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Article

Nationwide Surveillance of Antifungal Resistance of Candida Bloodstream Isolates in South Korean Hospitals: Two Year Report from Kor-GLASS

by
Eun Jeong Won
1,†,
Min Ji Choi
1,†,
Seok Hoon Jeong
2,
Dokyun Kim
2,
Kyeong Seob Shin
3,
Jeong Hwan Shin
4,
Young Ree Kim
5,
Hyun Soo Kim
6,
Young Ah Kim
7,
Young Uh
8,
Namhee Ryoo
9,
Jeong Su Park
10,
Kyoung Un Park
10,
Seung A. Byun
1,
Ga Yeong Lee
1,
Soo Hyun Kim
1,* and
Jong Hee Shin
1,*
1
Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju 61469, Korea
2
Department of Laboratory Medicine, Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul 03722, Korea
3
Department of Laboratory Medicine, Chungbuk National University College of Medicine, Cheongju 28644, Korea
4
Department of Laboratory Medicine, Paik Institute for Clinical Research, Inje University College of Medicine, Busan 47392, Korea
5
Department of Laboratory Medicine, Jeju National University Medical School, Jeju 63243, Korea
6
Department of Laboratory Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong 18450, Korea
7
Department of Laboratory Medicine, National Health Insurance Service Ilsan Hospital, Goyang 10444, Korea
8
Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea
9
Department of Laboratory Medicine, Keimyung University School of Medicine, Daegu 42601, Korea
10
Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul 03080, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
J. Fungi 2022, 8(10), 996; https://0-doi-org.brum.beds.ac.uk/10.3390/jof8100996
Submission received: 12 August 2022 / Revised: 16 September 2022 / Accepted: 19 September 2022 / Published: 22 September 2022
(This article belongs to the Special Issue Invasive Candidiasis)
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Abstract

:
We incorporated nationwide Candida antifungal surveillance into the Korea Global Antimicrobial Resistance Surveillance System (Kor-GLASS) for bacterial pathogens. We prospectively collected and analyzed complete non-duplicate blood isolates and information from nine sentinel hospitals during 2020–2021, based on GLASS early implementation protocol for the inclusion of Candida species. Candida species ranked fourth among 10,758 target blood pathogens and second among 4050 hospital-origin blood pathogens. Among 766 Candida blood isolates, 87.6% were of hospital origin, and 41.3% occurred in intensive care unit patients. Adults > 60 years of age accounted for 75.7% of cases. Based on species-specific clinical breakpoints, non-susceptibility to fluconazole, voriconazole, caspofungin, micafungin, and anidulafungin was found in 21.1% (154/729), 4.0% (24/596), 0.1% (1/741), 0.0% (0/741), and 0.1% (1/741) of the isolates, respectively. Fluconazole resistance was determined in 0% (0/348), 2.2% (3/135, 1 Erg11 mutant), 5.3% (7/133, 6 Pdr1 mutants), and 5.6% (6/108, 4 Erg11 and 1 Cdr1 mutants) of C. albicans, C. tropicalis, C. glabrata, and C. parapsilosis isolates, respectively. An echinocandin-resistant C. glabrata isolate harbored an F659Y mutation in Fks2p. The inclusion of Candida species in the Kor-GLASS system generated well-curated surveillance data and may encourage global Candida surveillance efforts using a harmonized GLASS system.

1. Introduction

Antimicrobial resistance (AMR) is a leading cause of human death around the world [1]. In 2015, the World Health Organization (WHO) launched the Global Antimicrobial Resistance Surveillance and Use System (GLASS), the first global collaborative effort to standardize AMR surveillance [2]. GLASS enabled standardized AMR surveillance worldwide, which combined patient, laboratory, and epidemiological surveillance data to provide a picture of the extent and impact of AMR on populations. Following the principles of GLASS, the Centers for Disease Control and Prevention of South Korea (KCDC) established a customized AMR surveillance system for South Korea (Kor-GLASS) in 2017. This system received good reviews internationally as a desirable example of AMR surveillance [3,4]. In its early implementation phase (2015–2019), the aim of GLASS was global monitoring of AMR in common bacteria that cause infections in humans. However, recognizing the growing threat of resistant fungal infections, GLASS catalyzed a collaborative global effort to compile available data on antifungal-resistant infections and developed an early implementation protocol for the inclusion of Candida species in 2019 [5].
Candida bloodstream infections (BSIs) are the most common nosocomial fungal infections and are associated with high rates of mortality [6,7,8]. Nationwide surveillance of the antifungal resistance of Candida BSI isolates is important because it provides an overview of the emerging resistance of Candida species [5,7,9,10,11]. Moreover, knowledge of the rank order of occurrence and resistance profiles of various Candida species causing BSIs is important to establish empirical treatment protocols [6,10,12]. However, unlike bacteria, accurate identification and antifungal susceptibility testing of Candida species remain a major challenge, as many laboratories worldwide lack this capability [5]. Few countries have effective surveillance systems for fungal diseases and are thus ill-equipped to address the threat of antifungal-resistant fungi at the global level [5]. In response, the WHO developed the early implementation protocol to help countries create or strengthen their national fungal AMR surveillance systems [5]. We have incorporated a national AMR surveillance system for invasive Candida into the existing Kor-GLASS bacterial surveillance system., We also assessed antifungal resistance mechanisms for common Candida species in this Candida surveillance to understand the extent of resistance determinants in South Korean clinical settings, in line with the Kor-GLASS bacterial surveillance system [3]. In the following, we report the data obtained during the first 2 years (2020–2021) of the operation of the surveillance system for Candida species, which is based on the GLASS early implementation protocol.

2. Materials and Methods

2.1. Collection of Candida Blood Isolates

Along with Kor-GLASS bacterial pathogens, Candida blood isolates were prospectively collected from all patients with Candida BSIs at nine sentinel hospitals from January 2020 to December 2021. All hospitals were general hospitals that even treated pediatric patients, with a total of 7551 beds (655–1092 beds per hospital) and located in nine districts throughout South Korea (Figure S1). At each hospital, the first Candida-positive blood isolate per patient per species was collected. All isolates of Candida species in the MycoBank Database that had a Candida anamorph name or were previously called Candida were included [5]. The collected blood isolates were transferred to the analysis center (Chonnam National University Hospital) twice a month through a cold chain delivery system. For long-term storage, subsamples of each isolate were independently kept at three separate sites: one in the sentinel hospital, two in the analysis center, and two in the national reference laboratory [3].

2.2. Collection of Clinical Data from Sentinel Hospitals

Demographic data (age and sex), infection origin [hospital origin (HO) or community origin (CO)], and admission type (intensive care unit [ICU] or ward) were recorded at each sentinel hospital for all patients for whom blood cultures were performed during the study period [3,4,13,14]. An HO infection as indicated by a blood specimen taken from an inpatient hospitalized for 2 days, including the hospitalization days in another healthcare facility before transfer. A CO infection was indicated by a blood specimen taken from an out- or inpatient hospitalized for <2 days. All other considerations for Kor-GLASS bacterial pathogens were applied when setting up the national AMR surveillance system for Candida species [3,4]. The incidence of candidemia was calculated based on the number of cases of candidemia per 10,000 patient days (PD) at each hospital [15,16]. This study was approved by the Institutional Review Board (IRB) of Chonnam National University Hospital (CNUH-2020-080) and all sentinel hospitals. The IRBs of nine sentinel hospitals waived the requirement for informed consent because of the observational nature of the study and the very low risk of breaches of participant privacy.

2.3. Species Identification and Antifungal Susceptibility Testing

All collected isolates were re-identified using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (Bruker Biotyper, Bruker Daltonics GmbH, Bremen, Germany) at the analysis center. Isolates with discrepant identification between the collection and the analysis centers, and isolates of uncommon species, were further analyzed by sequencing the D1/D2 domains of the 26S rRNA gene [7,11]. In vitro antifungal susceptibility testing of fluconazole, voriconazole, posaconazole, itraconazole, amphotericin B, caspofungin, micafungin, anidulafungin, and 5-flucytosine (5-FC) was performed using the Sensititre Yeast One (SYO) system (Thermo Scientific, Cleveland, OH, USA). Two reference strains, Candida parapsilosis ATCC 22019 and Candida krusei ATCC 6258 were included in each antifungal susceptibility test as quality control isolates. The interpretative guideline in the Clinical and Laboratory Standards Institute (CLSI) document M60 ED1 was used to classify isolates according to species-specific clinical breakpoints (CBPs) [17,18]. For external quality control of the species identification and antifungal susceptibility test results, 5% of the results obtained by the analysis center were reevaluated by comparison with those conducted in an independent quality control center. The analysis center was certified every 3 months by the external quality assurance program of the quality control center [13,14].

2.4. Molecular Mechanisms of Antifungal Resistance

The analysis center performed an advanced characterization of the isolates to assess the molecular mechanisms of antifungal resistance. The ERG11 gene was sequenced in all fluconazole-resistant or susceptible dose-dependent (fluconazole minimum inhibitory concentration [MIC] ≥ 4 mg/L) isolates of C. albicans, C. parapsilosis and C. tropicalis [7,11,19]. The sequence of the CDR1 gene was analyzed in fluconazole-resistant (fluconazole MIC ≥ 8 mg/L) C. parapsilosis isolates without mutations in ERG11 [19]. PDR1 was sequenced in all fluconazole-resistant (fluconazole MIC ≥ 64 mg/L) isolates of C. glabrata [11]. Echinocandin resistance was confirmed for all common Candida isolates with echinocandin MIC values higher than the CLSI CBPs (either intermediate [I] or resistant) through DNA sequence analysis of FKS1 (all Candida species) and FKS2 (C. glabrata) [20].

2.5. Statistical Analysis

Fisher’s exact test or the chi-squared test was used to compare categorical variables, and a t-test was used to compare quantitative variables. All statistical analyses were performed using the Diagnostic Test Evaluation Calculator (MedCalc, Ostend, Belgium) and GraphPad Prism software (version 9.3.1; GraphPad Software Inc., San Diego, CA, USA). A p-value < 0.05 was considered to indicate statistical significance.

3. Results

3.1. Ranking of Candida Species among the Target Blood Pathogens

Among the 10,758 target blood pathogens obtained from Kor-GLASS (2020–2021), Escherichia coli (n = 4374, 40.7%) was the most common, followed by Klebsiella pneumonia (n = 1827, 17.0%), Staphylococcus aureus (n = 1501, 14.0%), Candida species (n = 766, 7.1%), Enterococcus faecium (n = 764, 7.1%), Acinetobacter species (n = 494, 4.6%), Pseudomonas aeruginosa (n = 454, 4.2%), Enterococcus faecalis (n = 448, 4.2%), Streptococcus pneumoniae (n = 82, 0.8%), and Salmonella species (n = 48, 0.4%) (Figure 1). Among the 4048 (37.6%) target blood pathogens of hospital origin, E. coli (n = 780) was the most common, followed by Candida species (n = 671), S. aureus (n = 657), E. faecium (n = 583), K. pneumonia (n = 498), Acinetobacter species (n = 386), P. aeruginosa (n = 241), and E. faecalis (n = 232). Among the 1983 BSI pathogens from ICU patients, E. coli (n = 362) was the most common, followed by Candida species (n = 316), S. aureus (n = 305), K. pneumonia (n = 265), Acinetobacter species (n = 252), E. faecium (n = 245), P. aeruginosa (n = 119), and E. faecalis (n = 103).

3.2. Species Distribution of Candida BSI Isolates

The species distributions of 766 non-duplicate bloodstream isolates of 15 Candida species are listed in Table 1. C. albicans was the most common of the Candida species identified, accounting for 45.4% of all cases, followed by C. tropicalis (17.6%), C. glabrata (17.4%), and C. parapsilosis (14.1%). The order of non-albicans Candida species (NAC) differed by year, but C. tropicalis and C. glabrata were the most common NAC in 2020 and 2021, respectively. Overall, the average incidence of candidemia was 1.58 cases per 10,000 PD, and the incidence of candidemia differed among the hospitals (1.06–2.22 cases per 10,000 PD). Species identification discrepancy between the collection center and the analysis center was noticed in nine (1.2%) isolates. The discrepancy rates varied according to the collection centers (0.0–4.4%). Two isolates of C. albicans were misidentified as C. glabrata and C. tropicalis, and two isolates of C. parapsilosis were misidentified as C. albicans and C. tropicalis. Four isolates (one isolate each of C. glabrata, C. guilliermondii, C. dubliniensis, and C. ciferrii) were misidentified as C. albicans. One isolate of C. utilis was misidentified as C. fabianii.

3.3. Clinical Characteristics of Patients with Candidemia

Of the 766 candidemia cases, patients aged >60 years accounted for 75.7% (580 cases), and pediatric patients (aged 1–19 years) accounted for 1.9% (15 cases) (Figure 2). C. glabrata BSI was more frequent in the elderly (>70 years) than BSIs caused by all other Candida species (60.9% vs. 50.6%, p = 0.029). In total, there were 450 (58.7%) cases in men, 671 (87.6%) were classified as HO, and 316 (41.3%) occurred in the ICU (Figure 3A–C). C. parapsilosis BSIs were more frequent than BSIs caused by other Candida species in men (70.4% vs. 56.8%, p = 0.008), and C. glabrata BSIs were more frequently associated with CO candidemia than were BSIs caused by other Candida species (18.0% vs. 11.2%, p = 0.034). Outpatients accounted for 5.9% of all candidemia cases and inpatients for 94.1%.

3.4. Antifungal Resistance of Candida Bloodstream Isolates

Table 2 shows the antifungal susceptibility of 741 BSI isolates of six common Candida species to antifungal agents for which CLSI CBPs were available. Based on species-specific CBPs, non-susceptibility to fluconazole, voriconazole, caspofungin, micafungin, and anidulafungin was determined in 21.1% (154/729), 4.0% (24/596), 0.1% (1/741), 0.0% (0/741), and 0.1% (1/741) of the isolates, respectively. The rate of fluconazole resistance was 0% (0/348) in C. albicans, but was higher in NAC, particularly C. parapsilosis (5.6%, 6/108), C. glabrata (5.3%, 7/133), and C. tropicalis (2.2%, 3/135). All isolates were susceptible to echinocandins, except for a C. glabrata isolate that was resistant to caspofungin (MIC, 0.5 µg/mL) and had intermediate resistance to anidulafungin (MIC, 0.25 µg/mL). The rate of fluconazole resistance was higher in isolates from ICU patients (14/301, 4.7%) than ward patients (7/428, 1.6%) (p = 0.017) (Figure 3D). The rate of fluconazole resistance was significantly higher in the ICU than ward for C. glabrata (9.5% vs. 1.4%, p = 0.037), but not for the other species. Table 3 lists the MIC range, MIC50 and MIC90 values of antifungal agents for which CBPs were not available for six common Candida species. There were no significant differences in the MIC50 and MIC90 values of these species between 2020 and 2021. The MIC distributions of nine antifungal agents for 25 isolates of nine uncommon species of Candida are shown in Table 4. Although CBPs were not available, four isolates had elevated fluconazole MIC values (≥8 mg/L), including one isolate each of C. auris, C. fabianii, C. orthopsilosis, and C. haemulonii. One isolate of C. haemulonii had elevated MIC values for amphotericin B (8 mg/L), fluconazole (64 mg/L), voriconazole (8 mg/L), and posaconazole (8 mg/L).

3.5. Molecular Mechanisms of Antifungal Resistance

Table 5 summarizes the antifungal resistance mechanisms of 24 Candida bloodstream isolates. All 23 fluconazole non-susceptible Candida isolates were from HO infections. Of the seven fluconazole-resistant isolates of C. glabrata from six hospitals, six harbored Pdr1p amino acid substitutions (E259G, C469R, F559S, T745A, or S942F). Of the eight fluconazole non-susceptible C. parapsilosis isolates, five exhibited either a Y132F mutation (four isolates from one hospital) or K143R mutation (one isolate from another hospital) in Erg11p, and one isolate from another hospital harbored an N1132D mutation in Cdr1p. Of the eight fluconazole non-susceptible isolates of C. tropicalis from four hospitals, two exhibited a Y132F or Y257H mutation in Erg11p. A caspofungin-resistant and anidulafungin intermediate C. glabrata isolate harbored an F659Y mutation in FKS2.

4. Discussion

To the best of our knowledge, this is the first study to incorporate a national surveillance system for Candida BSIs into the GLASS bacterial surveillance system. The results showed that a Kor-GLASS-like surveillance system including isolate collection and centralized analysis components can provide reliable data for both Candida and bacterial blood pathogens. During the two-year study period, 10,758 BSI cases were caused by 10 Kor-GLASS target pathogens, and 4048 (37.6%) BSIs were classified as HO. Candida species ranked fourth among all target blood pathogens, and second among all HO blood pathogens, thus highlighting the important casual role of Candida species in nosocomial BSIs in South Korea. Surveillance at nine sentinel hospitals showed that 87.6% of candidemia cases were of HO, similar to the findings of an Australian study [21]. The average incidence of candidemia was 1.58 cases per 10,000 PD, but the incidence differed among hospitals (range: 1.06–2.22), as also reported in a previous Asian study [22].
In earlier multicenter studies conducted in South Korea, C. parapsilosis was the most common NAC isolated from patients with candidemia [16,23,24]. However, we found that, for the period from 2020–2021, C. glabrata and C. tropicalis were the most common NACs causing candidemia, consistent with recent reports on the changes in species distributions of candidemia in South Korea [8,25]. In studies from the USA, northern Europe, and Australia, C. glabrata, which is less susceptible to antifungal drugs, was the second most common cause of candidemia [10,21,26], while in tropical and Asian countries, such as The Philippines and Thailand, C. tropicalis was the most prevalent NAC [22,27]. In the present study, most candidemia cases occurred in patients aged >60 years with C. glabrata BSIs being more frequent in the elderly (>70 years) and C. parapsilosis candidemia being more frequent in males, in line with our recent study [8]. The reasons for the changing epidemiology of NAC BSIs in South Korea are unclear, but the use of antifungal agents, infection control practices, and types of at-risk hospitalized patients enrolled may be factors [5,8,10,26]. Given that each Candida species is unique in terms of virulence potential, antifungal susceptibility, and clinical characteristics, understanding the changing epidemiology is important for the proper management of candidemia [8,28]. In South Korea, fluconazole or amphotericin B were mainly used for the treatment of candidemia until the approval of echinocandins as primary treatment for severe candidiasis by the National Health Insurance Service (NHIS) in 2014. Following the approval of echinocandin use by the NHIS, the use of echinocandins for candidemia treatment has increased after 2014, and attention is required because of echinocandin resistance emergence [29,30].
Sensititre Yeast One was used for surveillance in this study, as it has been widely adopted by clinical microbiology laboratories for antifungal susceptibility testing and shows good concordance with the CLSI reference method for Candida susceptibility testing [31]. In addition, we examined several molecular mechanisms of antifungal resistance to better understand AMR epidemiology. While echinocandin resistance remains rare in Korea for six common Candida species (<0.5%), we observed non-susceptibility to fluconazole in about 20% of these species, in addition to frequent azole resistance among BSI isolates of three common NACs. The singular mechanism of acquired azole resistance identified in clinical isolates of C. glabrata is mutation of the transcription factor pleiotropic drug-resistance (PDR1), which leads to overexpression of the drug-efflux transporter genes CgCDR1, CgCDR2, and CgSNQ2 [11,31]. Our recent Korean study showed that 98.5% of fluconazole-resistant BSI isolates of C. glabrata and 0.9% of fluconazole susceptible dose-dependent BSI isolates of C. glabrata harbored an additional one or two Pdr1p AAS after exclusion of five genotype-specific AAS. In addition, the results highlight the high mortality rate of patients infected with fluconazole-resistant C. glabrata BSI isolates harboring Pdr1p mutations [11]. By contrast, multiple mechanisms of azole resistance, such as ERG11 mutations and overexpression of efflux pumps, have been reported for C. albicans, C. parapsilosis and C. tropicalis [31]; however, Y132F in ERG11 and N1132D in CDR1 were the major mechanisms of fluconazole resistance in C. parapsilosis isolates from Korean hospitals [7,19]. Therefore, the PDR1 gene was sequenced for all fluconazole-resistant isolates of C. glabrata while ERG11 and CDR1 genes were sequenced for all fluconazole-non-susceptible isolates of C. parapsilosis, and ERG11 gene was sequenced for all fluconazole-non-susceptible isolates of C. tropicalis, although other mechanisms might contribute.
Six of the seven fluconazole-resistant isolates of C. glabrata harbored diverse Pdr1p amino acid substitutions, which suggests that PDR1 mutation is the main cause of azole resistance in C. glabrata, in line with previous studies [11,32]. An azole-resistant C. parapsilosis isolate harbored a N1132D substitution in CDR1, as in another recent report [19]. Notably, all four fluconazole-non-susceptible C. parapsilosis isolates harboring a Y132F substitution in Erg11p were collected at the same hospital, indicating possible clonal transmission of these isolates [7]. One C. glabrata isolate was classified as caspofungin-resistant (MIC, 0.5 mg/L), with intermediate resistance to anidulafungin (MIC, 0.25 mg/L) but susceptibility to micafungin (MIC, 0.06 mg/L). In this isolate, echinocandin resistance was determined by DNA sequence analysis of the FKS genes. The isolate harbored an F659Y mutation in Fks2p, which confers resistance to all echinocandins [17].
An increasing incidence of candidemia in ICUs has been reported in many parts of the world [15,33,34,35]. In a previous study based on Korean National Healthcare-Associated Infections Surveillance System, which included patients older than 15 years who developed candidemia during a stay of >2 days in the ICU, Candida species were the most frequently identified blood pathogens from 2013 to 2017 [15]. In the present study, 41.3% of candidemia cases occurred in ICU patients, and Candida species were the second most common BSI pathogen recovered from these patients (after E. coli). The rate of fluconazole resistance was significantly higher in ICU patients (4.7%) than ward patients (1.6%), as was the fluconazole resistance of C. glabrata (9.5% vs. 1.4%). Our recent study showed that, among patients with candidemia, mortality rates were approximately twofold higher in ICU than ward patients, and that fluconazole resistance was a predictor of C.-glabrata-associated mortality [8]. Taken together, these results highlight the importance of candidemia control in ICUs, including improved prevention and treatment strategies such as optimal use of antifungal treatments and less unnecessary use of catheters.
Accurate species identification is crucial considering the increasing rate of antifungal resistance among uncommon Candida species, such as Candida auris [36]. Our surveillance system used MALDI-TOF MS, supplemented by sequence-based identification of Candida species at an analysis center. In our study, discrepant identification results between the collection and analysis centers were seen for only 1.2% of the isolates (from five common and four uncommon Candida species). Given that all nine hospitals participating in Kor-GLASS used the MALDI-TOF MS system for the identification of yeast isolates, the misidentification of five isolates of common Candida species might be worthy of note. We found that a collection center using the MALDI-TOF Biotyper, which did not use FA extraction routinely, exhibited a relatively high misidentification rate (4.4%), even in common Candida species. For the analysis using the MALDI-TOF Biotyper, in-tube formic acid/acetonitrile (FA/ACN) extraction is recommended prior to the analysis; however, the use of a simple FA extraction method is preferable in order to facilitate the routine use in clinical microbiology laboratories [37]. Therefore, it should be considered that although MALDI-TOF system allows reliable and accurate identification of the clinical isolates of yeast species, their performance can be differed according to the protein extraction protocol (i.e., use of formic acid or not) or MALDI-TOF MS system databases used at the hospitals [37,38].
For some BSI isolates of rare Candida species for which CBPs were unavailable, including C. auris, C. fabianii, and C. orthopsilosis, resistance to fluconazole was higher than for other species (fluconazole MIC > 8 mg/L). In addition, a C. haemulonii isolate was determined to be multidrug-resistant (i.e., to both azole and amphotericin B), as reported previously [39]. These results suggest that the distribution of azole- and echinocandin-resistant NAC isolates should be continuously monitored at the national level, and the resistance mechanisms determined.
Several nationwide surveillance studies of the antifungal susceptibility of Candida species causing BSIs in South Korea have been published since 2007 [7,8,11,16,23,24,40,41]. A total of 20 university hospitals in South Korea participated in those studies, but the participating hospitals differed among years. In addition, in some of the studies, more than half of the Candida BSI isolates were from the two largest hospitals (>2000 beds), both of which are in Seoul, which is also where most of the antifungal-resistant isolates were found [7,11]. Also, in this study, hospital H, located at Jeju-island, off the peninsula’s southern tip, showed a bit of a different pattern in the epidemiology of candidemia, in which C. albicans did not exceed NAC. It can be partly explained by their geographical and ecological conditions that may have influenced the epidemiology of candidiasis. Overall, the incidence rate and AMR of Candida BSIs vary greatly among institutions, with factors such as the number of beds, patients, and PD in the ICU or hemato-oncology wards likely playing important roles. Although whether the participating hospitals are representative is always debatable in national candida AMR surveillance studies, this concern can be partly overcome by incorporating a national surveillance system for BSI into the GLASS system, which permits continuous monitoring of target blood pathogens and is free from collection bias and isolate duplication. The Kor-GLASS system was designed to collect and analyze complete, non-duplicate clinical isolates and information from sentinel hospitals located in various districts throughout South Korea (each with a capacity of 600–1100 beds) caring for both inpatients and outpatients. The surveillance data demonstrated both the changing epidemiology of Candida species causing BSIs during 2020–2021, and the continued emergence of azole and echinocandin resistance (and thus of new resistance mechanisms) among BSI isolates of NAC. Continuous monitoring is therefore warranted.

5. Conclusions

We incorporated AMR surveillance for invasive Candida into preexisting GLASS bacterial surveillance system, and herein, we describe results from the two year (2020–2021) of operation of Kor-GLASS Candida surveillance based on early implementation protocol. The well-curated surveillance data highlight the significance of candidemia both as the second-most common cause of BSIs of HO and the second-most common pathogen in ICU patients in South Korea. Our study showed that the inclusion of Candida species in the Kor-GLASS system allowed representative and accurate monitoring of the antifungal resistance of BSI-causing candida on a national scale. As such, it will support further global efforts aimed at candidemia AMR surveillance.

Supplementary Materials

The following supporting information can be downloaded at: https://0-www-mdpi-com.brum.beds.ac.uk/article/10.3390/jof8100996/s1, Figure S1: Distribution of the collection centers of the Kor-GLASS surveillance system in South Korea.

Author Contributions

Conceptualization, J.H.S. (Jong Hee Shin); Formal analysis, E.J.W. and M.J.C.; Funding acquisition, J.H.S. (Jong Hee Shin); Investigation, M.J.C., S.A.B. and G.Y.L.; Project administration, E.J.W.; Resources, S.H.J., D.K., K.S.S., J.H.S. (Jeong Hwan Shin), Y.R.K., H.S.K., Y.A.K., Y.U., N.R., J.S.P., K.U.P. and J.H.S. (Jong Hee Shin); Writing—original draft, E.J.W., S.H.K. and J.H.S. (Jong Hee Shin); Writing—review & editing, E.J.W., M.J.C., S.H.K. and J.H.S. (Jong Hee Shin). All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (grant 2020E540600).

Institutional Review Board Statement

This study was approved by the Institutional Review Board of Chonnam National University Hospital (CNUH-2020-080).

Informed Consent Statement

A written informed consent was waived by the nature of this study.

Data Availability Statement

All data generated or analyzed in this study are included in this published article, and the datasets are available from the corresponding author within the limits imposed by ethical and legal dispositions.

Acknowledgments

We thank all Kor-GLASS participants for their contribution to this study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet 2022, 399, 629–655. [Google Scholar] [CrossRef]
  2. Global Antimicrobial Resistance Surveillance System (GLASS). In Proceedings of the Technical Meeting on the Early Implementation Phase, WHO Regional Office for Europe, Copenhagen, Denmark, 22–23 October 2015; Meeting Report. World Health Organization: Geneva, Switzerland, 2016.
  3. Lee, H.; Yoon, E.J.; Kim, D.; Jeong, S.H.; Shin, J.H.; Shin, J.H.; Shin, K.S.; Kim, Y.A.; Uh, Y.; Park, C.; et al. Establishment of the South Korean national antimicrobial resistance surveillance system, Kor-GLASS, in 2016. Euro Surveill. 2018, 23, 1700734. [Google Scholar] [CrossRef] [PubMed]
  4. Lee, H.; Yoon, E.J.; Kim, D.; Jeong, S.H.; Won, E.J.; Shin, J.H.; Kim, S.H.; Shin, J.H.; Shin, K.S.; Kim, Y.A.; et al. Antimicrobial resistance of major clinical pathogens in South Korea, May 2016 to April 2017: First one-year report from Kor-GLASS. Euro Surveill. 2018, 23, 1800047. [Google Scholar] [CrossRef]
  5. World Health Organization. GLASS Early Implementation Protocol for Inclusion of Candida spp. Available online: https://www.who.int/publications/i/item/WHO-WSI-AMR-2019.4 (accessed on 11 December 2021).
  6. Falagas, M.E.; Apostolou, K.E.; Pappas, V.D. Attributable mortality of candidemia: A systematic review of matched cohort and case-control studies. Eur. J. Clin. Microbiol. Infect. Dis. 2006, 25, 419–425. [Google Scholar] [CrossRef]
  7. Choi, Y.J.; Kim, Y.J.; Yong, D.; Byun, J.H.; Kim, T.S.; Chang, Y.S.; Choi, M.J.; Byeon, S.A.; Won, E.J.; Kim, S.H.; et al. Fluconazole-Resistant Candida parapsilosis Bloodstream Isolates with Y132F Mutation in ERG11 Gene, South Korea. Emerg. Infect. Dis. 2018, 24, 1768–1770. [Google Scholar] [CrossRef] [PubMed]
  8. Kwon, Y.J.; Won, E.J.; Jeong, S.H.; Shin, K.S.; Shin, J.H.; Kim, Y.R.; Kim, H.S.; Kim, Y.A.; Uh, Y.; Kim, T.S.; et al. Dynamics and Predictors of Mortality Due to Candidemia Caused by Different Candida Species: Comparison of Intensive Care Unit-Associated Candidemia (ICUAC) and Non-ICUAC. J. Fungi 2021, 7, 597. [Google Scholar] [CrossRef]
  9. Kim, M.N.; Shin, J.H.; Sung, H.; Lee, K.; Kim, E.C.; Ryoo, N.; Lee, J.S.; Jung, S.I.; Park, K.H.; Kee, S.J.; et al. Candida haemulonii and closely related species at 5 university hospitals in Korea: Identification, antifungal susceptibility, and clinical features. Clin. Infect. Dis. 2009, 48, e57–e61. [Google Scholar] [CrossRef] [PubMed]
  10. Pfaller, M.A.; Diekema, D.J.; Turnidge, J.D.; Castanheira, M.; Jones, R.N. Twenty Years of the SENTRY Antifungal Surveillance Program: Results for Candida Species From 1997–2016. Open Forum Infect. Dis. 2019, 6, S79–S94. [Google Scholar] [CrossRef]
  11. Won, E.J.; Choi, M.J.; Kim, M.N.; Yong, D.; Lee, W.G.; Uh, Y.; Kim, T.S.; Byeon, S.A.; Lee, S.Y.; Kim, S.H.; et al. Fluconazole-Resistant Candida glabrata Bloodstream Isolates, South Korea, 2008–2018. Emerg. Infect. Dis. 2021, 27, 779–788. [Google Scholar] [CrossRef]
  12. Pappas, P.G.; Kauffman, C.A.; Andes, D.R.; Clancy, C.J.; Marr, K.A.; Ostrosky-Zeichner, L.; Reboli, A.C.; Schuster, M.G.; Vazquez, J.A.; Walsh, T.J.; et al. Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2016, 62, 409–417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Kim, D.; Yoon, E.J.; Hong, J.S.; Choi, M.H.; Kim, H.S.; Kim, Y.R.; Kim, Y.A.; Uh, Y.; Shin, K.S.; Shin, J.H.; et al. Major Bloodstream Infection-Causing Bacterial Pathogens and Their Antimicrobial Resistance in South Korea, 2017–2019: Phase I Report From Kor-GLASS. Front. Microbiol. 2021, 12, 799084. [Google Scholar] [CrossRef] [PubMed]
  14. Liu, C.; Yoon, E.J.; Kim, D.; Shin, J.H.; Shin, J.H.; Shin, K.S.; Kim, Y.A.; Uh, Y.; Kim, H.S.; Kim, Y.R.; et al. Antimicrobial resistance in South Korea: A report from the Korean global antimicrobial resistance surveillance system (Kor-GLASS) for 2017. J. Infect. Chemother. 2019, 25, 845–859. [Google Scholar] [CrossRef] [PubMed]
  15. Kim, E.J.; Lee, E.; Kwak, Y.G.; Yoo, H.M.; Choi, J.Y.; Kim, S.R.; Shin, M.J.; Yoo, S.Y.; Cho, N.H.; Choi, Y.H. Trends in the Epidemiology of Candidemia in Intensive Care Units From 2006 to 2017: Results From the Korean National Healthcare-Associated Infections Surveillance System. Front. Med. 2020, 7, 606976. [Google Scholar] [CrossRef] [PubMed]
  16. Won, E.J.; Shin, J.H.; Choi, M.J.; Lee, W.G.; Park, Y.J.; Uh, Y.; Kim, S.Y.; Lee, M.K.; Kim, S.H.; Shin, M.G.; et al. Antifungal susceptibilities of bloodstream isolates of Candida species from nine hospitals in Korea: Application of new antifungal breakpoints and relationship to antifungal usage. PLoS ONE 2015, 10, e0118770. [Google Scholar] [CrossRef]
  17. CLSI. Performance Standards for Antifungal Susceptibility Testing of Yeast, 1st ed.; CLSI supplement M60; Clinical and Laboratory Standards Institute: Wayne, PA, USA, 2017. [Google Scholar]
  18. Pfaller, M.A.; Diekema, D.J. Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, 2010 to 2012. J. Clin. Microbiol. 2012, 50, 2846–2856. [Google Scholar] [CrossRef]
  19. Asadzadeh, M.; Dashti, M.; Ahmad, S.; Alfouzan, W.; Alameer, A. Whole-Genome and Targeted-Amplicon Sequencing of Fluconazole-Susceptible and -Resistant Candida parapsilosis Isolates from Kuwait Reveals a Previously Undescribed N1132D Polymorphism in CDR1. Antimicrob. Agents Chemother. 2021, 65, e01633-20. [Google Scholar] [CrossRef]
  20. Rivero-Menendez, O.; Navarro-Rodriguez, P.; Bernal-Martinez, L.; Martin-Cano, G.; Lopez-Perez, L.; Sanchez-Romero, I.; Perez-Ayala, A.; Capilla, J.; Zaragoza, O.; Alastruey-Izquierdo, A. Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization. Front. Microbiol. 2019, 10, 1585. [Google Scholar] [CrossRef]
  21. Pfaller, M.A.; Moet, G.J.; Messer, S.A.; Jones, R.N.; Castanheira, M. Candida bloodstream infections: Comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008–2009. Antimicrob. Agents Chemother. 2011, 55, 561–566. [Google Scholar] [CrossRef]
  22. Tan, B.H.; Chakrabarti, A.; Li, R.Y.; Patel, A.K.; Watcharananan, S.P.; Liu, Z.; Chindamporn, A.; Tan, A.L.; Sun, P.L.; Wu, U.I.; et al. Incidence and species distribution of candidaemia in Asia: A laboratory-based surveillance study. Clin. Microbiol. Infect. 2015, 21, 946–953. [Google Scholar] [CrossRef]
  23. Jung, S.I.; Shin, J.H.; Song, J.H.; Peck, K.R.; Lee, K.; Kim, M.N.; Chang, H.H.; Moon, C.S.; Korean Study Group for Candidemia. Multicenter surveillance of species distribution and antifungal susceptibilities of Candida bloodstream isolates in South Korea. Med. Mycol. 2010, 48, 669–674. [Google Scholar] [CrossRef] [Green Version]
  24. Lee, J.S.; Shin, J.H.; Lee, K.; Kim, M.N.; Shin, B.M.; Uh, Y.; Lee, W.G.; Lee, H.S.; Chang, C.L.; Kim, S.H.; et al. Species distribution and susceptibility to azole antifungals of Candida bloodstream isolates from eight university hospitals in Korea. Yonsei Med. J. 2007, 48, 779–786. [Google Scholar] [CrossRef] [PubMed]
  25. Ko, J.H.; Jung, D.S.; Lee, J.Y.; Kim, H.A.; Ryu, S.Y.; Jung, S.I.; Joo, E.J.; Cheon, S.; Kim, Y.S.; Kim, S.W.; et al. Changing epidemiology of non-albicans candidemia in Korea. J. Infect. Chemother. 2019, 25, 388–391. [Google Scholar] [CrossRef] [PubMed]
  26. Lortholary, O.; Desnos-Ollivier, M.; Sitbon, K.; Fontanet, A.; Bretagne, S.; Dromer, F.; French Mycosis Study, G. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: A prospective multicenter study involving 2441 patients. Antimicrob. Agents Chemother. 2011, 55, 532–538. [Google Scholar] [CrossRef]
  27. Tan, T.Y.; Hsu, L.Y.; Alejandria, M.M.; Chaiwarith, R.; Chinniah, T.; Chayakulkeeree, M.; Choudhury, S.; Chen, Y.H.; Shin, J.H.; Kiratisin, P.; et al. Antifungal susceptibility of invasive Candida bloodstream isolates from the Asia-Pacific region. Med. Mycol. 2016, 54, 471–477. [Google Scholar] [CrossRef]
  28. Guinea, J. Global trends in the distribution of Candida species causing candidemia. Clin. Microbiol. Infect. 2014, 20 (Suppl. S6), 5–10. [Google Scholar] [CrossRef]
  29. Choi, H.; Kim, J.H.; Seong, H.; Lee, W.; Jeong, W.; Ahn, J.Y.; Jeong, S.J.; Ku, N.S.; Yeom, J.S.; Kim, Y.K.; et al. Changes in the utilization patterns of antifungal agents, medical cost and clinical outcomes of candidemia from the health-care benefit expansion to include newer antifungal agents. Int. J. Infect. Dis. 2019, 83, 49–55. [Google Scholar] [CrossRef]
  30. Kim, J.H.; Suh, J.W.; Kim, M.J. Epidemiological trends of candidemia and the impact of adherence to the candidemia guideline: Six-year single-center experience. J. Fungi 2021, 7, 275. [Google Scholar] [CrossRef]
  31. Lim, H.J.; Shin, J.H.; Kim, M.N.; Yong, D.; Byun, S.A.; Choi, M.J.; Lee, S.Y.; Won, E.J.; Kee, S.J.; Kim, S.H.; et al. Evaluation of Two Commercial Broth Microdilution Methods Using Different Interpretive Criteria for the Detection of Molecular Mechanisms of Acquired Azole and Echinocandin Resistance in Four Common Candida Species. Antimicrob. Agents Chemother. 2020, 64, e00740-20. [Google Scholar] [CrossRef]
  32. Healey, K.R.; Perlin, D.S. Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata. J. Fungi 2018, 4, 105. [Google Scholar] [CrossRef]
  33. Lortholary, O.; Renaudat, C.; Sitbon, K.; Madec, Y.; Denoeud-Ndam, L.; Wolff, M.; Fontanet, A.; Bretagne, S.; Dromer, F.; The French Mycosis Study Group. Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010). Intensive Care Med. 2014, 40, 1303–1312. [Google Scholar] [CrossRef]
  34. Colombo, A.L.; Guimaraes, T.; Sukienik, T.; Pasqualotto, A.C.; Andreotti, R.; Queiroz-Telles, F.; Nouer, S.A.; Nucci, M. Prognostic factors and historical trends in the epidemiology of candidemia in critically ill patients: An analysis of five multicenter studies sequentially conducted over a 9-year period. Intensive Care Med. 2014, 40, 1489–1498. [Google Scholar] [CrossRef] [PubMed]
  35. Chakrabarti, A.; Sood, P.; Rudramurthy, S.M.; Chen, S.; Kaur, H.; Capoor, M.; Chhina, D.; Rao, R.; Eshwara, V.K.; Xess, I.; et al. Incidence, characteristics and outcome of ICU-acquired candidemia in India. Intensive Care Med. 2015, 41, 285–295. [Google Scholar] [CrossRef]
  36. Kwon, Y.J.; Shin, J.H.; Byun, S.A.; Choi, M.J.; Won, E.J.; Lee, D.; Lee, S.Y.; Chun, S.; Lee, J.H.; Choi, H.J.; et al. Candida auris Clinical Isolates from South Korea: Identification, Antifungal Susceptibility, and Genotyping. J. Clin. Microbiol. 2019, 57, e01624-18. [Google Scholar] [CrossRef] [PubMed]
  37. Lee, H.S.; Shin, J.H.; Choi, M.J.; Won, E.J.; Kee, S.J.; Kim, S.H.; Shin, M.G.; Suh, S.P. Comparison of the Bruker Biotyper and VITEK MS Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Systems Using a Formic Acid Extraction Method to Identify Common and Uncommon Yeast Isolates. Ann. Lab. Med. 2017, 37, 223–230. [Google Scholar] [CrossRef] [PubMed]
  38. Won, E.J.; Shin, J.H.; Lee, K.; Kim, M.N.; Lee, H.S.; Park, Y.J.; Joo, M.Y.; Kim, S.H.; Shin, M.G.; Suh, S.P.; et al. Accuracy of species-level identification of yeast isolates from blood cultures from 10 university hospitals in South Korea by use of the matrix-assisted laser desorption ionization-time of flight mass spectrometry-based Vitek MS system. J. Clin. Microbiol. 2013, 51, 3063–3065. [Google Scholar] [CrossRef] [PubMed]
  39. Hou, X.; Xiao, M.; Chen, S.C.; Wang, H.; Cheng, J.W.; Chen, X.X.; Xu, Z.P.; Fan, X.; Kong, F.; Xu, Y.C. Identification and Antifungal Susceptibility Profiles of Candida haemulonii Species Complex Clinical Isolates from a Multicenter Study in China. J. Clin. Microbiol. 2016, 54, 2676–2680. [Google Scholar] [CrossRef]
  40. Jang, M.J.; Shin, J.H.; Lee, W.G.; Kim, M.N.; Lee, K.; Lee, H.S.; Lee, M.K.; Chang, C.L.; Jang, H.C.; Song, E.S.; et al. In vitro fluconazole and voriconazole susceptibilities of Candida bloodstream isolates in Korea: Use of the CLSI and EUCAST epidemiological cutoff values. Ann. Lab Med. 2013, 33, 167–173. [Google Scholar] [CrossRef]
  41. Jung, S.I.; Shin, J.H.; Choi, H.J.; Ju, M.Y.; Kim, S.H.; Lee, W.G.; Park, Y.J.; Lee, K.; Korean Study Group for Candidemia. Antifungal susceptibility to amphotericin B, fluconazole, voriconazole, and flucytosine in Candida bloodstream isolates from 15 tertiary hospitals in Korea. Ann. Lab Med. 2012, 32, 426–428. [Google Scholar] [CrossRef] [Green Version]
Jof 08 00996 g001 550
Figure 1. Number of patients with bloodstream infections (BSIs) for each target pathogen collected via the Kor-GLASS surveillance system (2010–2021). (A) Total number of BSIs caused by each target pathogen. (B) Number of hospital-origin BSIs caused by each pathogen. (C) Number of BSIs caused by each pathogen in ICU patients.
Figure 1. Number of patients with bloodstream infections (BSIs) for each target pathogen collected via the Kor-GLASS surveillance system (2010–2021). (A) Total number of BSIs caused by each target pathogen. (B) Number of hospital-origin BSIs caused by each pathogen. (C) Number of BSIs caused by each pathogen in ICU patients.
Jof 08 00996 g001
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Figure 2. Overall distributions of the Candida species causing BSIs by candidemia patient age group.
Figure 2. Overall distributions of the Candida species causing BSIs by candidemia patient age group.
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Jof 08 00996 g003 550
Figure 3. Clinical information of cases of candidemia caused by different Candida species: sex (A), origin (hospital origin [HO] or community origin [CO]) (B) and location (ICU vs. ward) (C). In (A–C), the results are based on the 766 patients enrolled in this study. Rates of fluconazole resistance of Candida isolates recovered from the ICU and wards (D): the 729 isolates included C. albicans (n = 348), C. tropicalis (n = 135), C. glabrata (n = 133), C. parapsilosis (n = 108), and C. krusei (n = 5), for which clinical breakpoints were available in the CLSI M60. * p < 0.05 between a Candida species and all other Candida species within a given category (i.e., number of patients, sex [female vs. male], origin [HO vs. CO], or location [ICU vs. ward]). ** p < 0.05 between ICU and ward patients in the rate of fluconazole resistance according to the Candida species.
Figure 3. Clinical information of cases of candidemia caused by different Candida species: sex (A), origin (hospital origin [HO] or community origin [CO]) (B) and location (ICU vs. ward) (C). In (A–C), the results are based on the 766 patients enrolled in this study. Rates of fluconazole resistance of Candida isolates recovered from the ICU and wards (D): the 729 isolates included C. albicans (n = 348), C. tropicalis (n = 135), C. glabrata (n = 133), C. parapsilosis (n = 108), and C. krusei (n = 5), for which clinical breakpoints were available in the CLSI M60. * p < 0.05 between a Candida species and all other Candida species within a given category (i.e., number of patients, sex [female vs. male], origin [HO vs. CO], or location [ICU vs. ward]). ** p < 0.05 between ICU and ward patients in the rate of fluconazole resistance according to the Candida species.
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Table
Table 1. The incidence of candidemia collected from Kor-GLASS surveillance system during the two-year periods.
Table 1. The incidence of candidemia collected from Kor-GLASS surveillance system during the two-year periods.
Candida SpeciesNo. of Candidemia Episodes at Each HospitalNo (%) in Each Year:
ABCDEFGHI20202021Total
C. albicans552540364843281063172 (48.3)176 (42.9)348 (45.4)
C. tropicalis1615101321121353061 (17.1)74 (18)135 (17.6)
C. glabrata179277151616111557 (16)76 (18.5)133 (17.4)
C. parapsilosis1861510121111101546 (12.9)62 (15.1)108 (14.1)
C. guilliermondii10020141310 (2.8)2 (0.5)12 (1.6)
C. lusitaniae3020210014 (1.1)5 (1.2)9 (1.2)
C. krusei0021100102 (0.6)3 (0.7)5 (0.7)
C. fabianii0000121001 (0.3)3 (0.7)4 (0.5)
C. dubliniensis0010100011 (0.3)2 (0.5)3 (0.4)
C. metapsilosis1000200000 (0)3 (0.7)3 (0.4)
C. orthopsilosis1010000000 (0)2 (0.5)2 (0.3)
C. pelliculosa0000000010 (0)1 (0.2)1 (0.1)
C. bracarensis1000000001 (0.3)0 (0)1 (0.1)
C. haemulonii0000100001 (0.3)0 (0)1 (0.1)
C. auris0000100000 (0)1 (0.2)1 (0.1)
Total No.113559869105867338129356 (100)410 (100)766 (100)
Incidence/10,000 patient-days
1.921.072.221.151.761.691.481.061.761.451.721.58
Table
Table 2. Antifungal susceptibilities of 741 isolates of six common Candida species which clinical breakpoints are available in CLSI M60.
Table 2. Antifungal susceptibilities of 741 isolates of six common Candida species which clinical breakpoints are available in CLSI M60.
Antifungal Agent *
/Species		20202021Total
No%R%SDD/INo%R%SDD/INo%R%SDD/I%NS
FLUC. albicans1720.00.01760.00.03480.00.00.0
C. tropicalis611.61.6742.75.41352.23.75.9
C. glabrata575.394.7765.394.71335.394.7100.0
C. parapsilosis464.30.0626.53.21085.61.97.4
C. krusei2100.00.03100.00.05100.00.0100.0
Total3382.416.33913.319.97292.918.221.1
VORC. albicans1720.00.01760.00.03480.00.00.0
C. tropicalis611.69.8742.713.51352.211.914.1
C. parapsilosis460.02.2620.06.51080.04.64.6
C. krusei20.00.030.00.050.00.00.0
Total2810.42.53150.64.45960.53.54.0
CASC. albicans1720.00.01760.00.03480.00.00.0
C. tropicalis610.00.0740.00.01350.00.00.0
C. glabrata570.00.0761.30.01330.80.00.8
C. parapsilosis460.00.0620.00.01080.00.00.0
C. guilliermondii100.00.020.00.0120.00.00.0
C. krusei20.00.030.00.050.00.00.0
Total3480.00.03930.30.07410.10.00.1
MICAC. albicans1720.00.01760.00.03480.00.00.0
C. tropicalis610.00.0740.00.01350.00.00.0
C. glabrata570.00.0760.00.01330.00.00.0
C. parapsilosis460.00.0620.00.01080.00.00.0
C. guilliermondii100.00.020.00.0120.00.00.0
C. krusei20.00.030.00.050.00.00.0
Total3480.00.03930.00.07410.00.00.0
ANIC. albicans1720.00.01760.00.03480.00.00.0
C. tropicalis610.00.0740.00.01350.00.00.0
C. glabrata5700760.01.31330.00.80.8
C. parapsilosis460.00.0620.00.01080.00.00.0
C. guilliermondii100.00.020.00.0120.00.00.0
C. krusei20.00.030.00.050.00.00.0
Total348003930.00.37410.00.10.1
Abbreviations: R, resistant; SDD, susceptible dose-dependent; I, intermediate; NS, non-susceptible; FLU, fluconazole; VOR, voriconazole; CAS, caspofungin; ANI, anidulafungin; MICA, micafungin. * Numbers (%) of isolates categorized by the Clinical and Laboratory Standards Institute (CLSI M60) species-specific breakpoints [17].
Table
Table 3. Antifungal susceptibilities of 741 isolates of six common Candida species which clinical breakpoints are not available in CLSI M60.
Table 3. Antifungal susceptibilities of 741 isolates of six common Candida species which clinical breakpoints are not available in CLSI M60.
Antifungal Agent/
Species		MICs * (mg/L) in 2020MICs * (mg/L) in 2021
No.RangeMIC50MIC90No.RangeMIC50MIC90
FLUC. guilliermondii104–1641624–848
VORC. glabrata570.03–40.51760.12–40.51
C. guilliermondii100.06–0.250.250.2520.06–0.250.250.25
POSC. albicans1720.008–0.250.030.031760.008–0.250.030.06
C. glabrata570.5–1612760.5–>812
C. tropicalis610.03–0.50.120.5740.03–0.50.120.25
C. parapsilosis460.015–0.120.030.06620.015–0.250.060.12
C. guilliermondii100.12–0.50.250.520.25–0.50.250.5
C. krusei20.12–0.250.120.2530.25–0.50.50.5
ITCC. albicans1720.008–0.120.030.121760.015–0.250.060.12
C. glabrata570.06–>160.51760.25–>1611
C. tropicalis610.06–0.50.250.5740.12–10.250.5
C. parapsilosis460.008–0.250.060.12620.015–0.250.060.12
C. guilliermondii100.25–0.50.50.520.25–0.50.250.5
C. krusei20.12–0.250.120.2530.25–0.50.250.5
AMBC. albicans1720.12–10.511760.12–10.51
C. glabrata570.5–211760.25–111
C. tropicalis610.25–111740.5–111
C. parapsilosis460.12–20.51620.12–10.51
C. guilliermondii100.12–0.50.250.520.12–0.250.120.25
C. krusei211130.5–111
5-FCC. albicans1720.06–1280.060.251760.06–>640.060.25
C. glabrata570.06–20.060.06760.06–20.060.06
C. tropicalis610.008–0.250.060.12740.06–0.120.060.06
C. parapsilosis460.008–0.120.060.06620.06–0.250.060.06
C. guilliermondii100.060.060.0620.060.060.06
C. krusei288838–16816
* The MIC50 and MIC90, MICs at which 50% and 90% of isolates are inhibited, respectively. Abbreviations: MIC, minimum inhibitory concentration; FLU, fluconazole; VOR, voriconazole; POS, posaconazole; ITC, itraconazole; AMB, amphotericin B; 5-FC, flucytosine.
Table
Table 4. Distributions of MIC values to antifungal agents of uncommon Candida species which clinical breakpoints are unavailable in CLSI M60.
Table 4. Distributions of MIC values to antifungal agents of uncommon Candida species which clinical breakpoints are unavailable in CLSI M60.
Antifungal Agent/SpeciesN of Isolates for Which the MIC (mg/L) Was:
0.010.020.030.060.120.250.51248163264≥128
FLU
C. lusitaniae 162
C. fabianii 21 1
C. dubliniensis 12
C. metapsilosis 21
C. orthopsilosis 1 1
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
VOR
C. lusitaniae36
C. fabianii1 2 1
C. dubliniensis21
C. metapsilosis 12
C. orthopsilosis 1 1
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
POS
C. lusitaniae 9
C. fabianii 1 21
C. dubliniensis 111
C. metapsilosis 111
C. orthopsilosis 2
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
ITC
C. lusitaniae 45
C. fabianii 1 111
C. dubliniensis 21
C. metapsilosis 1 11
C. orthopsilosis 2
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
CAS
C. lusitaniae 54
C. fabianii 112
C. dubliniensis 12
C. metapsilosis 2 1
C. orthopsilosis 11
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
MICA
C. lusitaniae 9
C. fabianii 22
C. dubliniensis 21
C. metapsilosis 1 2
C. orthopsilosis 2
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
ANI
C. lusitaniae 9
C. fabianii 1 3
C. metapsilosis 11 1
C. orthopsilosis 2
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
C. dubliniensis 12
AMB
C. lusitaniae 27
C. fabianii 121
C. dubliniensis 12
C. metapsilosis 12
C. orthopsilosis 2
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
5-FC
C. lusitaniae 9
C. fabianii 4
C. dubliniensis 3
C. metapsilosis 3
C. orthopsilosis 2
C. auris 1
C. bracarensis 1
C. haemulonii 1
C. pelliculosa 1
Abbreviations: FLU, fluconazole; VOR, voriconazole; POS, posaconazole; ITC, itraconazole; CAS, caspofungin; ANI, anidulafungin; MICA, micafungin; AMB, amphotericin B; 5-FC, flucytosine.
Table
Table 5. Antifungal resistance mechanisms of 24 fluconazole or echinocandins resistant or non-susceptible Candida bloodstream isolates obtained from Kor-GLASS surveillance (2020–2021).
Table 5. Antifungal resistance mechanisms of 24 fluconazole or echinocandins resistant or non-susceptible Candida bloodstream isolates obtained from Kor-GLASS surveillance (2020–2021).
Year/OriginSex/Age/ICUSpeciesMIC (µg/mL)Amino Acid SubstitutionsGenbank Accession No. *
FLU/VOR/POS/ITCCAS/ANI/MICAErg11pCdr1pPdr1pFks2p
2020/HOM/85/WardCG64/1/2/20.06/0.03/0.015 E259G OP125549
2020/HOM/80/ICUCG256/4/>8/>160.12/0.03/0.015 C469R OP125550
2020/HOF/73/ICUCG128/2/>8/>160.12/0.03/0.015 F559S OP125551
2021/HOF/80/ICUCG128/2/2/20.12/0.06/0.03 T745A OP125552
2021/HOF/68/ICUCG64/1/2/10.06/0.015/0.015 E259G OP125553
2021/HOM/77/ICUCG128/2/2/20.06/0.03/0.015 None OP125554
2021/HOM/78/ICUCG128/4/>8/>160.12/0.03/0.015 S942F OP125555
2020/HOF/78/WardCP8/0.06/0.015/0.030.25/1/1Y132F OP125556
2020/HOM/48/ICUCP64/0.25/0.12/0.250.5/1/1K143R OP125557
2021/HOF/77/ICUCP32/0.25/0.03/0.060.5/1/2Y132F --OP125558
2021/HOF/53/ICUCP32/0.25/0.03/0.060.25/1/1Y132F OP125559
2021/HOF/67/ICUCP16/0.5/0.25/0.250.5/0.5/1NoneN1132D OP125560 (ERG11), OP125572 (CDR1)
2021/HOM/84/WardCP8/0.25/0.25/0.250.5/1/1NoneNone OP125561 (ERG11), OP125573 (CDR1)
2021/HOF/53/WardCP4/0.12/0.25/0.250.5/1/2None OP125567
2021/HOF/38/WardCP4/0.12/0.03/0.060.25/1/2Y132F OP125566
2020/HOF/78/ICUCT32/2/0.25/0.250.06/0.06/0.03Y132F OP125562
2020/HOM/82/ICUCT4/0.25/0.5/0.50.03/0.015/0.03None OP125568
2021/HOM/65/ICUCT8/1/1/10.06/0.06/0.03None OP125563
2021/HOM/39/WardCT8/1/0.25/0.250.06/0.06/0.03None OP125564
2021/HOF/93/WardCT4/0.5/0.25/0.250.03/0.06/0.015None OP125569
2021/HOF/49/WardCT4/0.5/0.5/0.50.03/0.06/0.03Y257H OP125565
2021/HOF/54/ICUCT4/0.5/0.5/0.50.03/0.015/0.015None OP125570
2021/HOM/65/ICUCT4/0.12/0.06/0.120.06/0.015/0.03None OP125571
2021/COF/66/WardCG8/0.25/1/0.50.5/0.25/0.06 F659YOP125574
* Sequences were deposited in GenBank under accession numbers OP125549-OP125571, OP125574, respectively. Abbreviations: HO, hospital Origin; CO, community origin; ICU, intensive care unit; FLU, fluconazole; VOR, voriconazole; POS, posaconazole; ITC, itraconazole; CAS, caspofungin; ANI, anidulafungin; MICA, micafungin; CG, C. glabrata; CP, C. parapsilosis; CT, C. tropicals; none, no amino acid substitutions.
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Won, E.J.; Choi, M.J.; Jeong, S.H.; Kim, D.; Shin, K.S.; Shin, J.H.; Kim, Y.R.; Kim, H.S.; Kim, Y.A.; Uh, Y.; et al. Nationwide Surveillance of Antifungal Resistance of Candida Bloodstream Isolates in South Korean Hospitals: Two Year Report from Kor-GLASS. J. Fungi 2022, 8, 996. https://0-doi-org.brum.beds.ac.uk/10.3390/jof8100996

AMA Style

Won EJ, Choi MJ, Jeong SH, Kim D, Shin KS, Shin JH, Kim YR, Kim HS, Kim YA, Uh Y, et al. Nationwide Surveillance of Antifungal Resistance of Candida Bloodstream Isolates in South Korean Hospitals: Two Year Report from Kor-GLASS. Journal of Fungi. 2022; 8(10):996. https://0-doi-org.brum.beds.ac.uk/10.3390/jof8100996

Chicago/Turabian Style

Won, Eun Jeong, Min Ji Choi, Seok Hoon Jeong, Dokyun Kim, Kyeong Seob Shin, Jeong Hwan Shin, Young Ree Kim, Hyun Soo Kim, Young Ah Kim, Young Uh, and et al. 2022. "Nationwide Surveillance of Antifungal Resistance of Candida Bloodstream Isolates in South Korean Hospitals: Two Year Report from Kor-GLASS" Journal of Fungi 8, no. 10: 996. https://0-doi-org.brum.beds.ac.uk/10.3390/jof8100996

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