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

Abstract

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.

Fidaxomicin Inhibits Clostridium difficile Toxin A-Mediated Enteritis in the Mouse Ileum

“…Our results indicate that pretreatment with metronidazole and vancomycin, commonly used for therapy of CDI, did not significantly alter the histologic damage, IL-1␤ expression, or ERK activation in response to toxin A in vivo and did not affect cell rounding in response to this toxin in vitro. On the other hand, both metronidazole and vancomycin have been shown to possess anti-inflammatory effects under different in vivo and in vitro conditions (34)(35)(36)(37). The different inflammatory stimuli (Staphylococcus aureus toxin or lipopolysaccharide) used in the studies mentioned above may account for the inability of metronidazole and vancomycin to alter C. difficile toxin A-associated responses that was shown in our study.…”

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…Although CLP is the gold standard animal model for sepsis, it is characterized by an intense acute inflammatory response, and because of the polymicrobial nature of the infection, the immune response could be unique to this model. Therefore, we determined whether blocking SOCS1 will also influence the outcome of sepsis induced by MRSA, a common cause of this condition (26)(27)(28)(29). We observed that mice pretreated with iKIR, followed by MRSA-induced peritonitis with bioluminescent S. aureus, exhibited increased bacterial dissemination 24 hours after infection, as compared with controls ( Figure 1, H and I).…”

Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections

“…linezolid may improve disease outcomes by inhibiting bacterial toxin synthesis (24)(25)(26). Previous experimental studies in rabbits have used linezolid at doses up to 75 mg/kg (27).…”