Effect of Levofloxacin Coadministration on the International Normalized Ratios During Warfarin Therapy

Weeranuj Yamreudeewong, Pharm.D., Dennis L. Lower, M.D., David M. Kilpatrick, M.D., Ann M. Enlow, F.N.P., Margo M. Burrows, F.N.P., Mark C. Greenwood, M.S.


Pharmacotherapy. 2003;23(3) 

In This Article

Abstract and Introduction

Study Objective: To evaluate the effect of levofloxacin coadministration on the international normalized ratio (INR) in patients receiving warfarin therapy.
Design: Prospective analysis.
Setting: Outpatient clinic at a Veterans Affairs medical center.
Patients: Eighteen adult patients receiving warfarin.
Intervention: On the basis of clinical diagnosis and judgment, levofloxacin was prescribed to the 18 patients for treatment of various types of infection. The INR was measured before and at 2-8-day intervals after the coadministration of levofloxacin therapy, and once after completing therapy. Warfarin dosages were adjusted when necessary.
Measurements and Main Results: Warfarin dosages were changed in seven patients as a result of the first nontherapeutic INR values obtained after start of levofloxacin therapy. Owing to a concern regarding noncompliance and the adverse effect of bleeding, warfarin dosage was adjusted in one patient even though his first INR value was in the high end of the therapeutic range (2.98, therapeutic range 2-3). One patient withdrew from the study after the first INR measurement after levofloxacin coadministration. Because of a concern about the possible bleeding complication, warfarin dosage was also adjusted in this patient after obtaining his first INR value. Therefore, only the INR values obtained before and the first INR values obtained after levofloxacin administration were compared to evaluate the effect of levofloxacin on INR determination of warfarin therapy. The INR values obtained before levofloxacin administration did not differ significantly from the first INR values obtained after levofloxacin coadministration (mean ± SD 2.61 ± 0.44 vs 2.74 ± 0.83, 95% confidence interval -0.449-0.196, p=0.419).
Conclusion: The INR values measured before and after concomitant levofloxacin therapy were not significantly different. However, the ability to detect a significant difference may be affected by the small number of patients studied. Further studies with a larger sample are required to better determine the effect of levofloxacin coadministration on INR monitoring during warfarin therapy.

Levofloxacin is a broad-spectrum, fluoroquinolone agent that possesses antimicrobial activity against both gram-positive (e.g., Streptococcus pneumoniae and Enterococcus faecalis) and gram-negative (e.g., Haemophilus influenzae and Pseudomonas aeruginosa) bacteria.[1] In addition, it is active against atypical pathogens (e.g., Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae) and some anaerobic bacteria (e.g., Clostridium perfingens).[1,2] Other fluoroquinolones such as ciprofloxacin and ofloxacin have been reported to interact with warfarin, resulting in prolongation of prothrombin time.[3,4,5] There are conflicting reports about the interaction between ciprofloxacin and warfarin, however, because no interaction between the two drugs was reported in some studies.[6,7] The proposed mechanisms of previously reported interactions between warfarin and fluoroquinolones include inhibition of warfarin metabolism and depletion of vitamin K-dependent clotting factors by inhibition of vitamin K-producing intestinal flora.[8,9] The interactions between warfarin and other fluoroquinolones appear to be delayed in onset.[10] The mean time to detection of an increased hypo-prothrombinemic effect of warfarin after coadministration of ciprofloxacin and warfarin is 5.5 days.[11] Results from a single-dose study involving 16 healthy volunteers indicated no significant effect of levofloxacin on peak plasma warfarin concentrations when these two drugs were administered concurrently.[12] In addition, no significant changes in prothrombin times were detected in that study. According to the manu-facturer, however, levofloxacin has been reported to increase the anticoagulant effect of warfarin, which resulted in bleeding episodes such as epistaxis and purpura.[13] Depending on the international normalized ratio (INR) values, the patients' ages, and their clinical conditions, these bleeding episodes may be severe and require hospitalization.

To our knowledge, no clinical studies have been published about the effect of levofloxacin on the INR values in patients who have been stabilized with warfarin. We, therefore, designed this study to evaluate the effect of levofloxacin on INR values in patients receiving long-term warfarin (3 months to indefinitely).