Fluconazole-Resistant Cryptococcus neoformans Isolated from an Immunocompetent Patient without Prior Exposure to Fluconazole

Fluconazole has been shown to be an effective alternative to amphotericin B in the treatment of cryptococcal meningitis [1–4] and is the most commonly used antifungal agent in maintenance therapy for this disease [5, 6]. A few cases of meningitis due to Cryptococcus neoformans resistant to fluconazole have been reported, all of which occurred in patients with AIDS who were previously treated with fluconazole [5–9]. Herein, we describe a case of meningitis due to fluconazole-resistant C. neoformans in an immunocompetent patient without prior exposure to fluconazole. A previously healthy 32-year-old Philippine male employed as a nurse in Israel was admitted to the hospital with a 5-day history of headache, nausea, vomiting, and dizziness. Physical examination revealed only right-sided optic neuritis. Brain CT was unremarkable. During lumbar puncture, the opening pressure was 50 cm H2O. Analysis of CSF revealed the following: glucose level, 50 mg/dL; protein level, 85 mg/dL; and WBC count, 149/mm3 (96% lymphocytes). India ink capsule staining of CSF was positive, and culture of CSF yielded cryptococci, subsequently identified as C. neoformans variety neoformans serotype A. Cryptococcal antigen was present in CSF and blood at titers of 1 : 800 and 1 : 700, respectively (CALAS; Meridian Diagnostics, Cincinnati, OH). Serology for HIV was negative as was the viral load, and the CD4/CD8 cell ratio was normal. Therapy with amphotericin B (0.7 mg/kg/d) was started with resolution of all symptoms after 7 days. Repeated India ink capsule staining and cultures of CSF were negative. The cryptococcal antigen titer in CSF decreased to 1 : 100. After 5 weeks, amphotericin B treatment was discontinued, and therapy with oral fluconazole (400 mg/d) was initiated. Nine days later, headache, dizziness, and diplopia appeared, and left abducens nerve paralysis was found. Therapy failure was suspected, and treatment with amphotericin B combined with flucytosine was given for another 5 weeks with significant clinical improvement. The patient was well during a follow-up 1 month later. The patient denied ever having taken antifungal drugs, and his employer confirmed this. MICs determined by Etest (AB BIODISK, Solna, Sweden) with use of RPMI medium—4-morpholinepropanesulfonic acid were as follows: fluconazole, >256 µg/mL; ketoconazole, 0.38 µg/mL; itraconazole, 3.0 µg/mL; and amphotericin B, 0.5 µg/mL. Resistance to fluconazole was also confirmed at the National Institute of Allergy and Infectious Diseases (Bethesda, MD). Although CSF remained sterile after the onset of treatment, clinical deterioration after the start of oral fluconazole therapy is highly suggestive of treatment failure and is in accord with the high MIC of fluconazole for the isolate. All previously reported cases of meningitis due to C. neoformans resistant to fluconazole occurred in patients with AIDS who had been treated with fluconazole [5–9]. Petter et al. [9] showed heterogeneity in susceptibility when only 1% of cryptococci were resistant to fluconazole at the beginning of therapy, whereas 35% of isolates were resistant after the sixth episode of meningitis in the same patients. To the best of our knowledge, this is the first reported case of meningitis due to fluconazole-resistant C. neoformans in an immunocompetent patient who had never been exposed to azoles. The increasingly wide use of azoles might cause an increase in resistance to these agents. Fluconazole susceptibility testing should be performed whenever resistance is suspected clinically or epidemiologically.