Accuracy of Sensititre YeastOne echinocandins epidemiological cut-off values for identification of FKS mutant Candida albicans and Candida glabrata: a ten year national survey of the Fungal Infection Network of Switzerland (FUNGINOS)

Abstract

This 10-year nationwide survey showed that the rate of echinocandin resistance among C. albicans and C. glabrata remains low in Switzerland despite increased echinocandin use. SYO-ECV could discriminate FKS mutants from wild-type isolates tested by SYO in this population.

Candida albicans Antifungal Resistance and Tolerance in Bloodstream Infections: The Triad Yeast-Host-Antifungal

“…Acquired mutations in FKS1 and FKS2 genes have been predominantly found at position 645 (Serine), S645F (serine to phenylalanine), S645P (serine to proline), and S645Y (serine to tyrosine), and have now been identified in a wide range of Candida clinical isolates [84,85,87]. In C. albicans mutations encoding an FKS1, HS1 alteration S645P, S629P, S654P, F641S, and F641I and in FKS1, HS2 alteration R1361G are common [88,89]. Nevertheless, the prevalence of Fks mutations in geographically distinct clinical isolates remains low [86].…”

“…Nevertheless, the prevalence of Fks mutations in geographically distinct clinical isolates remains low [86]. A survey of C. albicans and C. glabrata bloodstream isolates in Switzerland showed that echinocandin resistance remained at a low level despite a significant increase in echinocandin use and was mainly associated with individual pre-echinocandin exposure of prolonged duration [89]. Hot spot mutations are more likely to confer resistance to caspofungin than to anidulafungin or micafungin.…”

Emerging echinocandin-resistant Candida albicans and glabrata in Switzerland

“…Susceptibility (S), dose-dependent susceptibility (SDD) or resistance (R) were defined according to the CLSI breakpoints, which are for anidulafungin and caspofungin (in µg/mL): C. albicans S ≤ 0.25, R ≥ 1, C. glabrata S ≤ 0.12, R ≥ 0.5, for micafungin: C. albicans S ≤ 0.25, R ≥ 1, C. glabrata S ≤ 0.06, R ≥ 0.25, and for fluconazole: C. albicans S ≤ 2, R ≥ 8, C. glabrata SDD ≤ 32, R ≥ 64. Isolates for which MICs were confirmed to be above the susceptibility clinical breakpoints (i.e., classified as non-susceptible according to the CLSI breakpoints) for micafungin and/or anidulafungin were selected for genotypic characterization of FKS genes (of note, isolated elevated caspofungin MIC was not considered as a reliable predictor of FKS mutations on the basis of previous publications [10,12]). PCR and sequencing of the hotspot regions (HS) of the FKS genes (HS1 and HS2 of FKS1 for C. albicans and C. glabrata and HS1 and HS2 of FKS2 for C. glabrata) were performed using the primers previously described [10].…”

“…Because of the limited therapeutic alternatives, in particular for C. glabrata candidemia, mortality rates are high (60%) [5]. In Switzerland, a recent nationwide survey of candidemia (2004-2013) reported a very low rate of FKS-mutant C. albicans and C. glabrata (2 out of 1624 isolates, 0.12%) [10]. However, several echinocandin-resistant isolates harbouring various types of FKS mutations have been reported from different centers since that time.…”

Susceptibility Testing of Fungi to Antifungal Drugs

“…Despite their sensitivity for identifying hot spot mutations, the positive and negative predictive values of these ECVs in routine clinical application were not determined. Very recently, Kritikos et al [ 38 ] calculated echinocandin ECVs for C. albicans ( n = 1277) and C. glabrata ( n = 347) tested by SYO and assessed their ability to identify FKS mutants in a 10-year candidemia survey from the FUNGINOS network. Among 70 isolates with MIC ≥ ECV for any echinocandin and then sequenced, no FKS mutation was found in the 52 “limit WT” isolates (MIC = ECV for at least one echinocandin), suggesting an excellent negative predictive value of these ECVs.…”