Resistant P45051A1 activity in azole antifungal tolerant <i>Cryptococcus neoformans</i> from AIDS patients

Lamb, David C.; Corran, Andrew J.; Baldwin, Brian C.; Kwon‐Chung, June; Kelly, Steven L.

doi:10.1016/0014-5793(95)00684-2

Cited by 65 publications

(39 citation statements)

References 25 publications

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“…As relapses began to be associated with high fluconazole MICs and/or a 4-fold MIC increase (1,24,37,38), several aspects of sterol metabolism in these isolates were investigated to determine azole resistance mechanisms in C. neoformans. A point mutation in the ERG11 (CnCYP51) gene resulting in a G484S substitution in the target enzyme has been observed in C. neoformans strains with high fluconazole MICs (Ն32 g/ml); this mutation alters the affinity of the drug for the target enzyme (32,48,54). The overexpression of the gene CnAFR1 that encodes the membrane efflux pumps has been found to reduce cell drug (fluconazole) content in C. neoformans (29,45).…”

Section: Resultsmentioning

confidence: 99%

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Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

Espinel-Ingroff

Aller

Cantón

et al. 2012

Antimicrob Agents Chemother

223

214

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MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium for C. neoformans were evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included >95% of the modeled WT population, were as follows: fluconazole, 8 g/ml (VNI, C. gattii nontyped, VGI, VGIIa, and VGIII), 16 g/ml (C. neoformans nontyped, VNIII, and VGIV), and 32 g/ml (VGII); itraconazole, 0.25 g/ml (VNI), 0.5 g/ml (C. neoformans and C. gattii nontyped and VGI to VGIII), and 1 g/ml (VGIV); posaconazole, 0.25 g/ml (C. neoformans nontyped and VNI) and 0.5 g/ml (C. gattii nontyped and VGI); and voriconazole, 0.12 g/ml (VNIV), 0.25 g/ml (C. neoformans and C. gattii nontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 g/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.

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Section: Resultsmentioning

confidence: 99%

“…The wide use of fluconazole and other triazoles has led to in vitro resistance among Candida and Cryptococcus isolates, especially to fluconazole more than to the newer triazoles, voriconazole, and posaconazole (38). Two azole resistance mechanisms have been identified in C. neoformans (18,32,46,54).…”

mentioning

confidence: 99%

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

Espinel-Ingroff

Aller

Cantón

et al. 2012

Antimicrob Agents Chemother

223

214

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“…In the first instance, point mutations in the gene (ERG11) encoding the target enzyme, 14-␣-demethylase, lead to an altered target with decreased affinity for azoles (14)(15)(16). In the second, overexpression of ERG11 or a change in the ERG11 copy number results in the production of high concentrations of the target enzyme, creating the need for higher intracellular azole concentrations to effectively inhibit the target enzyme present in the cell (17).…”

mentioning

confidence: 99%

Fluconazole Susceptibility in Cryptococcus gattii Is Dependent on the ABC Transporter Pdr11

Yang

Uhrig

et al. 2016

Antimicrob Agents Chemother

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cCryptococcus gattii isolates from the Pacific Northwest have exhibited higher fluconazole MICs than isolates from other sites. The mechanism of fluconazole resistance in C. gattii is unknown. We sought to determine the role of the efflux pumps Mdr1 and Pdr11 in fluconazole susceptibility. Using biolistic transformation of the parent isolate, we created a strain lacking Mdr1 (mdr1⌬) and another strain lacking Pdr11 (pdr11⌬). Phenotypic virulence factors were assessed by standard methods (capsule size, melanin production, growth at 30 and 37°C). Survival was assessed in an intranasal murine model of cryptococcosis. Antifungal MICs were determined by the M27-A3 methodology. No differences in key virulence phenotypic components were identified. Fluconazole susceptibility was unchanged in the Mdr1 knockout or reconstituted isolates. However, fluconazole MICs decreased from 32 g/ml for the wild-type isolate to <0.03 g/ml for the pdr11⌬ strain and reverted to 32 g/ml for the reconstituted strain. In murine models, no difference in virulence was observed between wild-type, knockout, or reconstituted isolates. We conclude that Pdr11 plays an essential role in fluconazole susceptibility in C. gattii. Genomic and expression differences between resistant and susceptible C. gattii clinical isolates should be assessed further in order to identify other potential mechanisms of resistance.

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“…Mutations in the ERG11 gene resulting in alterations in the affinity of azoles for Erg11p have been reported as a mechanism of acquired resistance to azoles in C albicans [31] and Cryptococcus neoformans [32]. Reduced affinity of azoles for altered ERG11 protein has been reported as the basis of C krusei's innate resistance to fluconazole [33].…”

Section: Alterations In Erg11p and Up Regulation Of Erg11mentioning

confidence: 99%

Emerging fungal resistance

Baddley¹,

Moser²

2004

Clinics in Laboratory Medicine

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Resistant P45051A1 activity in azole antifungal tolerant Cryptococcus neoformans from AIDS patients

Cited by 65 publications

References 25 publications

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

Cryptococcus neoformans-Cryptococcus gattii Species Complex: an International Study of Wild-Type Susceptibility Endpoint Distributions and Epidemiological Cutoff Values for Fluconazole, Itraconazole, Posaconazole, and Voriconazole

Fluconazole Susceptibility in Cryptococcus gattii Is Dependent on the ABC Transporter Pdr11

Emerging fungal resistance

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