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Thromb Haemost 2018; 118(05): 818-829
DOI: 10.1055/s-0038-1639586
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Targeting Coagulase Activity in Staphylococcus aureus Bacteraemia: A Randomized Controlled Single-Centre Trial of Staphylothrombin Inhibition

Marijke Peetermans
1   Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
2   Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
,
Laurens Liesenborghs
1   Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
2   Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
,
Kathelijne Peerlinck
1   Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
3   Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium
,
Eric Van Wijngaerden
2   Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
4   Department of Immunology and Microbiology, University of Leuven, Leuven, Belgium
,
Olivier Gheysens
5   Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven, Belgium
,
Karolien E. Goffin
5   Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven, Belgium
,
Marc F. Hoylaerts
1   Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
,
Marc Jacquemin
1   Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
6   Department of Haemostasis in Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
,
Jan Verhaegen
7   Department of Clinical Bacteriology and Mycology, University Hospitals Leuven, Leuven, Belgium
,
Willy E. Peetermans
2   Department of Internal Medicine, University Hospitals Leuven, Leuven, Belgium
4   Department of Immunology and Microbiology, University of Leuven, Leuven, Belgium
,
Peter Verhamme
1   Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
3   Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium
,
Thomas Vanassche
1   Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
3   Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium
,
for the Staphylothrombin Investigators › Author Affiliations 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.
Further Information

Publication History

07 December 2017

09 February 2018

Publication Date:
03 April 2018 (online)

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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.

Keywords

anticoagulants - bacteraemia - coagulase - Staphylococcus aureus - thrombin

* 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.


Supplementary Material

 

  • References

  • 1 de Kraker ME, Jarlier V, Monen JC, Heuer OE, van de Sande N, Grundmann H. The changing epidemiology of bacteraemias in Europe: trends from the European Antimicrobial Resistance Surveillance System. Clin Microbiol Infect 2013; 19 (09) 860-868
    CrossrefPubMedGoogle Scholar
  • 2 Holland TL, Arnold C, Fowler Jr VG. Clinical management of Staphylococcus aureus bacteremia: a review. JAMA 2014; 312 (13) 1330-1341
    CrossrefPubMedGoogle Scholar
  • 3 Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler Jr VG. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015; 28 (03) 603-661
    CrossrefPubMedGoogle Scholar
  • 4 Kern WV. Management of Staphylococcus aureus bacteremia and endocarditis: progresses and challenges. Curr Opin Infect Dis 2010; 23 (04) 346-358
    CrossrefPubMedGoogle Scholar
  • 5 Thwaites GE, Edgeworth JD, Gkrania-Klotsas E. , et al; UK Clinical Infection Research Group. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis 2011; 11 (03) 208-222
    CrossrefPubMedGoogle Scholar
  • 6 Huang J, Qian W, Gan M. A study on antimicrobial resistance of coagulase negative staphylococci [in Chinese]. Zhonghua Nei Ke Za Zhi 1995; 34 (09) 620-622
    PubMedGoogle Scholar
  • 7 Qian Q, Eichelberger K, Kirby JE. Rapid identification of Staphylococcus aureus in blood cultures by use of the direct tube coagulase test. J Clin Microbiol 2007; 45 (07) 2267-2269
    CrossrefPubMedGoogle Scholar
  • 8 Vanassche T, Verhaegen J, Peetermans WE. , et al. Inhibition of staphylothrombin by dabigatran reduces Staphylococcus aureus virulence. J Thromb Haemost 2011; 9 (12) 2436-2446
    CrossrefPubMedGoogle Scholar
  • 9 Panizzi P, Nahrendorf M, Figueiredo JL. , et al. In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation. Nat Med 2011; 17 (09) 1142-1146
    CrossrefPubMedGoogle Scholar
  • 10 Peetermans M, Verhamme P, Vanassche T. Coagulase activity by Staphylococcus aureus: a potential target for therapy?. Semin Thromb Hemost 2015; 41 (04) 433-444
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 McAdow M, Kim HK, Dedent AC, Hendrickx AP, Schneewind O, Missiakas DM. Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood. PLoS Pathog 2011; 7 (10) e1002307
    CrossrefPubMedGoogle Scholar
  • 12 Vanassche T, Kauskot A, Verhaegen J. , et al. Fibrin formation by staphylothrombin facilitates Staphylococcus aureus-induced platelet aggregation. Thromb Haemost 2012; 107 (06) 1107-1121
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Vanassche T, Peetermans M, Van Aelst LN. , et al. The role of staphylothrombin-mediated fibrin deposition in catheter-related Staphylococcus aureus infections. J Infect Dis 2013; 208 (01) 92-100
    CrossrefPubMedGoogle Scholar
  • 14 Kahn SR, Lim W, Dunn AS. , et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e195S-e226S
    CrossrefPubMedGoogle Scholar
  • 15 Soulier JP, Prou-Wartelle O. Study of thrombin-coagulase. Thromb Diath Haemorrh 1967; 17 (3-4): 321-334
    PubMedGoogle Scholar
  • 16 Vanassche T, Verhaegen J, Peetermans WE, Hoylaerts MF, Verhamme P. Dabigatran inhibits Staphylococcus aureus coagulase activity. J Clin Microbiol 2010; 48 (11) 4248-4250
    CrossrefPubMedGoogle Scholar
  • 17 Hijikata-Okunomiya A, Kataoka N. Argatroban inhibits staphylothrombin. J Thromb Haemost 2003; 1 (09) 2060-2061
    CrossrefPubMedGoogle Scholar
  • 18 Alatri A, Armstrong AE, Greinacher A. , et al. Results of a consensus meeting on the use of argatroban in patients with heparin-induced thrombocytopenia requiring antithrombotic therapy - a European Perspective. Thromb Res 2012; 129 (04) 426-433
    CrossrefPubMedGoogle Scholar
  • 19 Parker MJ, Manan A, Duffett M. Rapid, easy, and cheap randomization: prospective evaluation in a study cohort. Trials 2012; 13: 90
    CrossrefPubMedGoogle Scholar
  • 20 Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8 (01) 202-204
    CrossrefPubMedGoogle Scholar
  • 21 Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23 (02) 138-143
    CrossrefPubMedGoogle Scholar
  • 22 Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM. The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 1988; 28 (07) 609-618
    CrossrefPubMedGoogle Scholar
  • 23 Claes J, Vanassche T, Peetermans M. , et al. Adhesion of Staphylococcus aureus to the vessel wall under flow is mediated by von Willebrand factor-binding protein. Blood 2014; 124 (10) 1669-1676
    CrossrefPubMedGoogle Scholar
  • 24 Vos FJ, Bleeker-Rovers CP, Sturm PD. , et al. 18F-FDG PET/CT for detection of metastatic infection in Gram-positive bacteremia. J Nucl Med 2010; 51 (08) 1234-1240
    CrossrefPubMedGoogle Scholar
  • 25 Bernard GR, Vincent JL, Laterre PF. , et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344 (10) 699-709
    CrossrefPubMedGoogle Scholar
  • 26 Desjardins L, Bara L, Boutitie F. , et al. Correlation of plasma coagulation parameters with thromboprophylaxis, patient characteristics, and outcome in the MEDENOX study. Arch Pathol Lab Med 2004; 128 (05) 519-526
    PubMedGoogle Scholar
  • 27 Reilly PA, Lehr T, Haertter S. , et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
    CrossrefPubMedGoogle Scholar
  • 28 Chapman GH, Berens C, Peters A, Curcio L. Coagulase and hemolysin tests as measures of the pathogenicity of Staphylococci. J Bacteriol 1934; 28 (04) 343-363
    CrossrefPubMedGoogle Scholar
  • 29 Begins K, Church W, Maddur A. , et al. An anti-staphylocoagulase monoclonal antibody inhibits prothrombin activation and prolongs survival in mice following Staphylococcus aureus infection. J Thromb Haemost 2015; 13: 257-258
    PubMedGoogle Scholar