A multicenter, randomized trial of prophylactic fluconazole in preterm neonates

N Engl J Med. 2007 Jun 14;356(24):2483-95. doi: 10.1056/NEJMoa065733.


Background: Invasive candida infections are a major cause of morbidity and mortality in preterm infants. We performed a multicenter, randomized, double-blind, placebo-controlled trial of fluconazole for the prevention of fungal colonization and infection in very-low-birth-weight neonates.

Methods: During a 15-month period, all neonates weighing less than 1500 g at birth from eight tertiary Italian neonatal intensive care units (322 infants) were randomly assigned to receive either fluconazole (at a dose of either 6 mg or 3 mg per kilogram of body weight) or placebo from birth until day 30 of life (day 45 for neonates weighing <1000 g at birth). We performed weekly surveillance cultures and systematic fungal susceptibility testing.

Results: Among infants receiving fluconazole, fungal colonization occurred in 9.8% in the 6-mg group and 7.7% in the 3-mg group, as compared with 29.2% in the placebo group (P<0.001 for both fluconazole groups vs. the placebo group). The incidence of invasive fungal infection was 2.7% in the 6-mg group and 3.8% in the 3-mg group, as compared with 13.2% in the placebo group (P=0.005 for the 6-mg group and P=0.02 for the 3-mg group vs. the placebo group). The use of fluconazole did not modify the relationship between colonization and the subsequent development of invasive fungal infection. Overall mortality was similar among groups, as was the incidence of cholestasis. No evidence for the emergence of resistant candida species was observed, but the study did not have substantial power to detect such an effect.

Conclusions: Prophylactic fluconazole reduces the incidence of colonization and invasive candida infection in neonates weighing less than 1500 g at birth. The benefit of treating candida colonization is unclear. (Current Controlled Trials number, ISRCTN85753869 [controlled-trials.com]).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / therapeutic use*
  • Candida / isolation & purification
  • Candidiasis / epidemiology
  • Candidiasis / mortality
  • Candidiasis / prevention & control*
  • Cholestasis / epidemiology
  • Double-Blind Method
  • Female
  • Fluconazole / therapeutic use*
  • Humans
  • Incidence
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases / mortality
  • Infant, Premature, Diseases / prevention & control*
  • Infant, Very Low Birth Weight*
  • Male
  • Microbial Sensitivity Tests


  • Antifungal Agents
  • Fluconazole

Associated data

  • ISRCTN/ISRCTN85753869