Significant impairment of high-dose methotrexate clearance following vancomycin administration in the absence of overt renal impairment

Background: Methotrexate is an anti metabolite cytotoxic drug which is predominantly renally excreted. Vancomycin, a glycopeptide antibiotic that is used in the febrile neutropaenic patient, can be nephrotoxic. There are no previous reports of any interactions between these two drugs. Patients and methods: We describe two patients with osteosarcoma treated with high-dose methotrexate-containing chemotherapy who had significantly delayed methotrexate clearance several weeks following exposure to vancomycin. Results: These patients were treated with alternating chemotherapy consisting of 12 g/m(2) methotrexate, 60 mg/m(2) cisplatin, 75 mg/m(2) adriamycin and 15 g/m(2) ifosfamide. In both patients, serum methotrexate levels fell to below 0.2 mumol/l within 48-96 h during initial treatment cycles. However, following recent exposure to therapeutic vancomycin in the preceding 10 days and in the absence of overt renal impairment, both patients manifested markedly prolonged methotrexate clearance, requiring 170-231 h to reach serum levels of less than 0.2 muM. Subclinical renal impairment was documented by impaired glomerular filtration rates in both cases by technetium 99 in diethylene triamine penta-acetic acid scanning. Subsequent methotrexate cycles using an unmodified schedule were cleared within 72 h. Both cases had their glomerular filtration rate re-assessed, which showed marked improvement. Conclusions: Recent exposure to vancomycin, even in the absence of overt renal impairment, may adversely affect methotrexate excretion, which can subsequently lead to increased toxicity of the anti metabolite. The glomerular filtration rate should be measured in such cases so that appropriate dose modification of methotrexate can be made.