High-Dose Ketoconazole for Treatment of Fungal Infections of the Central Nervous System

Abstract

Mortality and complication rates remain unacceptably high with conventional i.v. and intrathecal therapy for patients with coccidioidal meningitis and intracerebral fungal lesions. The ventricular and lumbar CSF penetration of ketoconazole and the responses to therapy were studied in 2 patients receiving ketoconazole orally, 800 mg daily, and amphotericin B intraventricularly for meningeal and extrameningeal coccidioidomycosis. Five patients received only 1200 mg of ketoconazole: 1 had uncomplicated coccidioidal meningitis, 3 had obstructive hydrocephalus due to coccidioidal meningitis and 1 had a histoplasmal brain abscess. Ketoconazole concentrations in ventricular and lumbar fluid ranged from 0.05 to 1.65 .mu.g/ml 4 and 8 h after the dose. The mean penetration of ketoconazole (.+-. SD) was 1.9% .+-. 0.8% for ventricular fluid and 5.4% .+-. 2.6% for lumbar fluid. Ketoconazole concentrations in CSF varied directly with those in serum and with CSF protein content. The encouraging clinical responses, convenience, safety and the consistent penetration of ketoconazole into obstructed and nonobstructed CSF support the use of these regimens as alternatives to conventional therapy.