Abstract
Background
Candida lusitaniae, currently taxonomically classified as Clavispora lusitaniae, is a candidemia due to non-albicans Candida species, featuring unusual antifungal susceptibility profile and rapid resistance acquisition. This multicenter cohort study aimed to identify mortality risk factors in Korean patients with C. lusitaniae candidemia.
Methods
We retrospectively analyzed 53 C. lusitaniae candidemia cases from six university hospitals in Korea between January 2019 and December 2024. Demographic and clinical characteristics were compared between survivors and patients who died during their hospital stay (non-survivors). Univariate and multivariate Cox regression analyses were conducted to determine independent risk factors for 30- and 60-day mortality.
Results
During the study period, C. lusitaniae was the fifth most common cause of candidemia. The overall in-hospital mortality was 69.8%, with 30- and 60-day mortality rates of 39.6% and 47.2%, respectively. The non-survivor group comprised a significantly higher proportion of patients with lymphoma and those receiving immunosuppressive therapy. Independent risk factors for 30-day mortality included severe sepsis (hazard ratio 9.02), intensive care unit (ICU) admission (3.32), total parenteral nutrition use (7.60), moderate-to-severe kidney disease (3.34), fluconazole non-wild type (WT) isolates (105.06), and amphotericin B non-WT or multidrug-resistant (MDR) isolates (11.83). For 60-day mortality, independent risk factors were severe sepsis (3.66), ICU admission (3.44), moderate-to-severe kidney disease (2.72), fluconazole non-WT isolates (91.23), and amphotericin B non-WT or MDR isolates (8.63).
Conclusions
MDR or non-WT isolates, along with host factors such as severe sepsis, are associated with a worse prognosis in C. lusitaniae candidemia in Korea. These findings highlight the need for careful monitoring and management of high-risk patients.
Keywords: Candida lusitaniae, Candidemia, Mortality, Multidrug-resistant, Risk factors
INTRODUCTION
Candida albicans remains the most common species responsible for candidemia. However, the proportion of candidemia caused by non-albicans Candida species, including Candida lusitaniae, is increasing worldwide [1]. C. lusitaniae is a haploid, dimorphic yeast first described in 1970 [2] and one of the few Candida species undergoing a complete sexual cycle [3, 4]. C. lusitaniae accounts for 1%–3% of all candidemia cases [5–7] and ranks sixth to seventh among non-Candida species causing candidemia [5, 8]. Among non-albicans Candida species, C. lusitaniae is of particular interest because of its unusual antifungal susceptibility profile; it can rapidly acquire resistance to amphotericin B, the drug of choice for many systemic fungal infections, with some isolates exhibiting intrinsic resistance [9–11]. Additionally, C. lusitaniae can rapidly develop multidrug resistance (MDR), further complicating the management of infections caused by this species [12].
Candidemia is a serious and potentially life-threatening condition, with in-hospital all-cause mortality rates ranging from 25% to 40% worldwide [13]. Mortality varies considerably by species and is influenced by factors such as central venous catheter use, administration of total parenteral nutrition (TPN), and antifungal resistance [14–18]. However, data on the mortality and associated risk factors of C. lusitaniae candidemia remain limited because of its low incidence; most available studies are case reports or in-vitro analyses of isolates lacking clinical data [7, 9, 19–22]. We aimed to conduct the first multicenter cohort study in Korea to investigate the epidemiology and mortality-associated risk factors of C. lusitaniae candidemia over a 6-yr period (2019–2024).
MATERIALS AND METHODS
Study design and patient selection
This retrospective cohort study included patients with a first episode of C. lusitaniae candidemia from six Korean university hospitals (Asan Medical Center [Seoul], Samsung Medical Center [Seoul], Gyeongsang National University Hospital [Jinju], Wonkwang University Hospital [Iksan], Gangneung Asan Hospital [Gangneung], Kosin Gospel University Hospital [Busan]) during a 6-yr period (January 2019 to December 2024). Patients with polymicrobial BSIs or incomplete clinical data were excluded. The Institutional Review Board of Asan Medical Center approved this study (approval no. 2023-0703) and waived the requirement for informed consent because of its retrospective nature.
Demographic characteristics, laboratory parameters (such as C-reactive protein [CRP] and procalcitonin), and clinical factors potentially related to mortality at the time of candidemia onset, as described previously [23–26], were investigated. Neutropenia was defined as an absolute neutrophil count of <500/mm3. Moderate-to-severe kidney disease was defined as any of the following: i) receiving dialysis treatment, ii) post-kidney transplantation, or iii) serum creatinine >3.0 mg/dL (270 µmol/L) [27]. A high Candida score was defined as a score of ≥2 [28], and a high Charlson comorbidity index was defined as an index value of ≥10 [29]. Multifocal candidiasis was defined as the presence of Candida in more than two different foci. Previous antifungal use was defined as administration within three months prior to the onset of candidemia. Therapeutic failure was defined as either the persistence of Candida in the bloodstream or the development of breakthrough candidemia despite ≥72 h of antifungal therapy [23]. Survivors were defined as patients who were alive at hospital discharge, whereas non-survivors were those who died of any cause during their hospital stay. In addition to the overall in-hospital all-cause mortality, the all-cause mortality rates at 30 and 60 days after the first positive blood culture were assessed.
Microbiological analysis and antifungal susceptibility testing
All C. lusitaniae isolates were collected from routine blood cultures, with culture methods varying across laboratories. Initial identification was performed using matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI Biotyper; Bruker Daltonics, Bremen, Germany or VITEK MS; bioMérieux, Marcy-l’Étoile, France) or a biochemistry-based system (VITEK 2; bioMérieux). Only the first isolate from each patient was included; duplicates were excluded. All isolates were sent to the Clinical Microbiology Laboratory of Asan Medical Center for testing. Species identification was performed using MALDI Biotyper with library version 4.0, followed by sequencing of the internal transcribed spacer region and D1/D2 domains of the 26S rRNA gene for confirmation. In-vitro antifungal susceptibility was tested for four azoles (fluconazole, voriconazole, posaconazole, and itraconazole), three echinocandins (caspofungin, micafungin, and anidulafungin), amphotericin B, and 5-fluorocytosine using the Sensititre YeastOne (SYO) system (Thermo Fisher Scientific, Cleveland, OH, USA). SYO-specific epidemiological cutoff values (ECVs) for C. lusitaniae were applied for fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, micafungin, and anidulafungin, as previously reported [30, 31]. For amphotericin B, an ECV of 2 μg/mL was applied according to the CLSI guideline M57S [32]. 5-Fluorocytosine was excluded from the analysis because established ECVs were lacking. MDR isolates were defined as non-wild type (WT) to at least two different antifungal classes among fluconazole, amphotericin B, or echinocandins. Fluconazole was chosen as the representative azole because the single fluconazole non-WT isolate in our study was also non-WT to voriconazole and posaconazole, indicating true azole resistance. In contrast, isolates non-WT only to voriconazole or posaconazole were WT to fluconazole, suggesting that they did not represent true azole resistance. Echinocandin resistance was confirmed by sequencing the FKS1 hotspot regions (FKS1 HS1 and HS2), as described previously [33].
Statistical methods
Continuous variables are reported as mean and SD, and categorical variables are presented as number (%). Continuous variables were compared using Student’s t-test or the Mann–Whitney U test, and categorical variables were compared using the Pearson’s chi–squared test or Fisher’s exact test. Cox proportional hazards models were used to evaluate potential risk factors for 30- and 60-day mortality by calculating hazard ratios (HRs) and 95% confidence intervals (CIs). To avoid overfitting, variables with P<0.1 in univariate analysis were considered as candidate variables for multivariate analysis, added in a stepwise manner, and only those with significant contributions were retained in the final model. The Kaplan–Meier and log-rank (Mantel–Cox) tests were used to calculate 30- and 60-day survival probabilities in subgroup analyses. All data were analyzed using SPSS Statistics for Windows (version 31.0; SPSS, Armonk, NY, USA). Statistical significance was set to P<0.05.
RESULTS
Patient characteristics and clinical outcomes
The six hospitals included in our study are located in various regions of Korea, with a combined total of 7,558 beds, ranging from 804 to 2,432 beds per hospital. C. lusitaniae is the 5th or 6th most common species causing candidemia in these hospitals, accounting for 0.3%–3.0% of total candidemia cases. No definitive evidence of clonal transmission was observed, as all non-WT isolates from any hospital had different susceptibility profiles (Supplemental Data Table S1). Table 1 presents the overall characteristics of the 53 patients with C. lusitaniae candidemia enrolled in this study, as well as the differences between survivors and non-survivors. The mean age of the 53 patients was 62.2 yrs (SD, 16.9), and 34 patients (64.2%) were male. Chronic kidney disease was the most prevalent comorbidity (39.6%), followed by solid tumors (34.0%), diabetes (28.3%), lymphoma (18.9%), leukemia (13.2%), cerebrovascular disease (11.3%), liver disease (9.4%), and solid organ transplantation (9.4%). The mean Charlson comorbidity index was 7.1 (SD, 4.8). At the time of positive culture, 90.6% of the patients had a central venous catheter, 66.0% used a urinary catheter, 60.4% had severe sepsis, 43.4% received immunosuppressive therapy, 41.5% were in the intensive care unit (ICU), 32.1% had neutropenia, 30.2% were on TPN, and 20.8% had prior surgery. Polymicrobial infections occurred in the patients with severe sepsis; therefore, independent analysis was not possible. Prior antifungal therapy was reported in 18.9% of the patients. Antifungal therapy for C. lusitaniae candidemia was administered to 84.9% of the patients, with azoles used in 52.8%, echinocandins in 58.5%, and amphotericin B in 17.0%.
Table 1.
Demographic and clinical characteristics of the 53 patients with C. lusitaniae candidemia enrolled in this study
| Clinical characteristics | Total | Survivors | Non-survivors | P |
|---|---|---|---|---|
| Cases, N | 53 | 16 | 37 | |
| Demographics | ||||
| Age, yrs, mean±SD | 62.2±16.9 | 56.5±24.1 | 64.6±12.3 | 0.107 |
| Male, N (%) | 34 (64.2) | 10 (62.5) | 24 (64.9) | 1 |
| Clinical status at positive culture | ||||
| Prior antifungal therapy | 10 (18.9) | 3 (18.8) | 7 (18.9) | 0.307 |
| Total parenteral nutrition, N (%) | 16 (30.2) | 2 (12.5) | 14 (37.8) | 0.103 |
| Immunosuppressive therapy, N (%) | 23 (43.4) | 3 (18.8) | 20 (54.1) | 0.033 |
| Neutropenia, N (%) | 17 (32.1) | 3 (18.8) | 14 (37.8) | 0.214 |
| Prior surgery, N (%) | 11 (20.8) | 5 (31.3) | 6 (16.2) | 0.275 |
| Severe sepsis, N (%) | 32 (60.4) | 9 (56.3) | 23 (62.2) | 0.764 |
| Intensive care unit admission, N (%) | 22 (41.5) | 4 (25.0) | 18 (48.6) | 0.137 |
| Central venous catheter, N (%) | 48 (90.6) | 15 (93.8) | 33 (89.2) | 1 |
| Urinary catheter, N (%) | 35 (66.0) | 11 (68.8) | 24 (64.9) | 1 |
| Multifocal candidiasis, N (%) | 3 (5.7) | 1 (6.3) | 2 (5.4) | 1 |
| C-reactive protein, mean±SD | 10.0±7.3 | 8.0±6.9 | 10.9±7.4 | 0.192 |
| Procalcitonin, mean±SD | 1.5±1.7 | 1.8±1.3 | 1.4±1.8 | 0.608 |
| Underlying condition | ||||
| Diabetes, N (%) | 15 (28.3) | 5 (31.3) | 10 (27.0) | 0.751 |
| Liver disease, N (%) | 5 (9.4) | 3 (18.8) | 2 (5.4) | 0.155 |
| Moderate-to-severe kidney disease, N (%) | 21 (39.6) | 3 (18.8) | 18 (48.6) | 0.066 |
| Congestive heart failure, N (%) | 3 (5.7) | 2 (12.5) | 1 (2.7) | 0.213 |
| Chronic lung disease, N (%) | 3 (5.7) | 1 (6.3) | 2 (5.4) | 1 |
| Cerebrovascular disease, N (%) | 6 (11.3) | 1 (6.3) | 5 (13.5) | 0.655 |
| Solid tumors, N (%) | 18 (34.0) | 4 (25.0) | 14 (37.8) | 0.530 |
| Leukemia, N (%) | 7 (13.2) | 1 (6.3) | 6 (16.2) | 0.661 |
| Lymphoma, N (%) | 10 (18.9) | 0 (0) | 10 (27.0) | 0.023 |
| HIV/AIDS, N (%) | 0 (0) | 0 (0) | 0 (0) | N/A |
| Solid organ transplantation, N (%) | 5 (9.4) | 2 (12.5) | 3 (8.1) | 0.632 |
| High Charlson comorbidity index, N (%) | 18 (34.0) | 5 (31.3) | 13 (35.1) | 1 |
| High Candida score, N (%) | 13 (24.5) | 1 (6.3) | 12 (32.4) | 0.079 |
| Therapeutic modality | ||||
| Any antifungal therapy, N (%) | 45 (84.9) | 13 (81.3) | 32 (86.5) | 0.685 |
| Azole therapy, N (%) | 28 (52.8) | 8 (50.0) | 20 (54.1) | 1 |
| Echinocandin therapy, N (%) | 31 (58.5) | 9 (56.3) | 22 (59.5) | 1 |
| Amphotericin B therapy, N (%) | 9 (17.0) | 2 (12.5) | 7 (18.9) | 0.706 |
| Outcome | ||||
| Therapeutic failure, N (%) | 28 (52.8) | 11 (68.8) | 17 (45.9) | 0.147 |
| Duration of hospital stay | ||||
| Before candidemia onset, mean±SD | 32.6±42.5 | 34.8±64.5 | 31.7±29.5 | 0.813 |
| After candidemia onset, mean±SD | 30.4±38.1 | 44.7±48.5 | 24.3±31.5 | 0.073 |
| Isolates | ||||
| Fluconazole non-WT, N (%) | 1 (1.9) | 0 (0) | 1 (2.7) | 1 |
| Voriconazole non-WT, N (%) | 10 (18.9) | 1 (6.3) | 9 (24.3) | 0.250 |
| Posaconazole non-WT, N (%) | 7 (14.9) | 3 (23.1) | 4 (11.8) | 0.377 |
| Caspofungin non-WT, N (%) | 3 (5.7) | 0 (0) | 3 (8.1) | 0.545 |
| Micafungin non-WT (%) | 3 (5.7) | 1 (6.3) | 2 (5.4) | 1 |
| Anidulafungin non-WT (%) | 2 (3.8) | 0 (0) | 2 (5.4) | 1 |
| Amphotericin B non-WT, N (%) | 2 (3.8) | 0 (0) | 2 (5.4) | 1 |
| MDR*, N (%) | 2 (3.8) | 0 (0) | 2 (5.4) | 1 |
*Two isolates that were non-WT to both echinocandins and amphotericin B were defined as MDR.
Abbreviations: WT, wild type; N/A, not applicable; MDR, multidrug-resistant.
Therapy failed in 52.8% of the patients. Thirty-seven patients (69.8%) died during hospitalization, and the 30- and 60-day mortality rates were 39.6% and 47.2%, respectively. When comparing the baseline characteristics, therapeutic modalities, and clinical outcomes between survivors and non-survivors during hospital stay, the non-survivor group had a significantly higher proportion of patients with lymphoma or those receiving immunosuppressive therapy. However, there were no significant differences in CRP or procalcitonin levels at candidemia onset, other immunocompromised conditions such as HIV/AIDS or solid organ transplantation, or duration of hospital stay before candidemia onset. The proportions of non-WT isolates based on SYO-specific or the CLSI ECVs are presented in Supplemental Data Table S2. Among the 46 available isolates, one (2.2%), zero (0.0%), nine (19.6%), and seven (15.2%) were non-WT to fluconazole, itraconazole, voriconazole, and posaconazole, respectively. Four isolates (7.5%) were non-WT to at least one echinocandin, three of which harbored nonsynonymous substitutions (H657Y, L1334F, and I1374V) outside the two FKS1 hotspot regions. All four isolates were WT to fluconazole, but two were non-WT to amphotericin B, and therefore, classified as MDR.
Risk factors for 30- and 60-day mortality
Univariate Cox regression analyses revealed that the following factors were significantly associated with 30-day mortality: presence of a urinary catheter (HR, 4.13; P=0.023), severe sepsis (2.78; P=0.047), ICU admission (2.58; P=0.037), TPN use (3.34; P=0.006), leukemia (3.58; P=0.009), moderate-to-severe kidney disease (2.46; P=0.042), fluconazole non-WT (51.4; P=0.005), caspofungin non-WT (6.11; P=0.007), anidulafungin non-WT (7.82; P=0.008), amphotericin B non-WT (7.82; P= 0.008), and MDR (7.82; P=0.008) (Table 2). Multivariate Cox regression analyses revealed that severe sepsis (adjusted HR, 9.02; P=0.008), ICU admission (3.32; P=0.04), TPN use (7.6, P=0.018), moderate-to-severe kidney disease (3.34; P=0.022), fluconazole non-WT (105.06; P=0.004), and amphotericin B non-WT or MDR isolates (11.83; P=0.012) were independent risk factors for 30-day mortality (Table 2).
Table 2.
Results of univariate and multivariate Cox regression analyses performed to identify risk factors for 30-day mortality in patients with C. lusitaniae candidemia
| Factors | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | ||
| Male sex | 0.69 (0.42–1.15) | 0.155 | |||
| Age | 1.00 (0.97–1.04) | 0.846 | |||
| Presence of central venous catheter | 24.56 (0.08–7822.00) | 0.276 | |||
| Presence of urinary catheter | 4.13 (1.21–14.07) | 0.023 | |||
| Severe sepsis | 2.78 (1.02–7.60) | 0.047 | 9.02 (1.76–46.41) | 0.008 | |
| ICU admission | 2.58 (1.06–6.26) | 0.037 | 3.32 (1.05–10.46) | 0.040 | |
| Prior surgery | 1.19 (0.44–3.25) | 0.735 | |||
| Total parenteral nutrition | 3.34 (1.41–7.92) | 0.006 | 7.60 (1.41–40.86) | 0.018 | |
| Immunosuppressive therapy | 1.15 (0.49–2.71) | 0.749 | |||
| C-reactive protein | 1.05 (1.00–1.11) | 0.076 | |||
| Procalcitonin | 0.90 (0.65–1.26) | 0.545 | |||
| Solid organ transplantation | 1.77 (0.52–6.03) | 0.364 | |||
| Hospital stay before candidemia | 1.00 (0.99–1.01) | 0.864 | |||
| High Charlson comorbidity index >10 | 0.98 (0.39–2.42) | 0.961 | |||
| High Candida score >2 | 2.32 (0.96–5.63) | 0.062 | |||
| Neutropenia | 1.84 (0.77–4.38) | 0.168 | |||
| Multifocal candidiasis | 0.21 (0.01–8.16) | 0.404 | |||
| Lymphoma | 1.58 (0.58–4.33) | 0.371 | |||
| Leukemia | 3.58 (1.37–9.36) | 0.009 | |||
| Tumor | 0.57 (0.21–1.57) | 0.279 | |||
| Diabetes | 1.22 (0.49–3.03) | 0.664 | |||
| Moderate-to-severe kidney disease | 2.46 (1.03–5.85) | 0.042 | 3.34 (1.19–9.36) | 0.022 | |
| Chronic liver disease | 0.42 (0.06–3.11) | 0.394 | |||
| Chronic lung disease | 0.83 (0.11–6.20) | 0.858 | |||
| Cerebrovascular disease | 0.71 (0.17–3.06) | 0.647 | |||
| Prior antifungal exposure | 2.44 (0.94–6.34) | 0.068 | |||
| Prior azole exposure | 3.91 (0.49–31.57) | 0.200 | |||
| Prior echinocandin exposure | 2.11 (0.77–5.79) | 0.146 | |||
| Any antifungal therapy | 0.86 (0.25–2.92) | 0.809 | |||
| Azole therapy | 0.54 (0.23–1.28) | 0.159 | |||
| Echinocandin therapy | 1.09 (0.45–2.63) | 0.852 | |||
| Amphotericin B therapy | 1.09 (0.37–3.23) | 0.883 | |||
| Any therapeutic failure | 0.74 (0.32–1.75) | 0.494 | |||
| Fluconazole non-WT | 51.4 (3.22–823.30) | 0.005 | 105.06 (4.47–2466.99) | 0.004 | |
| Caspofungin non-WT | 6.11 (1.70–21.972) | 0.006 | |||
| Micafungin non-WT | 2.66 (0.62–11.48) | 0.189 | |||
| Anidulafungin non-WT | 7.82 (1.73–35.40) | 0.008 | |||
| Amphotericin B non-WT | 7.82 (1.73–35.40) | 0.008 | 11.83 (1.72–81.24) | 0.012 | |
| MDR* isolates | 7.82 (1.73–35.40) | 0.008 | 11.83 (1.72–81.24) | 0.012 | |
*Two isolates that were non-WT to both echinocandins and amphotericin B were defined as MDR.
Abbreviations: HR, hazard ratio; CI, confidence intervals; WT, wild type; MDR, multidrug-resistant; ICU, intensive care unit.
Table 3 summarizes the univariate and multivariate Cox regression results for 60-day mortality. In addition to the risk factors for 30-day mortality, high CRP level (HR, 1.06; P=0.032) was associated with 60-day mortality in univariate Cox regression analyses. Multivariate Cox regression analyses revealed that severe sepsis (adjusted HR, 3.66; P=0.035), ICU admission (3.44; P=0.019), moderate-to-severe kidney disease (2.72; P=0.039), fluconazole non-WT (91.23; P=0.004), and amphotericin B non-WT or MDR isolates (8.63; P=0.022) were independent risk factors for 60-day mortality (Table 3).
Table 3.
Results of univariate and multivariate Cox regression analyses performed to identify risk factors for 60-day mortality in patients with C. lusitaniae candidemia
| Factors | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | ||
| Male sex | 0.76 (0.49–1.18) | 0.222 | |||
| Age | 1.00 (0.98–1.04) | 0.615 | |||
| Presence of central venous catheter | 3.54 (0.48–26.25) | 0.216 | |||
| Urinary catheter | 3.90 (1.33–11.43) | 0.013 | |||
| Severe sepsis | 2.30 (0.96–5.53) | 0.062 | 3.66 (1.10–12.26) | 0.035 | |
| ICU admission | 3.11 (1.36–7.10) | 0.007 | 3.44 (1.22–9.68) | 0.019 | |
| Prior surgery | 1.21 (0.48–3.02) | 0.690 | |||
| Total parenteral nutrition | 3.18 (1.43–7.07) | 0.005 | |||
| Immunosuppressive therapy | 1.38 (0.63–3.04) | 0.417 | |||
| C-reactive protein | 1.06 (1.01–1.12) | 0.032 | |||
| Procalcitonin | 1.01 (0.80–1.28) | 0.932 | |||
| Solid organ transplantation | 1.50 (0.45–5.03) | 0.514 | |||
| Hospital stay before candidemia | 1.00 (0.99–1.01) | 0.693 | |||
| High Charlson comorbidity index >10 | 0.94 (0.41–2.18) | 0.887 | |||
| High Candida score >2 | 2.70 (1.21–6.04) | 0.016 | |||
| Neutropenia | 1.65 (0.74–3.69) | 0.219 | |||
| Multifocal candidiasis | 0.71 (0.26–1.92) | 0.497 | |||
| Lymphoma | 1.96 (0.82–4.69) | 0.132 | |||
| Leukemia | 3.24 (1.27–8.28) | 0.014 | |||
| Tumor | 0.70 (0.29–1.69) | 0.430 | |||
| Diabetes | 1.19 (0.51–2.76) | 0.686 | |||
| Moderate-to-severe kidney disease | 2.45 (1.11–5.42) | 0.026 | 2.72 (1.05–7.05) | 0.039 | |
| Chronic liver disease | 0.33 (0.05–2.45) | 0.279 | |||
| Chronic lung disease | 0.71 (0.10–5.22) | 0.733 | |||
| Cerebrovascular disease | 0.95 (0.28–3.16) | 0.929 | |||
| Prior antifungal exposure | 2.02 (0.80–5.11) | 0.137 | |||
| Prior azole exposure | 3.91 (0.49–31.57) | 0.200 | |||
| Prior echinocandin exposure | 1.75 (0.66–4.69) | 0.263 | |||
| Any antifungal therapy | 1.09 (0.327–3.67) | 0.883 | |||
| Azole therapy | 0.66 (0.30–1.44) | 0.296 | |||
| Echinocandin therapy | 1.00 (0.45–2.24) | 0.992 | |||
| Amphotericin B therapy | 1.16 (0.44–3.10) | 0.764 | |||
| Any therapeutic failure | 0.64 (0.29–1.40) | 0.260 | |||
| Fluconazole non-WT | 51.4 (3.22–823.30) | 0.005 | 91.23 (4.26–1953.73) | 0.004 | |
| Caspofungin non-WT | 6.11 (1.70–21.97) | 0.006 | |||
| Micafungin non-WT | 2.24 (0.53–9.51) | 0.276 | |||
| Anidulafungin non-WT | 7.82 (1.73–35.40) | 0.008 | |||
| Amphotericin B non-WT | 7.82 (1.73–35.40) | 0.008 | 8.63 (1.37–54.49) | 0.022 | |
| MDR* isolates | 7.82 (1.73–35.40) | 0.008 | 8.63 (1.37–54.49) | 0.022 | |
*Two isolates that were non-WT to both echinocandins and amphotericin B were defined as MDR.
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence intervals; WT, wild type; MDR, multidrug-resistant; ICU, intensive care unit.
Impact of antifungal resistance on survival
Table 4 describes the clinical and microbiological characteristics of antifungal-resistant isolates. Four of five patients with antifungal-resistant isolates died within 2 weeks of candidemia onset, and three of them were immunocompromised or in septic condition on ICU admission. Four patients experienced breakthrough infections: two were non-WT to only echinocandins, and two were non-WT to both amphotericin B and echinocandins. One patient with a fluconazole non-WT isolate died without receiving any antifungal therapy. The only immunocompetent patient, who developed catheter-related candidemia caused by a micafungin non-WT isolate, survived with fluconazole therapy. The mean survival of candidemia patients with non-WT to fluconazole was significantly shorter than that of those with WT (non-WT vs. WT to fluconazole, 1.0 days vs. 466.4 days, log-rank test, P<0.001). The mean survival of candidemia patients with non-WT to echinocandin was significantly shorter than that of those with WT (non-WT vs. WT to echinocandin, 5.5 days vs. 438.7 days, log-rank test, P=0.002). The mean survival of candidemia patients with non-WT to amphotericin B or MDR isolates was significantly shorter than that of those with WT (non-WT vs. WT to amphotericin B, 5.5 days vs. 475.6 days, log-rank test, P=0.001).
Table 4.
Clinical and microbiological characteristics of antifungal-resistant C. lusitaniae bloodstream isolates
| Isolate No. | Isolate 19 | Isolate 1 | Isolate 25 | Isolate 11 | Isolate 26 |
|---|---|---|---|---|---|
| Isolate information | |||||
| Hospital | Hospital D | Hospital E | Hospital D | Hospital E | Hospital D |
| Collection date | July 2022 | November 2023 | December 2023 | May 2021 | June 2024 |
| Azole (Flu/Itra/Vor/Posa) MICs, µg/mL | 16/0.5/0.5/0.5 | 1/0.25/0.03/0.25 | 0.25/0.06/0.015/0.03 | 1/0.25/0.03/0.12 | 0.25/0.12/0.015/0.12 |
| Echinocandin (Caspo/Mica/Anidula) MICs, µg/mL | 0.5/0.12/0.12 | 1/0.25/0.25 | 2/0.12/0.25 | 2/2/0.5 | 2/1/0.5 |
| AMB MIC, µg/mL | 0.5 | 2 | 1 | 4 | 4 |
| Resistance (azoles/echinocandins/AMB) | R/S/S | S/R/S | S/R/S | S/R/R | S/R/R |
| FKS1 mutation | Not tested | H657Y, L1334F, I1374V | H657Y, L1334F | Not detected | H657Y, L1334F |
| Patient information | |||||
| Age/sex | 40/M | 76/F | 46/M | 79/F | 50/M |
| Underlying diseases | DLBCL | Catheter-related blood stream infection | DLBCL, s/p liver transplantation | Liver graft versus host disease, s/p liver transplantation | Infective endocarditis, septic shock |
| Solid organ transplantation/neutropenia/immunosuppressive therapy | No/Yes/Yes | No/No/No | Yes/Yes/Yes | Yes/Yes/Yes | No/No/No |
| TPN/urinary cath/CVC | Yes/Yes/Yes | No/No/Yes | Yes/Yes/Yes | Yes/Yes/Yes | Yes/Yes/Yes |
| ICU admission/concomitant bacteremia | No/No | No/No | Yes/Yes | Yes/Yes | Yes/Yes |
| Hospital stay before candidemia (days) | 25 | 4 | 23 | 94 | 51 |
| Antifungal therapy | No treatment | Mica 50 mg (D–3 to D+3), Flu 400 mg (D+4 to D+10) | Caspo 50 mg (D–20 to D–6, D–1 to D+2), L-AMB 270 mg (D+2~D+10) | AMB 50 mg (D–4 to D+1), Vor 200 mg (D+2 to D+6) | Anidula 100 mg (D–23 to D0) |
| Outcome | Death (D+1) | Survive | Death (D+12) | Death (D+11) | Death (D0) |
Abbreviations: AMB, amphotericin B; Anidula, anidulafungin; Caspo, caspofungin; cath, catheter; CVC, central venous catheter; DLBCL, diffuse large B-cell lymphoma; Flu, fluconazole; ICU, intensive care unit; Itra, itraconazole; MIC, minimum inhibitory concentration; Mica, micafungin; Posa, posaconazole; s/p, status post; TPN, total parenteral nutrition; Vor, voriconazole.
DISCUSSION
C. lusitaniae is an emerging non-albicans Candida species associated with breakthrough candidemia and high mortality; however, multicenter data remain limited. In this multicenter cohort study across six Korean university hospitals, we identified C. lusitaniae candidemia and characterized its epidemiologic and clinical features. The infections occurred mainly in patients with chronic kidney disease and solid tumors, and TPN use was found to be an independent risk factor. To the best of our knowledge, this is the first report of C. lusitaniae candidemia in a multicenter cohort in Korea. A previous study investigating 13 C. lusitaniae candidemia at a single institution reported that hematological malignancies were the most prevalent comorbidity and stem cell transplantation and neutropenia were independent factors in C. lusitaniae candidemia patients [34]. These findings suggest that the host factors associated with C. lusitaniae candidemia may differ according to the study cohort (e.g., number or composition of patients).
C. lusitaniae fungemia is reportedly more likely to be persistent than C. albicans fungemia [34]. In our cohort, therapeutic failure was frequently observed (52.8% of cases), in line with previous findings [34, 35]. Virulence factors of C. albicans, including cell wall barriers, adherence, dimorphism, biofilm formation, stress tolerance proteins, hydrolytic enzymes, and toxin production, have been well studied [36]. In contrast, virulence factors in C. lusitaniae remain largely obscure. One recent study reported that C. lusitaniae isolates featured adherence and biofilm formation that showed interspecies variability [37]. Adherence contributes to persistence within the host and is, therefore, considered essential for fungal colonization and dissemination [38]. In our cohort, 90.6%, 66.0%, and 30.2% of patients had a central venous or urinary catheter or used TPN, respectively. C. lusitaniae biofilm formation on central venous and indwelling urinary catheters has been documented [39]. This ability may contribute to persistent colonization within the host and the development of bloodstream infection.
Mortality rates associated with C. lusitaniae candidemia vary across studies, with all-cause mortality rates ranging from 5% to >60% [6, 7, 20, 34, 35]. In our study, the overall in-hospital all-cause mortality rate was 69.8%, whereas the 30-day mortality rate was 39.6%, comparable to previously reported rates of 38%–53% [34, 35]. Immunocompromised or septic status on ICU admission is a major factor influencing the prognosis of candidemia. We found that non-WT isolates can emerge as breakthrough infections under immunocompromised conditions, potentially representing a risk factor for mortality in C. lusitaniae candidemia. Notably, three patients with candidemia caused by echinocandin non-WT isolates harboring nonsynonymous substitutions (i.e., H657Y, L1334F, and I1374V) outside the two FKS1 hotspot regions experienced breakthrough during echinocandin therapy, supporting non-response to these drugs. Of the four isolates that were non-WT to echinocandins, two were also non-WT to amphotericin B, and candidemia caused by these MDR isolates resulted in fatal outcomes. Increased drug resistance has been associated with various virulence factors in Candida [40]. Our study showed that the use of the SYO system for voriconazole and posaconazole susceptibility testing in C. lusitaniae may lead to an overestimation of minimum inhibitory concentrations. Although SYO-specific ECVs were applied, the non-WT rates for voriconazole and posaconazole were 19.6% and 15.2%, respectively; however, all but one isolate were WT to fluconazole, suggesting that these do not represent true azole-resistant isolates. These findings indicate that when using the SYO system for azole susceptibility testing in C. lusitaniae, it is important to apply SYO-specific ECVs and evaluate cross-resistance to other azoles and, when necessary, confirm resistance using molecular methods.
A major limitation of our study is its retrospective design and the small number of C. lusitaniae candidemia cases collected from six Korean university hospitals; therefore, our observations may not fully reflect the nationwide or global reality. Nevertheless, the increasing use of fluconazole and echinocandins may increase the incidence of candidemia caused by non-albicans Candida species such as C. lusitaniae, which is often associated with breakthrough infections and high mortality. Notably, this multicenter study provided fundamental epidemiological data on C. lusitaniae candidemia in Korea. Our findings highlight the need for careful monitoring and management of patients at risk, particularly those infected with MDR strains, to improve survival rates in patients with infections caused by this emerging pathogen. Further prospective study incorporating a larger cohort may be essential to better understand the epidemiological changes of C. lusitaniae candidemia.
ACKNOWLEDGEMENTS
We are grateful to all members of the Tropical Medicine Study Group of the Korean Society of Clinical Microbiology for their valuable contributions to this study.
SUPPLEMENTARY MATERIALS
Supplementary materials can be found via https://doi.org/10.3343/alm.2025.0320.
Footnotes
AUTHOR CONTRIBUTIONS
Won EJ, Kim TY, and Byun JH had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; Liu C, Yang D, Lee HS, Sung H, and Kim M were responsible for data acquisition, analysis, and interpretation; Liu C, Yang D, Lee HS, and Won EJ were responsible for the statistical analysis; Won EJ, Kim TY, and Byun JH were responsible for the drafting of the manuscript. All authors reviewed and approved the final manuscript.
CONFLICTS OF INTEREST
None declared.
RESEARCH FUNDING
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF- 2022R1C1C 1002741).
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