Cited by 67Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Positions and Numbers of FKS Mutations in Candida albicans Selectively Influence In Vitro and In Vivo Susceptibilities to Echinocandin Treatment

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Lackner, M., Tscherner, M., Schaller, M., Kuchler, K., Mair, C., Sartori, B., Istel, F., Arendrup, M. C. +1 more·2014·Antimicrobial Agents and Chemotherapy

Abstract

Candidemia is the fourth most common kind of microbial bloodstream infection, with Candida albicans being the most common causative species. Echinocandins are employed as the first-line treatment for invasive candidiasis until the fungal species is determined and confirmed by clinical diagnosis. Echinocandins block the FKS glucan synthases responsible for embedding β-(1,3)-d-glucan in the cell wall. The increasing use of these drugs has led to the emergence of antifungal resistance, and elevated MICs have been associated with single-residue substitutions in specific hot spot regions of FKS1 and FKS2. Here, we show for the first time the caspofungin-mediated in vivo selection of a double mutation within one allele of the FKS1 hot spot 1 in a clinical isolate. We created a set of isogenic mutants and used a hematogenous murine model to evaluate the in vivo outcomes of echinocandin treatment. Heterozygous and homozygous double mutations significantly enhance the in vivo resistance of C. albicans compared with the resistance seen with heterozygous single mutations. The various FKS1 hot spot mutations differ in the degree of their MIC increase, substance-dependent in vivo response, and impact on virulence. Our results demonstrate that echinocandin EUCAST breakpoint definitions correlate with the in vivo response when a standard dosing regimen is used but cannot predict the in vivo response after a dose escalation. Moreover, patients colonized by a C. albicans strain with multiple mutations in FKS1 have a higher risk for therapeutic failure.

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Crossref · 10.1128/aac.00123-14

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Authors
Lackner, M., Tscherner, M., Schaller, M., Kuchler, K., Mair, C., Sartori, B., Istel, F., Arendrup, M. C., & Lass-Flörl, C.
Affiliations
  • Innsbruck Medical University (AT)
  • Max Perutz Labs (AT)
  • University of Tübingen (DE)
  • Statens Serum Institut (DK)
  • Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria
Venue
Antimicrobial Agents and Chemotherapy
Published
2014-07
Volume
58
Issue
7
Pages
3626-3635
ISSN
  • 0066-4804 (ISSN-L)
  • 1098-6596
OpenAlex
W2111448607
Cited by
67
References
40
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 8 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 6
FWCI
5.16
Type
journal article
Language
en
Open access
Locations
  • Antimicrobial Agents and Chemotherapy (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Austrian Science Fund
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords
Candida albicans, echinocandin resistance, FKS1 mutations, FKS2, caspofungin, antifungal resistance, candidemia, invasive candidiasis, hot spot mutations, double mutations, isogenic mutants, mouse model, virulence, EUCAST breakpoints, dose escalation, treatment failure
MeSH terms
Adult, Animals, Antifungal Agents, Candida albicans, Chitin, Female, Fungal Proteins, Glucosyltransferases, Humans, Microbial Sensitivity Tests, Mutation, Virulence, DNA Fingerprinting, Polymorphism, Single Nucleotide, Drug Resistance, Fungal, Mice, Echinocandins, Candidemia

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