Article

Brief Communication

Ann Lab Med 2023; 43(6): 614-619

Published online November 1, 2023 https://doi.org/10.3343/alm.2023.43.6.614

Copyright © Korean Society for Laboratory Medicine.

Molecular and Clinical Features of Fluconazole Non-susceptible Candida albicans Bloodstream Isolates Recovered in Korean Multicenter Surveillance Studies

Min Ji Choi, Ph.D.1,* , Yong Jun Kwon, M.D.2,* , Seung A Byun, M.S.2 , Mi-Na Kim, M.D., Ph.D.3 , Wee Gyo Lee, M.D., Ph.D.4 , Jaehyeon Lee, M.D., Ph.D.5,6 , Dongeun Yong, M.D., Ph.D.7 , Chulhun L. Chang, M.D., Ph.D.8 , Eun Jeong Won, M.D., Ph.D.3 , Soo Hyun Kim, M.D., Ph.D.2 , Seung Yeob Lee, M.D., Ph.D.5,6 , and Jong Hee Shin, M.D., Ph.D.2

1Microbiological Analysis Team, Biometrology Group, Korea Research Institute of Standards and Science (KRISS), Daejeon, Korea; 2Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea; 3Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 4Department of Laboratory Medicine, Ajou University School of Medicine, Suwon, Korea; 5Department of Laboratory Medicine, Jeonbuk National University Medical School and Hospital, Jeonju, Korea; 6Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea; 7Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea; 8Department of Laboratory Medicine, Pusan National University School of Medicine, Yangsan, Korea

Correspondence to: Jong Hee Shin, M.D., Ph.D.
Department of Laboratory Medicine, Chonnam National University Medical School, 42 Jebong-ro, Dong-gu, Gwangju 61469, Korea
Tel: +82-62-220-5342
Fax: +82-62-224-2518
E-mail: shinjh@chonnam.ac.kr

Seung Yeob Lee, M.D., Ph.D.
Department of Laboratory Medicine, Jeonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea
Tel: +82-63-250-2148
Fax: +82-63-250-1200
E-mail: seungyeoblee@jbnu.ac.kr

* These authors equally contributed to this study.

Received: January 5, 2023; Revised: February 14, 2023; Accepted: June 2, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acquired fluconazole resistance (FR) in bloodstream infection (BSI) isolates of Candida albicans is rare. We investigated the FR mechanisms and clinical features of 14 fluconazole non-susceptible (FNS; FR and fluconazole-susceptible dose-dependent) BSI isolates of C. albicans recovered from Korean multicenter surveillance studies during 2006–2021. Mutations causing amino acid substitutions (AASs) in the drug-target gene ERG11 and the FR-associated transcription factor genes TAC1, MRR1, and UPC2 of the 14 FNS isolates were compared with those of 12 fluconazole-susceptible isolates. Of the 14 FNS isolates, eight and seven had Erg11p (K143R, F145L, or G464S) and Tac1p (T225A, R673L, A736T, or A736V) AASs, respectively, which were previously described in FR isolates. Novel Erg11p, Tac1p, and Mrr1p AASs were observed in two, four, and one FNS isolates, respectively. Combined Erg11p and Tac1p AASs were observed in seven FNS isolates. None of the FR-associated Upc2p AASs were detected. Of the 14 patients, only one had previous azole exposure, and the 30-day mortality rate was 57.1% (8/14). Our data show that Erg11p and Tac1p AASs are likely to contribute to FR in C. albicans BSI isolates in Korea and that most FNS C. albicans BSIs develop without azole exposure.

Keywords: Amino acid substitution, Azoles, Candida albicans, ERG11, Fluconazole, MRR1, Mutation, Sepsis, TAC1, UPC2

Candida albicans, a predominant human fungal pathogen, causes both mucosal and bloodstream infections (BSIs), and fluconazole is one of the most widely prescribed antifungal agents used to treat these infections [1, 2]. Acquired fluconazole resistance (FR) in C. albicans has been reported at its highest frequency in HIV-infected patients with oropharyngeal candidiasis as well as in patients with recurrent vaginal candidiasis [2, 3]. The long-term use of fluconazole for prophylaxis or treatment of mucosal C. albicans infections can lead to selective pressure, resulting in the emergence of acquired FR in C. albicans [2, 3]. The main mechanisms responsible for acquired FR in C. albicans from mucosal infections include mutations or overexpression of ERG11, which encodes an enzyme targeting the drug (lanosterol 14α-demethylase), and the overexpression of genes encoding efflux pumps (CDR1, CDR2, and MDR1) [2, 4, 5]. The overexpression of FR-associated genes occurs mainly due to gain-of-function (GoF) mutations in the transcription factor-encoding genes TAC1 (involved in CDR1 and CDR2 regulation), MRR1 (involved in MDR1 regulation), and UPC2 (involved in ERG11 regulation) [2, 5-7].

In contrast to mucosal isolates with FR rates of 12%–22%, the rates of FR among BSI isolates of C. albicans are low (0.06%–2.3%); this could be partly because of the relatively short-term use of antifungal agents for the treatment of candidemia [2, 8-10]. Among 2,712 C. albicans BSI isolates obtained from Korean multicenter surveillance studies during 2006–2021, only 14 (0.5%) were determined to be fluconazole non-susceptible (FNS; minimum inhibitory concentration [MIC] ≥4 μg/mL). To date, only few studies have characterized the molecular and clinical features of BSI isolates of C. albicans with acquired FR [8]. Therefore, we investigated the gene mutations causing amino acid substitutions (AASs) in ERG11, TAC1, MRR1, and UPC2; their genotypic relationships; and the clinical features of FNS BSI isolates of C. albicans that were submitted to Chonnam National University Hospital from Korean multicenter surveillance studies over 15 years (2006–2021).

We assessed 26 BSI isolates of C. albicans: 11 FR (MIC ≥8 μg/mL), three fluconazole-susceptible dose-dependent (F-SDD; MIC, 4 μg/mL), and 12 control fluconazole-susceptible (FS; MIC, 0.25–0.5 μg/mL) isolates. All isolates were identified using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (Bruker Biotyper library v. 4.0; Bruker Daltonics GmbH, Bremen, Germany) or by sequencing the D1/D2 domains of the 26S rRNA gene [11]. In vitro antifungal susceptibility testing was performed with the Sensititre Yeast One system (Thermo Fisher Scientific Inc., Cleveland, OH, USA). Sequence analyses of ERG11, TAC1, MRR1, and UPC2 were conducted as described previously [6, 12, 13]. All isolates were genotyped using multi-locus sequence typing (MLST); each strain was assigned a diploid sequence type (DST) reflecting the combination of the genotypes of seven genes in the MLST database (https://pubmlst.org/organisms/candida-albicans), and a dendrogram was constructed [14]. Clinical information for all 14 patients with FNS C. albicans BSI isolates was collected retrospectively [15]. This study was approved by the Institutional Review Board of Chonnam National University Hospital, Gwangju, Korea (approval No. CNUH-2014-290) that also waived the requirement for informed consent.

Table 1 shows the results of antifungal susceptibility testing and ERG11, TAC1, MRR1, and UPC2 sequencing of all 14 FNS (11 FR [R1–R11] and 3 F-SDD [D1–D3]) and 12 FS (S1–S12) C. albicans BSI isolates. No isolate was found to be resistant to amphotericin B or the three echinocandins. The sequencing results of all 14 FNS C. albicans isolates were compared with those of 12 FS control isolates and previously reported data [2, 6, 7, 16-20]; five Erg11p, seven Tac1p, and one Mrr1p AASs were found in only the FNS isolates. Of the five Erg11p AASs that were found in only the FNS isolates, two (R264T and D428N) were potentially novel; three AAS (K143R, F145L, and G464S) that were found in eight FNS isolates were confirmed to cause FR through in vitro experiments [16]. Of the seven AASs in Tac1p that were not present in the FS isolates, three (T225A, A736T, and A736V) AASs that were found in six FNS isolates were previously described as GoF mutations [2]; another (R673L) AAS found in one FNS isolate was previously described in azole-resistant isolates [2, 18-20]. The remaining three (Y269H, L744I, and N972K) Tac1p AASs from four FNS isolates were potentially novel, although N972K occurred at a position already described in FR isolates [19]. Only one substitution in Mrr1p (N33S), which was found in one FNS isolate, was not described previously [2, 7]. Although it is unclear whether the newly identified AASs in this study result in FR, the Erg11p, Tac1p, Mrr1p, and Upc2p AASs that were either novel or described in azole-resistant isolates were found in 8 (57.1%), 11 (78.6%), 1 (7.1%), and 0 (0%) isolates, respectively. A previous study characterized azole resistance mechanisms in five invasive FNS C. albicans isolates that had been collected in 29 countries in 2014 and 2015. The authors found that MDR1 overexpression (three isolates) was more common than CDR2 expression (one isolate) or ERG11 mutation (one isolate) [10]. In contrast, our results suggested that ERG11 mutations and CDR overexpression are likely the dominant mechanisms of FR in C. albicans BSI isolates from Korean hospitals.

Table 1 . Comparison of azole antifungal susceptibility testing and sequencing of azole-resistant related genes between fluconazole non-susceptible and fluconazole susceptible bloodstream isolates of Candida albicans

Isolate No.MIC (μg/mL)*Erg11p AAS found inTac1p AAS found inMrr1p AAS found inUpc2p AAS found in





FLC/VOR/ITRA/POSAFNS isolates onlyBoth FNS and FS isolatesFNS isolates onlyBoth FNS and FS isolates||FNS isolates onlyBoth FNS and FS isolates||FNS isolates onlyBoth FNS and FS isolates
R1> 256/> 8/> 16/>8NoneD116E, K128TL744I§N772K, S935LNoneL171P, L248V, V341ENoneNone
R2> 256/> 8/> 16/>8K143RD116E, K128TNoneI558V, N772KNone-NoneI142S
R316/0.12/0.25/0.25K143RD116E, K128TA736TN772K, S935LNoneL171P, L248V, V341ENoneNone
R416/0.12/0.25/0.25K143RD116E, K128TA736TN772K, S935LNoneL171P, L248V, V341ENoneNone
R516/0.12/0.25/0.25K143RD116E, K128TA736TN772K, S935LNoneN159H, I160T, A162P, L171P, L248V, V341ENoneNone
R616/0.5/0.5/0.5R264T§, G464SD116E, K128TN972K§N772K, S935LNoneV27I, L171P, L248V, V341ENoneNone
R78/0.12/0.25/0.25NoneD116E, E266D, V488IR673LI895T, N896SNoneL171P, V341ENoneNone
R88/0.12/0.06/0.03NoneD116E, E266D, V488INoneI895T, N896SNoneL171P, V341ENoneNone
R98/0.12/0.25/0.25F145LK342RY269H§N896SNoneL171P, V341ENoneI142S
R108/0.12/0.25/0.25NoneD116E, K128TA736VN772K, S935LNoneN159H, I160T, A162P, L171P, L248V, V341ENoneNone
R118/0.03/0.12/0.06K143RD116E, K128TA736TN772K, S935LNoneN159H, I160T, A162P, L171P, L248V, V341ENoneNone
D14/0.12/0.25/0.25F145L, D428N§K342RY269H§N896SN33S§L171P, V341ENoneI142S, P299L
D24/0.015/0.06/0.03NoneE266D, V437INoneK87N, M170I, N174D, F189SNoneL171P, L248K, V341ENoneI142S
D34/0.06/0.25/0.25NoneE266D, V488IT225AK87N, M170I, N174D, F189S, N772K, N896SNone-NoneI142S, S190N, S228N
S10.5/0.03/0.03/0.015NoneD153ENoneI895T, N896SNoneL171PNoneR68K, I142S, S228N
S20.5/0.03/0.06/0.03NoneE266D, V488INoneN896SNoneS16I, T73K, L171PNoneNone
S30.25/0.008/0.015/0.015NoneD116E, D153ENoneI895T, N896SNoneL171PNoneR68K, I142S, S228N
S40.25/0.015/0.03/0.015NoneD116E, D153ENoneI895T, N896SNoneL171PNoneI142S, S228N
S50.25/0.008/0.03/0.03NoneE266D, V437INoneK87N, A90T, M170I, N174D, F189S, F222LNoneP19L, G75R, N937K, F1032LNoneR68K, I142S, S190N, S228N
S60.25/0.008/0.03/0.015NoneE266D, V437INoneM170I, N174D, F189SNoneN937K, F1032LNoneR68K, I142S, S190N, S228N
S70.25/0.008/0.03/0.015NoneE266D, V437INoneA90TNoneN937K, F1032LNoneR68K, I142S, S190N, S228N
S80.25/0.015/0.03/0.03NoneD116E, D153ENoneI895T, N896SNone-NoneR68K, I142S, S288N, P299L, A300P
S90.25/0.015/0.03/0.03NoneD116E, K128TNoneN772KNoneL171P, L248V, V341ENoneNone
S100.25/0.008/0.015/0.015NoneE266D, V488INoneN772K, N896SNoneL171PNoneNone
S110.25/0.008/0.015/0.03NoneE266D, V488INoneN896SNoneL171P, S219FNoneNone
S120.25/0.008/0.03/0.015NoneD116ENoneI895T, N896SNoneL171PNoneI142S, S228N

*Antifungal MICs were determined using the Sensititre Yeast One system (Thermo Fisher Scientific Inc., Cleveland, OH, USA); The sequences of the isolates were compared and analyzed based on the reference sequences for ERG11 (GenBank accession No. X13296), TAC1 (GenBank accession No. DQ393587), MRR1 (GenBank accession no. XM711520), and UPC2 (GenBank accession No. EU583451) from C. albicans [6]; homozygous alleles are underlined; AASs that were previously detected in fluconazole-resistant C. albicans isolates are shown in bold; §New AASs (Erg11p R264T and D428N AASs, Tac1p Y269H, N744I, and N972K, and Mrr1p N33S) that were found in the FNS isolates of C. albicans in this study have been deposited into GenBank with accession numbers OQ161592, OQ161593, OQ161595, OQ383350, OQ161594, and OQ161598, respectively; ||Eight common Tac1p AASs (F104V, S199N, R206H, V207A, N396S, D776N, E829Q, and L941P) and one Mrr1p ASS (E1020Q) that were found in almost all (≥23) isolates were excluded; Erg11p K342R AAS and Mrr1p V27I AAS were reported previously in FS isolates [7, 17].

Abbreviations: MIC, minimal inhibitory concentration; AAS, amino acid substitution; FLC, fluconazole; VOR, voriconazole; ITRA, itraconazole; POSA, posaconazole; FNS, fluconazole non-susceptible; FS, fluconazole-susceptible.



Of the 14 FNS isolates, 12 exhibited weak FR (MICs: 4–16 mg/L) without voriconazole resistance, whereas the remaining two isolates (R1 and R2) showed high MICs for fluconazole (>256 mg/L) and voriconazole (>8 mg/L). Isolate R1 harbored L744I in Tac1p (new AAS), which might be the major contributor to CDR-mediated azole resistance; isolate R2 harbored Erg11p K143R. Of the five Erg11p K143R isolates with variable MICs for fluconazole (8–>256 mg/L), isolate R2 showed the highest fluconazole MIC; however, it did not show FR-specific Tac1p, Mrr1p, or Upc2p AASs. Two FNS isolates (R8 and D2) did not show any of the FR-associated AASs that were evaluated in this study. CDR1/CDR2 and MDR1 overexpression can be explained by TAC1 and MRR1 GoF mutations, but ERG11 overexpression is not always associated with UPC2 GoF mutations, suggesting the existence of additional regulators [21]. Thus, these isolates might have other resistance mechanisms, such as the overexpression of ERG11, which could not be detected in this study.

The MLST results for the 14 FNS isolates showed that nine isolates had different DSTs, whereas three and two isolates belonged to the DSTs 1179 and 1539, respectively (Fig. 1). Three DST 1179 isolates (R3–R5) were isolated at three different hospitals but had the same AASs in Erg11p (K143R) and Tac1p (A736T). Two isolates of DST 1539 (R9 and D1) were also isolated at different hospitals, and they had similar Erg11p AASs (F145L and F145L+D428N) and the same Tac1p (Y269H) AAS. TAC1 is located on the left arm of chromosome 5, where ERG11 is also located, and a combination of TAC1 and ERG11 point mutations has been suggested to contribute to an increased MIC for fluconazole among azole-resistant isolates [17]. Overall, 50.0% (7/14) of the FNS isolates showed combined Erg11p and Tac1p AASs in this study.

Figure 1. Dendrogram based on a combination of seven housekeeping genes (AAT1a, ACC1, ADP1, MPIb, SYA1, VPS13, and ZWF1b) of 14 fluconazole non-susceptible Candida albicans isolates, constructed based on the UPGMA using MEGA 11 software [14]. Three isolates of DST 1179 (R3–R5) are more closely related to four FNS isolates (R1, R6, R10, and R11), all of which share the same Erg11p (D116E and K128T), Tac1p (N772K and S935L), and Mrr1p (L171P, L248V, and V341E) AASs. See Table 1 for detailed information regarding each isolate.
Abbreviations: UPGMA, unweighted pair group method with arithmetic averages; DST, diploid sequence type; MLST, multi-locus sequence typing; AAS, amino acid substitution; FNS, fluconazole non-susceptible.

The clinical features of all 14 patients are summarized in Table 2. All 14 patients were adults with various underlying diseases, but no patient was infected with HIV. Previous amphotericin B (two patients) or fluconazole (one patient) exposure was identified in only three patients, indicating that almost all (92.9%) FNS C. albicans BSI isolates were from patients not previously exposed to azole. Among the 14 patients with FNS BSIs, eight had a fatal outcome within 30 days, three (R5, R7, and D3) died without receiving antifungal therapy, two (R4 and D1) died despite fluconazole therapy, and three (R1, R6, and R8) with a hematological malignancy died despite >3 days of echinocandin or amphotericin B therapy. The overall 30-day mortality rate of the patients was 57.1% (8/14), which was higher than the mean 30-day mortality rate (36.4%, 123/338) of patients with C. albicans BSIs reported at 11 Korean hospitals from 2017 to 2018, although the difference was not significant [15].

Table 2 . Clinical features of 14 patients with fluconazole non-susceptible bloodstream isolates of Candida albicans

Isolate No.Age (yr)/sexDiagnosisPrior antifungal exposureImmuno-suppressionCVCDuration of fungemia (days)Antifungal treatmentPatient outcome (days)*
R130/FAcute myeloid leukemiaYes (AMB)YesYes5AMB, ANIDeath (6)
R263/FPancreatic cancerNoYesYes1CASDeath (52)
R352/MDiabetes mellitusNoNoNo10AMBImproved
R475/MCOPDNoNoNo3FLCDeath (19)
R549/FBreast cancerNoNoYes1NoneDeath (2)
R652/MT/NK-cell lymphomaNoNoYes5CASDeath (7)
R774/MDiabetes mellitusNoNoYes1NoneDeath (1)
R874/FChronic myeloid leukemiaYes (FLC)YesNo2CASDeath (4)
R962/MRheumatoid arthritisNoNoYes4MICAImproved
R1079/FTraumatic subdural hemorrhageNoNoYes1FLCImproved
R1180/MSpinal abscessNoNoYes2CASImproved
D179/MDiabetes mellitusYes (AMB)NoYes8FLCDeath (15)
D243/MDown syndromeNoYesYes6AMBImproved
D367/FFulminant myocarditis, COPDNoNoYes1NoneDeath (3)

*Time to death after the first positive culture.

Abbreviations: F, female; M, male; COPD, chronic obstructive pulmonary disease; AMB, amphotericin B; FLC, fluconazole; CVC, central venous catheter; ANI, anidulafungin; CAS, caspofungin; MICA, micafungin.



Given the marked genetic diversity among Korean C. albicans BSI isolates in our previous MLST study [14], it is interesting that in the present study, five FNS isolates shared two DSTs (1179 and 1539). Additionally, the dendrogram obtained through MLST testing revealed that three isolates of DST 1179 (isolates R3–R5) were more closely related to four FNS isolates (R1, R6, R10, and R11) (Fig. 1). However, there was no time- or location-based clustering of these isolates, which excludes the potential of cross-transmission in the hospitals. Alternatively, some patients could accidentally acquire clonal FNS isolates of C. albicans already present in the environment of healthcare settings in Korea, leading to the development of healthcare-associated BSIs; further studies are needed to confirm this possibility.

In summary, our results showed that most FNS C. albicans BSI isolates from Korean hospitals harbor mutations in ERG11 or TAC1 and that fungemia can develop without azole exposure. This is the first study to describe both the molecular and clinical features of FNS BSI isolates of C. albicans obtained from candidemia surveillance studies.

Shin JH designed the study; Choi MJ and Byun SA performed the laboratory measurements and molecular studies; Kim MN, Lee WG, Lee J, Yong D, Chang CL, Won EJ, and Kim SH collected the clinical isolates and data; Shin JH, Kwon YJ, and Lee SY wrote the preliminary manuscript; Shin JH, Kwon YJ, and Lee SY analyzed the data; Shin JH revised the manuscript; Kim MN, Lee WG, Lee J, Chang CL, Won EJ, and Kim SH provided valuable comments and recommendations. All authors revised and accepted the final version of the manuscript.

No potential conflicts of interest relevant to this article are reported.

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (grant no. NRF-2022R1A2B5B0100322).

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