Multilocus Sequence Typing (MLST) Genotypes of Candida glabrata Bloodstream Isolates in Korea: Association With Antifungal Resistance, Mutations in Mismatch Repair Gene (Msh2), and Clinical Outcomes

Abstract

Candida glabrata bloodstream infection (BSI) isolates from a particular geographic area have been reported to comprise a relatively small number of the major sequence types (STs) by multilocus sequence typing (MLST) analysis. Yet little is known about the characteristics of major ST strains of C. glabrata. To address this question in Korea, we investigated antifungal resistance and non-synonymous mutations of the mismatch repair gene (msh2 mutations) in C. glabrata BSI isolates, as well as associated clinical characteristics, and compared the results according to MLST genotype. We assessed a total of 209 C. glabrata BSI isolates from seven hospitals in Korea for 2 years (2009 and 2014). Clinical features of candidemia and their outcomes were analyzed for 185 available cases. According to MLST, ST7 (47.8%) was the most common type, followed by ST3 (22.5%); the remainder represented 28 types of minor STs (29.7%). Fluconazole-resistance (FR) rates for ST7, ST3, and other strains were 9.0% (9/100), 8.5% (4/47), and 4.8% (3/62), respectively, and all were susceptible to amphotericin B and micafungin. All ST7 isolates harbored the V239L mutation in msh2, known to confer hypermutability, while 91.5% of ST3 isolates did not harbor the msh2 mutation. Overall, isolates of the same ST had identical msh2 mutations, with the exception of nine isolates. The msh2 mutations were identified in 68.8% (11/16) of the FR isolates and 67.4% (130/193) of the fluconazole susceptible-dose dependent isolates. There was no significant difference in all clinical characteristics between ST3 and ST7. However, the 30-day mortality of C. glabrata candidemia due to the two major ST (ST3 or ST7) strains was significantly higher than that of candidemia due to other minor ST strains (45.1 vs. 25.0%, p < 0.05). Multivariate logistic regression analysis also showed that two major STs (ST3 and ST7) were independent predictors of 30-day mortality. This study showed for the first time that two STs (ST7 and ST3) were predominant among BSI isolates in Korea, and that C. glabrata BSI isolates belonging to two major MLST genotypes are characterized by higher mortality. In addition, most msh2 mutations align with MLST genotype, irrespective of FR.

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

“…All 107 isolates exhibited the susceptibility of the wild type for VRZ, ITZ and AMB and two isolates (G53 and G103) showed intermediate susceptibility to MCF and AND (0.125 µg/mL and 0.25 µg/mL, respectively). The low rate or apparent absence of antifungal resistance observed in our study is consistent with a previous multicentre candidaemia study conducted in Turkey 31 as well as reports from several other Asian, 29,30,41,42,46 South American 47 and European 45,48‐50 countries; however, it is in contrast with the data from USA, where echinocandin resistance in C glabrata is a major public health problem 12 …”

“…We found a low level of antifungal resistance among isolates, which is consistent with a previous study performed in Turkey, 31 and showed that sequencing together with AFST could provide more reliable data to guide clinicians in their choice of treatment for patients with C glabrata candidaemia. Together with similar studies conducted in China, 40,41 USA, 23 South Korea, 30 India 42 and Iran, 29 our study should contribute to better understanding of clinical and microbiological profiles of C glabrata bloodstream isolates.…”

“…However, some molecular typing studies indicate that a possibility of horizontal transfer, suggesting that clonal enrichment of fluconazole‐resistant C glabrata isolates cannot be excluded 27,28 . Furthermore, it has been shown that some C glabrata genotypes are associated with a higher mortality rate, 29,30 reinforcing the importance of strain profiling using genotyping techniques in clinical practice.…”

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

“…Importantly, we and others have found that different MSH2 genotypes are characteristic of distinct STs/clades, suggesting that different STs may have different propensity towards mutability and acquiring drug resistant gene variants [82,[94][95][96]. This is significant because the distribution of C. glabrata STs varies both by geography and over time.…”

A Comparison of the Ability of Fungal Internal Transcribed Spacers and D1/D2 Domain Regions to Accurately Identify Candida glabrata Clinical Isolates Using Sequence Analysis

“…and constitutes a normal floral yeast in the human gastrointestinal tract, urogenital tract, and oral cavity. C. glabrata causes critical BSIs in hospitalized patients (Byun et al, 2018) and yet, despite its increased incidence, little is known of its molecular structure, epidemiology, and basic biological properties. Its prevalence has increased in the last decade and these species now rank as the second most frequently isolated Candida spp.…”