Measurement of antifungal drug levels in cerebrospinal fluid for cryptococcal meningoencephalitis

We report a rare case of cryptococcal meningoencephalitis in which antifungal therapy was monitored by measuring the cerebrospinal fluid (CSF) levels of the antifungal drugs. A 78-year-old man with diabetes mellitus being treated with oral agents. He had no history of human immunodeficiency virus infection. The patient showed abnormal behavior and fever (>38°C) on November 20, 2009, and was admitted for disturbance of consciousness on November 24. CSF examination showed an increased cell count, and a yeast-like fungus, suggesting cryptococcal meningoencephalitis, was observed by India ink staining. Initial treatment was liposomal amphotericin B (L-AMB) plus flucytosine. Cryptococcus neoformans was isolated by CSF culture on day 2. MIC was 0.25 μg/ml for amphotericin B (AMPH-B), 4 μg/ml for flucytosine, 4 μg/ml for fluconazole (FLCZ), and 0.03 μg/ml for voriconazole (VRCZ). Despite treatment, his disturbance of consciousness persisted. The CSF level of AMPH-B was ≤0.05 μg/ml on day 8. Therefore, L-AMB was switched to fosfluconazole. The CSF level of FLCZ was sufficient (22.6 μg/ml) on day 25, but there was a decrease in glucose and the fungus could still be detected in CSF smears. Consequently, FLCZ was switched to VRCZ. On day 47, CSF level of VRCZ was 1.97 μg/ml, exceeding its MIC, so treatment was continued. On day 77, the patient was generally lucid, and CSF smears did not detect any fungi. The patient was then transferred for rehabilitation. On day 84, voriconazole was discontinued, with no evidence of fungal recurrence.