Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia

Abstract

To give an indication of a fitness cost conferred by FKS mutation-associated echinocandin resistance in Candida glabrata during human infection. Six C. glabrata clinical strains sequentially isolated from blood and a hepatic abscess in a solid organ transplant recipient were analysed. The patient had received long-term azole and echinocandin therapy for invasive aspergillosis and persistent candidaemia. Minimal inhibitory concentrations were determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. Molecular mechanisms of antifungal resistance were determined by sequencing hot spots of the FKS. Strain relatedness was determined using a microsatellite-based typing method. Typing analysis revealed an identical microsatellite pattern for all isolates, supporting a close relation. The first C. glabrata isolate showed wild-type phenotype (i.e. susceptibility to echinocandins and low level of azole resistance). After voriconazole therapy, the C. glabrata quickly acquired pan-azole resistance. Later, echinocandin treatment led to the emergence of a FKS2 S663P alteration and echinocandin resistance. After disruption of both azole and echinocandin therapy in favour of liposomal amphotericin B, C. glabrata isolates regained full susceptibility to echinocandin and lost the FKS2 S663P alteration while nonetheless maintaining their pan-azole resistance. Our clinical report supports the potential existence of a fitness cost conferred by FKS mutation in C. glabrata, as disruption of treatment led to a rapid disappearance of the resistant clone. This suggests that a more restricted use and/or a discontinuous administration of echinocandins may limit the spread of clinical resistance to this class.

The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Murine Model of Candida glabrata Colonization and Systemic Dissemination

“…We also found that mixed genotypes could arise in the gut ( Tables 1 and 2 ), particularly if a phenotype (i.e., Fks2-P667T) that leads to low-level resistance (<2 μg/ml) develops. This finding is consistent with clinical studies involving serial isolates from patients with recurrent bloodstream infections that show breakthrough isolates with different FKS alleles ( 35 , 36 ). Most of our studies included colonization with the Δ msh2 mutator strain.…”

Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization

“…Nevertheless, this experiment had some limitations, as the original samples sent from the hospital could be an already isolated colony. Serial C. glabrata isolates from the same patient showing different antifungal resistance profiles due to the selective pressure induced by changes in antifungal treatment have been previously reported (Cho et al, 2015; Imbert et al, 2016).…”

Potential Use of MALDI-ToF Mass Spectrometry for Rapid Detection of Antifungal Resistance in the Human Pathogen Candida glabrata

“…Outside of the US or Northern Europe 6 , C. glabrata is less commonly isolated 7 . Nonetheless, C. glabrata manifests an intrinsically low susceptibility to azoles in vitro or tends to easily develop azole resistance during the course of antifungal therapy 8 , 9 . Alarmingly, exposure of C. glabrata cells to an antifungal agent may lead to highly variable, “evolvable” genomes capable of quick development of resistance to multiple antifungal drug classes 10 , including triazoles ( e.g .…”