Multidrug-resistant Candida glabrata strains obtained by induction of anidulafungin resistance in planktonic and biofilm cells

Abstract

Candida glabrata has emerged as a common cause of serious life-threatening fungal infections, largely owing to their low susceptibility to azole antifungals. Recent guidance indicates the use of echinocandins as the first-choice drug for the treatment of systemic infections of C. glabrata; however, C. glabrata resistance to echinocandins is reportedly increasing. Herein, we present the induction of anidulafungin resistance in planktonic and sessile cells of C. glabrata and the development of fluconazole crossresistance. MICs of 21 clinical C. glabrata strains were determined by a broth microdilution method using anidulafungin and fluconazole. Biofilm formation on a tracheal catheter was determined using 1-× 1-cm 2 polyvinyl polychloride catheter fragments. Induction of anidulafungin resistance in planktonic and sessile cells and evaluation of its stability were performed by exposing the strains to successively higher concentrations of the antifungal. The induction resulted in strains strongly resistant to anidulafungin (MICs: 1−2 μg/mL) and fluconazole (≥64 μg/mL). Most of the sessile cells of C. glabrata presented slightly reduced susceptibility compared with the planktonic cells. Clinically, this cross-resistance could lead to therapeutic failure while using fluconazole in patients previously exposed to subinhibitory concentrations of anidulafungin for extended periods.

Long-term stability of acquired drug resistance and resistance associated mutations in the fungal pathogen Nakaseomyces glabratus (Candida glabrata)

“…Of note, our study is limited to in vitro conditions and therefore cannot consider external factors that may influence fitness of resistant strains, including activity of the host immune system, or exposure to clinical settings (e.g., use of disinfectants). Nevertheless, our results are consistent with previous, smaller-scale studies ( Borst et al., 2005 ; Imbert et al., 2016 ; Hatwig et al., 2019 ) and extend these by providing a more comprehensive, quantitative, and mechanistic understanding of the process based on a large number of distinct samples in strictly controlled conditions. The implications of these observations are of major clinical relevance.…”

“…Persistence of the resistance phenotype has been reported in clinical and in vitro studies ( Borst et al., 2005 ; Imbert et al., 2016 ; Hatwig et al., 2019 ). Imbert et al.…”

Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata

“…Importantly, these findings are consistent with a recent report of flz cross-resistance in ani-adapted C. glabrata isolates. 38 We consider that our results can inform future clinical trials or therapy guidelines. For instance, our data suggest that flz resistance may be common after the failure of ani therapy, so that flz treatment following ani may also result in therapy failure.…”