Fluconazole prophylaxis in the neonatal intensive care unit.

The disease burden attributable to invasive candidiasis in very low birthweight (VLBW, 1500 g) infants in neonatal intensive care units (NICU) is considerable. Also, candidiasis causes disseminated disease, prolonged hospitalization, and death or neurodevelopmental impairment in almost 75% of infected extremely low birthweight (ELBW, 1000 g) infants. Many necessary manipulations and conditions of these premature neonates predispose to development of invasive candidiasis. The antifungal agent, fluconazole, has a long half-life, excellent tissue and body fluid concentrations, impairs adherence of Candida to endothelial and epithelial surfaces, decreases biofilm formation, and enhances the killing of Candida species. These characteristics make it an ideal candidate for antifungal prophylaxis. To date, the only untoward effects reported with fluconazole use in preterm infants are reversible elevations in hepatic enzymes or bilirubin without sequelae. FLUCONAZOLE PROPHYLAXIS STUDIES Four randomized controlled trials (RCTs) and 7 retrospective cohort studies have evaluated fluconazole for the prevention of invasive candidiasis in ELBW or VLBW infants (Table 1). These studies used fluconazole dosages of 3 or 6 mg/kg, orally or parenterally, using 7 different schedules. All RCTs demonstrated significant reductions in invasive candidiasis without any serious adverse effects. In a RCT that targeted ELBW infants 5 days of age requiring central vascular catheter (CVC) access or mechanical ventilation, fluconazole (3 mg/kg/dose given every third day for 2 weeks, every other day for 2 weeks, then daily for 2 weeks) or saline was administered intravenously (IV) to 100 infants for 42 days or until IV access (central or peripheral) no longer was required. This prophylaxis regimen appeared safe and significantly reduced invasive candidiasis rates both in infants 24 weeks gestation and in those who were more mature. These investigators later demonstrated that fluconazole given in a dosage of 3 mg/kg twice a week was equally effective in preventing invasive candidiasis. In a recent multicenter RCT, 322 VLBW infants received placebo or fluconazole at a dose of 3 or 6 mg/kg in a 1:1:1 ratio for 30 days (1000–1500 g BW) or 45 days (ELBW infants). Each fluconazole dose had similar efficacy in preventing Candida sp. colonization and invasive candidiasis. Two recent meta-analyses also concluded that fluconazole prophylaxis reduces the incidence of invasive candidiasis in VLBW infants, although they urge that this finding be interpreted cautiously and studied further. Seven single center retrospective cohort studies with historical controls, using similar criteria and regimens for fluconazole prophylaxis as the RCTs, also have demonstrated significant reductions in invasive candidiasis rates with use of prophylaxis (Table 1). No center had a Candida-related death following the introduction of fluconazole prophylaxis. Two studies required risk factors for invasive candidiasis as well as birthweight/gestational age criteria to target prophylaxis. Although this approach does not prevent Candida colonization from birth, an implicit strategy when fluconazole prophylaxis is initiated shortly after birth, these studies also showed benefit from prophylaxis. One center observed that targeting fluconazole prophylaxis for ELBW infants at birth shifted invasive candidiasis to larger, more mature infants who were older at the time invasive candidiasis developed, and no infected infant died of their infection.