Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance
Open accessAbstract
Candida glabrata is the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment of C. glabrata disease due to the high rate of resistance to fluconazole. Recent case reports indicate that C. glabrata resistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates of C. glabrata collected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions of FKS1 and FKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 in FKS1 and 35 in FKS2. All of the isolates with an FKS mutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S. C. glabrata isolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S. C. glabrata isolates for echinocandin resistance is warranted.
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Other studies on C. glabrata report that 14% of fluconazole-resistant strains exhibit resistance to at least one echinocandin, with 3.5% MDR at Duke University hospital, 7% MDR at MD Anderson Cancer Center, and azole resistance in 36% of echinocandin-resistant strains in a five-year USA surveillance study.
“Other studies on C. glabrata report that 14% of fluconazole-resistant strains exhibit resistance to at least one echinocandin and a total of 3.5% of MDR cases were noted in Duke University hospital [48], 7% of MDR at MD Anderson Cancer Center [45], and a resistance to azoles in 36% echinocandin-resistant strains was indicated in a five-year surveillance study in the USA [49].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [49]
In C. glabrata, echinocandin resistance has increased from 2-3% to more than 13% in a 10-year period and can be present in up to one-third of isolates in the US.
“In C. glabrata, this phenomenon has increased from 2–3% to more than 13% in a 10-year period [48] and can be present in up to one-third of isolates in the US [49].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [49]
The F659-DEL in C. glabrata confers resistance to all three echinocandins.
“For example, the F659-DEL in C. glabrata confers resistance to all three echinocandins, whereas the F659S substitution at the same codon gives rise to anidulafungin and caspofungin resistance, whereas the micafungin MIC and in vivo efficacy in a murine animal model remains unchanged (23;25;27–30).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [28]
The F659S substitution at the same codon gives rise to anidulafungin and caspofungin resistance, whereas the micafungin MIC and in vivo efficacy in a murine animal model remain unchanged.
“For example, the F659-DEL in C. glabrata confers resistance to all three echinocandins, whereas the F659S substitution at the same codon gives rise to anidulafungin and caspofungin resistance, whereas the micafungin MIC and in vivo efficacy in a murine animal model remains unchanged (23;25;27–30).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [28]
Recently, EUCAST breakpoints were developed for anidulafungin and micafungin and the former CLSI breakpoints were revised, providing species-specific breakpoints for all three echinocandins and their value confirmed.
“Recently, EUCAST breakpoints were developed for anidulafungin and micafungin and the former CLSI breakpoints were revised providing species specific breakpoints for all three echinocandins and their value confirmed (28;39–42).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [28]
The MIC increase caused by a specific FKS alteration may be species specific.
“Finally, the MIC increase caused by a specific alteration may be species specific.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [28]
Echinocandin MICs were elevated at least 5-fold above the breakpoints for C. krusei harbouring D662Y, compared to 1-fold above the breakpoint for C. albicans and an MIC below the breakpoint for C. glabrata harbouring the corresponding alterations (D648Y in C. albicans and D666Y in Fks2p for C. glabrata).
“Thus, the echinocandin MICs were elevated at least 5-foldabove the breakpoints for C. krusei harbouring the D662Y compared to 1-foldabove the breakpoint for C. albicans and an MIC below the breakpoint for C. glabrata harbouring the corresponding alterations (D648Y in C. albicans and D666Y in the Fks2p protein for C. glabrata)(20;28).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [28]
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References 42 · Cited by 231
- Authors
- Pham, C. D., Iqbal, N., Bolden, C. B., Kuykendall, R. J., Harrison, L. H., Farley, M. M., Schaffner, W., Beldavs, Z. G., Chiller, T. M., Park, B. J., Cleveland, A. A., & Lockhart, S. R.
- Affiliations
- Centers for Disease Control and Prevention (US)
- Johns Hopkins University (US)
- Emory University (US)
- Vanderbilt University (US)
- Oregon Public Health Authority, Portland, Oregon, USA
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2014-08
- Volume
- 58
- Issue
- 8
- Pages
- 4690-4696
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4136002
- OpenAlex
- W2026308901
- Cited by
- 231
- References
- 42
- Citations by year
- 2026: 18 · 2025: 13 · 2024: 12 · 2023: 10 · 2022: 12 · 2021: 24 · 2020: 22 · 2019: 20 · 2018: 28 · 2017: 31 · 2016: 17 · 2015: 19 · 2014: 5
- FWCI
- 16.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centers for Disease Control and Prevention Foundation
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida glabrata, echinocandin resistance, FKS1 mutations, multidrug resistance, fluconazole resistance, anidulafungin, caspofungin, micafungin, candidemia, antifungal susceptibility, hot spot mutations
- MeSH terms
- Caspofungin, Micafungin, Anidulafungin, Antifungal Agents, Fungal Proteins, Glucosyltransferases, Microbial Sensitivity Tests, Mutation, United States, Fluconazole, Drug Resistance, Multiple, Fungal, Candida glabrata, Echinocandins, Lipopeptides, Candidemia
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