Isolation and characterization of fluconazole- and amphotericin B-resistant Candida albicans from blood of two patients with leukemia

Abstract

Infections with fluconazole-resistant Candida albicans isolate have rarely been described in clinical settings other than oropharyngeal candidiasis in patients with late-stage AIDS. We report on two patients with leukemia who developed fungemia caused by fluconazole-resistant C. albicans after receiving fluconazole prophylaxis (400 mg/day) and empiric amphotericin B therapy (0.5 mg/kg of body weight per day). The fluconazole MICs for the isolates were > or = 64 micrograms/ml, and the isolates were resistant to other azoles and had membrane sterol changes consistent with a mutation in the delta 5,6-sterol desaturase gene. The lack of ergosterol in the cytoplasmic membrane of the fluconazole-resistant strains also imparted resistance to amphotericin B. Both patients were successfully treated with high-dose amphotericin B (1 to 1.25 mg/kg/day) and flucytosine (150 mg/kg/day).

Regulation of multidrug resistance in pathogenic fungi

“…Similarly, mutations in ERG11, which encodes sterol 14a-demethylase, can affect binding of azoles to the enzyme, resulting in increased drug resistance of the cells (Kelly et al, 1999a(Kelly et al, , 1999bLamb et al, 2000). Increased expression of ERG11 can also contribute to azole resistance (Du et al, 2004;Marichal et al, 1997), and alterations in the sterol biosynthesis pathway that bypass the accumulation of toxic sterols result in azole-resistant Candida strains (Kelly et al, 1994;Nolte et al, 1997;Pinjon et al, 2003). Such mutations may cause cross-resistance to several drugs with the same mode of action.…”

“…Mutations that cause defects in the uptake of flucytosine or in its intracellular conversion are a frequent cause of resistance to this drug (Dodgson et al, 2004;Florent et al, 2009;Hope et al, 2004;Noel et al, 2003;Papon et al, 2007). A decrease in the membrane ergosterol content can lead to reduced polyene susceptibility (Kelly et al, 1994Nolte et al, 1997;Pinjon et al, 2003;Vandeputte et al, 2007;Young et al, 2003), although this type of resistance is rarely observed and of minor importance. Mutations in the FKS1 gene, encoding a subunit of the b-1,3-glucan synthase complex, result in resistance to echinocandin drugs (Perlin, 2007).…”

cDNA microarray analysis of differential gene expression and regulation in clinically drug-resistant isolates of Candida albicans from bone marrow transplanted patients

“…Phenotypically stable resistance to azole antifungal agents in C. albicans can result from mutations or increased expression of genes involved in the ergosterol synthesis pathway (including the target enzyme 14-a demethylase), and increased expression of ATP-binding cassette (ABC) transporter and major facilitator efflux pumps . Moreover, the resistance can be rapidly developed in C. albicans after short exposures to the drug, both in vitro (Calvet et al, 1997) and in vivo (Marr et al, 1997;Nolte et al, 1997), notably in a strain of C. albicans that caused disseminated infection in a patient after bone marrow transplantation (BMT) (Marr et al, 1997).…”

Recent insights into the mechanisms of antifungal resistance

“…They further concluded that disruption of ergosterol biosynthesis in general would confer resistance to AmB. Similarly, examination of AmB-resistant, clinical C. albicans isolates indicated that these cells exhibited alternate sterol composition in their cell membranes consistent with ERG3 disruption [2,3].…”