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: Fabiola Fernández-Silva, Michaela Lackner, Javier Capilla, Emilio Mayayo, Deanna Sutton, Mariana Castanheira, Annette W Fothergill, Cornelia Lass-Flörl, Josep Guarro
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 7 Pg. 3646-9 (Jul 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 24733474 (Publication Type: Journal Article)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antifungal Agents
• Echinocandins
• Fungal Proteins
• Lipopeptides
• Glucosyltransferases
• 1,3-beta-glucan synthase
• Caspofungin

Topics

• Animals
• Antifungal Agents (pharmacology)
• Candida glabrata (drug effects, genetics)
• Candidiasis (drug therapy, microbiology)
• Caspofungin
• Drug Resistance, Fungal (genetics)
• Echinocandins (pharmacology)
• Fungal Proteins (genetics)
• Glucosyltransferases (genetics)
• Kidney (microbiology)
• Lipopeptides
• Male
• Mice
• Microbial Sensitivity Tests
• Mutation (physiology)
• Survival Rate