title: Positions and numbers of FKS mutations in Candida albicans selectively influence in vitro and in vivo susceptibilities to echinocandin treatment.
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.
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria michaela.lackner@i-med.ac.at.
authors.forename: M
authors.initials: M
authors.lastname: Lackner
authors.affiliation: Medical University of Vienna, Department for Medical Biochemistry, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Tscherner
authors.affiliation: Universitäts-Hautklinik Tübingen, Eberhard-Karls-Universität Tübingen, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Medical University of Vienna, Department for Medical Biochemistry, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Kuchler
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Mair
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Sartori
authors.affiliation: Medical University of Vienna, Department for Medical Biochemistry, Max F. Perutz Laboratories, Vienna, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Istel
authors.affiliation: Unit of Mycology, Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: M C
authors.initials: MC
authors.lastname: Arendrup
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Lass-Flörl
mesh_terms: D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002176:Candida albicans / Q000235:genetics* / Q000378:metabolism; D058387:Candidemia / Q000188:drug therapy* / Q000382:microbiology*; D002686:Chitin / Q000378:metabolism; D016172:DNA Fingerprinting; D025141:Drug Resistance, Fungal / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D005964:Glucosyltransferases / Q000235:genetics*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014774:Virulence / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D002686:Chitin; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase
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