Methicillin-resistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration

Abstract

Summary Methicillin-resistant Staphylococcus aureus (MRSA) induces a pro-thrombotic and pro-inflammatory milieu. Although timely antibiotic administration in MRSA sepsis may improve outcomes by arresting bacterial growth, the effects of antibiotics on mitigating injurious thrombo-inflammatory cellular responses remains unexplored. Using a newly developed human whole blood model and an in vivo mouse model of MRSA infection, we examined how antibiotics inhibit MRSA induced thrombo-inflammatory pathways. Human whole blood was inoculated with MRSA. Thrombin generation and inflammatory cytokine synthesis was measured in the presence or absence of linezolid and vancomycin. C57BL/6 mice were injected with MRSA and the effect of vancomycin administration was examined. MRSA accelerated thrombin generation in a time- and concentration-dependent manner and induced the release of cytokines, including interleukin (IL)-6, IL-8, and monocyte chemotactic protein (MCP)-1. The increase in thrombin generation and inflammatory responses was mediated through the synthesis of tissue factor and cytokines, respectively, and the release of microparticles. The early administration of antibiotics restored normal thrombin generation patterns and significantly reduced the synthesis of cytokines. In contrast, when antibiotic administration was delayed, thrombin generation and cytokine synthesis were not significantly reduced. In mice infected with MRSA, early antibiotic administration reduced thrombin anti-thrombin complexes and cytokine synthesis, whereas delayed antibiotic administration did not. These data provide novel mechanistic evidence of the importance of prompt antibiotic administration in infectious syndromes.

The role of platelets in mediating a response to human influenza infection

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Linezolid and Its Immunomodulatory Effect: In Vitro and In Vivo Evidence

“…Franks et al (2013) developed a human whole blood model to evaluate the benefits of early antibiotic administration in reducing the MRSA-induced thrombo-inflammatory “cytokine storm.” LZD and vancomycin both suppressed the synthesis of IL-6, IL-8, and MCP-1 when they were added within 3 h of MRSA inoculation. LZD alone significantly reduced the cytokine synthesis within 6 h of MRSA inoculation compared with vancomycin.…”

Differential effects of antibiotics on neutrophils exposed to lipoteichoic acid derived from Staphylococcus aureus

“…Studies of other virulence factors and S. aureus components have demonstrated differential immunomodulatory effects of antibiotics. For example, Franks et al showed that linezolid is more potent than vancomycin in suppressing pro-inflammatory cytokine production and that the effect diminishes when addition of the antibiotic to monocytes infected with MRSA ex vivo is delayed from 3 to 9 h [ 53 ]. Pichereau et al found daptomycin to inhibit production of pro-inflammatory cytokines in monocytes after exposure to S. aureus toxins such as Panton-Valentine leukocidin and alpha-toxin [ 41 ].…”