Abstract
Candida glabrata is a major pathogenic yeast in humans that is known to rapidly acquire resistance to triazole and echinocandin antifungal drugs. A mutator genotype (MSH2 polymorphism) inducing a mismatch repair defect has been recently proposed to be responsible for resistance acquisition in C. glabrata clinical isolates. Our objectives were to evaluate the prevalence of antifungal resistance in a large cohort of patients in Saint-Louis hospital, Paris, France, some of whom were pre-exposed to antifungal drugs, as well as to determine whether MSH2 polymorphisms are associated with an increased rate of fluconazole or echinocandin resistance. We collected 268 isolates from 147 patients along with clinical data and previous antifungal exposure. Fluconazole and micafungin minimal inhibition concentrations (MICs) were tested, short tandem repeat genotyping was performed, and the MSH2 gene was sequenced. According to the European Committee on Antimicrobial Susceptibility breakpoints, 15.7% of isolates were resistant to fluconazole (MIC > 32 mg/L) and 0.7% were resistant to micafungin (MIC > 0.03 mg/L). A non-synonymous mutation within MSH2 occurred in 44% of the isolates, and 17% were fluconazole resistant. In comparison, fluconazole resistant isolates with no MSH2 mutation represented 15% (P = 0.65). MSH2 polymorphisms were associated with the short tandem repeat genotype. The rate of echinocandin resistance is low and correlates with prior exposure to echinocandin. The mutator genotype was not associated with enrichment in fluconazole resistance but instead corresponded to rare and specific genotypes.
Highlights
Ascomycetous yeasts are the most common agents responsible for fungal infections in humans, and the incidence of Candida spp. infections has significantly increased over the last two decades (Lass-Flörl, 2009)
Fluconazole and micafungin Etest R minimal inhibition concentrations (MICs) were determined for the 268 C. glabrata isolates
Essential agreement (± 2 dilutions) for fluconazole and micafungin MICs was observed for the 20 isolates tested with Etest R and European Committee on Antimicrobial Susceptibility (EUCAST) methods
Summary
Ascomycetous yeasts are the most common agents responsible for fungal infections in humans, and the incidence of Candida spp. infections has significantly increased over the last two decades (Lass-Flörl, 2009). Even though C. glabrata cannot form hyphae, a well-known virulence factor in C. albicans, its pathogenic traits and rapid acquisition of resistance, especially to azoles and echinocandins, are a matter of concern (Cleveland et al, 2012; Wisplinghoff et al, 2014; Vale-Silva and Sanglard, 2015). This yeast has intrinsically low susceptibility to fluconazole, with 10–30% of C. glabrata isolates harboring high fluconazole MICs (MIC >32 mg/L) (Pfaller and Diekema, 2007). Simultaneous resistance to all echinocandins (caspofungin, micafungin, and anidulafungin) has been detected using various susceptibility-testing methods after specific hotspot polymorphisms develop
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