From the Guidelines
Patients on warfarin should be cautious when taking antibiotics such as sulfonamides, metronidazole, ciprofloxacin, and macrolides, as these can significantly prolong INR and increase the risk of bleeding. The interaction between these antibiotics and warfarin can be attributed to their ability to inhibit the CYP2C9 isoenzyme, alter the gut microbiome, or inhibit other cytochrome P450 enzymes 1.
Key Interactions
- Sulfonamides, including sulfaphenazole and sulfamethoxazole, can increase the risk of serious bleeding when co-administered with warfarin 1.
- Metronidazole can further exacerbate this interaction, and pre-emptive warfarin dose reductions of 33% are recommended when co-administered 1.
- Ciprofloxacin, a strong CYP1A2 inhibitor, can increase serum R-warfarin concentrations, leading to elevated INR and increased risk of adverse bleeding 1.
- Macrolide antibiotics, such as clarithromycin and erythromycin, can also potentiate warfarin's effects by inhibiting CYP3A4 1.
Monitoring and Dose Adjustments
- Patients on warfarin who require these antibiotics should have more frequent INR monitoring, typically within 3-5 days of starting the antibiotic and after completing the course 1.
- Dose adjustments of warfarin may be necessary during antibiotic treatment to minimize the risk of bleeding 1.
Alternative Antibiotics
- Alternative antibiotics with minimal warfarin interaction include penicillins, most cephalosporins, tetracyclines, and clindamycin, though individual patient factors may still affect response 1.
From the FDA Drug Label
The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs. Classes of Drug also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations * Increased and decreased PT/INR responses have been reported (oral) (17-Alkyl Penicillins, intravenous, Gout Treatment Agents Testosterone Derivatives) (fluoroquinolones) ... trimethoprim/sulfamethoxazole
The antibiotics that may prolong INR in a patient on warfarin are:
- 17-Alkyl Penicillins
- Fluoroquinolones (e.g. nalidixic acid, norfloxacin, ofloxacin)
- Trimethoprim/sulfamethoxazole
- Doxycycline
- Erythromycin
- Diclofenac and naproxen may also increase PT/INR response, although they are not strictly antibiotics, they can be used in combination with antibiotics 2. It is essential to monitor PT/INR closely when these medications are initiated or stopped in patients taking warfarin.
From the Research
Antibiotics that Prolong INR in Patients on Warfarin
The following antibiotics have been found to prolong INR in patients on warfarin:
- Trimethoprim/sulfamethoxazole (TMP/SMX) 3
- Ciprofloxacin 3, 4, 5
- Levofloxacin 3, 4, 5
- Metronidazole 3
- Fluconazole 3, 6
- Azithromycin 3, 5, 6
- Clarithromycin 3
- Amoxicillin 5
- Moxifloxacin 5
- Cotrimoxazole 6
- Penicillins 6
- Cephalosporins 6
Mechanism of Interaction
The proposed mechanism of this interaction is displacement of warfarin from protein binding sites, reduction in gut flora producing vitamin K, and decreased warfarin metabolism 4.
Risk of Bleeding
The risk of bleeding is increased when these antibiotics are co-prescribed with warfarin, particularly in older adults 3, 7, 5, 6.
Monitoring INR
Regular monitoring of INR is essential when antibiotics are co-prescribed with warfarin to mitigate the risk of bleeding 3, 7, 5.