Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants

A randomized clinical trial

Daniel K. Benjamin, Mark L. Hudak, Shahnaz Duara, David A. Randolph, Margarita Bidegain, Gratias T. Mundakel, Girija Natarajan, David J. Burchfield, Robert D. White, Karen Shattuck, Natalie Neu, Catherine M. Bendel, M. Roger Kim, Neil N. Finer, Dan L. Stewart, Antonio C. Arrieta, Kelly C. Wade, David A. Kaufman, Paolo Manzoni, Kristi O. Prather & 3 others Daniela Testoni, Katherine Y. Berezny, P. Brian Smith

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

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 studywas 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 pointwas 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.

Original languageEnglish (US)
Pages (from-to)1742-1749
Number of pages8
JournalJAMA - Journal of the American Medical Association
Volume311
Issue number17
DOIs
StatePublished - 2014

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Fluconazole
Candidiasis
Premature Infants
Invasive Candidiasis
Randomized Controlled Trials
Mortality
Placebos
Extremely Low Birth Weight Infant
Safety
Deaf-Blind Disorders
Periventricular Leukomalacia
Intestinal Perforation
Retinopathy of Prematurity
Necrotizing Enterocolitis
Patent Ductus Arteriosus
Intracranial Hemorrhages
Neonatal Intensive Care Units
Incidence
Cerebral Palsy
Bacterial Infections

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Benjamin, D. K., Hudak, M. L., Duara, S., Randolph, D. A., Bidegain, M., Mundakel, G. T., ... Smith, P. B. (2014). Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: A randomized clinical trial. JAMA - Journal of the American Medical Association, 311(17), 1742-1749. https://doi.org/10.1001/jama.2014.2624

Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants : A randomized clinical trial. / Benjamin, Daniel K.; Hudak, Mark L.; Duara, Shahnaz; Randolph, David A.; Bidegain, Margarita; Mundakel, Gratias T.; Natarajan, Girija; Burchfield, David J.; White, Robert D.; Shattuck, Karen; Neu, Natalie; Bendel, Catherine M.; Kim, M. Roger; Finer, Neil N.; Stewart, Dan L.; Arrieta, Antonio C.; Wade, Kelly C.; Kaufman, David A.; Manzoni, Paolo; Prather, Kristi O.; Testoni, Daniela; Berezny, Katherine Y.; Smith, P. Brian.

In: JAMA - Journal of the American Medical Association, Vol. 311, No. 17, 2014, p. 1742-1749.

Research output: Contribution to journalArticle

Benjamin, DK, Hudak, ML, Duara, S, Randolph, DA, Bidegain, M, Mundakel, GT, Natarajan, G, Burchfield, DJ, White, RD, Shattuck, K, 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 2014, 'Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: A randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 311, no. 17, pp. 1742-1749. https://doi.org/10.1001/jama.2014.2624
Benjamin, Daniel K. ; Hudak, Mark L. ; Duara, Shahnaz ; Randolph, David A. ; Bidegain, Margarita ; Mundakel, Gratias T. ; Natarajan, Girija ; Burchfield, David J. ; White, Robert D. ; Shattuck, Karen ; Neu, Natalie ; Bendel, Catherine M. ; Kim, M. Roger ; Finer, Neil N. ; Stewart, Dan L. ; Arrieta, Antonio C. ; Wade, Kelly C. ; Kaufman, David A. ; Manzoni, Paolo ; Prather, Kristi O. ; Testoni, Daniela ; Berezny, Katherine Y. ; Smith, P. Brian. / Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants : A randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2014 ; Vol. 311, No. 17. pp. 1742-1749.
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TY - JOUR

T1 - Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants

T2 - A randomized clinical trial

AU - Benjamin, Daniel K.

AU - Hudak, Mark L.

AU - Duara, Shahnaz

AU - Randolph, David A.

AU - Bidegain, Margarita

AU - Mundakel, Gratias T.

AU - Natarajan, Girija

AU - Burchfield, David J.

AU - White, Robert D.

AU - Shattuck, Karen

AU - Neu, Natalie

AU - Bendel, Catherine M.

AU - Kim, M. Roger

AU - Finer, Neil N.

AU - Stewart, Dan L.

AU - Arrieta, Antonio C.

AU - Wade, Kelly C.

AU - Kaufman, David A.

AU - Manzoni, Paolo

AU - Prather, Kristi O.

AU - Testoni, Daniela

AU - Berezny, Katherine Y.

AU - Smith, P. Brian

PY - 2014

Y1 - 2014

N2 - 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 studywas 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 pointwas 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.

AB - 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 studywas 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 pointwas 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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