Fluconazole and Echinocandin Resistance of Candida glabrata Correlates Better with Antifungal Drug Exposure Rather than with MSH2 Mutator Genotype in a French Cohort of Patients Harboring Low Rates of Resistance

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.

MSH2 Gene Point Mutations Are Not Antifungal Resistance Markers in Candida glabrata

“…We did not find any correlation between the presence of MSH2 gene mutations and the acquisition of antifungal resistance either in vitro or in clinical settings. This is in line with previous studies in which this lack of correlation was also highlighted (16,17,19).…”

“…Here, the rate of isolates harboring mutations in the MSH2 gene (44.4%) is similar to that reported in some other studies (15,17) but lower than the 77.2% reported by Hou et al (19). Certain mutations, such as V239L and P208S/N890I, have been associated with resistance (15,17), whereas others that are less common, E7K, E456D, or E459K, have not (15)(16)(17).…”

“…An MSH2 gene mismatch repair in C. glabrata and Candida albicans may lead to a hypermutable phenotype prone to developing antifungal resistance (14,15). Furthermore, certain C. glabrata genotypes seem to harbor specific polymorphisms in the MSH2 gene (16).…”

“…There are other aspects that require attention. First, only a small number of invasive isolates have been studied (16,17). Second, studies have been reported without genotyping procedures (15,17).…”

Comparative genomics of two sequentialCandida glabrataclinical isolates

“…In the context of adhesins, which are enriched in repetitive elements, MSH2 defects may perhaps contribute to increase the diversity of this gene family over generations. It has been observed that 44-50% of investigated isolates (n=625) were carrying MSH2 defects and thus indicate that MSH2 defect may confer some selective advantage in C. glabrata (Healey, Zhao, et al 2016; Healey, Jimenez-Ortigosa, et al 2016; Dellière et al 2016). In agreement with our hypothesis, it is interesting to mention that CBS138 and CCTCC M202019 do not exhibit MSH2 defects and contains a limited repertoire of adhesins as compared to DSY562/DSY565.…”