First Case of Bloodstream Infection by Candida auris (Candidozyma auris) Resistant to Three Major Antifungal Classes in Korea

Dear Editor,

Candida auris (reclassified as Candidozyma auris), a multidrug-resistant yeast, has rapidly spread globally, challenging clinical management and infection control [1, 2]. Approximately 90% and 30% of C. auris isolates are resistant to fluconazole and amphotericin B (AMB), respectively, whereas echinocandin resistance remains rare (~5%) [1]. Echinocandin resistance due to FKS1 mutations, particularly following echinocandin treatment, highlights risks regarding resistance to all three major antifungal classes (azoles, polyenes, and echinocandins) [3, 4]. To our knowledge, for the first time, we isolated the C. auris bloodstream isolates in Korea that acquired echinocandin resistance during antifungal therapy, resulting in resistance to all three major antifungal classes. This study was exempt from institutional review board review at a 700-bed hospital in Gyeonggi Province, Korea (HDT 2025-09-015), and the requirement for informed consent was waived.

A 92-yr-old man with a history of prostate cancer, Parkinson’s disease, diabetes mellitus, and hypertension was transferred from a long-term care hospital in October 2024 for pneumonia. C. auris was first isolated from the blood on hospital day (HD) 17, and micafungin therapy (100 mg intravenously [IV] daily) was initiated on HD 21. Blood cultures remained positive on HDs 21, 23, and 26 but cleared on HD 30. On HD 34, therapy was switched to fluconazole (400 mg IV daily) based on clinical improvement. C. auris recurred on HD 40, prompting reinitiation of micafungin on HD 41. Liposomal AMB (200 mg IV daily) was initiated on HD 50 due to persistent fungemia on HD 47. Blood cultures remained positive on HDs 51 and 54 but were negative on HDs 58, 61, and 67. On HD 68, C. auris was recovered from the groin, nasopharynx, urine, and pulse oximeter across 28 surveillance cultures. The patient died on HD 72 from septic shock following Klebsiella pneumoniae bacteremia.

We analyzed eight C. auris isolates (four from blood [HDs 17, 44, 51, and 54] and four from surveillance cultures [HD 68]). Antifungal susceptibility was tested using Sensititre YeastOne (Thermo Fisher Scientific, Waltham, MA, USA) and interpreted using US Centers for Disease Control and Prevention tentative breakpoints for C. auris (≥32 μg/mL for fluconazole, ≥2 μg/mL for AMB, ≥4 μg/mL for anidulafungin, ≥2 μg/mL for caspofungin, and ≥4 μg/mL for micafungin) [5]. AMB results were confirmed by retesting using the CLSI M27 broth microdilution method [6]. Antifungal resistance-associated genes ERG11 and TAC1B were sequenced in fluconazole-resistant isolates, and FKS1 in echinocandin-non-susceptible isolates [7]. Clade was determined via multilocus sequence typing based on the internal transcribed spacer, D1/D2, RPB1, and RPB2 [7]. All isolates tested were clade I and fluconazole-resistant, carrying both Erg11p Y132F and Tac1bp A583S (Table 1). All but two isolates tested AMB-resistant by both the methods. While the first blood isolate was echinocandin-susceptible, after micafungin treatment, echinocandin-resistant isolates harboring an FKS1 mutation were detected (Fig. 1).

Table 1. Antifungal susceptibility profiles and genetic analysis of Candida auris isolates obtained during clinical course.

Hospital day	Source	MIC (μg/mL)*										Genetic analysis results
		AMB‡	AND	CAS	FLC	5-FC	MCF	PSC	VRC	ITC		ERG11	TAC1B	FKS1	Clade†
17	Blood	4 (2)	0.25	0.25	128	0.06	0.12	0.06	0.5	0.25		Y132F	A583S	-	I
44	Blood	0.5 (1)	8	>8	128	0.06	>8	0.03	0.5	0.12		Y132F	A583S	F635del	I
51	Blood	2 (2)	>8	>8	128	0.06	>8	0.06	0.5	0.12		Y132F	A583S	F635del	I
54	Blood	2 (2)	>8	>8	128	0.06	>8	0.06	0.5	0.25		Y132F	A583S	F635del	I
68	Groin	4 (2)	0.25	0.25	128	0.06	0.12	0.06	0.5	0.12		Y132F	A583S	-	I
68	Nasopharynx	2 (4)	0.25	0.25	128	0.06	0.12	0.03	0.5	0.12		Y132F	A583S	-	I
68	Oximeter	2 (2)	0.12	0.25	128	0.06	0.12	0.12	0.5	0.12		Y132F	A583S	-	I
68	Urine	1 (1)	1	8	128	0.06	8	0.03	0.5	0.12		Y132F	A583S	F635del	I

*MICs were determined using the Sensititre YeastOne system. Isolates that were resistant according to US Centers for Disease Control and Prevention tentative breakpoints for C. auris [5] are shown in bold.

^†Clades were determined using multilocus sequence typing based on four loci (ITS, D1/D2, RPB1, and RPB2) as previously described [7].

^‡Sensititre YeastOne results, with CLSI M27 broth microdilution results in parentheses.

Abbreviations: MIC, minimum inhibitory concentration; AMB, amphotericin B; AND, anidulafungin; CAS, caspofungin; FLC, fluconazole; 5-FC, flucytosine; MCF, micafungin; PSC, posaconazole; VRC, voriconazole; ITC, itraconazole; ITS, internal transcribed spacer.

Fig. 1. Timeline illustrating the clinical course, culture results, antifungal susceptibility profiles, and antifungal therapy of the patient.

Abbreviations: R, resistant; S, susceptible; HD, hospital day.

Clade I C. auris, initially linked to South Asia, is now globally distributed and commonly multidrug-resistant, with approximately 90% of isolates resistant to at least two antifungal classes [1, 3, 8]. In the first clade I C. auris outbreak in Korea in 2022, isolates exhibited low fluconazole resistance (25.0%) and no ERG11 or TAC1B mutations [7, 9]. In our case, however, all isolates were clade I and fluconazole-resistant and carried Erg11p Y132F and Tac1bp A583S, suggesting the emergence of a fluconazole-resistant clone. Echinocandin resistance developed during micafungin therapy due to F635del in the FKS1 hotspot, which is known to confer echinocandin resistance [10]. The discrepant antifungal susceptibility profiles of HD 68 isolates may reflect heterogeneous C. auris subpopulations related to site-specific colonization under variable antifungal selective pressure [3, 7]. Despite variability in AMB susceptibility testing, six of the eight isolates had MICs ≥2 µg/mL by both the methods and were classified as resistant. While we did not evaluate AMB resistance-associated mutations, AMB resistance in C. auris is known to be genetically heterogeneous, with candidate genes such as ERG6 inconsistently identified in resistant isolates [3]. In our case, stepwise emergence of resistance to three or more antifungal classes during persistent C. auris candidemia occurred in a patient with advanced age, multiple comorbidities, and prolonged long-term care exposure. In similar cases reported in New York, echinocandins were used as first-line therapy, along with early AMB alternation, combination regimens, or investigational agents [1, 3, 4]. These approaches might have been considered in our case, although supporting clinical evidence remains limited. Our case represents the first bloodstream infection by C. auris isolates resistant to three major antifungal classes in Korea and underscores the risk of stepwise resistance acquisition and treatment failure, emphasizing the need for continued antifungal resistance surveillance.