Study year |
No. participating hospitals† | % C. glabrata of all Candida BSI isolates | No. BSI isolates of C. glabrata tested | No. (%) C. glabrata BSI isolates‡ | ||
---|---|---|---|---|---|---|
Fluconazole resistance | Echinocandin resistance§ | Multidrug resistance¶ | ||||
2008 | 13 | 11.7 | 68 | 0 | 0 | 0 |
2009 | 8 | 16.0 | 67 | 4 (6.0) | 0 | 0 |
2010 | 8 | 16.8 | 60 | 4 (6.7) | 0 | 0 |
2011 | 10 | 16.0 | 85 | 4 (4.7) | 0 | 0 |
2012 | 11 | 17.0 | 108 | 3 (2.8) | 0 | 0 |
2013 | 7 | 16.9 | 73 | 4 (5.5) | 1 (1.4) | 1 (1.4) |
2014 | 7 | 22.1 | 123 | 11 (8.9) | 0 | 0 |
2015 | 10 | 17.2 | 110 | 5 (4.5) | 3 (2.7) | 0 |
2016 | 10 | 21.2 | 123 | 4 (3.3) | 4 (3.3) | 2 (1.6) |
2017 | 13 | 21.6 | 173 | 13 (7.5) | 4 (2.3) | 1 (0.6) |
2018 | 13 | 23.9 | 168 | 14 (8.3) | 4 (2.4) | 2 (1.2) |
Total | 19 | 18.6 | 1158 | 66 (5.7) | 16 (1.4) | 6 (0.5) |
Table 1. Incidence of antifungal resistance in Candida glabrata BSI isolates, based on cultures collected during a multicenter surveillance study, South Korea, 2008–2018*
*BSI, bloodstream infection.
†Hospitals participating in this laboratory-based nationwide multicenter surveillance system differed each year.
‡Antifungal susceptibility was determined by using the Clinical and Laboratory Standards Institute M27–4ED broth microdilution method[16]. Interpretive categories of resistance were determined by using Clinical and Laboratory Standards Institute document M60-ED[17]. We deposited 76 antifungal-resistant isolates of C. glabrata in the Korea Collection for Type Culture (KCTC; Jeongeup-si, Korea), including those showing resistance to fluconazole alone (60 isolates, KCTC nos. 37113–37172), echinocandin alone (10 isolates, KCTC nos. 37176–37185), and both fluconazole and echinocandin (6 multidrug-resistant isolates, KCTC nos. 37110–37112, 37173–37175). All 76 isolates were identified as C. glabrata by sequence analysis using the D1/D2 domain (GenBank accession nos. MW349716–90 and MW351777).
§Echinocandin resistance was confirmed by the identification of resistance hot-spot mutations in FKS1 and FKS2 in isolates that exhibited full or intermediate resistance to micafungin (MIC ≥0.12 mg/L) or caspofungin MIC (≥0.25 mg/L).
¶Multidrug resistance was defined as resistance to both fluconazole and echinocandins.
MLST genotype | Fluconazole susceptibility | No. isolates tested | No. with echinocandin resistance | No. isolates with 5 Pdr1p AAS found in both FR and F-SDD isolates | No. isolates with additional Pdr1p AAS except for 5 Pdr1p AAS | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
P76S | P143T | D243N | E259G | T745A | 1 | 2 | Total | |||||
ST7 | FR | 37 | 6† | 34 | 3 | 37 | ||||||
F-SDD | 98 | 3 | 0 | 0 | ||||||||
ST3 | FR | 7 | 0 | 7 | 7 | 7 | 6 | 1 | 7 | |||
F-SDD | 43 | 1 | 43 | 43 | 43 | 0 | 0 | |||||
ST26 | FR | 7 | 0 | 6 | 6 | |||||||
F-SDD | 10 | 1 | 0 | 0 | ||||||||
ST22 | FR | 1 | 0 | 1 | 1 | |||||||
F-SDD | 16 | 1 | 0 | 0 | ||||||||
ST10 | FR | 2 | 0 | 2 | 2 | |||||||
F-SDD | 9 | 0 | 0 | 0 | ||||||||
ST55 | FR | 2 | 0 | 2 | 2 | 2 | ||||||
F-SDD | 6 | 1 | 6 | 1 | 1 | |||||||
ST2 | FR | 2 | 0 | 2 | 2 | |||||||
F-SDD | 3 | 0 | 0 | 0 | ||||||||
ST6 | FR | 1 | 0 | 1 | 1 | |||||||
F-SDD | 5 | 2 | 0 | 0 | ||||||||
ST59 | FR | 1 | 0 | 1 | 1 | 1 | ||||||
F-SDD | 3 | 1 | 3 | 0 | 0 | |||||||
ST1 | FR | 2 | 0 | 2 | 2 | |||||||
ST12 | F-SDD | 2 | 0 | 0 | 0 | |||||||
Other STs‡ | FR | 4 | 0 | 1 | 2 | 2 | 4 | |||||
F-SDD | 17 | 0 | 2 | 2 | 2 | 1 | 1 | |||||
Total, no. (%) | FR | 66 | 6 | 7 | 7 | 7 | 3 | 1 | 59 | 6§ | 65 (98.5) | |
F-SDD | 212 | 10 | 45 | 45 | 45 | 6 | 3 | 2¶ | 2 (0.9) |
Table 2. Pdr1 AAS in 66 FR isolates and 212 F-SDD BSI isolates of Candida glabrata and their MLST genotypes, based on cultures collected during a multicenter surveillance study, South Korea, 2008–2018*
*AAS, amino acid substitution; BSI, bloodstream infection; FR, fluconazole-resistant; F-SDD, fluconazole-susceptible dose-dependent; MLST, multilocus sequence typing; ST, sequence type.
†All 6 isolates showed multidrug resistance, defined as resistance to both fluconazole and echinocandins.
‡Includes 21 STs that were each unique to a single isolate.
§Each of 6 FR isolates harbored 2 additional Pdr1 AAS (E340G/D919Y [ST7], Y556C/F580I [ST7], N132S/G1099S [ST7], F832L/L833V [ST3], G189V/E340G [other ST], and L366P/E555D [other ST]).
¶Two F-SDD isolates harbored additional Pdr1 AAS (V502I [ST55] and R250K [other ST]).
MLST genotype | No. isolates | Pdr1 AAS (no. isolates)† | |||
---|---|---|---|---|---|
Inhibition domain | Fungal-specific transcription factor domain | Activation domain | Other regions | ||
ST7 | 34 | P327L (2), G334V (1), E340G (1), E340K (1), G346S (1), L347F (1), L375P (1), R376Q (1), S391L (1) | H576Y (2), G583C (1) | P927S (1), G943S (1), S947L (1), D954N (1), G1088E (1), Y1106N (1) | S236N (1), P258S (1), P258L (1), V260A (1),L280S (1), Y556C (1), E714D (1), T752I (1), N768D (1), R772K (1), K776E (1), G788W (2), L825P (1), T885A (1) |
ST26 | 6 | K365E (1), R376Q (1), F377I (1), E388Q (1) | N1091D (1) | S316I (1) | |
ST3 | 6 | L347F (1) | Y584D (1) | T1080N (1), Y1106N (1) | A731E (1), N764D (1) |
ST1 | 2 | T607A (2) | |||
ST2 | 2 | G346S (2) | |||
ST10 | 2 | S337F (1), I392M (1) | |||
ST55 | 2 | F294S (1), P258S (1) | |||
ST6 | 1 | G1079R (1) | |||
ST22 | 1 | Y932C (1) | |||
ST59 | 1 | E369K (1) | |||
Others | 2 | L935F (1) | P696L (1) | ||
No. (%) isolates | 59 | 20 (33.9) | 7 (11.9) | 11 (18.6) | 21 (35.6) |
No. (%) Pdr1 AAS | 49 | 15 (30.6) | 5 (10.2) | 10 (20.4) | 19 (38.8) |
Table 3. Pdr1 AAS in 59 FR isolates of Candida glabrata BSI isolates and their MLST genotypes, based on cultures collected during a multicenter surveillance study, South Korea, 2008–2018*
*AAS, amino acid substitutions; BSI, bloodstream infection; FR, fluconazole-resistant; MLST, multilocus sequence typing; ST, sequence type.
†Previously reported Pdr1 AAS are shown in bold.
This activity is intended for infectious disease clinicians, public health officials, internists, intensivists, and other clinicians caring for patients with Candida glabrata fluconazole-resistant bloodstream infections.
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We investigated the clinical outcomes and molecular mechanisms of fluconazole-resistant (FR) Candida glabrata bloodstream infections. Among 1,158 isolates collected during multicenter studies in South Korea during 2008–2018, 5.7% were FR. For 64 patients with FR bloodstream infection isolates, the 30-day mortality rate was 60.9% and the 90-day mortality rate 78.2%; these rates were significantly higher than in patients with fluconazole-susceptible dose-dependent isolates (30-day mortality rate 36.4%, 90-day mortality rate 43.8%; p<0.05). For patients with FR isolates, appropriate antifungal therapy was the only independent protective factor associated with 30-day (hazard ratio 0.304) and 90-day (hazard ratio 0.310) mortality. Sequencing of pleiotropic drug-resistance transcription factor revealed that 1–2 additional Pdr1p amino acid substitutions (except genotype-specific Pdr1p amino acid substitutions) occurred in 98.5% of FR isolates but in only 0.9% of fluconazole-susceptible dose-dependent isolates. These results highlight the high mortality rate of patients infected with FR C. glabrata BSI isolates harboring Pdr1p mutations.
Candida glabrata is a commensal yeast in the human gut, genitourinary tract, or oral cavity; however, it can cause serious bloodstream infections (BSIs) that result in substantial illness and death[1]. Unlike other common Candida species, C. glabrata exhibits intrinsically low susceptibility to azole drugs, especially fluconazole, and rapidly acquires antifungal resistance in response to azole or echinocandin exposure[1–3]. Although the incidence of echinocandin- and multidrug-resistant (MDR) C. glabrata BSIs is low, fluconazole resistant (FR) C. glabrata BSI isolates have been increasingly reported worldwide, typically at rates of 2.6%–10.6%, although these rates can reach 17%[4–6]. Fluconazole resistance in C. glabrata is of particular concern because of the increased incidence of BSIs caused by this species in various locations worldwide[1,4,5]. Acquired azole resistance in C. glabrata is most commonly mediated by overexpression of the drug-efflux transporter genes CgCDR1, CgCDR2, and CgSNQ2 through a gain-of-function (GOF) mutation in the transcription factor pleiotropic drug-resistance (PDR1)[2,7,8], although other mechanisms might contribute[9–11].
PDR1 mutations in C. glabrata associated with azole resistance have been shown to cause hypervirulence in a mouse model of systemic candidiasis, suggesting the need for careful monitoring of FR C. glabrata BSI isolates and their PDR1 mutations[7,12]. To date, little substantial research has been conducted on PDR1 mutation incidence among FR C. glabrata BSI isolates from multicenter surveillance cultures or on mortality rates of patients infected with these PDR1 mutants. This deficit might be attributable to Pdr1p amino acid substitutions (AAS) found in FR and fluconazole-susceptible dose-dependent (F-SDD) isolates[7,13,14], which can impede determination of whether specific Pdr1p AAS result in fluconazole resistance. Therefore, the aim of this study was to investigate the clinical outcomes, molecular mechanisms, and genotypes associated with antifungal-resistant BSI isolates of C. glabrata collected during multicenter studies in South Korea during an 11-year period (2008–2018). We focused on the mortality rates of patients infected with FR C. glabrata BSI isolates harboring the Pdr1p mutation.