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Warfarin Interactions with Antimicrobial Agents: Part I
By Gregory Aung, PharmD Candidate: Crystal Leung, PharmD Candidate; Laura Kawamoto, PharmD Candidate, PharmD Candidates for the University of the Pacific; and Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
They all report no financial relationships relevant to this field of study.
Warfarin, the most common vitamin K antagonist in clinical use, consists of two optically active isomers, the R and S enantiomers.1 The S enantiomer primarily undergoes metabolism by the cytochrome P450 (CYP) enzyme 2C9 pathway, and is 3- to 4-fold more potent than the R enantiomer. The CYP1A2 and CYP3A4 pathways are involved in the metabolism of the less potent R enantiomer.1 Warfarin dosing requirements vary greatly among individuals and can be impacted by genetic and environmental factors. Environmental factors include medications, diet, and a variety of disease states, such as liver disease and hypermetabolic conditions.1
Antimicrobials represent a short-term change in patient therapy that can have devastating consequences if certain drug interactions are disregarded or overlooked. The objective of this article is to compile and analyze case reports and other studies showing the interaction between various antimicrobial agents and warfarin. Moreover, this article is intended to heighten clinicians' awareness of the potential interactions between antimicrobial agents and warfarin, such that supratherapeutic or subtherapeutic INRs (international normalized ratios) are prevented and managed.
Overview of Interactions
Table 1 provides a summary of the most commonly implicated antibiotics, with a focus on the probability of the reaction, the proposed mechanism responsible for the interaction, the time of onset/offset (if available) of the interaction, and recommendations for preventing supratherapeutic or subtherapeutic INRs. The probabilities of the interactions were derived from the findings cited in the eighth edition of the American College of Chest Physicians' Clinical Practice Guidelines.
Fifteen antibiotic agents have been shown to interact with warfarin in published case reports over the past four decades. Of note, linezolid, vancomycin, telavancin, daptomycin, quinupristin/dalfopristin, amikacin, gentamicin, neomycin, streptomycin, tobramycin, colistimethate, nitrofurantoin, ethambutol, and pyrazinamide have not been shown to interact with warfarin.
Metronidazole potentiates the effect of warfarin through inhibition of CYP2C9, whereas rifampin induces the metabolism of warfarin through CYP1A2, CYP2C9, and CYP3A4. Ciprofloxacin, erythromycin, clarithromycin, and telithromycin most likely inhibit the metabolism of the R enantiomer of warfarin. Other antibiotics may enhance the anticoagulant effects of warfarin through displacement of warfarin from albumin, or through disruption of intestinal flora responsible for vitamin K synthesis.
In summary, concomitant use of warfarin with metronidazole, trimethoprim/sulfamethoxazole, ciprofloxacin, and erythromycin necessitates dose reduction of warfarin in order to prevent supratherapeutic INRs and/or major bleeding events. In contrast, patients taking warfarin and rifampin concurrently will require more frequent INR monitoring, along with gradual changes in warfarin dosing during the time of dual therapy and up to several months after discontinuation of rifampin therapy. The propensity of other antibiotics to interact with warfarin has not been validated by published case reports, but warrants closer INR monitoring during each treatment course.