Double-Blind Placebo-Controlled Trial of Fluconazole to Prevent Candidal Infections in Critically Ill Surgical Patients

Abstract

ObjectiveTo evaluate the prophylactic use of enteral fluconazole to prevent invasive candidal infections in critically ill surgical patients. Summary Background DataInvasive fungal infections are increasingly common in the critically ill, especially in surgical patients. Although fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant patients, few studies have focused on surgical patients and prevention of fungal infection. MethodsThe authors conducted a prospective, randomized, placebocontrolled trial in a single-center, tertiary care surgical intensive care unit (ICU). A total of 260 critically ill surgical patients with a length of ICU stay of at least 3 days were randomly assigned to receive either enteral fluconazole 400 mg or placebo per day during their stay in the surgical ICU at Johns Hopkins Hospital. ResultsThe primary end point was the time to occurrence of fungal infection during the surgical ICU stay, with planned secondary analysis of patients "on-therapy" and alternate definitions of fungal infections. In a time-to-event analysis, the risk of candidal infection in patients receiving fluconazole was significantly less than the risk in patients receiving placebo. After adjusting for potentially confounding effects of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, days to first dose, and fungal colonization at enrollment, the risk of fungal infection was reduced by 55% in the fluconazole group. No difference in death rate was observed between patients receiving fluconazole and those receiving placebo. ConclusionsEnteral fluconazole safely and effectively decreased the incidence of fungal infections in high-risk, critically ill surgical patients.Fungal pathogens increasingly cause nosocomial infections, especially among surgical patients and the high-risk critically ill, with an attributable death rate estimated at 38%. [1][2][3][4][5][6][7][8][9] In our institution, yeast species accounted for 15% of bloodstream isolates in the period from 1992 to 1995.

Prophylactic Fluconazole Is Effective in Preventing Fungal Colonization and Fungal Systemic Infections in Preterm Neonates: A Single-Center, 6-Year, Retrospective Cohort Study

“…Despite convincing evidence of the efficacy of prophylactic fluconazole in immunocompromised adult [19][20][21][22] or infant patients, 20,23 only 2 studies involving preterm high-risk neonates are available. 11,24 They demonstrate that fluconazole prevents rectal colonization in VLBW 24 and colonization and infection in ELBW neonates.…”

“…The reduction of morbidity and mortality by Candida species confirms data from other categories of patients, both adults and infants, in which this strategy has already been implemented as a routine preventive practice. [20][21][22] The increase of the presumed/proven SFI ratio in the fluconazole group (1.0 vs 0.48 in group A) could mean an increased frequency of less paradigmatic (and less severe) fungal infectious features in the neonates who undergo prophylaxis. The use of prophylactic fluconazole may have enhanced the host response to fungal agents once the infection has occurred 20 ; however, blood cultures, whose sensitivity is basically poor, 12 may have given more often negative results depending on the continuous administration of low-dosage fluconazole.…”

“…Prophylactic use of fluconazole in both adult [19][20][21][22] and pediatric patients with hematologic malignancies and immunodeficiencies is well established, 20,23 whereas controversial results have been observed in the few smallscale studies devoted to prophylaxis with antifungal agents in neonates. Two studies showed that oral or intravenous fluconazole 24 and oral nystatin 25,26 can prevent rectal colonization by Candida, whereas topical miconazole oral gel failed to prevent colonization and systemic infection.…”

Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem

“…This has prompted the development of several strategies or risk stratification rules to predict the true risk of disease and to more efficiently identify patients for early diagnostic and therapeutic interventions and thus reduce infection-related deaths (66,69,82,128,181,187,196,232,308).…”

“…These risk-assessment strategies have been derived either from primary studies to determine risk factors or from clinical trials of prophylaxis (181), and they encompass selection (risk) criteria as simple as a Candida colonization index alone (232) or an ICU stay of Ͼ3 days (196) to more-complicated formulae, including LOS plus various independent risk factors (66,82,128,187,308). In each instance, the strategies have been shown to be successful in identifying a subpopulation in which the incidence of IC was increased (10% to 38%) or where the probability of developing IC was increased substantially over the baseline rate or probability for all patients in the ICU.…”