Date Published: April 19, 2019
Publisher: Public Library of Science
Author(s): Christian J. Lerche, Lars J. Christophersen, Jens Peter Goetze, Pia R. Nielsen, Kim Thomsen, Christian Enevold, Niels Høiby, Peter Ø. Jensen, Henning Bundgaard, Claus Moser, Pablo Garcia de Frutos.
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.
Staphylococcus aureus is the most frequent cause of infectious endocarditis (IE)  and is associated with serious clinical manifestations and fatal course in two out of five patients  despite appropriate antibiotic therapy, appropriate management of sepsis and intensive care treatment often combined with cardiac valve surgery. New therapeutic targets enhancing bacterial clearance and dampening the adverse host responses caused by S. aureus in IE are needed.
Expanded versions of the Methods are presented in the Supplemental material (S1 File).
In the present study of experimental aortic valve S. aureus IE, we demonstrated that adjunctive dabigatran therapy combined with gentamicin reduces the valve vegetation size, bacterial load on the valves, in the myocardium, spleen and fewer persistently positive blood cultures of dabigatran treated rats.