Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations

Alexander, Barbara D.; Johnson, Melissa D.; Pfeiffer, Christopher D.; Jiménez-Ortigosa, Cristina; Catania, Jelena; Booker, Rachel; Castanheira, Mariana; Messer, Shawn A.; Perlin, David S.; Pfaller, Michael A.

doi:10.1093/cid/cit136

Cited by 778Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal and yeast genetics research

Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations

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Alexander, Barbara D., Johnson, Melissa D., Pfeiffer, Christopher D., Jiménez-Ortigosa, Cristina, Catania, Jelena, Booker, Rachel, Castanheira, Mariana, Messer, Shawn A. +2 more·2013·Clinical Infectious Diseases

DOI 10.1093/cid/cit136PMC PMC3658363

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Abstract

BACKGROUND: Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first-line therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations. METHODS: We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001-2010) and correlated treatment outcome with minimum inhibitory concentration (MIC) results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin, caspofungin, and micafungin) and FKS1 and FKS2 gene sequences were determined. RESULTS: Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 7.19-58.1]). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but experienced a recurrence. CONCLUSIONS: Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.

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Recent reports indicate an increase in multidrug-resistant C. glabrata isolates in the United States.
“Recent reports indicate an increase in multidrug-resistant C. glabrata isolates in the United States (19,20).”
From Population-Based Active Surveillance for Culture-Confirmed Candidemia — Four Sites, United States, 2012–2016 (2019) · cites this paper as [20]
The Discussion reports increasing resistance to both fluconazole and echinocandins in C. glabrata, including coemergence in the same isolates. But the study’s data come from a single center, Duke Hospital, and the Discussion notes substantial variation between centers; it does not establish an increase across the United States. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
12 out of 59 (20.34%) descendant strains carry proved clinically significant FKS2 point mutations, including F659del, F659S, F659C, and S663F.
“12 out of 59 (20.34%) descendant strains carry proved clinically significant FKS2 point mutations, including F659del, F659S, F659C, and S663F [38, 39, 40].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in Candida Glabrata (2026) · cites this paper as [40]
The Treatment and Mortality Outcomes section links FKS1/FKS2 mutants with treatment failure or recurrence, supporting the general clinical relevance of FKS mutations. But this paper does not establish that 12 of 59 descendant strains carried the listed FKS2 mutations; Table 2 lists F659V and S663P rather than the specific variants named in the claim. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Fluconazole resistance has been reported in up to 75% of C. glabrata isolates in single center surveys, and resistance to the echinocandins ranges from 0% to 24% in larger studies.
“Fluconazole resistance has been reported in up to 75% of C. glabrata isolates in single center surveys, and resistance to the echinocandins ranges from 0% to 24% in larger studies.27,111–113”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [111]
The Discussion (page unavailable) reports <1% echinocandin resistance in a survey of 747 isolates from 90 hospitals and none detected at one institution, supporting the low end of the claimed range. The MIC/Susceptibility Results (page unavailable) report fluconazole resistance reaching 30.1% at this study’s center, but our copy does not substantiate the claimed 75% fluconazole or 24% echinocandin figures. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Rates of echinocandin resistance tend to parallel increases in fluconazole resistance as demonstrated by Alexander et al. at a 10-year single center survey.
“Rates of echinocandin resistance tend to parallel increases in fluconazole resistance as demonstrated by Alexander et al at a 10-year single center survey.111”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [111]
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 [48]

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 [48]
Candida strains with acquired resistance to echinocandins, specifically C. glabrata, while still generally infrequent, are increasing in incidence in some hospitals.
“Candida strains with acquired resistance to echinocandins, specifically C. glabrata, while still generally infrequent, are increasing in incidence in some hospitals [10,14].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [14]
Acquired echinocandin resistance has been described in all major Candida species, but is most frequently encountered in C. glabrata, where an association with echinocandin treatment failure has been described.
“Acquired echinocandin resistance has been described in all major Candida species, but is most frequently encountered in C. glabrata, where an association with echinocandin treatment failure has been described [14,42].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [14]
A Duke Hospital study in 2010 found that 14% of fluconazole-resistant isolates also exhibited resistance to at least one echinocandin and that 3.5% of all C. glabrata isolates were MDR.
“Another study, performed at Duke Hospital in 2010, found that 14% of fluconazole-resistant isolates also exhibited resistance to at least one echinocandin and that 3.5% of all C. glabrata isolates were MDR (Alexander et al., 2013).”
From Genetic Drivers of Multidrug Resistance in Candida glabrata (2016) · cites this paper as Alexander et al., 2013
Rates of echinocandin resistance have increased the greatest (from 3 to 12%) in C. glabrata.
“the rates of resistance have increased the greatest (from 3 to 12%) in C. glabrata (Alexander et al., 2013)”
From Genetic Drivers of Multidrug Resistance in Candida glabrata (2016) · cites this paper as Alexander et al., 2013
Resistance in C. glabrata increased from 4.9% to 12.3% between 2001 and 2010.
“In fact, resistance in C. glabrata increased from 4.9% to 12.3% between 2001 and 2010 [115].”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [115]
Emergence of coresistance to both echinocandins and azoles in clinical isolates of C. glabrata has been reported.
“Even more, emergence of coresistance to both echinocandins and azoles in clinical isolates of C. glabrata has been reported [115].”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [115]
Reports of echinocandin resistance in patients with infections due to C. albicans, C. glabrata, C. tropicalis, and C. krusei are rising.
“However, reports of echinocandin resistance in patients with infections due to C. albicans, C. glabrata, C. tropicalis, and C. krusei are rising [111–116].”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [115]
Among 78 fluconazole resistant isolates, 14.1% were resistant to one or more echinocandin and almost 8% had a FKS mutation (FKS1/FKS2), which appeared due to prior echinocandin therapy.
“among the 78 fluconazole resistant isolates, 14.1% were resistant to one or more echinocandin and almost 8% of the isolates had a FKS mutation (FKS1/FKS2 mutations), which appeared due to a prior echinocandin therapy.”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [124]
In patients with Candida glabrata bloodstream infections, resistance to echinocandins increased from 4.9% to 12.3% between 2001 and 2010.
“A study performed from patients with C. glabrata bloodstream infections showed that the resistance to echinocandins increased from 4.9% to 12.3% between 2001 and 2010.”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [124]

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Authors: 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.
Affiliations: Duke University (US)
Campbell University (US)
JMI Laboratories (US)
Rutgers New Jersey Medical School (US)
Corresponding author: Alexander, Barbara D.
ORCID: Alexander, Barbara D.
Johnson, Melissa D.
Pfeiffer, Christopher D.
Castanheira, Mariana
Messer, Shawn A.
Perlin, David S.
Pfaller, Michael A.
Venue: Clinical Infectious Diseases
Publisher: Oxford University Press (OUP)
Published: 2013-03-13
Volume: 56
Issue: 12
Pages: 1724-1732
ISSN: 1058-4838 (ISSN-L)
1537-6591
DOI: 10.1093/cid/cit136
PMC: PMC3658363
OpenAlex: W2128917111
Semantic Scholar: 602994a6a7d31fd45a531977af77372f1c4aeb38
Cited by: 778
References: 43
Citations by year: 2026: 33 · 2025: 39 · 2024: 54 · 2023: 49 · 2022: 40 · 2021: 58 · 2020: 64 · 2019: 68 · 2018: 62 · 2017: 79 · 2016: 62 · 2015: 73 · 2014: 78 · 2013: 19
FWCI: 56.42
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Clinical Infectious Diseases (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Allergy and Infectious Diseases (AI069397, K24AI072522, R01AI069397, AI072522)
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, fluconazole resistance, FKS1 mutations, bloodstream infection, anidulafungin, caspofungin, micafungin, minimum inhibitory concentration, treatment failure, antifungal susceptibility testing, clinical breakpoints
MeSH terms: Adolescent, Adult, Aged, Aged, 80 and over, Antifungal Agents, Candidiasis, Child, Child, Preschool, Female, Fungal Proteins, Glucosyltransferases, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Microbial Sensitivity Tests, Middle Aged, Mutation, Retrospective Studies, Treatment Outcome, Drug Resistance, Fungal, Candida glabrata, Echinocandins

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Increasing Echinocandin Resistance in Candida glabrata: Clinical Failure Correlates With Presence of FKS Mutations and Elevated Minimum Inhibitory Concentrations

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