Adjunctive dabigatran therapy improves outcome of experimental left-sided Staphylococcus aureus endocarditis

• Published in: PloS one Vol. 14; no. 4; p. e0215333
• Main Authors: Lerche, Christian J, Christophersen, Lars J, Goetze, Jens Peter, Nielsen, Pia R, Thomsen, Kim, Enevold, Christian, Høiby, Niels, Jensen, Peter Ø, Bundgaard, Henning, Moser, Claus
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.04.2019; Public Library of Science (PLoS)
• Subjects: Aminoglycosides; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Antidotes; Antithrombins - pharmacology; Aorta; Aortic valve; Aortic Valve - drug effects; Aortic Valve - microbiology; Bacteria; Bacterial Load - drug effects; Cell size; Chemokines; Chemotherapy, Adjuvant; Coagulase; Cytokines; Dabigatran - pharmacology; Dabigatran etexilate; Disease Models, Animal; Drug Therapy, Combination; Endocarditis; Endocarditis, Bacterial - drug therapy; Endocarditis, Bacterial - microbiology; Fibrin; Gentamicin; Gentamicins - pharmacology; Heart valve diseases; Humans; Immunology; Infection; Infective endocarditis; Inflammation; Integrins; Intercellular adhesion molecule 1; Interleukin 6; L-selectin; Leukocytes (neutrophilic); Male; Medical research; Neutrophils; Patient outcomes; Platelets; Random Allocation; Rats, Wistar; Rheumatology; Risk factors; Sepsis; Staphylococcal infections; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - physiology; Staphylococcus aureus infections; Staphylococcus infections; Tissue inhibitor of metalloproteinase 1; Vegetation; Denmark
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0215333

Staphylococcus aureus is the most frequent and fatal cause of left-sided infective endocarditis (IE). New treatment strategies are needed to improve the outcome. S. aureus coagulase promotes clot and fibrin formation. We hypothesized that dabigatran, could reduce valve vegetations and inflammation in S. aureus IE. We used a rat model of severe aortic valve S. aureus IE. All infected animals were randomized to receive adjunctive dabigatran (10 mg/kg b.i.d., n = 12) or saline (controls, n = 11) in combination with gentamicin. Valve vegetation size, bacterial load, cytokine, cell integrins expression and peripheral platelets and neutrophils were assessed 3 days post-infection. Adjunctive dabigatran treatment significantly reduced valve vegetation size compared to controls (p< 0.0001). A significant reduction of the bacterial load in aortic valves was seen in dabigatran group compared to controls (p = 0.02), as well as expression of key pro-inflammatory markers keratinocyte-derived chemokine, IL-6, ICAM-1, TIMP-1, L-selectin (p< 0.04). Moreover, the dabigatran group had a 2.5-fold increase of circulating platelets compared to controls and a higher expression of functional and activated platelets (CD62p+) unbound to neutrophils. Adjunctive dabigatran reduced the vegetation size, bacterial load, and inflammation in experimental S. aureus IE.