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Linezolid (L), a potent antibiotic for Methicillin Resistant  Staphylococcus aureus  (MRSA), inhibits bacterial protein synthesis. By contrast, vancomycin (V) is a cell wall active agent. Here, we used a murine sepsis model to test the hypothesis that L treatment is associated with differences in bacterial and host characteristics as compared to V. Mice were injected with  S. aureus  USA300, and then intravenously treated with 25 mg/kg of either L or V at 2 hours post infection (hpi).  In vivo  alpha-hemolysin production was reduced in both L and V-treated mice compared to untreated mice but the reduction did not reach the statistical significance [ P  = 0.12 for L;  P  = 0.70 for V). PVL was significantly reduced in L-treated mice compared to untreated mice ( P  = 0.02). However the reduction of  in vivo  PVL did not reach the statistical significance in V- treated mice compared to untreated mice ( P  = 0.27). Both antibiotics significantly reduced IL-1β production [ P  = 0.001 for L;  P  = 0.006 for V]. IL-6 was significantly reduced with L but not V antibiotic treatment [ P <0.001 for L;  P  = 0.11 for V]. Neither treatment significantly reduced production of TNF-α. Whole-blood gene expression profiling showed no significant effect of L and V on uninfected mice. In  S. aureus -infected mice, L altered the expression of a greater number of genes than V (95 vs. 42;  P  = 0.001). Pathway analysis for the differentially expressed genes identified toll-like receptor signaling pathway to be common to each  S. aureus -infected comparison. Expression of immunomodulatory genes like  Cxcl9, Cxcl10, Il1r2, Cd14  and  Nfkbia  was different among the treatment groups. Glycerolipid metabolism pathway was uniquely associated with L treatment in  S. aureus  infection. This study demonstrates that, as compared to V, treatment with L is associated with reduced levels of toxin production, differences in host inflammatory response, and distinct host gene expression characteristics in MRSA sepsis.

plos one

Host Gene Expression Profiling and In Vivo Cytokine Studies to Characterize the Role of Linezolid and Vancomycin in Methicillin-Resistant Staphylococcus aureus (MRSA) Murine Sepsis Model