title: Fluconazole and Echinocandin Resistance ofCandida glabrataCorrelates Better with Antifungal Drug Exposure Rather than withMSH2Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance.
abstract: Candida glabratais a major pathogenic yeast in humans that is known to rapidly acquire resistance to triazole and echinocandin antifungal drugs. A mutator genotype (MSH2polymorphism) inducing a mismatch repair defect has been recently proposed to be responsible for resistance acquisition inC. glabrataclinical 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 whetherMSH2polymorphisms 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 theMSH2gene 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 withinMSH2occurred in 44% of the isolates, and 17% were fluconazole resistant. In comparison, fluconazole resistant isolates with noMSH2mutation 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.
authors.affiliation: Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dellière
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers Newark, NJ, USA.
authors.forename: Kelley
authors.initials: K
authors.lastname: Healey
authors.affiliation: Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-WidalParis, France; Université Paris Diderot, Sorbonne Paris CitéParis, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Gits-Muselli
authors.affiliation: Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal Paris, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Carrara
authors.affiliation: Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal Paris, France.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barbaro
authors.affiliation: Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guigue
authors.affiliation: Service de Pharmacie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lecefel
authors.affiliation: Service de Pharmacie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Touratier
authors.affiliation: Unité de Mycologie Moléculaire, Institut Pasteur, Centre National de la Recherche Scientifique, Centre National de Référence Mycoses Invasives et Antifongiques, URA3012 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Desnos-Ollivier
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers Newark, NJ, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.affiliation: Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-WidalParis, France; Université Paris Diderot, Sorbonne Paris CitéParis, France; Unité de Mycologie Moléculaire, Institut Pasteur, Centre National de la Recherche Scientifique, Centre National de Référence Mycoses Invasives et Antifongiques, URA3012Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bretagne
authors.affiliation: Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-WidalParis, France; Université Paris Diderot, Sorbonne Paris CitéParis, France; Unité de Mycologie Moléculaire, Institut Pasteur, Centre National de la Recherche Scientifique, Centre National de Référence Mycoses Invasives et Antifongiques, URA3012Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alanio
keywords: Candida glabrata; MSH2; antifungal resistance; echinocandin; fluconazole; genotyping; mutator genotype; short tandem repeat