Ann Lab Med.  2023 Nov;43(6):614-619. 10.3343/alm.2023.43.6.614.

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

• Choi MJ
• Kwon YJ
• Byun SA
• Kim MN
• Lee WG
• Lee J
• Yong D
• Chang CL
• Won EJ
• Kim SH
• Lee SY
• Shin JH

• KMID: 2552039
• DOI: http://doi.org/10.3343/alm.2023.43.6.614

Abstract

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.

Keyword

Amino acid substitution; Azoles; Candida albicans; ERG11; Fluconazole; MRR1; Mutation; Sepsis; TAC1; UPC2

Figure

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  Fig. 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.

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