Changing Epidemiology of Clinical Isolates of Candida Species during the Coronavirus Disease 2019 Pandemic: Data Analysis from a Korean Tertiary Care Hospital for 6 Years (2017–2022)

This study assessed the changes in Candida species distribution and antifungal susceptibility patterns during the coronavirus disease 2019 (COVID-19) pandemic compared with a pre-pandemic period in Korea. We retrospectively investigated the specimen, species type, and antifungal susceptibility of Candida isolates obtained between 2016 and 2022. Data between two periods were compared: 2016–2019 (pre-pandemic) and 2020–2022 (pandemic). We included 11,396 clinical isolates of Candida species (5137 isolates in the pre-pandemic and 6259 isolates in the pandemic). The most prevalent species was Candida albicans (50.4%), followed by Candida glabrata (22.7%), Candida tropicalis (12.5%), and Candida parapsilosis complex (12.5%). Their ranks were unchanged; however, their relative isolation ratios varied during the pandemic, exhibiting differences ranging from 0.4 to 2.5 across species. The incidence of candidemia increased during the pandemic (average 1.79 episodes per 10,000 patient days) compared with pre-pandemic levels (average 1.45 episodes per 10,000 patient days) in both intensive-care-unit (ICU) and non-ICU patients. Additionally, C. parapsilosis complex candidemia increased by 1.6-fold during the pandemic. During the pandemic, C. albicans and C. tropicalis candidemia significantly increased by 1.5- and 1.4-fold in ICU patients. In contrast, C. parapsilosis complex candidemia surged 2.1-fold in non-ICU patients. These species exhibited reduced resistance to fluconazole, voriconazole, caspofungin, and micafungin in the pandemic compared with the pre-pandemic. This study underscores the heightened incidence of Candida-related infections during the COVID-19 pandemic and emphasizes the importance of ongoing surveillance of Candida species epidemiology beyond the pandemic’s scope.


Introduction
In March 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19), a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic, with the final declaration of the end to COVID-19 as a Global Health Emergency made on 4 May 2023 [1,2].The emergence of COVID-19 caused an unprecedented public health crisis and brought new healthcare challenges, including the development of fungal coinfections [3].Invasive candidiasis, comprising deep-seated tissue candidiasis and candidemia, is the most common fungal disease in hospitalized patients in developed countries [4].The epidemiology of Candida infection has changed over the past several decades and in different geographical regions [5].These changes have occurred because of different predisposing factors in patients, more aggressive therapy practices (e.g., chemotherapy, transplantation, and intensive care use), antifungal use, and other factors, as well as the recent COVID-19 pandemic [6].Candidemia incidence during the pandemic was five times higher than that before the pandemic, and a 10-fold increase in candidemia frequency was observed in hospitalized patients with COVID-19 receiving corticosteroids compared with patients without COVID-19 [7][8][9].This trend has been partly explained by immune paralysis or enhanced intestinal translocation in the patients [10] or a switch of microbiota toward Candida species [11], which then proceed to dominate the viral species.Recent data from the Korean Global Antimicrobial Resistance Surveillance System (Kor-GLASS) showed that Candida species ranked fourth among all target blood pathogens and second among all hospital-onset blood pathogens [12].However, longitudinal epidemiological studies elucidating the changes in the distribution and antimicrobial susceptibility of Candida species related to the COVID-19 pandemic are still lacking.Thus, this study aimed to assess the changes in the distribution and antifungal susceptibility patterns of Candida species during the COVID-19 pandemic compared with a pre-pandemic period in Korea.

Materials and Methods
We collected the specimen type and antifungal susceptibility data of all clinical isolates of Candida species from the laboratory information system including the electronic medical record system (EMR) of a single-tertiary medical center in Korea containing 2732 beds from January 2017 to December 2022.We collected the data of all isolates of Candida species in the MycoBank database with a Candida anamorph name or previously classified as Candida [12].A positive blood culture for Candida species in a person residing within our surveillance area was defined as a candidemia case.A Candida blood culture collected more than 30 days after the initial positive culture in the same person was considered a new case.The incidence of candidemia was defined as the number of cases of candidemia per 10,000 patient days (10,000 PD) [12].Study periods were divided into two parts: January 2017 to December 2019 (COVID-19 pre-pandemic) and January 2020 to December 2022 (COVID-19 pandemic).Species identifications were performed using the Vitek 2 yeast identification card (Vitek 2 Yeast ID; bioMérieux, Marcy l'Etoile, France) according to the manufacturer's instructions or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Bruker Biotyper; Bruker Daltonics GmbH, Bremen, Germany).In vitro antifungal testing results for susceptibility to fluconazole, voriconazole, caspofungin, and micafungin were performed by Vitek 2 (bioMérieux, Marcy l'Etoile, France) and were interpreted according to the guidelines in the CLSI document M60 ED1 using speciesspecific clinical breakpoints (CBPs) [13].This study was approved by the Institutional Review Board (IRB) of Asan Medical Center (approval no.2023-0467).The IRB waived the requirement for informed consent because of the retrospective nature of this study.

Overall Distribution of Candida Species Obtained from Clinical Samples during the Two Study Periods
Table 1 shows the overall distribution of Candida species obtained from clinical samples during the two study periods (2017-2022).A total of 11,396 clinical isolates of Candida species were included, with 5137 isolated in the pre-pandemic period and 6259 isolated in the pandemic period.The number of clinical isolates of Candida species increased annually from 17.29 per 10,000 PD in 2017 to 23.98 per 10,000 PD in 2022.The most prevalent species was Candida albicans (n = 5743, 50.4%), followed by Candida glabrata (n = 2588, 22.7%), Candida tropicalis (n = 1419, 12.5%), Candida parapsilosis complex (n = 893, 12.5%), Clavispora lusitaniae (n = 187, 1.6%), Candida auris (n = 181, 1.6%), Pichia kudriavzevii (n = 163, 1.4%), and other species (n = 212, 1.8%).The rank of the first four common Candida species was the same every year.During the pandemic period, these four Candida species were isolated 1.2-to 1.4-fold more than in the pre-pandemic period.The relative ratio of isolation (pandemic/pre-pandemic) was different for each Candida species, ranging from 0.4 to 2.5 (Supplementary Figure S1).Other than four common Candida species, C. auris was frequently isolated from clinical isolates.However, more than 90% of C. auris isolates were recovered from ear discharge and there was no bloodstream infection outbreak.The isolation of C. auris was decreased during the pandemic compared with the pre-pandemic.

Dynamics of Candidemia Incidence Pre-Pandemic and Pandemic Periods
Table 2 summarizes the incidence of candidemia during the study periods.The incidence of candidemia increased during the pandemic (average 1.79 per 10,000 PD) compared with the pre-pandemic period (average 1.45 per 10,000 PD).Candidemia cases caused by C. albicans, C. glabrata, C. tropicalis, and C. parapsilosis complex during the prepandemic/pandemic were 0.49/0.60,0.46/0.57,0.27/0.34,and 0.12/0.18per 10,000 PD, respectively.The incidence of candidemia caused by C. parapsilosis complex significantly increased 1.6-fold during the pandemic compared with the pre-pandemic.

Distribution of Candidemia Incidence between Intensive-Care-Unit (ICU) and Non-ICU Patients
Analyzing the distribution of candidemia incidence between intensive-care-unit (ICU) and non-ICU patients, a relative increment in candidemia cases was observed in the pandemic period, with a 1.1-fold increase in ICU patients and a 1.2-fold increase in non-ICU patients (Table 3).In ICU patients, candidemia cases caused by C. albicans and C. tropicalis were significantly increased during the pandemic (1.5-and 1.4-fold more compared with the pre-pandemic, respectively).In contrast, candidemia cases caused by C. glabrata and C. parapsilosis complex were slightly decreased during the pandemic (0.9-and 0.7-fold lower compared with the pre-pandemic, respectively).In non-ICU patients, candidemia cases caused by the four common Candida species and P. kudriavzevii increased during the pandemic, ranging from 1.1-to 2.1-fold compared with the pre-pandemic period.

Discussion
The recent emergence of COVID-19 has resulted in an unprecedented public health crisis and brought new healthcare challenges, including the development of fungal coinfections such as candidemia [3].The increase in the incidence of candidemia during the pandemic reported in our study is consistent with the results of previous studies conducted in different geographic regions [3,7,15].A Brazilian single-center study observed a 5.7-fold increment in candidemia during the COVID-19 pandemic, although their incidence of candidemia had been stable over the past 18 years [7].As shown in Kor-GLASS data obtained from nine collection centers, the average incidence of candidemia was 1.45 cases per 10,000 PD in 2020 and 1.72 cases per 10,000 PD in 2021 [12].This was partly in line with our single center data showing 1.79 episodes per 10,000 PD during the pandemic.This increment in the incidence of candidemia may be explained by two factors: an increase in the absolute number of episodes of candidemia (404 episodes in pre-pandemic vs. 484 episodes in pandemic) and a decrease in the number of PDs during the pandemic (average PDs per year, 931,086 PDs in pre-pandemic vs. 902,741 PDs in pandemic).Previous research has suggested that COVID-19 could easily contribute to the development of candidemia due to common risk factors between the diseases, such as the use of antibiotics, corticosteroids, venous catheters, and dialysis; furthermore, mucosal barrier disruption caused by COVID-19 could facilitate the translocation of Candida species from the gut to the bloodstream [16].Moreover, patients with severe COVID-19 are predisposed to acquire secondary fungal infections such as COVID-19-associated candidemia and are associated with poor clinical outcomes despite receiving antifungal treatment [17].Our study highlights the importance of cautiously monitoring invasive candidiasis in the post-pandemic era.
Given that each Candida species has a unique virulence potential, antifungal susceptibility pattern, and clinical characteristics [18], the changing epidemiology of candidemia may have different implications for the management of-and mortality due to-ICU-associated candidemia depending on the Candida species.In this study, in ICU patients, candidemia caused by C. albicans and C. tropicalis was significantly increased by 1.5-and 1.4-fold during the pandemic.This is a cause for concern, considering that the mortality rates of C. albicans and C. tropicalis candidemia in ICU patients are approximately 2-fold higher than those in non-ICU patients [19].Meanwhile, C. parapsilosis complex candidemia surged 2.1-fold in non-ICU patients and 1.6-fold overall during the pandemic.Moreover, candidemia due to C. parapsilosis was 2-fold more persistent than that caused by other common Candida species, and this persistence was strengthened during the pandemic.Previously, the clinical implication of C. parapsilosis was relatively less recognized than those of other common Candida species.Recently, candidemia caused by fluconazole-non-susceptible C. parapsilosis isolates has been increasingly reported worldwide, and outbreaks of fluconazole-resistant isolates have been reported from several countries during the pandemic [20][21][22][23][24].Besides sporadic infections, C. parapsilosis is well known to cause nosocomial outbreaks through direct and indirect contact via the hands of healthcare workers and through contaminated patient care equipment.It is likely that the limited availability of personal protective equipment and the congestion in hospital units during the pandemic created a permissive environment for the emergence of such outbreaks [24][25][26].The persistence of such infections has led to changes in clinical practice and the replacement of fluconazole with echinocandins [22,27,28].Notably, a recent Korean study proposed that the long-term clonal transmission of C. parapsilosis isolates in Korean hospitals may be linked to specific sinking phenotypes [28].Their microbiological characteristics could make them prone to azole-resistant mutation, causing them to persist for a long time in the environment, where they may cause bloodstream infections in vulnerable patients with indwelling catheters or azole exposure.In our study, antifungal resistance remained low and clonal spreading was not a big concern during the pandemic, similar to previous reports [12,29].However, it is necessary to monitor the changing epidemiology of indigenous C. parapsilosis in Korea, considering their persistent nature and potential to become antifungal-resistant.
In this study, we found that C. auris was frequently isolated from ear discharge, rather causing a bloodstream infection or outbreak, and the isolation of C. auris was decreased during the pandemic.This might be explained by characteristics of the East Asian clade (clade II), which were inherently different from other clades [19,30,31].A recent study suggested that several factors such as reduced thermal tolerance at 42 • C, reduced virulence in the G. mellonella model, and a reduced competitive growth ability compared to non-clade II isolates might contribute to the decreased colonization by clade II C. auris in hospital settings and at various body sites and to their absence in nosocomial transmissions [31].However, further surveillance should be continued considering the recent emergence of six clade I isolates of C. auris in a Korean hospital [31], harboring the potential to be a nosocomial cluster in Korea.

Conclusions
Infections due to Candida species increased during the COVID-19 pandemic.A rise in candidemia cases caused by C. parapsilosis was observed in Korea during the pandemic.Such changes in the epidemiology of Candida species should be continuously monitored in the post-pandemic period.This research underscores the heightened incidence of Candidarelated infections during the COVID-19 pandemic and emphasizes the importance of ongoing surveillance of Candida species epidemiology beyond the pandemic's scope.

Table 1 .
Distribution of clinical isolates of Candida species at a single-tertiary medical center in Korea from 2017 to 2022.

Table 2 .
Incidence of candidemia during the pre-pandemic and the COVID-19 pandemic in this study. Incidence/

Table 3 .
Distribution of Candida species isolated from blood cultures of intensive-care-unit (ICU) patients or non-ICU patients and relative ratio of candidemia incidence between the pre-pandemic and COVID-19 pandemic periods.

Table 4 .
Antifungal susceptibilities of the six common Candida species obtained from blood cultures according to the pre-pandemic and COVID-19 pandemic.