We performed a retrospective 1:3 matched case-control study. The study was conducted at the Seoul National University Hospital, a tertiary care center in Korea. Seoul National University Hospital has 5 ICUs: a medical ICU, a surgical ICU (for patients who underwent abdominal and orthopedic surgery), an emergency ICU (for patients who presented at the emergency room), a pediatric ICU (for patients <15 yr old), and a cardio-pulmonary ICU (for patients who underwent thoracic surgery). We studied patients who were admitted to the MICU. The MICU has 22 beds and admits medical and neurological patients. All patients in the MICU were ≥15 yr old. The duration of the study was 6 yr and 7 months (1 January 2000 to 31 July 2006).

Nosocomial candidemia was defined as one or more blood cultures positive for Candida species at least 48 hr after admission. Blood cultures were tested routinely if a patient's temperature was greater than 38℃. The onset of candidemia was defined as the date on which the first positive blood culture was detected. In-hospital mortality was defined as death during the same period of hospitalization.

Hemodynamic instability was defined as systolic blood pressure (BP) <90 mmHg, diastolic BP <60 mmHg, mean arterial BP <70 mmHg, or administration of a vasopressor on admission to the ICU. Patients were considered as having neutropenia if their absolute neutrophil count was <500 cells/mm³ on admission to the ICU. Acute renal failure was defined as a 0.5 mg/dL increase in serum creatinine level on admission to the ICU. Hepatic failure was defined as aspartate aminotransferase (AST) level >200 IU/L, alanine aminotransferase (ALT) level >200 IU/L, albumin level <3.0 g/dL, and prothrombin INR >2.0 on admission to the ICU. Central venous catheters (including internal jugular venous catheters, Hickman catheters, Swan-Ganz catheters, or femoral catheters), nasogastric tubes, and Foley catheters were considered risk factors for candidemia if they were used for more than 3 days before the onset of candidemia. Previous total parenteral nutrition (TPN), transfusion with any blood product, including red blood cells, platelets and fresh, frozen plasma, gastrointestinal (GI) bleeding, and steroid therapy were regarded as risk factors for candidemia when they occurred within 2 weeks of the onset of candidemia (15). Steroid therapy was defined as administration of ≥10 mg/day of prednisolone (or the equivalent dose of an alternative corticosteroid) or administration of <10 mg/day of prednisolone or its equivalent for more than 7 days. The use of immunosuppressive agents was defined as the administration of chemotherapeutic or antirheumatic agents within 2 weeks of the onset of candidemia (15). An immunocompromised state was defined as the presence of a malignancy or the use of immunosuppressive agents during the same admission. Candida colonization was defined as a Candida species-positive culture of a sputum, urine, or fecal sample collected at any time before the onset of candidemia.

Control patients were selected from patients who did not have candidemia and were admitted to the MICU at about the same time as the candidemia patients. Control patients had no evidence of bacterial or fungal growth in blood cultures at any time during their hospitalization in the MICU. Control patients were selected according to the following matching criteria: sex, age (±5 yr), and an Acute Physiology and Chronic Health Evaluation (APACHE) II score (16) of at least 5 on the day of admission to the MICU.

Continuous variables are expressed as the mean±standard deviation or as the median and interquartile range. Patient characteristics were compared between groups using the Mann-Whitney test for continuous variables and the chi-square test for categorical variables. To identify risk factors independently associated with candidemia, variables that were significant according to a univariate analysis were subjected to binary logistic regression analysis. A P value <0.05 was considered significant. Kaplan-Meier survival curves were compared using the log-rank test. All statistical analyses were performed using SPSS software, version 12.0 (SPSS Inc., Chicago, IL, USA).

During the study period, 52 of 5,383 MICU admissions were identified as having fungemia. Three patients were infected with species other than Candida (1 patient was positive for Aspergillus species and 2 patients were positive for Trichosporon beigelli). Therefore, we analyzed data from 49 patients.

The incidence of candidemia in the MICU was 9.1 per 1,000 admissions. The mean age of the patients was 57.6±14.1 yr. There were more men than women in the sample (28:21). Among the candidemia patients, there was no significant difference in APACHE II score between the day of admission to the ICU and the day of onset of candidemia (23.8±7.7 vs. 23.3±6.4, respectively; P=0.473).

Albicans was the predominant Candida species (32 cases, 65%); non-albicans Candida species accounted for 35% of infections (13 patients [27%] were infected with C. tropicalis, 3 patients [6%] were infected with C. parapsilosis, and 1 patient [2%] was infected with C. glabrata). Thirty-five patients (71%) were treated with an antifungal agent: amphotericin B was administered to 25 patients and fluconazole was administered to 10 patients. Eight of the 35 patients were treated with an antifungal agent before candidemia was diagnosed. The median duration of antifungal treatment was 11 days (range, 1-45 days). Bacteremia was present before diagnosis of candidemia in 20 patients (41%). Various causative organisms of bacteremia were detected: Clostridium perfringens, Escherichia coli, Enterobacter cloacae, Enterococcus faecium, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Staphylococcus epidermidis. The median duration of antibiotic use before the onset of candidemia was 16 days (range, 1-92 days). All patients were treated with antibiotics before the onset of candidemia.

There were no significant differences in demographic characteristics or underlying diseases between the candidemia patients and the controls, except for the presence of malignancy (Table 1). Malignancy was more prevalent in patients with candidemia than in the control patients (P=0.048). This difference was not associated with solid malignancies (12 candidemia patients [25%] vs. 35 control patients [24%]; P=0.923) but with hematological malignancies (18 candidemia patients [37%] vs. 31 control patients [21%]; P=0.028). The dialysis method used for patients with chronic renal failure did not differ between the 2 groups. Patients with candidemia had longer stays in hospital and in the MICU compared with the control group, but there was no difference in their pre-ICU hospital stays (Table 1). Patients with candidemia were mechanically ventilated for a longer period during their total MICU stay than the controls (P=0.001) and had a longer MICU stay than the controls (P=0.001). At the time of MICU admission, patients with candidemia were more hemodynamically unstable than the controls (P<0.001).

Univariate analysis identified 8 variables that differed significantly between the candidemia patients and the controls (Table 2). These were central venous catheterization, candida colonization, an immunocompromised state, previous steroid therapy, transfusion, TPN, hepatic failure, and neutropenia on MICU admission. Multivariate analysis of these 8 variables using logistic regression revealed that central venous catheterization, previous steroid therapy, transfusion during the same admission, and hepatic failure on MICU admission were independent risk factors for candidemia (Table 3).

In-hospital mortality was 96% (47 of 49 patients) for patients with candidemia and 52% (77 of 147 patients) for control patients with odds ratio (OR) 21.4 (95% confidence interval [CI] 5.0-91.2). The significance of this difference in mortality rate was confirmed using Kaplan-Meier survival curves (P=0.024; Fig. 1).