Candida species are commonly found as normal flora, but they can cause a variety of opportunistic infections such as oropharyngitis, esophagitis, vulvovaginitis, urinary tract infection, meningitis, endophthalmitis, endocarditis, peritonitis, osteomyelitis, and candidemia^1,2. Candidiasis control should include monitoring the Candida species' epidemiology and resistance to various antifungal agents^1,2. Antifungal usage is associated with the distribution and antifungal susceptibility of Candida species^3-5. According to previous multicenter studies conducted in South Korea since 2004^3,5,6, the pattern of antifungal drug usage, the rank order of occurrence, and antifungal susceptibilities of disease-causing Candida species varied across hospitals and different time periods. This multicenter study was performed in order to investigate the antifungal drug usage in Korean hospitals and the antifungal susceptibility of Candida species recovered from clinically relevant specimens.

A prospective surveillance study was conducted in 10 Korean hospitals (A-J). Data was collected over a one-year period regarding the usage of systemic antifungal agents by patients admitted in a particular hospital. This was then determined by calculating the number of defined daily doses per 1,000 patient days (DDD/1,000 PD), as specified by the WHO ATC/ DDD system (www.whocc.no/atcddd/) and DDD measurement methodology⁷. The non-duplicated clinical isolates of the Candida species, which were collected from clinically relevant specimens over a three-month period (from October 2016 to December 2016), were sent to Chonnam National University Hospital for species identification and antifungal susceptibility testing. The identification results of Candida species were obtained using the conventional laboratory tests of each hospital. After gathering the results, the final identification was performed using CHROMagar Candida (BBL; Becton Dickinson, Sparks, MD, USA), VITEK 2 system with a VITEK 2 YST card (bioMérieux, Marcy l'Étoile, France), MALDI Biotyper (software version 3.1, reference database version 4.0.0.1, Bruker Daltonics, Billerica, MA, USA), or sequencing, if further confirmation is needed⁸. The antifungal susceptibility test was performed to measure their resistance to fluconazole, voriconazole, amphotericin B, and micafungin, and it was done using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method M609. The minimum inhibitory concentration (MIC) of each isolate was categorized by applying CLSI clinical breakpoints (CBPs) or epidemiological cutoff values (ECVs)^10,11.

The data in Table 1 suggest that the total antifungal use varied considerably in 10 selected hospitals, ranging from 7.7 to 158.9 DDD/1,000 PD, with fluconazole being the most commonly used agent (with an average of 18.6 DDD/1,000 PD, or 37.1% of total DDD/1,000 PD), followed by amphotericin B (15.3, 30.6%), itraconazole (4.9, 9.7%), voriconazole (3.8, 7.5%), posaconazole (3.1, 6.3%), caspofungin (2.6, 5.2%), micafungin (1.6, 3.2%), and anidulafungin (0.2, 0.4%), respectively. Table 2 summarizes the species identification and in vitro susceptibility to fluconazole, voriconazole, amphotericin B, and micafungin for 274 Candida isolates obtained from clinically relevant specimens over a three-month period. C. albicans (n=140, 51.1%) was the most commonly recovered, followed by 43 C. glabrata (15.7%), 41 C. tropicalis (15.0%), 37 C. parapsilosis (13.5%), 4 C. krusei (1.5%), 3 C. guilliermondii (1.1%), 2 C. auris (0.7%), 1 C. fabianii (0.4%), 1 C. lusitaniae (0.4%), 1 C. magnoliae (0.4%), and 1 C. pelliculosa (0.4%) isolates. All the isolates showed an MIC range of 0.125 to > 64 μg/mL for fluconazole, 0.03~8 μg/mL for voriconazole, 0.25~2 μg/mL for amphotericin B, and 0.015~ 2 μg/mL for micafungin. Upon applying CBPs or ECVs to available Candida species, the resistance and non-susceptible rates for these species to fluconazole, voriconazole, amphotericin B, and micafungin were found to be 5.2% and 20.7%; 3.3% and 5.6%; 0.0% and 0.0%; and 0.0% and 0.0%, respectively.

This nationwide multicenter study aims to investigate the antifungal drug usage and the antifungal susceptibility of Candida species recovered from clinically relevant specimens. We found that the total antifungal use varied considerably according to each hospital. The average total usage of antifungals was 50.1 DDD/1,000 PD, which was similar to reports shown by previous Korean multicenter studies (63.2 DDD/ 1,000 PD in 2011 and 39.2 in 2005)^3,5; however, the pattern of antifungal agent usage was different in each hospital. Fluconazole was the most commonly used agent in seven hospitals, while amphotericin B was the most commonly used in three hospitals, specifically hospitals B, C, and E. The average usages of fluconazole, itraconazole, voriconazole, amphotericin B, caspofungin, and micafungin showed a 0.6-, 0.4-, 0.8-, 1.2-, 1.6-, and 1.1-fold increase, respectively, compared with those found in the 2011 study¹⁰. Consistent with previous studies, fluconazole was still the most commonly used antifungal agent5, but the overall echinocandin use has increased (average of 4.4 DDD/1,000 PD and 8.8% of total DDD/1,000 PD in this study; 3.1 DDD/1,000 PD and 4.9% in 2011; 0.5 DDD/1,000 PD and 1.2% in 2005)^3,5 as well. The use of fluconazole has been associated with an increased risk of candidemia caused by non-albicans Candida species due to their inherently higher level of resistance to certain antifungal agents5. In addition, the increasing trend in echinocandin use is important because it could pose a risk of emerging echinocandin-resistant Candida species⁴.

The overall epidemiology of the Candida species agreed with the data of previous studies conducted in Korea^3,6. More importantly, in the current study, C. glabrata was the most frequently found non-albicans Candida species, followed by C. tropicalis and C. parapsilosis, while the 2011 study found slightly different rates, where C. parapsilosis (17.8%) was the most common non-albicans Candida species, followed by C. glabrata (14.4%) and C. tropicalis (12.7%)⁶. When applying CBPs, 11 of 265 Candida isolates were found to be resistant to fluconazole, specifically three C. glabrata, one C. tropicalis, three C. parapsilosis, and four C. krusei isolates. The overall resistance rate was not much higher than that of other geographic regions^12,13. The fluconazole resistance and non-susceptibility rates, however, showed a 2.0- and 1.3-fold increase, respectively, compared with the data provided by previous Korean studies (2.6% and 16.4% in 2011, respetively)⁵. Moreover, among nine isolates of uncommon Candida species, five showed fluconazole MICs of > 64 μg/mL (two C. auris, one C. guilliermondii, one C. lusitaniae, and one C. pelliculosa isolates). Recently, C. auris has been highlighted to be less susceptible to fluconazole compared with the other Candida species, and it was reported to have developed a high-level resistance to fluconazole like that of C. glabrata¹⁴. In addition, C. auris was reported to be misidentified as C. haemulonii by the conventional identification method^8,14. In the present study, two C. auris isolates were identified as C. haemulonii using conventional laboratory tests conducted in each particular hospital, which required sequencing to confirm the identification. Two candidemia cases with echinocandin-resistant Candida isolates (C. albicans and C. glabrata) were reported in South Korea¹⁵; however, the researchers found no Candida isolate that was resistant to micafungin, confirming the low resistance rates of echinocandins in South Korea when compared with those of the traits of micafungin that were documented in the previous study of other geographic regions, such as 0.4% in North America, 0.5% in Europe, 0% in Latin America, and 0.3% in the Asia Pacific region¹².

We investigated the nationwide antifungal use, species distribution, and antifungal susceptibility in South Korea. The overall antifungal usage was similar with the established previous usage, but the use of echinocandins has increased, which might affect echinocandin non-susceptibility rates in Candida species. The Candida species distribution was similar as it was in the past, but the rank order and frequency of non-albicans Candida species was changing. The overall resistance rates of Candida species were still low, but fluconazole resistance and non-susceptibility rates have increased in South Korea. Although echinocandin resistance is still uncommon in Korea, we should be aware of its emergence in the near future, considering the increment of echinocandin use.