Phenytoin intoxication during treatment with parenteral miconazole.

We describe a patient in whom phenytoin toxicity developed soon after treatment with parenteral miconazole. A 51 year old man was admitted for treatment of recurrent severe haemoptysis associated with pulmonary aspergillosis. He was in chronic respiratory failure. He was a non-smoker. Biochemical 'indices of liver function were normal. There was a past history of asthma and also of epilepsy for 20 years, for which he was receiving phenytoin capsules 300 mg daily. The epilepsy was well controlled and the dose of phenytoin had remained unchanged for five years. During this time he had complained of intermittent dizziness and unsteadiness, but the plasma phenytoin concentration had not been estimated. He began treatment with intravenous miconazole 500 mg every eight hours and oral flucytosine 2 g every six hours. The phenytoin dosage and formulation remained unchanged. The next day he complained of nausea, vomiting, and blurred vision and was treated with metoclopramide. Three days later his symptoms were more severe and pronounced nystagmus was noted. These symptoms and signs were attributed to the miconazole and the dose was decreased to 400 mg every eight hours; however, his symptoms persisted. One week after beginning the antifungal treatment his plasma phenytoin concentration (EMIT, Syva Industries) was found to be 170 ,tmol/l (43 Hg/ ml) (our recommended therapeutic range is 40-80 ,umol/l; 10-20 ,ug/ml). Phenytoin was stopped for 12 days, during which time the plasma concentration fell to 39 j.mol/l (9-8 /Lg/ml) and his symptoms and signs subsided. During this time miconazole was stopped for four days and then reinstituted (figure). Phenytoin was restarted at 100 mg/day, and 20 days later the plasma concentration was 91 jtmol/l (23 jg/ml). Miconazole and flucytosine were then stopped, and 10 days later the plasma phenytoin concentration had fallen to 57 Hmol/l (14-3 ,Hg/ml). When we realised that phenytoin toxicity was the cause of the patient's symptoms, two samples of blood which had been collected and stored for other purposes were analysed retrospectively for phenytoin concentration. The value from the day before beginning miconazole and flucytosine was 114 itmol/l (29 jig/ml) (figure), which, together with his history of intermittent dizziness, suggested that he had had mild phenytoin toxicity before the antifungal treatment.