Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure.
Open accessAbstract
Mutations in Candida glabrata FKS genes, which encode the echinocandin target enzyme, are independent risk factors for treatment failures during invasive candidiasis. We retrospectively compared the ability of caspofungin susceptibility testing methods to identify C. glabrata FKS mutant isolates and predict outcomes among patients at our center. Eight percent (10/120) of sterile-site C. glabrata isolates harbored FKS1 (n = 3) or FKS2 (n = 7) mutations, including 32% (10/32) recovered from patients with prior echinocandin exposure. Median echinocandin exposures for mutant and nonmutant isolates were 55 (range, 7 to 188) and 13 (3 to 84) days, respectively (P = 0.004). Sensitivity and specificity of the CLSI caspofungin resistance breakpoint MIC (>0.12 μg/ml by broth microdilution using RPMI medium [BMD-RPMI]) were 90% (9/10) and 3% (3/110), respectively, for identifying FKS mutants. Sensitivity and specificity of receiver-operator characteristic (ROC) curve-derived breakpoints by BMD-RPMI, BMD-antibiotic medium 3, Etest, and YeastOne ranged from 70 to 100% and 89 to 95%, respectively; susceptibility rates varied from 83 to 90%. The 14-day echinocandin treatment success rate was 67% (44/66); failure was more likely with prior echinocandin exposure (P = 0.002) or infection with an FKS mutant (P = 0.0001) or echinocandin-resistant isolates by BMD-AM3, Etest, and YeastOne (P ≤ 0.03). The failure rate among patients with prior exposure and infection with a resistant isolate was 91% (10/11); it was 22% (12/55) among others (P < 0.0001). In conclusion, ROC-derived caspofungin MIC breakpoints by several methods were sensitive and specific for identifying C. glabrata FKS mutant isolates. Mutations were seen exclusively among patients with prior echinocandin exposure. A paradigm that considers prior echinocandin exposure and caspofungin MICs accurately classified treatment outcomes for C. glabrata invasive candidiasis.
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Caspofungin has an inherently lower ability to identify FKS mutations compared to anidulafungin and micafungin, with a 90% sensitivity and 3% specialty.
“caspofungin held an inherit lower ability to identify FKS mutations compared to anidulafungin and micafungin, with a 90% sensitivity and 3% specialty [44, 45].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [44]
Echinocandin resistance predominantly emerges under specific drug selection pressure, as evidenced by its strong association with prior echinocandin exposure.
“Clinically, echinocandin resistance predominantly emerges under specific drug selection pressure, as evidenced by their strong association with prior echinocandin exposure [44, 45, 46].”
From Calcineurin‐Dependent Stress Adaptation Enables Caspofungin Heteroresistance Leading to Stable Resistance in <i>Candida Glabrata</i> (2026) · cites this paper as [44]
Echinocandin resistance is associated with a dismal outcome.
“It is most commonly detected after 3–4 weeks of treatment and is associated with a dismal outcome.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [23]
Resistance in C. glabrata is on the rise.
“Nevertheless, resistance in C. glabrata is on the rise.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [23]
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 [23]
In two recent studies, 80% and 78.5% of candidaemia patients with an echinocandin-resistant C. glabrata isolate failed therapy, respectively.
“Not only has an unsuccessful outcome been reported in most case reports, but it was also documented in two recent studies that 80% and 78.5% candidaemia patients with an echinocandin resistant C. glabrata isolate fail therapy, respectively (23;25).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [23]
The outcome for patients with increased echinocandin MICs is significantly poorer.
“However, there is solid documentation that the outcome for patients with increased MICs is significantly poorer.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [23]
In a 10-year survey at the Duke University hospital, the echinocandin resistance rate in C. glabrata increased from 4.9% to 12.3% in 2001-10.
“This was recently documented in a 10-year survey at the Duke University hospital where the echinocandin resistance rate increased from 4.9% to 12.3% in 2001–10 (23).”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [23]
The outcome for patients with resistant isolates on echinocandin therapy is dismal.
“The outcome for patients with resistant isolates on echinocandin therapy is dismal.”
From Echinocandin resistance: an emerging clinical problem? (2014) · cites this paper as [23]
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References 34 · Cited by 105
- Authors
- Shields, R. K., Nguyen, M. H., Press, E. G., Updike, C. L., & Clancy, C. J.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2013-08
- Volume
- 57
- Issue
- 8
- Pages
- 3528-3535
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3719767
- OpenAlex
- W2130900751
- Cited by
- 105
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 12 · 2016: 9 · 2015: 20 · 2014: 15 · 2013: 5
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000005, KL2TR000146)
- National Center for Research Resources (KL2RR024154)
- National Center for Advancing Translational Sciences
- 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, invasive candidiasis, caspofungin, echinocandin resistance, FKS1 mutations, antifungal susceptibility breakpoints, treatment failure, E-test, broth microdilution, RPMI medium, antifungal susceptibility testing
- MeSH terms
- Caspofungin, Antifungal Agents, Humans, Microbial Sensitivity Tests, Mutation, Predictive Value of Tests, Retrospective Studies, ROC Curve, Sensitivity and Specificity, Treatment Outcome, Drug Resistance, Fungal, Candida glabrata, Echinocandins, Lipopeptides, Candidiasis, Invasive
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