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DOI: 10.1055/s-0038-1639586
Targeting Coagulase Activity in Staphylococcus aureus Bacteraemia: A Randomized Controlled Single-Centre Trial of Staphylothrombin Inhibition
Funding This work was supported by the “Instituut voor Wetenschap en Technologie” (Agency for Innovation by Science and Technology) [TBM project grant number 130249]; by the Fund for Academic Trials of the University Hospital Leuven and by “FWO-Vlaanderen” (Research Foundation Flanders) [grant numbers 11I0113N to M.P., 11S5416N to L.L., 1801414N to P.V. and 1831812N to O.G.]. Boehringer Ingelheim provided non-financial support (dabigatran assay with mass spectrometry) during the conduct of the study. The funders of the study had no role in study design and conduct, data collection and management, data analysis, data interpretation or writing, revision and submission of the report.Publication History
07 December 2017
09 February 2018
Publication Date:
03 April 2018 (online)
Abstract
Background Staphylococcus aureus (S. aureus) bacteraemia is frequent and carries a high morbidity and mortality. Coagulases secreted by S. aureus initiate blood coagulation by directly activating prothrombin. This pathogen-activated coagulation is insensitive to most antithrombotic drugs, with the exception of small molecule direct thrombin inhibitors (DTIs). DTIs inhibit the coagulase-prothrombin complex, or staphylothrombin, and improve outcome in preclinical models of S. aureus infection.
Objective A single-centre, randomized, controlled feasibility and safety trial of staphylothrombin inhibition with DTIs in patients with S. aureus bacteraemia.
Patients and Methods Consecutive eligible adult patients with S. aureus positive blood cultures in the University Hospitals Leuven (Belgium) were randomized 1:1 to DTI (oral dabigatran 110 mg twice daily or intravenous argatroban according to activated partial thromboplastin time [aPTT]) for 7 to 10 days, or subcutaneous enoxaparin 40 mg once daily. Primary outcomes were feasibility and safety of DTI in patients with S. aureus bacteraemia. Secondary outcomes include D-dimer evolution (day 0–4) as marker of coagulation activation; inflammatory and microbiological parameters; and clinical outcomes including metastatic infections.
Results Thirty-one percent (94/303) of screened patients were enrolled. Dabigatran plasma levels inhibited staphylothrombin. Clinically relevant bleeding (5/47 vs. 5/47) and thrombotic (7/47 vs. 7/47) complications were similar in both groups. Coagulase inhibition with DTIs was associated with a trend towards faster D-dimer decrease at day 4 (–662 ± 249 ng/mL vs. –40 ± 213 ng/mL for DTI-treated patients vs. control; p = 0.06) and a numerically lower number of persistently positive blood cultures. No differences in inflammatory parameters or other clinical outcomes were observed.
Conclusion Targeting staphylothrombin with DTIs is feasible in a subset of S. aureus bacteraemic patients, with comparable safety to standard thromboprophylaxis. In future studies of staphylothrombin inhibition, feasibility can be further improved by rapid diagnostics and by strategies without concomitant anticoagulant effect.
* The Staphylothrombin Investigators members are listed in the Appendix.
Authors' Contributions
M.P., T.V. and P.V. designed the trial, in collaboration with M.J., J.V., W.E.P. and O.G. J.V. was responsible for notification of positive blood cultures and microbiological diagnosis. M.J. supervised the laboratory assays of coagulation parameters. M.P., T.V., P.V. and L.L. participated in patient evaluation and inclusion. O.G. and K.E.G. reviewed PET/CT scans. E.V.W. and K.P. performed data and safety monitoring. M.P., T.V. and P.V. analysed the data and wrote the manuscript. M.P. and P.V. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. L.L., K.P., E.V.W., O.G., K.E.G., M.F.H., M.J., J.V. and W.E.P. assisted in manuscript preparation and revision. All authors read and approved the final manuscript.