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Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.

Publication ,  Journal Article
Benjamin, DK; Hudak, ML; Duara, S; Randolph, DA; Bidegain, M; Mundakel, GT; Natarajan, G; Burchfield, DJ; White, RD; Shattuck, KE; Neu, N ...
Published in: JAMA
May 7, 2014

IMPORTANCE: 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. DESIGN, SETTING, AND PATIENTS: 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. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00734539.

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Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

May 7, 2014

Volume

311

Issue

17

Start / End Page

1742 / 1749

Location

United States

Related Subject Headings

  • Single-Blind Method
  • Male
  • Length of Stay
  • Intensive Care Units, Neonatal
  • Infant, Very Low Birth Weight
  • Infant, Premature, Diseases
  • Infant, Newborn
  • Infant, Low Birth Weight
  • Infant Mortality
  • Humans
 

Citation

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Benjamin, D. K., Hudak, M. L., Duara, S., Randolph, D. A., Bidegain, M., Mundakel, G. T., … Fluconazole Prophylaxis Study Team, . (2014). Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA, 311(17), 1742–1749. https://doi.org/10.1001/jama.2014.2624
Benjamin, Daniel K., Mark L. Hudak, Shahnaz Duara, David A. Randolph, Margarita Bidegain, Gratias T. Mundakel, Girija Natarajan, et al. “Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.JAMA 311, no. 17 (May 7, 2014): 1742–49. https://doi.org/10.1001/jama.2014.2624.
Benjamin DK, Hudak ML, Duara S, Randolph DA, Bidegain M, Mundakel GT, et al. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014 May 7;311(17):1742–9.
Benjamin, Daniel K., et al. “Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.JAMA, vol. 311, no. 17, May 2014, pp. 1742–49. Pubmed, doi:10.1001/jama.2014.2624.
Benjamin DK, Hudak ML, Duara S, Randolph DA, Bidegain M, Mundakel GT, Natarajan G, Burchfield DJ, White RD, Shattuck KE, Neu N, Bendel CM, Kim MR, Finer NN, Stewart DL, Arrieta AC, Wade KC, Kaufman DA, Manzoni P, Prather KO, Testoni D, Berezny KY, Smith PB, Fluconazole Prophylaxis Study Team. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014 May 7;311(17):1742–1749.
Journal cover image

Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

May 7, 2014

Volume

311

Issue

17

Start / End Page

1742 / 1749

Location

United States

Related Subject Headings

  • Single-Blind Method
  • Male
  • Length of Stay
  • Intensive Care Units, Neonatal
  • Infant, Very Low Birth Weight
  • Infant, Premature, Diseases
  • Infant, Newborn
  • Infant, Low Birth Weight
  • Infant Mortality
  • Humans