Antibiotic and Anticoagulation: Watching Warfarin Levels Emily Seamans, PharmD Candidate Monday February 26, 2018
Warfarin (Coumadin) is the most commonly prescribed anticoagulant to prevent thromboembolisms in patients with atrial fibrillation, venous thromboembolism, and prosthetic heart valves. Providers must closely monitor the degree of anticoagulation in patients on warfarin using the international normalized ratio (INR). Many patients have an INR target range between 2 and 3 or between 2.5 and 3.5, depending on the indication for anticoagulant therapy, ensuring appropriate anticoagulation and avoiding thrombosis and bleeds.1 For patients to achieve an INR in their therapeutic range, they must maintain consistent vitamin K intake and adhere to their medication.2 Providers must titrate warfarin doses appropriately and regularly review patients’ medications for possible interactions. A patient’s INR can increase or decrease with newly prescribed or discontinued medications. Retail health care providers are in an optimal position to monitor for drug interactions between warfarin and antibiotics because 80% to 90% of all antibiotics are prescribed in an outpatient setting.3 WHEN TO WORRY Prescribers must consider how adding and removing medications will affect a patient’s INR. Medications that interact with warfarin often have a unidirectional effect on INR. If a patient’s INR is already stabilized on warfarin and an INR-increasing antibiotic but the antibiotic is discontinued, the patient’s INR could drop below the therapeutic range. Similarly, if a patient is controlled on warfarin but a provider begins an INR-increasing antibiotic, the patient’s INR could rise above the therapeutic range.1
MANY INTERACTIONS, SEVERAL CAUSES Warfarin is metabolized by the cytochrome (CYP) P450 enzyme system, specifically, CYPs 1A2, 3A4, and 2C9.2 Medications that inhibit these CYP enzymes reduce warfarin's metabolism, increasing its effect, and increase INR. Medications that induce these CYP enzymes increase warfarin's metabolism, decreasing its therapeutic effect, and decrease INR. Medications can also directly
affect the clotting cascade, induce warfarin's metabolism, or affect its protein binding. Warfarin is highly protein bound.2 If other medications displace warfarin on protein-binding sites, the free concentration will increase, creating a bleeding risk. Antibiotics in the same class have similar effects on INR: Cephalosporins may increase INR by inhibiting production of vitamin K-dependent clotting factors.6,13 Fluoroquinolones may increase INR by inhibiting warfarin metabolism, displacing warfarin from protein-binding sites, or disturbing intestinal flora that synthesizes vitamin K.7,13
Isoniazid may increase INR by inhibiting warfarin's metabolism.9,13 Macrolides and metronidazole may increase INR by inhibiting warfarin's metabolism.4,8,13 Penicillin may increase bleeding risk by inhibiting platelet function.12,13 Rifampin may decrease INR by inducing warfarin's metabolism.10,13 Sulfonamides may increase INR by inhibiting warfarin metabolism, displacing warfarin from protein-binding sites, or disturbing intestinal flora that synthesizes vitamin K.5,13 Tetracyclines increase INR by an unknown mechanism, potentially inhibiting warfarin metabolism and plasma prothrombin activity.11,13 TAKE ACTION Providers can gauge the clinical relevance of a drug interaction based on its anticipated onset and offset and dose-adjust accordingly. Specific clinically significant warfarin-antibiotic interactions are included in the table14 with recommendations for whether and how a provider should change the warfarin dose. TABLE. DRUG INTERACTIONS BETWEEN WARFARIN AND COMMONLY PRESCRIBED ANTIBIOTICS14
Drug
Direction and Severity of Effect on INR
Anticipated Anticipated AMS† Suggested Onset Offset Management
Inhibits warfarin metabolism via 3 to 5 days ~2 days CYP2C9
Metronidazole
Moxifloxacin
Mechanism
May inhibit warfarin Major increase in metabolism via INR CYP1A2+
2 to 5 days 2-3 days
Consider empiric 25% to 40% warfarin dose reduction.
Consider empiric 0% to 25% warfarin dose reduction.
Inhibits warfarin metabolism, 2 to 5 days 2-14 days displaces protein binding
Consider empiric 25% to 40% warfarin dose reduction.
Possibly decreases warfarin metabolism*
Not 3 to 7 days reported
Inconsistent effect; no dose change unless other factors affect INR.
Ciprofloxacin
May be due to CYP1A2 inhibition+
2 to 5 days 2-4 days
Consider empiric 10% to 15% warfarin dose reduction.
Clarithromycin
Inhibits warfarin Not metabolism via 3 to 7 days reported CYP3A4
Consider empiric 15% to 25% warfarin dose reduction.
Not reported
Inconsistent effect; no dose change unless other factors affect INR.
Sulfamethoxazole
Azithromycin
Moderate increase in INR
Cloxacillin
Unknown
Delayed
Doxycycline
May inhibit
2 to 5 days Not
Inconsistent effect; no
warfarin metabolism via CYP3A4
reported
dose change unless other factors affect INR.
Erythromycin
Inhibits warfarin metabolism via 3 to 5 days 3-5 days CYP3A4
Consider empiric 10% to 15% warfarin dose reduction.
Isoniazid
Inhibits warfarin metabolism via 3 to 5 days Delayed CYP2C9
Consider empiric 10% to 15% warfarin dose reduction; monitor INR weekly.
Levofloxacin
May inhibit warfarin metabolism via CYP1A2+
Consider empiric 0% to 15% warfarin dose reduction.
Tetracycline
Reduces plasma Not pro- thrombin 2 to 5 days reported activity
3 to 5 days 5-10 days
Monitor INR closely.
Rifampin
Moderate to Induces hepatic 1 to 3 severe decrease warfa- rin weeks in INR metabolism
Consider empiric 25% 1-5 weeks to 50% warfarin dose increase.**
Terbinafine
Can increase or decrease INR
Not reported
Unknown
Unknown
Monitor INR closely.
Retail health care providers are accessible and reliable and should monitor warfarin-treated patients carefully. Initiating and discontinuing antibiotic therapy, even for a short duration, may increase or decrease a patient's INR. The longer that INR is outside the therapeutic range the higher the risk is for bleeds, clots, and even further complications.
Emily Seamans is a PharmD candidate at the University of Connecticut School of Pharmacy in Storrs, Connecticut.
References 1. Wigle P, Hein B, Bloomfield HE, Tubb M, Doherty M. Updated guidelines on outpatient anticoagulation. Am Fam Physician. 2013;87(8):556-66.2. 2. Coumadin [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2011. accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf. Accessed August 24, 2017. 3. CDC: Measuring outpatient antibiotic prescribing. cdc.gov/getsmart/community/programs-measurement/measuring-antibioticprescribing.html. Updated March 22, 2017. Accessed August 22, 2017. 4. Azithromycin [prescribing information]. New York, NY: Pfizer Labs; 2017. labeling.pfizer.com/ShowLabeling.aspx?id=511. Accessed August 24, 2017. 5. Bactrim [prescribing information]. Philadelphia, PA: Mutual Pharmaceutical Company Inc; 2013. accessdata.fda.gov/drugsatfda_docs/label/2003/17377slr057_Bactrim_lbl.pdf. Accessed August 24, 2017. 6. Rocephin [prescribing information]. Nutley, NJ: Roche Pharmaceuticals; 1998. accessdata.fda.gov/drugsatfda_docs/label/2009/0550585s063lbl.pdf. Accessed August 24, 2017. 7. Cipro [prescribing information]. West Haven, CT: Bayer Corp; 2000. dartmouth.edu/~genchem/0102/spring/6winn/pdfs/ciprotab.pdf. Accessed August 24, 2017.