Amoxicillin and Acenocoumarol: Interaction Details

a) Initiation of antibiotics in patients on continuous warfarin therapy resulted in a significantly increased risk of serious bleeding requiring hospitalization 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 matched controls on warfarin who were not exposed to antibiotics (adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5). Additionally, continuous-warfarin users were twice as likely to have a bleeding event that required hospitalization within 60 days of antibiotic exposure compared with non-exposure. Antibiotic exposure greater than 60 days from the index bleed was not significantly associated with increased risk of bleeding. Specific antibiotics with the highest bleeding risk were azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), followed by cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05), cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), 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) ².

b) In a prospective, double-blind, two-phase crossover study in patients (n=12; mean age 41.3 years; range, 22 to 68 years) on stable warfarin therapy, addition of amoxicillin/clavulanate did not significantly increase the INR compared with placebo. Patients who had received warfarin for at least 1 month with a stable INR (3 consecutive values over a minimum of 5 days) and had no recent infection or inflammatory disease were randomized to receive a 7-day course of either oral amoxicillin 1000 mg/clavulanate 125 mg twice daily or matching placebo during each 10 day period; warfarin doses remained stable during each period. Mean maximal INR elevations from baseline to day 10 were similar between the amoxicillin/clavulanate and placebo groups (0.22 +/- 0.3 and 0.24 +/- 0.6, respectively); correspondingly, the mean maximum INR was not significantly different between the groups (2.57 +/- 0.4 vs 2.67 +/- 0.5). Warfarin plasma concentrations (factor II, R(-) and S(-)) were also comparable between either treatment period and between days 1 and 7. The study was only powered to detect significant differences in INR (increase of 1.1). It was suggested that previous case reports of an INR increase with concomitant amoxicillin may not be due to a drug-drug interaction and that the infection itself may be the factor altering the INR ⁴.

c) A case report described an elevated INR and hematuria in a 58-year-old woman following concomitant use of amoxicillin/clavulanate with warfarin. The patient, whose medical history included atrial fibrillation, hypertension, rheumatoid arthritis, and hysterectomy, was admitted to the emergency room (ER) with a diagnosis of warfarin toxicity. She had been taking warfarin 7.5 mg/day for greater than 1 year for stroke prophylaxis. Her INRs during that time had been in the therapeutic range of 2 to 3. Her INR in the ER was 6.2. One month before the current events, she was prescribed amoxicillin 500 mg/clavulanate potassium 125 mg for 7 days for an ear infection. An INR drawn 3 weeks prior to initiation of the antibiotic was 3.2. The dose of warfarin was not changed. The patient was also taking lisinopril/hydrochlorothiazide, zolpidem, verapamil, loratadine, gabapentin, and acetaminophen/oxycodone. An INR drawn 4 days after completion of antibiotic therapy was 2.55. Two and a half weeks after the course of amoxicillin/clavulanate potassium was completed the patient's INR was 6.2. A repeat INR was 8.7, and microscopic hematuria was noted. She was treated with 2 units of fresh frozen plasma and 1 subQ dose of vitamin K in the ER. The next day, her INR was 3.43. An additional dose of oral vitamin K 2.5 mg was given on hospital day 2 and the patient was discharged home without warfarin. The patient's INR on follow-up was 1.9 and she was restarted on warfarin 5 mg/day alternating with 7.5 mg/day, and later on stabilized on a maintenance dose of 6.5 mg/day ⁵.

d) A case report described an increase in INR and the subsequent death of an 85-year-old woman following coadministration of amoxicillin/clavulanate with warfarin. The patient had been on long-term warfarin anticoagulation for a DVT. Amoxicillin/clavulanate was prescribed for one week for a chest infection while she maintained her other medications of warfarin, digoxin, and furosemide. The patient was found collapsed at home and was admitted to the emergency room with oral and rectal bleeding. Hemoglobin was 6.6 g/dL and her INR was greater than 10. The patient died and postmortem evidence of profuse bleeding throughout her body was documented ⁶.

e) A case report described an increased INR in a 65-year-old man following coadministration of amoxicillin and warfarin. The patient had 6 lower anterior teeth extracted and was given amoxicillin 3 g orally one hour before the extractions. One week later, the patient's INR was 9.1. He was admitted to the hospital and given 4 units of fresh frozen plasma, 2 units of blood over several days and vitamin K. Warfarin was stopped and his INR fell to 4.3 after 24 hours. His warfarin regimen was eventually reestablished to allow his INR to be within the therapeutic range ⁶.

f) A case of increased INR is described in a patient maintained on acenocoumarol who was prescribed a course of amoxicillin. An 81-year-old female patient was hospitalized for treatment of osteoarthritis and a hip prosthesis was inserted. The patient developed DVT in both legs for which anticoagulation was performed. The patient received a continuous IV infusion of sodium heparin, and 5 days later oral anticoagulant therapy with acenocoumarol. The dose of acenocoumarol was titrated to maintain an INR of between 2.5 and 4. Other medications included terbutaline, amiloride, and hydrochlorothiazide. The patient was discharged on 3 mg/day of acenocoumarol with an INR of 3.8. Five weeks later, the patient experienced coughing and increased expectoration for which amoxicillin was prescribed. A week later, bruising on both buttocks was observed. Although there was no evidence of bleeding, her INR at this point was 7.1. Treatment with acenocoumarol was stopped for 2 days and amoxicillin was discontinued. Acenocoumarol was resumed at 2 mg/day. Six days later her INR was 1.6 and the dose of acenocoumarol was increased to 3 mg/day. The author concluded that the interaction between amoxicillin and acenocoumarol was produced either by an alteration in the intestinal microflora by amoxicillin, or by inhibition by amoxicillin of the hepatic metabolism of acenocoumarol ⁷.

g) A case report described an increase in INR in a 54-year-old woman who was already taking warfarin and was prescribed amoxicillin. Amoxicillin 3 g was prescribed as prophylactic cover before routine dental treatment. She had been taking warfarin for several years with a stable INR in the range of 2.8 to 3.1. Five days after receiving a single dose of amoxicillin, her INR was 6.4. Warfarin was stopped for 2 days. She then received her usual maintenance dose of 10 mg daily. Her INR returned to the therapeutic range ⁶.