Low level of antifungal resistance of Candida glabrata blood isolates in Turkey: Fluconazole minimum inhibitory concentration and FKS mutations can predict therapeutic failure

Background Candida glabratais the third leading cause of candidaemia in Turkey; however, the data regarding antifungal resistance mechanisms and genotypic diversity in association with their clinical implication are limited. Objectives To assess genotypic diversity, antifungal susceptibility and mechanisms of drug resistance ofCglabratablood isolates and their association with patients' outcome in a retrospective multicentre study. Patients/Methods Isolates from 107 patients were identified by ITS sequencing and analysed by multilocus microsatellite typing, antifungal susceptibility testing, and sequencing ofPDR1andFKS1/2hotspots (HSs). Results Candida glabrataprevalence in Ege University Hospital was twofold higher in 2014-2019 than in 2005-2014. Six of the analysed isolates had fluconazole MICs >= 32 mu g/mL; of them, five harboured uniquePDR1mutations. Although echinocandin resistance was not detected, three isolates had mutations in HS1-Fks1 (S629T, n = 1) and HS1-Fks2 (S663P, n = 2); one of the latter was also fluconazole-resistant. All patients infected with isolates carrying HS-FKSmutations and/or demonstrating fluconazole MIC >= 32 mu g/mL (except one without clinical data) showed therapeutic failure (TF) with echinocandin and fluconazole; seven such isolates were collected in Ege (n = 4) and Gulhane (n = 3) hospitals and six detected recently. Among 34 identified genotypes, none were associated with mortality or enriched for fluconazole-resistant isolates. Conclusion Antifungal susceptibility testing should be supplemented with HS-FKSsequencing to predict TF for echinocandins, whereas fluconazole MIC >= 32 mu g/mL may predict TF. Recent emergence ofC glabrataisolates associated with antifungal TF warrants future comprehensive prospective studies in Turkey.
Major National R&D Projects of the National Health Department [2018ZX10101003]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31770161]; Shanghai Science and Technology CommitteeShanghai Science & Technology Committee [17DZ2272900, 14495800500]; Shanghai Municipal Commission of Health and Family Planning [2017ZZ01024-001]; Shanghai Sailing Program [19YF1448000]; Chinese Academy of Engineering [2019-XY-33]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI10902]
This work was supported by the Major National R&D Projects of the National Health Department [2018ZX10101003], National Natural Science Foundation of China [31770161], Shanghai Science and Technology Committee [17DZ2272900 and 14495800500], Shanghai Municipal Commission of Health and Family Planning [2017ZZ01024-001], Shanghai Sailing Program [19YF1448000], and the Chinese Academy of Engineering [2019-XY-33]. DSP was supported by NIH grant #AI10902.