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‡
Study year	No. participating hospitals†	% C. glabrata of all Candida BSI isolates	No. BSI isolates of C. glabrata tested	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
MLST genotype	Fluconazole susceptibility	No. isolates tested	No. with echinocandin resistance	P76S	P143T	D243N	E259G	T745A	1	2	Total
ST7	FR	37	6†						34	3	37
ST7	F-SDD	98	3						0		0
ST3	FR	7	0	7	7	7			6	1	7
ST3	F-SDD	43	1	43	43	43			0		0
ST26	FR	7	0						6		6
ST26	F-SDD	10	1						0		0
ST22	FR	1	0						1		1
ST22	F-SDD	16	1						0		0
ST10	FR	2	0						2		2
ST10	F-SDD	9	0						0		0
ST55	FR	2	0				2		2		2
ST55	F-SDD	6	1				6		1		1
ST2	FR	2	0						2		2
ST2	F-SDD	3	0						0		0
ST6	FR	1	0						1		1
ST6	F-SDD	5	2						0		0
ST59	FR	1	0					1	1		1
ST59	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
Other STs‡	F-SDD	17	0	2	2	2			1		1
Total, no. (%)	FR	66	6	7	7	7	3	1	59	6§	65 (98.5)
Total, no. (%)	F-SDD	212	10	45	45	45	6	3	2¶		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)†
MLST genotype	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.

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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, PhD
CME / ABIM MOC Released: 2/19/2021
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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)

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Faculty

Eun Jeong Won, MD, PhD

Chonnam National University Medical School
Gwangju
Republic of Korea

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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

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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

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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

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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

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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

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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

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

Seung Ah Byeon, MS

Chonnam National University Medical School
Gwangju
Republic of Korea

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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

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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

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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

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

CME Author

Laurie Barclay, MD

Freelance writer and reviewer
Medscape, LLC

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

Editor

Jude Rutledge, BA

Copyeditor
Emerging Infectious Diseases

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

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Stephanie Corder, ND, RN, CHCP

Associate Director
Accreditation and Compliance
Medscape, LLC

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

Associate Director
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From Emerging Infectious Diseases

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

CME / ABIM MOC Released: 2/19/2021

Valid for credit through: 2/19/2022

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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.

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Materials and Methods

CME / ABIM MOC Information

Abstract and Introduction
Materials and Methods
Results
Discussion

References

References

Disclaimer

The educational activity presented above may involve simulated, case-based scenarios. The patients depicted in these scenarios are fictitious and no association with any actual patient, whether living or deceased, is intended or should be inferred. The material presented here does not necessarily reflect the views of Medscape, LLC, or any individuals or commercial entities that support companies that support educational programming on medscape.org. These materials may include discussion of therapeutic products that have not been approved by the US Food and Drug Administration, off-label uses of approved products, or data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal. Readers should verify all information and data before treating patients or employing any therapies described in this or any educational activity. A qualified healthcare professional should be consulted before using any therapeutic product discussed herein.

Table 1.

Table 2.

Table 3.

References

Faculty and Disclosures

Faculty

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 Author

Laurie Barclay, MD

Editor

Jude Rutledge, BA

CME Reviewer

Stephanie Corder, ND, RN, CHCP

CE Reviewer

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

CME / ABIM MOC

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

Target Audience and Goal Statement

Disclosures

Faculty

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 Author

Laurie Barclay, MD

Editor

Jude Rutledge, BA

CME Reviewer

Stephanie Corder, ND, RN, CHCP

CE Reviewer

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

Accreditation Statements

For Physicians

Instructions for Participation and Credit

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

Abstract and Introduction

Abstract

Introduction

Table of Contents