Methicillin-resistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration.
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.
University of Utah, Department of Internal Medicine, 50 North Medical Drive, Room 4B120, SLC, Utah 84132, USA.
Zechariah
Z
Franks
Robert A
RA
Campbell
Adriana
A
Vieira de Abreu
Jeffrey T
JT
Holloway
James E
JE
Marvin
Bjoern F
BF
Kraemer
Guy A
GA
Zimmerman
Andrew S
AS
Weyrich
Matthew T
MT
Rondina
D000081:Acetamides / Q000008:administration & dosage*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000097:blood; D004334:Drug Administration Schedule; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D023303:Oxazolidinones / Q000008:administration & dosage*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013997:Time Factors; D014640:Vancomycin / Q000008:administration & dosage*
D000081:Acetamides; D000900:Anti-Bacterial Agents; D016207:Cytokines; D018836:Inflammation Mediators; D023303:Oxazolidinones; D014640:Vancomycin; D013917:Thrombin; D000069349:Linezolid