Low Prevalence of
            <i>fks1</i>
            Hot Spot 1 Mutations in a Worldwide Collection of
            <i>Candida</i>
            Strains

Castanheira, Mariana; Woosley, Leah N.; Diekema, Daniel J.; Messer, S. A.; Jones, Ronald N.; Pfaller, Michael A.

doi:10.1128/aac.01711-09

Cited by 115 publications

(79 citation statements)

References 17 publications

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“…tested against all three echinocandins using the CLSI BMD method (31). The application of these ECVs allowed both the assessment of the CA between methods and a means of discriminating WT strains (MIC less than or equal to the ECV) from those with acquired resistance mutations (MIC greater than the ECV) (2,4,31).…”

Section: Resultsmentioning

confidence: 99%

“…Species identification was established using Vitek (bioMerieux, Hazelwood, MO), conventional reference methods (20), and 28S and internal transcribed spacer (ITS) sequencing as described elsewhere (27). All isolates were further characterized regarding the presence or absence of mutations in the hot spot (HS) regions of fks1 and fks2 (C. glabrata only) as described previously (4).…”

Section: Organismsmentioning

confidence: 99%

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Comparison of European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Etest Methods with the CLSI Broth Microdilution Method for Echinocandin Susceptibility Testing of Candida Species

et al. 2010

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The antifungal broth microdilution (BMD) method of the European Committee on Antibiotic Susceptibility Testing (EUCAST) and the Etest agar diffusion method were compared with the Clinical and Laboratory Standards Institute (CLSI) BMD method M27-A3 for anidulafungin, caspofungin, and micafungin susceptibility testing of 133 clinical isolates of Candida species. The isolates were characterized for the presence or absence of fks1 and/or fks2 gene mutations and included 34 isolates of C. glabrata (4 mutant strains), 32 of C. albicans (1 mutant strain), 25 of C. parapsilosis, 19 of C. guilliermondii, 12 of C. tropicalis (2 mutant strains), and 11 of C. krusei. Excellent essential agreement (EA; within 2 dilutions) between the CLSI and EUCAST and CLSI and Etest MIC results was observed. The overall EA between the EUCAST and CLSI results ranged from 89.5% (caspofungin) to 99.2% (micafungin), whereas the EA between the Etest and CLSI results ranged from 90.2% (caspofungin) to 93.2% (anidulafungin). The categorical agreement (CA) between methods for each antifungal agent was assessed using previously determined epidemiological cutoff values (ECVs). Excellent CA (>90%) was observed for all comparisons between the EUCAST and CLSI results with the exceptions of C. glabrata and caspofungin (85.3%) and C. krusei and caspofungin (54.5%). The CA between the Etest and CLSI results was also excellent for all comparisons, with the exception of C. krusei and caspofungin (81.8%). All three methods were able to differentiate wild-type (WT) strains from those with fks mutations. With anidulafungin as the test reagent, the CLSI method identified 5 of 7 mutant strains, whereas the EUCAST method and the Etest identified 6 of 7 mutant strains. With either caspofungin or micafungin as the test reagent, the CLSI method identified all 7 mutant strains and the EUCAST method identified 6 of 7 mutant strains. The Etest identified all 7 mutant strains using caspofungin as the reagent. All three test methods showed a high level of agreement and of ability to distinguish fks mutant strains of Candida species from WT strains using each of the echinocandins.

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Section: Resultsmentioning

confidence: 99%

Section: Organismsmentioning

confidence: 99%

Comparison of European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Etest Methods with the CLSI Broth Microdilution Method for Echinocandin Susceptibility Testing of Candida Species

et al. 2010

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“…that were resistant to Ն1 of the echinocandins were further characterized regarding the presence or absence of a mutation in the hot spot (HS) regions of fks1 and fks2 (C. glabrata only), as described previously (13,33). Table 1 shows species distribution by geographic region of the fungi implicated in IFIs during 2010 and 2011.…”

Section: Methodsmentioning

confidence: 99%

“…The recent surveillance focus has been on how best to detect the emergence of resistance within a population of a given fungal species (2,7,8,(12)(13)(14)36). The development of epidemiological cutoff values (ECVs) has aided in the detection of non-WT strains in given populations, allowing a more focused approach to the molecular definition of strains presenting less-susceptible profiles (6,8,11,13,33,37).…”

mentioning

confidence: 99%

Echinocandin and Triazole Antifungal Susceptibility Profiles for Clinical Opportunistic Yeast and Mold Isolates Collected from 2010 to 2011: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values for Characterization of Geographic and Temporal Trends of Antifungal Resistance

et al. 2013

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The SENTRY Antimicrobial Surveillance Program monitors global susceptibility and resistance rates of newer and established antifungal agents. We report the echinocandin and triazole antifungal susceptibility patterns for 3,418 contemporary clinical isolates of yeasts and molds. The isolates were obtained from 98 laboratories in 34 countries during 2010 and 2011. Yeasts not presumptively identified by CHROMagar, the trehalose test, or growth at 42°C and all molds were sequence identified using internal transcribed spacer (ITS) and 28S (yeasts) or ITS, translation elongation factor (TEF), and 28S (molds) genes. Susceptibility testing was performed against 7 antifungals (anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, and voriconazole) using CLSI methods. Rates of resistance to all agents were determined using the new CLSI clinical breakpoints and epidemiological cutoff value criteria, as appropriate. Sequencing of fks hot spots was performed for echinocandin non-wildtype (WT) strains. Isolates included 3,107 from 21 Candida spp., 146 from 9 Aspergillus spp., 84 from Cryptococcus neoformans, 40 from 23 other mold species, and 41 from 9 other yeast species. Among Candida spp., resistance to the echinocandins was low (0.0 to 1.7%). Candida albicans and Candida glabrata that were resistant to anidulafungin, caspofungin, or micafungin were shown to have fks mutations. Resistance to fluconazole was low among the isolates of C. albicans (0.4%), Candida tropicalis (1.3%), and Candida parapsilosis (2.1%); however, 8.8% of C. glabrata isolates were resistant to fluconazole. Among echinocandin-resistant C. glabrata isolates from 2011, 38% were fluconazole resistant. Voriconazole was active against all Candida spp. except C. glabrata (10.5% non-WT), whereas posaconazole showed decreased activity against C. albicans (4.4%) and Candida krusei (15.2% non-WT). All agents except for the echinocandins were active against C. neoformans, and the triazoles were active against other yeasts (MIC 90 , 2 g/ml). The echinocandins and triazoles were active against Aspergillus spp. (MIC 90 /minimum effective concentration [MEC 90 ] range, 0.015 to 2 g/ml), but the echinocandins were not active against other molds (MEC 90 range, 4 to >16 g/ml). Overall, echinocandin and triazole resistance rates were low; however, the fluconazole and echinocandin coresistance among C. glabrata strains warrants continued close surveillance.

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“…Echinocandins also are the preferred empiric therapy for suspected candidiasis in nonneutropenic patients in the intensive care unit (Pappas et al, 2009; Pappas et al, 2016). Overall, current frequency of echinocandin resistance remains relatively low (< 1%) with Candida albicans and most other Candida species except Candida glabrata (Castanheira et al, 2010; Pfaller et al, 2011; Pfaller et al, 2013). However, widespread echinocandin usage has been accompanied by reports of emerging multidrug resistance among clinical Candida isolates (Alexander et al, 2013; Fekkar et al, 2014), as well as epidemiological shifts with increased proportion of less susceptible Candida species (Lortholary et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

CD101: a novel long‐acting echinocandin

Zhao

Perez

Jiménez‐Ortigosa

et al. 2016

Cellular Microbiology

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SummaryCD101 is a novel echinocandin drug being developed to treat severe fungal infections including invasive candidiasis. We have performed a series of studies to evaluate the antifungal properties of CD101 against both echinocandin‐susceptible and ‐resistant Candida strains. Antifungal susceptibility testing performed on a collection of 95 Candida strains including 30 caspofungin‐resistant isolates containing fks mutations demonstrated comparable antifungal potency of CD101 relative to micafungin (MCF) across different Candida species. Comparable kinetic inhibition of glucan synthase activity was also observed for CD101 and MCF on both wild‐type (WT) and resistant fks mutant Candida strains. Similarly, both drugs yielded nearly identical values for a mutant prevention concentration. In a murine model of invasive candidiasis, CD101 displayed better or at least comparable efficacy relative to MCF in treating WT or fks mutant Candida albicans. An exceptional long‐lived pharmacokinetic profile was observed in mice following a single dose of CD101. Collectively, CD101 has great potential not only in treating invasive Candida infections but also in preventing emergence of resistance to currently approved echinocandin drugs.

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Low Prevalence of fks1 Hot Spot 1 Mutations in a Worldwide Collection of Candida Strains

Cited by 115 publications

References 17 publications

Comparison of European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Etest Methods with the CLSI Broth Microdilution Method for Echinocandin Susceptibility Testing of Candida Species

Comparison of European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Etest Methods with the CLSI Broth Microdilution Method for Echinocandin Susceptibility Testing of Candida Species

Echinocandin and Triazole Antifungal Susceptibility Profiles for Clinical Opportunistic Yeast and Mold Isolates Collected from 2010 to 2011: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values for Characterization of Geographic and Temporal Trends of Antifungal Resistance

CD101: a novel long‐acting echinocandin

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