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Table 1.  

Study
year
No. participating hospitals† % C. glabrata of all Candida BSI isolates No. BSI isolates of C. glabrata tested No. (%) C. glabrata BSI isolates‡
Fluconazole resistance Echinocandin resistance§ Multidrug resistance¶
2008 13 11.7 68 0 0 0
2009 8 16.0 67 4 (6.0) 0 0
2010 8 16.8 60 4 (6.7) 0 0
2011 10 16.0 85 4 (4.7) 0 0
2012 11 17.0 108 3 (2.8) 0 0
2013 7 16.9 73 4 (5.5) 1 (1.4) 1 (1.4)
2014 7 22.1 123 11 (8.9) 0 0
2015 10 17.2 110 5 (4.5) 3 (2.7) 0
2016 10 21.2 123 4 (3.3) 4 (3.3) 2 (1.6)
2017 13 21.6 173 13 (7.5) 4 (2.3) 1 (0.6)
2018 13 23.9 168 14 (8.3) 4 (2.4) 2 (1.2)
Total 19 18.6 1158 66 (5.7) 16 (1.4) 6 (0.5)

Table 1. Incidence of antifungal resistance in Candida glabrata BSI isolates, based on cultures collected during a multicenter surveillance study, South Korea, 2008–2018*

*BSI, bloodstream infection.
†Hospitals participating in this laboratory-based nationwide multicenter surveillance system differed each year.
‡Antifungal susceptibility was determined by using the Clinical and Laboratory Standards Institute M27–4ED broth microdilution method[16]. Interpretive categories of resistance were determined by using Clinical and Laboratory Standards Institute document M60-ED[17]. We deposited 76 antifungal-resistant isolates of C. glabrata in the Korea Collection for Type Culture (KCTC; Jeongeup-si, Korea), including those showing resistance to fluconazole alone (60 isolates, KCTC nos. 37113–37172), echinocandin alone (10 isolates, KCTC nos. 37176–37185), and both fluconazole and echinocandin (6 multidrug-resistant isolates, KCTC nos. 37110–37112, 37173–37175). All 76 isolates were identified as C. glabrata by sequence analysis using the D1/D2 domain (GenBank accession nos. MW349716–90 and MW351777).
§Echinocandin resistance was confirmed by the identification of resistance hot-spot mutations in FKS1 and FKS2 in isolates that exhibited full or intermediate resistance to micafungin (MIC ≥0.12 mg/L) or caspofungin MIC (≥0.25 mg/L).
¶Multidrug resistance was defined as resistance to both fluconazole and echinocandins.

Table 2.  

MLST genotype Fluconazole susceptibility No. isolates tested No. with echinocandin resistance No. isolates with 5 Pdr1p AAS found in both FR and F-SDD isolates   No. isolates with additional Pdr1p AAS except for 5 Pdr1p AAS
P76S P143T D243N E259G T745A 1 2 Total
ST7 FR 37 6†             34 3 37
F-SDD 98 3             0   0
ST3 FR 7 0 7 7 7       6 1 7
F-SDD 43 1 43 43 43       0   0
ST26 FR 7 0             6   6
F-SDD 10 1             0   0
ST22 FR 1 0             1   1
F-SDD 16 1             0   0
ST10 FR 2 0             2   2
F-SDD 9 0             0   0
ST55 FR 2 0       2     2   2
F-SDD 6 1       6     1   1
ST2 FR 2 0             2   2
F-SDD 3 0             0   0
ST6 FR 1 0             1   1
F-SDD 5 2             0   0
ST59 FR 1 0         1   1   1
F-SDD 3 1         3   0   0
ST1 FR 2 0             2   2
ST12 F-SDD 2 0             0   0
Other STs‡ FR 4 0       1     2 2 4
F-SDD 17 0 2 2 2       1   1
Total, no. (%) FR 66 6 7 7 7 3 1   59 65 (98.5)
F-SDD 212 10 45 45 45 6 3     2 (0.9)

Table 2. Pdr1 AAS in 66 FR isolates and 212 F-SDD BSI isolates of Candida glabrata and their MLST genotypes, based on cultures collected during a multicenter surveillance study, South Korea, 2008–2018*

*AAS, amino acid substitution; BSI, bloodstream infection; FR, fluconazole-resistant; F-SDD, fluconazole-susceptible dose-dependent; MLST, multilocus sequence typing; ST, sequence type.
†All 6 isolates showed multidrug resistance, defined as resistance to both fluconazole and echinocandins.
‡Includes 21 STs that were each unique to a single isolate.
§Each of 6 FR isolates harbored 2 additional Pdr1 AAS (E340G/D919Y [ST7], Y556C/F580I [ST7], N132S/G1099S [ST7], F832L/L833V [ST3], G189V/E340G [other ST], and L366P/E555D [other ST]).
¶Two F-SDD isolates harbored additional Pdr1 AAS (V502I [ST55] and R250K [other ST]).

Table 3.  

MLST genotype No. isolates Pdr1 AAS (no. isolates)†
Inhibition domain Fungal-specific transcription factor domain Activation domain Other regions
ST7 34 P327L (2), G334V (1), E340G (1), E340K (1), G346S (1), L347F (1), L375P (1), R376Q (1), S391L (1) H576Y (2), G583C (1) P927S (1), G943S (1), S947L (1), D954N (1), G1088E (1), Y1106N (1) S236N (1), P258S (1), P258L (1), V260A (1),L280S (1), Y556C (1), E714D (1), T752I (1), N768D (1), R772K (1), K776E (1), G788W (2), L825P (1), T885A (1)
ST26 6 K365E (1), R376Q (1), F377I (1), E388Q (1)   N1091D (1) S316I (1)
ST3 6 L347F (1) Y584D (1) T1080N (1), Y1106N (1) A731E (1), N764D (1)
ST1 2   T607A (2)    
ST2 2 G346S (2)      
ST10 2 S337F (1), I392M (1)      
ST55 2       F294S (1), P258S (1)
ST6 1     G1079R (1)  
ST22 1     Y932C (1)  
ST59 1 E369K (1)      
Others 2   L935F (1)   P696L (1)
No. (%) isolates 59 20 (33.9) 7 (11.9) 11 (18.6) 21 (35.6)
No. (%) Pdr1 AAS 49 15 (30.6) 5 (10.2) 10 (20.4) 19 (38.8)

Table 3. Pdr1 AAS in 59 FR isolates of Candida glabrata BSI isolates and their MLST genotypes, based on cultures collected during a multicenter surveillance study, South Korea, 2008–2018*

*AAS, amino acid substitutions; BSI, bloodstream infection; FR, fluconazole-resistant; MLST, multilocus sequence typing; ST, sequence type.
†Previously reported Pdr1 AAS are shown in bold.

CME / ABIM MOC

Fluconazole-Resistant Candida glabrata Bloodstream Isolates, South Korea, 2008-2018

  • Authors: Eun Jeong Won, MD, PhD; Min Ji Choi, PhD; Mi-Na Kim, MD, PhD; Dongeun Yong, MD, PhD; Wee Gyo Lee, MD, PhD; Young Uh, MD, PhD; Taek Soo Kim, MD; Seung Ah Byeon, MS; Seung Yeob Lee, MD, PhD; Soo Hyun Kim, MD, PhD; Jong Hee Shin, MD, PhD
  • CME / ABIM MOC Released: 2/19/2021
  • THIS ACTIVITY HAS EXPIRED FOR CREDIT
  • Valid for credit through: 2/19/2022, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for infectious disease clinicians, public health officials, internists, intensivists, and other clinicians caring for patients with Candida glabrata fluconazole-resistant bloodstream infections.

The goal of this activity is to describe clinical outcomes, molecular mechanisms, and genotypes associated with antifungal-resistant BSI isolates of C glabrata collected from South Korean multicenter surveillance cultures during an 11-year period (2008-2018).

Upon completion of this activity, participants will:

  • Assess the mortality and antifungal resistance (including fluconazole resistance) of C glabrata bloodstream isolates, based on a study of South Korean multicenter surveillance cultures collected during an 11-year period (2008-2018)
  • Evaluate antifungal resistance molecular mechanisms, including amino acid substitutions of fluconazole-resistant C glabrata bloodstream isolates, based on a study of South Korean multicenter surveillance cultures collected during an 11-year period (2008-2018)
  • Determine the clinical and public health implications of outcomes and antifungal-resistant molecular mechanisms of fluconazole-resistant C glabrata bloodstream isolates, based on a study of South Korean multicenter surveillance cultures collected during an 11-year period (2008-2018)


Disclosures

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Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Faculty

  • Eun Jeong Won, MD, PhD

    Chonnam National University Medical School
    Gwangju
    Republic of Korea

    Disclosures

    Disclosure: Eun Jeong Won, MD, PhD, has disclosed no relevant financial relationships.

  • Min Ji Choi, PhD

    Chonnam National University Medical School
    Gwangju
    Republic of Korea

    Disclosures

    Disclosure: Min Ji Choi, PhD, has disclosed no relevant financial relationships.

  • Mi-Na Kim, MD, PhD

    University of Ulsan College of Medicine and Asan Medical Center
    Seoul
    Republic of Korea

    Disclosures

    Disclosure: Mi-Na Kim, MD, PhD, has disclosed no relevant financial relationships.

  • Dongeun Yong, MD, PhD

    Yonsei University College of Medicine
    Seoul
    Republic of Korea

    Disclosures

    Disclosure: Dongeun Yong, MD, PhD, has disclosed no relevant financial relationships.

  • Wee Gyo Lee, MD, PhD

    Ajou University School of Medicine
    Suwon
    Republic of Korea

    Disclosures

    Disclosure: Wee Gyo Lee, MD, PhD, has disclosed no relevant financial relationships.

  • Young Uh, MD, PhD

    Yonsei University Wonju College of Medicine
    Wonju
    Republic of Korea

    Disclosures

    Disclosure: Young Uh, MD, PhD, has disclosed no relevant financial relationships.

  • Taek Soo Kim, MD

    Seoul National University College of Medicine
    Seoul
    Republic of Korea

    Disclosures

    Disclosure: Taek Soo Kim, MD, has disclosed no relevant financial relationships.

  • Seung Ah Byeon, MS

    Chonnam National University Medical School
    Gwangju
    Republic of Korea

    Disclosures

    Disclosure: Seung Ah Byeon, MS, has disclosed no relevant financial relationships.

  • Seung Yeob Lee, MD, PhD

    Chonnam National University Medical School
    Gwangju
    Republic of Korea

    Disclosures

    Disclosure: Seung Yeob Lee, MD, PhD, has disclosed no relevant financial relationships.

  • Soo Hyun Kim, MD, PhD

    Chonnam National University Medical School
    Gwangju
    Republic of Korea

    Disclosures

    Disclosure: Soo Hyun Kim, MD, PhD, has disclosed no relevant financial relationships.

  • Jong Hee Shin, MD, PhD

    Chonnam National University Medical School
    Gwangju
    Republic of Korea

    Disclosures

    Disclosure: Jong Hee Shin, MD, PhD, has disclosed no relevant financial relationships.

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Editor

  • Jude Rutledge, BA

    Copyeditor
    Emerging Infectious Diseases

    Disclosures

    Disclosure: Jude Rutledge, BA, has disclosed no relevant financial relationships.

CME Reviewer

  • Stephanie Corder, ND, RN, CHCP

    Associate Director
    Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Stephanie Corder, ND, RN, CHCP, has disclosed no relevant financial relationships.

CE Reviewer

  • Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE

    Associate Director
    Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.


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CME / ABIM MOC

Fluconazole-Resistant Candida glabrata Bloodstream Isolates, South Korea, 2008-2018

Authors: Eun Jeong Won, MD, PhD; Min Ji Choi, PhD; Mi-Na Kim, MD, PhD; Dongeun Yong, MD, PhD; Wee Gyo Lee, MD, PhD; Young Uh, MD, PhD; Taek Soo Kim, MD; Seung Ah Byeon, MS; Seung Yeob Lee, MD, PhD; Soo Hyun Kim, MD, PhD; Jong Hee Shin, MD, PhDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME / ABIM MOC Released: 2/19/2021

Valid for credit through: 2/19/2022, 11:59 PM EST

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Abstract and Introduction

Abstract

We investigated the clinical outcomes and molecular mechanisms of fluconazole-resistant (FR) Candida glabrata bloodstream infections. Among 1,158 isolates collected during multicenter studies in South Korea during 2008–2018, 5.7% were FR. For 64 patients with FR bloodstream infection isolates, the 30-day mortality rate was 60.9% and the 90-day mortality rate 78.2%; these rates were significantly higher than in patients with fluconazole-susceptible dose-dependent isolates (30-day mortality rate 36.4%, 90-day mortality rate 43.8%; p<0.05). For patients with FR isolates, appropriate antifungal therapy was the only independent protective factor associated with 30-day (hazard ratio 0.304) and 90-day (hazard ratio 0.310) mortality. Sequencing of pleiotropic drug-resistance transcription factor revealed that 1–2 additional Pdr1p amino acid substitutions (except genotype-specific Pdr1p amino acid substitutions) occurred in 98.5% of FR isolates but in only 0.9% of fluconazole-susceptible dose-dependent isolates. These results highlight the high mortality rate of patients infected with FR C. glabrata BSI isolates harboring Pdr1p mutations.

Introduction

Candida glabrata is a commensal yeast in the human gut, genitourinary tract, or oral cavity; however, it can cause serious bloodstream infections (BSIs) that result in substantial illness and death[1]. Unlike other common Candida species, C. glabrata exhibits intrinsically low susceptibility to azole drugs, especially fluconazole, and rapidly acquires antifungal resistance in response to azole or echinocandin exposure[1–3]. Although the incidence of echinocandin- and multidrug-resistant (MDR) C. glabrata BSIs is low, fluconazole resistant (FR) C. glabrata BSI isolates have been increasingly reported worldwide, typically at rates of 2.6%–10.6%, although these rates can reach 17%[4–6]. Fluconazole resistance in C. glabrata is of particular concern because of the increased incidence of BSIs caused by this species in various locations worldwide[1,4,5]. Acquired azole resistance in C. glabrata is most commonly mediated by overexpression of the drug-efflux transporter genes CgCDR1, CgCDR2, and CgSNQ2 through a gain-of-function (GOF) mutation in the transcription factor pleiotropic drug-resistance (PDR1)[2,7,8], although other mechanisms might contribute[9–11].

PDR1 mutations in C. glabrata associated with azole resistance have been shown to cause hypervirulence in a mouse model of systemic candidiasis, suggesting the need for careful monitoring of FR C. glabrata BSI isolates and their PDR1 mutations[7,12]. To date, little substantial research has been conducted on PDR1 mutation incidence among FR C. glabrata BSI isolates from multicenter surveillance cultures or on mortality rates of patients infected with these PDR1 mutants. This deficit might be attributable to Pdr1p amino acid substitutions (AAS) found in FR and fluconazole-susceptible dose-dependent (F-SDD) isolates[7,13,14], which can impede determination of whether specific Pdr1p AAS result in fluconazole resistance. Therefore, the aim of this study was to investigate the clinical outcomes, molecular mechanisms, and genotypes associated with antifungal-resistant BSI isolates of C. glabrata collected during multicenter studies in South Korea during an 11-year period (2008–2018). We focused on the mortality rates of patients infected with FR C. glabrata BSI isolates harboring the Pdr1p mutation.