title: Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.
abstract: OBJECTIVE
  Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants.
  
  
  METHODS
  This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013.
  
  
  METHODS
  Fluconazole (6 mg/kg of body weight) or placebo.
  
  
  METHODS
  The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age.
  
  
  RESULTS
  Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]).
  
  
  CONCLUSIONS
  Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00734539.
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.affiliation: University of Florida College of Medicine-Jacksonville.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Hudak
authors.affiliation: University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Duara
authors.affiliation: University of Alabama-Birmingham.
authors.forename: David A
authors.initials: DA
authors.lastname: Randolph
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Margarita
authors.initials: M
authors.lastname: Bidegain
authors.affiliation: Kings County Hospital, Brooklyn, New York.
authors.forename: Gratias T
authors.initials: GT
authors.lastname: Mundakel
authors.affiliation: Wayne State University, Detroit, Michigan.
authors.forename: Girija
authors.initials: G
authors.lastname: Natarajan
authors.affiliation: University of Florida Health Shands Hospital, Gainesville.
authors.forename: David J
authors.initials: DJ
authors.lastname: Burchfield
authors.affiliation: Memorial Hospital South Bend, South Bend, Indiana.
authors.forename: Robert D
authors.initials: RD
authors.lastname: White
authors.affiliation: University of Texas Medical Branch, Galveston.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Shattuck
authors.affiliation: Columbia University, New York, New York.
authors.forename: Natalie
authors.initials: N
authors.lastname: Neu
authors.affiliation: University of Minnesota Amplatz Children's Hospital, Minneapolis.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bendel
authors.affiliation: Brookdale University Hospital, Brooklyn, New York.
authors.forename: M Roger
authors.initials: MR
authors.lastname: Kim
authors.affiliation: University of California-San Diego Medical Center.
authors.forename: Neil N
authors.initials: NN
authors.lastname: Finer
authors.affiliation: University of Louisville, Louisville, Kentucky.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Stewart
authors.affiliation: Children's Hospital of Orange County, Orange, California.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Arrieta
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Wade
authors.affiliation: University of Virginia, Charlottesville.
authors.forename: David A
authors.initials: DA
authors.lastname: Kaufman
authors.affiliation: Sant'Anna Hospital, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manzoni
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Kristi O
authors.initials: KO
authors.lastname: Prather
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Daniela
authors.initials: D
authors.lastname: Testoni
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Katherine Y
authors.initials: KY
authors.lastname: Berezny
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: P Brian
authors.initials: PB
authors.lastname: Smith
mesh_terms: D000935:Antifungal Agents / Q000627:therapeutic use*; D058365:Candidiasis, Invasive / Q000517:prevention & control*; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D006801:Humans; D007226:Infant Mortality; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000517:prevention & control*; D019102:Infant, Very Low Birth Weight; D007363:Intensive Care Units, Neonatal; D007902:Length of Stay; D008297:Male; D016037:Single-Blind Method
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole