FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance

Zimbeck, Alicia J.; Iqbal, Naureen; Ahlquist, Angela M.; Farley, Monica M.; Harrison, Lee H.; Chiller, Tom; Lockhart, Shawn R.

doi:10.1128/aac.00836-10

Cited by 136Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal and yeast genetics research

FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance

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Zimbeck, Alicia J., Iqbal, Naureen, Ahlquist, Angela M., Farley, Monica M., Harrison, Lee H., Chiller, Tom, Lockhart, Shawn R.·2010·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.00836-10PMC PMC2981257

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Abstract

Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of ≥0.25 μg/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 (n = 2) or FKS2 (n = 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2. The predominant mutation was mutation of FKS2-encoded serine 663 to proline (S663P), found in 10 of the isolates with elevated echinocandin MICs. Two of the mutations, R631G for FKS1 and R665G for FKS2, have not been reported previously for C. glabrata. Multilocus sequence typing indicated that the predominance of the S663P mutation was not due to the clonal spread of a single sequence type. With a rising number of echinocandin therapy failures reported, it is important to continue to monitor rates of elevated echinocandin MIC values and the associated mutations.

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Non-synonymous changes in MOH1 were discovered in two out of the 10 additional unrelated C. glabrata clinical isolates harbouring Fks2 S663P.
“We discovered non-synonymous changes in MOH1 in two out of the 10 clinical isolates sequenced and non-synonymous changes in CDC6 in 7 out of 10 of the clinical isolates (Figure 4).”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [71]
The Results (page unavailable) report 10 C. glabrata isolates with Fks2p S663P and show that they belonged to multiple sequence types. The paper does not report MOH1 changes in two of those isolates; that discovery is presented as the citing authors’ own finding. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Non-synonymous changes in CDC6 were discovered in 7 out of 10 of the additional unrelated C. glabrata clinical isolates harbouring Fks2 S663P.
“We discovered non-synonymous changes in MOH1 in two out of the 10 clinical isolates sequenced and non-synonymous changes in CDC6 in 7 out of 10 of the clinical isolates (Figure 4).”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [71]
The Results (MLST analysis; page unavailable) report 10 C. glabrata isolates with Fks2p S663P across several sequence types, supporting the count and evidence against a single clone. The paper does not report CDC6 changes in seven of those isolates or establish that all 10 were unrelated; its Discussion says clonality cannot be ruled out in at least two cases. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Alternative technologies including molecular detection and MALDI-TOF are being developed for echinocandin resistance detection.
“Alternative technologies are being developed including molecular detection and MALDI-TOF.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [53]
Categorizations determined using MALDI-TOF MS-based AFST (ms-AFST) were consistent with the wild-type and mutant FKS1 genotypes and the AFST reference methodology.
“Categorizations determined using MALDI-TOF MS-based AFST (ms-AFST) were consistent with the wild-type and mutant FKS1 genotypes and the AFST reference methodology.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [53]
A simplified MALDI-TOF version facilitated discrimination of susceptible and resistant isolates of C. albicans after only 3 hours of incubation in the presence of two breakpoint-level drug concentrations (0.03 and 32 mg/L) of caspofungin.
“It was followed by a simplified version, which facilitated discrimination of susceptible and resistant isolates of C. albicans after only 3 hours of incubation in the presence of two “breakpoint” level drug concentrations (0.03 and 32 mg/L) of caspofungin (53).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [53]

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Role of FKS mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance
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., et al. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.03255-14 · Cited by 231 · see citing works
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Frequency of fks Mutations among Candida glabrata Isolates from a 10-Year Global Collection of Bloodstream Infection Isolates
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Detection of fks gene Hot Spot Mutations in Candida glabrata by CLSI Broth Microdilution Testing of Anidulafungin, Caspofungin and Micafungin Using Epidemiological Cutoff Values
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Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations
Alexander, B. D., Johnson, M. D., Pfeiffer, C. D., Jiménez-Ortigosa, C., Catania, J., Booker, R., Castanheira, M., Messer, S. A., Perlin, D. S., & Pfaller, M. A. (2013) · Clinical Infectious Diseases · doi:10.1093/cid/cit136 · Cited by 778 · see citing works
Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization
Rivero-Menéndez, O., Navarro-Rodríguez, P., Bernal‐Martínez, L., Martin-Cano, G., Lopez-Perez, L., Sánchez‐Romero, I., Pérez‐Ayala, A., Capilla, J., Zaragoza, Ó., & Alastruey‐Izquierdo, A. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01585 · Cited by 45 · see citing works

Authors: Zimbeck, A. J., Iqbal, N., Ahlquist, A. M., Farley, M. M., Harrison, L. H., Chiller, T., & Lockhart, S. R.
Affiliations: Centers for Disease Control and Prevention (US)
Emory University (US)
Johns Hopkins University (US)
ORCID: Farley, Monica M.
Harrison, Lee H.
Chiller, Tom
Lockhart, Shawn R.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2010-12
Volume: 54
Issue: 12
Pages: 5042-5047
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.00836-10
PMC: PMC2981257
OpenAlex: W2146779308
Cited by: 136
References: 38
Citations by year: 2026: 4 · 2025: 9 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 8 · 2020: 9 · 2019: 5 · 2018: 11 · 2017: 10 · 2016: 12 · 2015: 9 · 2014: 16 · 2013: 7 · 2012: 18
FWCI: 7.23
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Association of Public Health Laboratories
Centers for Disease Control and Prevention
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, FKS2, caspofungin, anidulafungin, micafungin, candidemia, bloodstream isolates, antifungal susceptibility, multilocus sequence typing, population-based surveillance
MeSH terms: Caspofungin, Micafungin, Anidulafungin, Antifungal Agents, Candidiasis, Fungal Proteins, Glucosyltransferases, Microbial Sensitivity Tests, Mutation, Polymerase Chain Reaction, Drug Resistance, Multiple, Fungal, Candida glabrata, Echinocandins, Lipopeptides

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FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance

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