Ceftriaxone Injection and Warfarin: Interaction Details

a) Initiation of antibiotics in patients on warfarin therapy resulted in a significantly increased risk of bleeding, according to a nested case-control study of United States Medicare part D beneficiaries aged 65 years and older (n=38,762). Patients on warfarin who received any antibiotic were twice as likely to be hospitalized for bleeding compared with a control group on warfarin who were not exposed to antibiotics (adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5). Specific antibiotics with the highest bleeding risk were azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), followed by cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21), and quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62). The mechanism for drug interactions between warfarin and antibiotics is suspected to be the disruption of intestinal flora responsible for vitamin K synthesis ¹.

b) In a retrospective chart review involving patients receiving chronic warfarin therapy (N=120) with a diagnosis of urinary tract infection (UTI), ceftriaxone use resulted in a significant increase in INR compared to other commonly administered antibiotics. Included patients were divided into 4 groups based on antibiotic used for UTI, ceftriaxone (n=27), a first-generation cephalosporin (n=14), a penicillin (n=57), or ciprofloxacin (n=22). The majority of patients were receiving warfarin for atrial fibrillation; only 45.8% of patients were in therapeutic range. The median number of days from antibiotic initiation to peak INR value was 2 days. Comparing peak INR values, the ceftriaxone group had a significantly higher peak compared to first-generation cephalosporins, penicillins, and ciprofloxacin treatment groups (3.56 vs 2.66, 2.98, and 2.3, respectively). The ceftriaxone group also had a greater total increase in INR from baseline compared to other antibiotic studied (1.19 vs 0.66, 0.8, and 0.275, respectively). The mechanism for the interaction between warfarin and ceftriaxone is unknown, however antibiotics are known to interfere with intestinal flora that produce vitamin K ³.

c) A 67-year-old Native American Indian woman, stabilized on warfarin, had significantly elevated INR levels 4 days after ceftriaxone administration. She had been on stable warfarin therapy for 8 years (INR goal, 2.5 to 3.5), and 4 to 5 weeks prior to receiving ceftriaxone, her INR levels were stable (INR, 1.9 to 3) with warfarin 52.5 to 54.5 mg weekly. Four days after receiving IM ceftriaxone 1 g for UTI, she presented with an INR was 10.74 compared with an INR of 3 the previous week. Although her current therapy included concomitant medications for comorbid conditions (diabetes mellitus type 2, COPD, dyslipidemia, GERD, and depression), she denied any changes to her medications or diet. Subsequently, the next warfarin dose was held and she received phytonadione 5 mg. The following day, her INR decreased to within goal range (INR, 3.4) and stabilized over the next 4 to 5 weeks at a warfarin weekly dose of 54.5 to 55.5 mg. About 2 months later, she received a second dose for UTI plus cefuroxime axetil 500 mg twice daily for 7 days and phenazopyridine 200 mg 3 times daily as needed. Again, 4 days later, her INR increased to 16.99. Her warfarin dose was held for 2 days, and she received phytonadione 5 mg. Subsequently, she resumed warfarin 7.5 mg daily and her INR reached her goal range ⁴.