Development of azole resistance during fluconazole maintenance therapy for AIDS-associated cryptococcal disease


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Excerpt

The ubiquitous encapsulated yeast Cryptococcus neoformans causes serious, life-threatening infections of the central nervous system in AIDS patients [1]. Fluconazole is the drug of choice for long-term suppressive therapy because it is effective and can be given by mouth. Anecdotal reports suggest that the use of fluconazole for long-term maintenance therapy in AIDS patients may be associated with the selection of less susceptible cryptococcal isolates to fluconazole. However, the impact of the development of resistance on the clinical management of recurrent cryptococcosis has not been particularly addressed. This case report relates the clinical course and treatment response in a patient with AIDS, who relapsed four times with severe cryptococcal meningitis during anti-fungal maintenance therapy, to in-vitro anti-fungal drug resistance profiles of serial C. neoformans isolates.In May 1998, a 33-year-old man with an 11 year history of HIV infection [CD4 cell count 9 cells/μl, 1.6%; HIV-RNA (nucleic acid sequence-based amplification) 20 000 copies/ml] presented with fever, non-productive cough, and clinical signs of meningitis. Chest X-ray showed diffuse bilateral reticular infiltration, whereas cranial computerized tomography was unremarkable. C. neoformans was found in cytospins obtained from both bronchoalveolar lavage and cerebrospinal fluid (CSF). Cryptococci grown from both sources were highly sensitive to fluconazole [minimum inhibitory concentration (MIC) < 8 μg/ml], intraconoazole (MIC < 0.5 μg/ml), flucytosine (MIC < 2 μg/ml) and amphotericin B (MIC < 2 μg/ml) when tested by broth microdilution technique in vitro. After intravenous triple therapy with amphotericin B (0.7 mg/kg a day), flucytosine (150 mg/kg a day) and fluconazole (400 mg twice a day) for 6 weeks cryptococcus meningitis and pneumonia resolved; maintenance therapy with fluconazole (200 mg twice a day) was started, together with antiretroviral therapy. After two meningitis relapses despite ongoing fluconazole maintenance therapy in March and August 1999, both again responsive to intravenous triple agent anti-fungal therapy, maintenance therapy was intensified to 400 mg fluconazole twice a day. This did not prevent a further cryptococcal meningitis relapse in November 1999, complicated by ocular involvement with chorioretinitis. At this time Cryptococci grown from the CSF were found to be resistant to fluconazole (MIC 64 μg/ml), itraconazole (MIC 0.5 μg/ml) and flucytosine (8 μg/ml) in microdilution assays, but remained sensitive to amphotericin B (MIC 0.125 μg/ml) and voriconazole (MIC 0.5 μg/ml). After treatment with amphotericin B (0.7 mg/kg a day) for 6 weeks, supplemented by prednisolone (40 mg a day) to control severe ocular disease, meningitis and chorioretinitis resolved. Oral maintenance therapy with voriconazole (200 mg twice a day after a 400 mg twice a day loading dose) in an approval study was initiated. However, this maintenance regimen did not prevent a fourth cryptococcal menigitis relapse in March 2000. Surprisingly, C. neoformans grown from the CSF during that relapse was still completely sensitive to voriconazole in vitro (MIC 1.0 μg/ml). After daily intravenous amphotericin B treatment for 6 weeks, an intravenous maintenance regimen with 50 mg amphotericin B three times a week was started, which effectively prevented further cryptococcal meningitis episodes. Antiretroviral therapy achieved only partial suppression of viral replication within the first 12 months. After modification in March 1999, plasma HIV levels were consistently below a detection limit of 50 copies/ml. In parallel, there was a continuous increase of CD4 cells to 197/mm3 in April 2001.The presented patient with severe disseminated cryptococcosis showed an excellent clinical response to established triple antifungal therapy with amphotericin B, flucytosine and fluconazole, but repeatedly relapsed despite fluconazole maintenance therapy initially dosed as recommended [2,3] and subsequently intensified.

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