Clonal Spread of Candida glabrata Bloodstream Isolates and Fluconazole Resistance Affected by Prolonged Exposure: a 12-Year Single-Center Study in Belgium

Abstract

Candida glabrata is a major cause of candidemia in immunocompromised patients and is characterized by a high-level of fluconazole resistance. In the present study, the acquisition of antifungal resistance and potential clonal spread of C. glabrata were explored at a single center over a 12-year period by analyzing 187 independent clinical C. glabrata bloodstream isolates. One strain was found to be micafungin resistant due to a mutation in the FKS2 gene. Fluconazole resistance remained stable throughout the period and was observed in 20 (10.7%) of the isolates. An analysis of the antifungal consumption data revealed that recent prior exposure to fluconazole increased the risk to be infected by a resistant strain. In particular, the duration of the treatment was significantly longer for patients infected by a resistant isolate, while the total and mean daily doses received did not impact the acquisition of resistance in C. glabrata No link between genotype and resistance was found. However, multilocus variable-number tandem-repeat analyses indicated a potential intrahospital spread of some isolates between patients. These isolates shared the same genetic profiles, and infected patients were hospitalized in the same unit during an overlapping period. Finally, quantitative real-time PCR analyses showed that, unlike that for other ABC efflux pumps, the expression of CgCDR1 was significantly greater in resistant strains, suggesting that it would be more involved in fluconazole (FLC) resistance. Our study provides additional evidence that the proper administration of fluconazole is required to limit resistance and that strict hand hygiene is necessary to avoid the possible spreading of C. glabrata isolates between patients.

Keywords: Candida glabrata; antifungal resistance; gene expression; genotypic identification.

FIG 1

Minimum spanning tree. The tree displays the different genotypes (MP1 to MP37) of 187 Candida glabrata bloodstream infection isolates based on 5 variable-number tandem-repeat loci. The genotypes are represented by circles. The size of the circles reflects the number of isolates with that particular genotype. The length and thickness of the connecting lines between the circles show the similarity between the profiles. The fluconazole susceptibility is indicated as follows: white, intermediate; and grey, resistant.

FIG 2

Gene expression. Boxplots of the fold increase in expression of CgCDR1, CgPDH1, CgSNQ2, and CgPDR1 separated on the basis of fluconazole susceptibility level: fluconazole (FLC)-intermediate Candida glabrata bloodstream infection isolates (n = 167) and fluconazole-resistant isolates (n = 20). The analyses were performed in triplicates and results were subjected to the Mann-Whitney U test. *, P < 0.05.