Drug-drug Interactions with Metronidazole and Itraconazole in Patients Using Acenocoumarol

Overview

Journal Eur J Clin Pharmacol

Specialty Pharmacology

Date 2020 Jun 12

PMID 32524154

Authors

Matthijs L Becker

Renate C A E van Uden

Thijs J Giezen

Karina Meijer

Ilse Houtenbos

Patricia M L A Van den Bemt

Affiliations

Soon will be listed here.

Abstract

Purpose: Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients.

Methods: We included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group.

Results: In the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47-9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37-4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79-9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing.

Conclusion: Co-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently.

References

Cannegieter S, Rosendaal F, Wintzen A, van der Meer F, Vandenbroucke J, Briet E . Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med. 1995; 333(1):11-7. DOI: 10.1056/NEJM199507063330103. View

van der Meer F, Rosendaal F, Vandenbroucke J, Briet E . Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost. 1996; 76(1):12-6. View

Teichert M, Eijgelsheim M, Rivadeneira F, Uitterlinden A, van Schaik R, Hofman A . A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet. 2009; 18(19):3758-68. DOI: 10.1093/hmg/ddp309. View

OReilly R, RYTAND D . "Resistance" to warfarin due to unrecognized vitamin K supplementation. N Engl J Med. 1980; 303(3):160-1. DOI: 10.1056/nejm198007173030317. View

Routledge P, Chapman P, Davies D, Rawlins M . Factors affecting warfarin requirements. A prospective population study. Eur J Clin Pharmacol. 1979; 15(5):319-22. DOI: 10.1007/BF00558434. View

Harder S, Thurmann P . Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet. 1996; 30(6):416-44. DOI: 10.2165/00003088-199630060-00002. View

Freedman M, Olatidoye A . Clinically significant drug interactions with the oral anticoagulants. Drug Saf. 1994; 10(5):381-94. DOI: 10.2165/00002018-199410050-00003. View

Self T, Oliphant C, Reaves A, Richardson A, Sands C . Fever as a risk factor for increased response to vitamin K antagonists: a review of the evidence and potential mechanisms. Thromb Res. 2014; 135(1):5-8. DOI: 10.1016/j.thromres.2014.10.015. View

van Meegen E, Rosendaal F, Stricker B . Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs. Clin Pharmacol Ther. 2001; 69(6):451-7. DOI: 10.1067/mcp.2001.115723. View

10.

Visser L, Kasbergen A, De Smet P, Vulto A, Hofman A, Stricker B . Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost. 2002; 88(5):705-10. View

11.

Abbas S, Ihle P, Harder S, Schubert I . Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy. A case-control study nested in a large insurance- and population-based German cohort. Thromb Haemost. 2014; 111(5):912-22. DOI: 10.1160/TH13-09-0723. View

12.

Jobski K, Behr S, Garbe E . Drug interactions with phenprocoumon and the risk of serious haemorrhage: a nested case-control study in a large population-based German database. Eur J Clin Pharmacol. 2011; 67(9):941-51. DOI: 10.1007/s00228-011-1031-6. View

13.

Penning-van Beest F, Erkens J, Petersen K, Koelz H, Herings R . Main comedications associated with major bleeding during anticoagulant therapy with coumarins. Eur J Clin Pharmacol. 2005; 61(5-6):439-44. DOI: 10.1007/s00228-005-0947-0. View

14.

Penning-van Beest F, Koerselman J, Herings R . Risk of major bleeding during concomitant use of antibiotic drugs and coumarin anticoagulants. J Thromb Haemost. 2007; 6(2):284-90. DOI: 10.1111/j.1538-7836.2008.02844.x. View

15.

Rosendaal F, Cannegieter S, van der Meer F, Briet E . A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993; 69(3):236-9. View

16.

Visser L, Penning-van Beest F, Kasbergen A, De Smet P, Vulto A, Hofman A . Overanticoagulation associated with combined use of antifungal agents and coumarin anticoagulants. Clin Pharmacol Ther. 2002; 71(6):496-502. DOI: 10.1067/mcp.2002.124470. View

17.

Kudo T, Endo Y, Taguchi R, Yatsu M, Ito K . Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes. Xenobiotica. 2014; 45(5):413-9. DOI: 10.3109/00498254.2014.990948. View

18.

OReilly R . The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med. 1976; 295(7):354-7. DOI: 10.1056/NEJM197608122950702. View

19.

Zhang K, Young C, Berger J . Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease interactions. J Manag Care Pharm. 2007; 12(8):640-8. PMC: 10437767. DOI: 10.18553/jmcp.2006.12.8.640. View

20.

Lane M, Zeringue A, McDonald J . Serious bleeding events due to warfarin and antibiotic co-prescription in a cohort of veterans. Am J Med. 2014; 127(7):657-663.e2. PMC: 4116816. DOI: 10.1016/j.amjmed.2014.01.044. View