at 48 hrs and 72 hrs. Neither compound had an impact on the process of removal of apoptotic neutrophils by alveolar macrophages.
  
  
  CONCLUSIONS
  Linezolid did not display an advantage over vancomycin in modulating pulmonary innate immune response in a murine model of methicillin-resistant S. aureus pneumonia.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, State University of New York at Buffalo School of Medicine and Biomedical Sciences and School of Public Health and Health Professions, Buffalo, NY, USA.
authors.forename: Morohunfolu E
authors.initials: ME
authors.lastname: Akinnusi
authors.forename: Angela
authors.initials: A
authors.lastname: Hattemer
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Ali A
authors.initials: AA
authors.lastname: El-Solh
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016001:Confidence Intervals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects*; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000166:cytology; D023303:Oxazolidinones / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D011897:Random Allocation; D015996:Survival Rate; D016896:Treatment Outcome; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D014640:Vancomycin; D009195:Peroxidase; D000069349:Linezolid