Effects of Voriconazole on Cryptococcus neoformans

Abstract

Voriconazole is a broad-spectrum triazole that offers extended activity against molds and yeasts that are not susceptible to earlier azole-type drugs. Recent studies indicate that melanization can severely reduce the susceptibility of certain antifungal drugs, but there is no information as to whether voriconazole is vulnerable to this effect. The activity of voriconazole on C. neoformans was assessed by MIC analysis and time-kill assays for melanized and nonmelanized cells. Cell morphology, capsule release, and phagocytosis of C. neoformans were studied in the presence or absence of subinhibitory concentrations of voriconazole. Voriconazole was fungicidal at concentrations of >8 g/ml in vitro against the strains of C. neoformans examined, and its efficacy was not diminished by melanization. Cells grown in subinhibitory concentrations of voriconazole had smaller cellular and capsular volumes than cells grown in the absence of drug. The induction of the capsule by serum was not affected by voriconazole. Cells grown in subinhibitory concentrations of voriconazole released their capsule and were phagocytosed at rates comparable with yeast grown without the antifungal. The high activity of voriconazole against both melanized and nonmelanized cells results suggest that voriconazole may be a particularly valuable drug for cryptococcosis.Cryptococcus neoformans is a relatively frequent cause of serious fungal infections in immunocompromised patients. The prevalence in the United States of cryptococcal meningoencephalitis in patients with AIDS receiving retroviral therapy is currently estimated to be Ͻ2% (23) but is Ͼ30% in areas of South East Asia and Sub-Saharan Africa (29). Patients with AIDS complicated by cryptococcosis often respond poorly to treatment and, in the setting of continued immunosuppression, require lifelong maintenance therapy since currently available antifungal agents seldom eradicate these fungal pathogens in the setting of severe immune suppression (16,41).Voriconazole, a synthetic derivative of fluconazole, is a broad-spectrum triazole antifungal that inhibits cytochrome P450-dependent 14␣-lanosterol demethylation, which is a critical step in fungal cell membrane ergosterol synthesis. Voriconazole demonstrates excellent in vitro activity against C. neoformans (17, 31) and achieves good levels in cerebrospinal fluid (35). Voriconazole is not currently licensed for use in cryptococcosis and no clinical trials have evaluated its efficacy for cryptococcal disease. There is limited published information regarding the clinical use of voriconazole for cryptococcosis (12, 30). In a study by Perfect et al., voriconazole therapy resulted in a 39% response rate in 18 patients with refractory cryptococcal meningoencephalitis (30).Given recent evidence that melanization can significantly reduce the efficacy of certain antifungal drugs against C. neoformans (36), we evaluated the activity of voriconazole against both melanized and nonmelanized yeast cells. Although we previously did not see a protective effect...

Dual Infections with Pigmented and Albino Strains ofCryptococcus neoformansin Patients with or without Human Immunodeficiency Virus Infection in India

“…Although standard MIC susceptibility testing did not show any differences between the strains, the strains that produced melanin in the presence of L-DOPA were significantly more resistant to killing by AMB than the albino isolates. This finding is consistent with prior publications, reporting that time-kill experiments reveal that C. neoformans melanization is protective against AMB (18,41,42). Melanotic C. neoformans strains have been reported to be more virulent in animal models than melaninlacking strains (23).…”

In vitro antifungal susceptibility profiles and genotypes of 308 clinical and environmental isolates of Cryptococcus neoformans var. grubii and Cryptococcus gattii serotype B from north-western India

“…As reported previously (Yildiran et al, 2000;van Duin et al, 2004;Souza et al, 2005;Khan et al, 2007), voriconazole exhibited the highest inhibitory activity against the isolates of C. neoformans var. grubii (GM 0.056 mg ml 21 ) and C. gattii (GM 0.138 mg ml 21 ).…”

Molecular Epidemiology of Clinical Cryptococcus neoformans Strains from India

“…Previous reports indicated that the polysaccharide capsule of C. neoformans in the brain is smaller than in the lung in a murine model of cryptococcosis (51), a finding that we could not confirm in this study. We also could not document a significant decrease in capsule size in sequential isolates pre-and posttreatment, although this had been shown in both in vitro (56) and in vivo (J. D. Nosanchuk, personal communication) studies.…”