We conducted a retrospective before-and-after study to evaluate the effects of the implementation of the EFTC protocol in the medical and surgical intensive care unit (ICU) and the departments of Hemato-Oncology and General Surgery in a tertiary center in Jeju Province in South Korea between January 2013 and December 2018. The study protocol was approved by the Institutional Review Board of Jeju National University Hospital (JNUH 17-12-001). Informed consent was waived because the study was based on a retrospective review of clinical and laboratory records.

To be eligible for inclusion in the study, patients had to have been > 18 years and to have been admitted to the hospital with candidemia. We excluded patients with other fungus and Candida species from other specimen such as sputum, urine, and wound. In addition, patients admitted from August 2015 onward had to have been treated according to the EFTC protocol.

The EFTC protocol included an automatic notification “Blood culture: yeast” by short message service (SMS) from the Department of Laboratory Medicine to the responsible physician’s cellular phone; standardized education about the importance for early antifungal treatment of candidemia by an infection control specialist every 6 months; and feedback to the relevant healthcare workers, such as doctors and nurses, in the departments of Hemato-Oncology and General Surgery, and the ICUs about antifungal coverage rate, adequate empirical antifungal drug, time from blood culture to antifungal drug administration, and time from yeast alert to antifungal drug administration. On receiving the SMS notification, the physician immediately prescribed an 800 mg loading dose of intravenous fluconazole, followed by intravenous 400 mg daily (in patients with normal renal function), followed by consultation with an infection control specialist (Fig. 1).

Blood cultures were performed using the Bact/Alert 3D system (bioMérieux Inc., Marcy l’Étiole, France), and the cultures were incubated for 24 to 48 hours and then inoculated onto blood agar. Colonies were collected from the plates for identification using an automated system (VITEK II, bioMérieux). Clinical data from the patients were obtained using a structured case report form, which included demographics, underlying diseases, diagnosis, results of laboratory tests, drug susceptibility tests of Candida species, antifungal drug treatment, duration of hospitalization, Multiple Organ Dysfunction Score (MODS), Charlson comorbidity index (CCI), Candida score, time to initiation of fluconazole after the notification alert had been sent to physicians (in the post-EFTC group), and 30-day mortality.

A calculation of the antifungal coverage rate was included as the antifungal drugs of fluconazole, echinocandin, amphotericin B deoxycholate, and lipid formulations of amphotericin B in the pre-EFTC group. In the postEFTC group, it included the antifungal drug of fluconazole. Adequate empirical fluconazole therapy for candidemia was defined as initiation of fluconazole therapy after identification of candidemia, at a dose ≥ 400 mg/day (in individuals with normal renal function), and isolation of an organism from the Candida genus that was determined to be sensitive to fluconazole on the basis of an in vitro susceptibility test. Time from blood culture to antifungal drug administration was defined as the number of days from the culture of the first blood sample to the administration of antifungal drugs. Time from Candida isolation to antifungal drug administration was defined as the number of days from the culture of the first blood sample positive for Candida species to the administration of antifungal drugs. Time from onset of yeast to antifungal drug administration was defined as the number of days from the culture of the first blood sample positive for yeast to the initiation of fluconazole. Empirical antifungal therapy was defined as any antifungal therapy started before the identification of the Candida species. Duration of antifungal drug was defined as the number of days from the initiation of empirical antifungal drugs to the end of definite antifungal drug administration. The Candida score is a scoring system that clinicians use to differentiate between patients with Candida colonization and those with ongoing but occult invasive fungal infection when considering starting early fungal treatment [5].

Data were analyzed using SPSS version 20.0 (IBM Corp., Armonk, NY, USA). Outcome measures were compared using either a chi-square or a t test for categorical and continuous measures, respectively. Multiple logistic regression analysis of Candida risk factors and other variables associated with mortality (p < 0.05) in the univariate analyses was performed to identify independent predictors of 30-day mortality. The Kaplan-Meier method was used to calculate 30-day survival probability in both groups. A p value < 0.05 was considered to be statistically significant.

A total of 109 patients with candidemia were admitted to our hospital during the study period. Fifty patients admitted before August 2015 were included in the preEFTC group. Of the 59 patients admitted from August 2015, 53 were included in the post-EFTC group and six were excluded because they were lost to follow-up. Finally, a total of 103 patients (50 before and 53 after) were included in the analysis. The characteristics of the two groups are summarized in Table 1. There was no statistically significant difference between the two groups in demographic characteristics, risk factors of candidemia, department of admission, or their laboratory results on admission. However, patients in the post-EFTC group had a significantly lower CCI and MODS than those in the pre-EFTC group. The distribution by hospital department (General Surgery or Hemato-Oncology); distribution of Candida species; and the proportion of patients who had a central catheter removed did not differ significantly between groups. The mean starting dose of fluconazole (excluding the loading dose) also did not differ significantly between groups.

The antifungal coverage rate; and the use adequate empirical antifungal drug was significantly higher; while the time from Candida isolation to antifungal drug initiation was significantly shorter (Table 1), and 30-day mortality rate was significantly lower in the post-EFTC group than the pre-EFTC group (Fig. 2). However, the mean time from blood culture to antifungal drug initiation did not differ significantly by group.

Univariate analysis of risk factors showed that age (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.99 to 1.04; p = 0.77), total parenteral nutrition (OR, 1.33; 95% CI, 0.59 to 2.97; p = 0.49), abdominal surgery (OR, 0.84; 95% CI, 0.33 to 2.16; p = 0.72), previous Candida infection (OR, 0.61; 95% CI, 0.11 to 3.29; p = 0.61), central catheter insertion (OR, 0.83; 95% CI, 0.33 to 2.06; p = 0.68), chemotherapy (OR, 1.10; 95% CI, 0.42 to 2.91; p = 0.84), ICU admission (OR, 1.78; 95% CI, 0.77 to 3.89; p = 0.19), and Candida score ≥ 3 (OR, 1.56; 95% CI, 0.57 to 3.78; p = 0.20) were not significantly associated with the 30-day mortality. CCI ≥ 6 points (OR, 3.24; 95% CI, 1.26 to 7.54; p = 0.01), MODS ≥ 6 points (OR, 3.04; 95% CI, 1.18 to 7.11; p = 0.01), and time to fluconazole initiation ≥ –5 hours (OR, 4.89; 95% CI, 1.45 to 9.57; p = 0.01) were associated with a significantly higher 30-day mortality.

The results of the multivariate logistic regression analysis to identify factors independently associated with 30-day mortality are shown in Table 2. When multivariate analysis was performed to compare the relative contribution of risk factors associated with 30-day mortality Implementation of EFTC protocol was independently associated with a significantly lower 30-day mortality (OR, 0.27; 95% CI, 0.12 to 0.63; p = 0.01). An antifungal administration after Candida isolation from blood culture, use of vasopressor, and a CCI ≥ 6 points was independently associated with a significantly higher 30-day mortality.