Ampicillin Injection and Methotrexate: Interaction Details

a) A study described a 47-year-old male who was receiving intravenous methotrexate 50 mg weekly for dermatomyositis whose white blood cell (WBC) count was stabilized in the 4000/cu mm-range. Furosemide 40 mg every other day and oral penicillin 250 mg every other day were added to his regimen for mild fluid retention and mild cellulitis, respectively. Within a week of the initiation of furosemide and penicillin, the patient experienced skin ulcerations, mouth ulcers, fatigue, cough, fever, and rigors. The patient's WBC count fell to 700/cu mm and he developed staphylococcal sepsis. The authors postulated that the renal clearance of the methotrexate dose was reduced by the presence of furosemide and penicillin competing for tubular secretion, thus producing low but toxic plasma concentrations of methotrexate ³.

b) An 18-year-old man experienced neurotoxicity and renal failure following coadministration of high-doses of methotrexate and piperacillin/tazobactam. He received 5 doses of piperacillin/tazobactam 4.5 g for a urinary tract infection in conjunction with methotrexate for osteosarcoma. Adjuvant treatment with methotrexate 4 weeks after surgery during course 1 was uneventful, however during the second course of methotrexate, the 24-hour post-infusion concentration rose to 75 mcmol/L, which was 10 times the expected level for leucovorin rescue. He experienced double vision and non-oliguric renal failure. Neurologic symptoms and renal function improved with intensified leucovorin rescue and hyperhydration. Piperacillin/tazobactam was discontinued and the patient successfully tolerated 2 more cycles of high-dose methotrexate without sequelae ⁴.

c) In one study, four of five low-dose methotrexate patients received penicillins prior to or shortly after admission to the hospital. Methotrexate clearances were probably reduced sufficiently by concomitant therapy with the penicillins, resulting in neutropenia. Three of the reported patients died, while the other two experienced lengthy recovery periods. Penicillins that were administered to these five patients included amoxicillin, amoxicillin with clavulanic acid, piperacillin, piperacillin in combination with flucloxacillin, and flucloxacillin in combination with benzylpenicillin. It was proposed that the penicillins, which are weak organic acids, competitively inhibited active tubular secretion of methotrexate, resulting in toxic methotrexate serum concentrations ⁵.

d) A 15-year-old female with osteogenic sarcoma received two courses of high-dose methotrexate (12 g/m(2)) 14 days apart. Leucovorin rescue at 15 mg/m(2) was administered during both methotrexate courses. During the first course, the patient also received empiric therapy with mezlocillin (330 mg/kg daily) and gentamicin (7.5 mg/kg daily). The patient experienced significantly more gastrointestinal toxicity, despite antiemetic therapy, during the first course of methotrexate. Methotrexate serum concentrations were monitored, and showed that terminal methotrexate elimination was 27.2 hours during the first course of treatment, when mezlocillin was also being administered, and only 10.1 hours during the second course. The authors suggested that if methotrexate elimination is indeed reduced by mezlocillin, then the concurrent use of these two drugs would require extensive monitoring of methotrexate concentrations and leucovorin doses may need to be increased and administered for longer periods of time ⁶.

e) A report described a 16-year-old male with malignant osteogenic sarcoma who received ten cycles of high-dose methotrexate (8 grams per meter squared). During the tenth cycle, amoxicillin 1 gram every six hours was started six hours after the initiation of the methotrexate infusion, and was discontinued after six doses. When compared to the first nine cycles, significant differences for total plasma clearance, mean residence time, and distribution half-life of methotrexate were noted during the tenth cycle. High methotrexate plasma levels persisted for at least eight days, probably as a result of reduced renal excretion as a consequence of methotrexate-induced acute renal failure ⁷.

f) In a literature review of potential drug interactions between low-dose methotrexate (LD-MTX, 25 mg/week or less) and NSAIDs, penicillins, and proton pump inhibitors using pharmacokinetic studies and clinical case reports/series, LD-MTX and penicillin coadministration was not associated with any clinically meaningful interaction. One prospective pharmacokinetic study in patients with rheumatoid arthritis demonstrated that concomitant flucloxacillin caused only a small, statistically significant reduction in MTX AUC without changes in Cmax, clearance, or clinical toxicity. The review also identified 6 case reports/case-series observations; only 1 case was rated "probable," utilizing the Drug Interaction Probability Score (DIPS) scale, while the remainder were classified as "possible" or "doubtful" and were heavily confounded by established MTX toxicity risk factors such as advanced age, renal impairment, hypoalbuminemia, low folate status, and concomitant nephrotoxic drugs. Assess the benefit and risk of LD-MTX regardless of concomitant drug use, including factors known to predispose patients to MTX toxicity, and continue to monitor clinical and laboratory parameters ².