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

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: http://dx.doi.org/10.1160/TH12-08-0543
Issue: 2013: 109/4 (Apr) pp. 569-768
Pages: 684-695

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

Online Supplementary Material

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Z. Franks (1), R. A. Campbell (1), A. Vieira de Abreu (1, 2), J. T. Holloway (1), J. E. Marvin (1, 3), B. F. Kraemer (1, 4), G. A. Zimmerman (1, 5), A. S. Weyrich (1, 3), M. T. Rondina (1, 6)

(1) Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, Utah, USA; (2) Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil; (3) University of Utah Health Sciences Center, Salt Lake City, Utah, USA; (4) Medizinische Klinik und Poliklinik I, Klinikum der Universitaet München, Germany; (5) Pulmonary and Critical Care Medicine, Department of Internal Medicine; (6) Divisions of General Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA

Summary

Methicillin-resistant Staphylococcus aureus (MRSA) induces a pro-thrombotic and pro-inflammatory milieu. Although timely antibiotic administration in MRSAsepsis 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 MRSAinfection, we examined how antibiotics inhibit MRSAinduced 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. MRSAaccelerated thrombin generation in a time- and concentration-dependent manner andinduced 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.

Keywords

cytokines, antibiotics, Tissue factor, thrombin, methicillin-resistant Staphylococcus aureus

DOI

http://dx.doi.org/10.1160/TH12-08-0543

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