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.

Seung A Byun,Young Uh,Kelley R Healey,Eun Jeong Won,Wee Gyo Lee,Soo Hyun Kim,Hye Soo Lee,Mi-Na Kim,Kyungwon Lee,David S Perlin,Min Ji Choi,Jong Hee Shin

doi:10.3389/fmicb.2018.01523

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.

Highlights

Candida glabrata is a commensal yeast in the human gastrointestinal tract, genitourinary tract, or oral cavity, but can cause serious bloodstream infections (BSI) in hospitalized patients
Differences in clinical characteristics, including mortality rate, according to the msh2 mutation type. This is the first study to report that two major sequence types (STs) (ST7 and ST3) strains, comprising 70.3% of all C. glabrata BSI isolates from Korean hospitals, are linked to higher mortality in candidemia patients
We found that occurrences of most msh2 mutations were associated with specific multilocus sequence typing (MLST) genotypes, irrespective of fluconazole resistant (FR)

Summary

Introduction

Candida glabrata is a commensal yeast in the human gastrointestinal tract, genitourinary tract, or oral cavity, but can cause serious bloodstream infections (BSI) in hospitalized patients. Compared with other common Candida species, C. glabrata has intrinsically low susceptibility to azole drugs, especially to fluconazole, but it can develop antifungal resistance rapidly in response to exposure to azoles or echinocandins (Pfaller et al, 2003; Barberino et al, 2006; Jensen et al, 2015). The frequency of BSI due to C. glabrata has increased significantly over the past two decades, and C. glabrata has become the second most commonly isolated bloodstream fungal pathogen in Europe and North America, with 10–30% of isolates being fluconazole resistant (FR) (Pfaller et al, 2007). C. glabrata is the fourth most common cause of candidemia, accounting for 14.2% of all cases of candidemia in Korea, and the incidence of C. glabrata candidemia and fluconazole resistance varies among hospitals (Won et al, 2015). The use of fluconazole is associated with an increased risk of BSIs caused by C. glabrata (Chow et al, 2008; Jensen et al, 2015; Won et al, 2015), many questions regarding the epidemiology of C. glabrata BSI remain unanswered (Lott et al, 2010)

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