title: In vitro antifungal susceptibility of Candida glabrata to caspofungin and the presence of FKS mutations correlate with treatment response in an immunocompromised murine model of invasive infection.
abstract: It has been argued that the in vitro activity of caspofungin (CSP) is not a good predictor of the outcome of echinocandin treatment in vivo. We evaluated the in vitro activity of CSP and the presence of FKS mutations in the hot spot 1 (HS1) region of the FKS1 and FKS2 genes in 17 Candida glabrata strains with a wide range of MICs. The efficacy of CSP against systemic infections from each of the 17 strains was evaluated in a murine model. No HS1 mutations were found in the eight strains showing MICs for CSP of ≤ 0.5 μg/ml, but they were present in eight of the nine strains with MICs of ≥ 1 μg/ml, i.e., three in the FKS1 gene and five in the FKS2 gene. CSP was effective for treating mice infected with strains with MICs of ≤ 0.5 μg/ml, showed variable efficacy in animals challenged with strains with MICs of 1 μg/ml, and did not work in those with strains with MICs of >1 μg/ml. In addition, mutations, including one reported for the first time, were found outside the HS1 region in the FKS2 gene of six strains with different MICs, but their presence did not influence drug efficacy. The in vitro activity of CSP was compared with that of another echinocandin, anidulafungin, suggesting that the MICs of both drugs, as well as mutations in the HS1 regions of the FKS1 and FKS2 genes, are predictive of outcome.
authors.affiliation: Unitat d'Anatomia Patològica, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Fernández-Silva
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Lackner
authors.affiliation: Unitat de Microbiologia, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Capilla
authors.affiliation: Unitat d'Anatomia Patològica, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Mayayo
authors.affiliation: Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Sutton
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.affiliation: Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Annette W
authors.initials: AW
authors.lastname: Fothergill
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.affiliation: Unitat de Microbiologia, Facultat de Medicina i Ciències de la Salut, IISPV, Universitat Rovira i Virgili, Reus, Spain josep.guarro@urv.cat.
authors.forename: Josep
authors.initials: J
authors.lastname: Guarro
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects* / Q000235:genetics; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D000077336:Caspofungin; D025141:Drug Resistance, Fungal / Q000235:genetics; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics*; D005964:Glucosyltransferases / Q000235:genetics*; D007668:Kidney / Q000382:microbiology; D055666:Lipopeptides; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000502:physiology*; D015996:Survival Rate
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; D000077336:Caspofungin
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