Patient characteristics
Table 1 outlined the baseline characteristics of recruited patients. The median age of these patients was 66 years (IQR, 53.0-75.5), and 64.1% (193/301) were male. 66.4% (200/301) of all candidemia occurred at an age of elder than 60 years old. The proportion of patients over 60 years of age with C. non-albicans candidemia was lower than that with C. albicans candidemia (60.9% vs 72.9%, P<0.05). The majority of patients with candidemia were from ICU (64.5%), followed by surgical wards (20.9%) and medical wards (14.6%), and 91.0% (274/301) of these candidemia were nosocomial infection. In terms of comorbidities, gastrointestinal (GI) disease (31.9%), solid tumor (23.6%), diabetes mellitus (18.3%) were common complications. A lower proportion of diabetes mellitus (13.0% vs. 24.5%, P<0.05) and GI diseases (26.1% vs. 28.6%, P<0.05) were observed in C. non-albicans candidemia, but more of hematological malignancies (6.8% vs. 0.7%, P<0.05) in comparison with C. albicans candidemia. There were no statistical significances between the two group in terms of CCI score, APACHE II score and SOFA score among all patients (all P>0.05) (Table 1). The percentage of antibiotic exposure before the onset of candidemia was up to 86.0%, followed by parenteral nutrition (TPN) and surgery with more than 50%. Compared to C. albicans candidemia, patients with C. non-albicans candidemia had a lower rate of surgery (47.2% vs. 67.9%, P<0.001), especially for abdominal surgery (14.3% vs. 34.3%, P<0.001). This result was consistent with the fact that most C. albicans candidemia were from surgical wards (26.4% vs. 16.1%, P<0.05). In contrast, patients with C. non-albicans candidemia were more exposed to antifungal drugs (12,4% vs. 4.3%, P<0.05). In addition, more than 70% of patients with candidemia had invasive procedures such as central venous catheter (CVC), urinary catheter, and gastric catheter. Compared with the catheterization of C. albicans candidemia, indwelling arterial catheter and CVC were less in patients with C. non-albicans candidemia (26.7% vs. 39.3%, 67.1% vs. 84.3% respectively, both P<0.05), and so did abdominal drainage tube indwelling (13.7% vs. 32.1%, P<0.001). However, presence of peripherally inserted central catheter (PICC) was more frequent in C. non-albicans candidemia (24.8% vs. 10.7%, P<0.05).
Biological parameters
In terms of biological parameters, patients with C. non-albicans candidemia had a higher percentage of white blood cell (WBC) count less than 4×109 /L (16.8% vs. 5.0%, P=0.001), a lower neutrophil count (NC) (median × 109/L, 7.0 vs. 8.6), a lower neutrophil to lymphocyte ratio (NLR) (median, 9.2 vs. 12.3), and a lower value of total bilirubin (TB) (median μmol/L, 15.0 vs. 18.5) (all P<0.05) in comparison with C. albicans candidemia (Table 2).
Independent risk factors for C. non-albicanscandidemia
Several variables with a significant P<0.05 level in univariate analysis were described in Table 4. After multivariate regression model analysis of these variables, prior antifungal exposure as a factor was independently associated with an increased risk of C. non-albicans candidemia (aOR, 0.312; 95% CI, 0.113-0.859). In terms of diabetes mellitus, it had higher risk in C. albicans candidemia than C. non-albicans candidemia (aOR, 2.267; 95% CI, 1.186-4.334).
Species distribution
A total of 301 patients with candidemia were recruited in this study, composed of C. albicans candidemia (46.5%) and C. non-albicans candidemia (53.5%). In C. non-albicans candidemia, the main species were C. tropicalis,C. parapsilosis and C. glabrata, accounting for 23.9%, 15.6%, and 10.3%, respectively. In terms of 12 hematological malignancy patients with candidemia, more than 90% (11/12) were caused by C. non-albicans, especially for C. tropicalis (10/12, 83.3%). The specific distribution of Candida species was shown inTable 7 and Figure 2.
In vitro susceptibilities
As seen from Table 4, C. non-albicans in patients with candidemia displayed higher resistance to common antifungal drugs than C. albicans. Particularly, C.tropicalis had high resistance rates to clotrimazole (68.6%), itraconazole (45.6%), fluconazole (50.0%), voriconazole (56.5%), whereas they were all less than 3% for C. albicans to these above four drugs. Both C. albicans and C. non-albicans showed a low resistance (less than 2.0%) to amphotericin B (Table 4).
In general, the resistance rate to ketoconazole (26.6%) was highest, followed by clotrimazole (23.5%), fluconazole (14.5%), and voriconazole (13.1%) (Table 5). In terms of specific azoles, they showed differences dependent on different species of Candida. C. albicans were sensitive to azoles, but that was apparently not the case for C. non-albicans as most of them were resistant to these azoles like fluconazole, voriconazole, and clotrimazole with a high rate of more than 50% (Table 5). Of note, 14.6% (44/301) of patients with candidemia occurred cross-resistance, especially for C. tropicalis among which the cross-resistance to azoles was as high as 50.0% (36/72). Among hematologic malignancies patients with C. tropicalis, the cross-resistance rate was even up to 90% (9/10) (Table 7). Besides C. tropicalis, C. glabrata was more prone to cross-resistance (9.7%) (Table 7). .
Clinical therapy
The details about clinical features and treatments at the onset of candidemia were shown in Table 6, which indicated significant differences in renal replacement therapy, source of infection (intra-abdomem), and antifungal resistance between the two types of candidemia. 10.6% of patients with C. non-albicans received renal replacement therapy, which was almost three times of patients with C. albicans (P=0.020). The mainly identified source of candidemia was from catheter-related candidemia (33.2%, 100/301) and from intra-abdominal infection (13.0%, 39/301), whereas 42.9% (129/301) candidemia were considered as primary infection as no obvious infection sources were confirmed. In further comparison, patients with C. non-albicans candidemia had less intraperitoneal source than patients with C. albicans candidemia (9.3% vs. 17.1%, P=0.044). In terms of source control, the percentage of catheter removal within 48h in all patients with indwelling catheters was 73.0% (73/100), though no statistical difference was found between these two groups. Regarding adequate antifungal treatment, the ratio of it in patients with C. non-albicans candidemia was similar to that in patients with C. albicans candidemia (31.7% vs. 34.1%, P>0.05), but both of them were below 50%. In addition, pyrroles antifungal agents were more used in patients with C. non-albicans, while echinocandins antifungal agents were more frequently applied for C. albicans (Table 6).
Outcomes
In patients with candidemia, the ICU length of stay was 14 days (IQR, 1.0-38.0), and the total length of hospitalization was 35 days (IQR, 19.3-65.0) (Table 8). Patients with C. non-albicans candidemia had a longer ICU stay and a longer total hospitalization in comparison with C. albicans candidemia [median days, 15.0(0.5-46.0) vs. 14.0(2.0-33.8), P=0.406; 37.5(20.2-70.0) vs. 34.0(19.0-60.0), P=0.303], but they did not obtain a statistical significance. Furthermore, no significant differences were noted about the mortalities of 14 days, 28 days and 60 days between these two groups, which were consistent with the result of survival curve (Figure 3).