The most common etiology of infection-related death or neurodevelopmental impairment in neonates with birthweight <750 g is invasive candidiasis. Invasive candidiasis is diagnosed by positive culture for Candida sp. from normally sterile body fluid. Over 70% of the premature infants who develop invasive candidiasis will die or suffer severe, permanent neurologic impairment. The highest-risk infants are the very young: the cumulative incidence in neonates with birthweight <750 g is 16%, and most of these infants experience infection by day of life 49. It has been shown that invasive candidiasis is safely prevented by administering fluconazole prophylaxis in immunocompromised adults. Fluconazole has been commonly used off-label in the neonatal intensive care unit, but definitive recommendations for its use in the nursery have been hampered by the limited number of well-designed trials. In neonates weighing <750 g, appropriate dosing is not known, definitive safety and long-term follow up trials have not been completed, and there have not been well-powered trials conducted to establish the efficacy of the product using mortality as part of the primary endpoint. Three recent proof-of-concept studies suggest that fluconazole will be safe and effective, and an ongoing pharmacokinetic study is providing data to give preliminary dosing guidance. The next logical step in drug development is proposed by this research: to conduct a pivotal trial to determine the safety and efficacy of fluconazole in premature infants with 2-year neurodevelopmental follow-up assessment. This will be accomplished by randomizing 360 infants, with a birth weight <750g, at 20 centers, to fluconazole or placebo. The primary efficacy endpoint will be Candida-free survival at study day 49. The research will establish definitive dosing, safety, and efficacy of fluconazole;it will also provide critical information on the effects of fluconazole on neurodevelopmental impairment and antifungal resistance. Our collaborative team is uniquely poised to conduct this research. The team includes internationally recognized experts with experience conducting FDA-compliant, randomized neonatal clinical trials, neurodevelopmental assessments, safety studies, and pharmacokinetic studies. The team has the requisite expertise regarding mycology, epidemiology, pharmacology, and regulatory compliance in the context of invasive candidiasis. In the last 6 years, team members have completed or are actively leading the following studies in neonatal candidiasis: the NICHD-sponsored Early Diagnosis of Candidiasis trial (Benjamin and Stoll);3 proof-of-concept randomized fluconazole studies (Kaufman and Manzoni);the NICHD-sponsored pharmacokinetic study of fluconazole (Wade);and several studies (Benjamin, Reed, and Walsh) of other antifungal agents in the nursery including pharmacokinetic and pharmacodynamic studies of amphotericin B, liposomal amphotericin B products, anidulafungin, and micafungin This research will show that fluconazole decreases invasive infection from Candida in neonates <750 grams birth weight. The research will provide guidance as to the efficacy, safety, and neurodevelopmental outcomes related to fluconazole use.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Pediatrics Subcommittee (CHHD)
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Raju, Tonse N
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Duke University
Schools of Medicine
United States
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Autmizguine, Julie; Hornik, Christoph P; Benjamin Jr, Daniel K et al. (2015) Anaerobic antimicrobial therapy after necrotizing enterocolitis in VLBW infants. Pediatrics 135:e117-25
Bain, J; Benjamin Jr, D K; Hornik, C P et al. (2014) Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects. J Perinatol 34:319-21
Tremoulet, Adriana; Le, Jennifer; Poindexter, Brenda et al. (2014) Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design. Antimicrob Agents Chemother 58:3013-20
Benjamin Jr, Daniel K; Hudak, Mark L; Duara, Shahnaz et al. (2014) Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA 311:1742-9
Greenberg, Rachel G; Benjamin Jr, Daniel K (2014) Neonatal candidiasis: diagnosis, prevention, and treatment. J Infect 69 Suppl 1:S19-22
Tunks, Robert D; Barker, Piers C A; Benjamin Jr, Daniel K et al. (2014) Sildenafil exposure and hemodynamic effect after Fontan surgery. Pediatr Crit Care Med 15:28-34
Aliaga, Sofia; Clark, Reese H; Laughon, Matthew et al. (2014) Changes in the incidence of candidiasis in neonatal intensive care units. Pediatrics 133:236-42
Autmizguine, Julie; Moran, Cassie; Gonzalez, Daniel et al. (2014) Vancomycin cerebrospinal fluid pharmacokinetics in children with cerebral ventricular shunt infections. Pediatr Infect Dis J 33:e270-2
Ericson, Jessica E; Benjamin Jr, Daniel K (2014) Fluconazole prophylaxis for prevention of invasive candidiasis in infants. Curr Opin Pediatr 26:151-6
Gonzalez, Daniel; Paul, Ian M; Benjamin Jr, Daniel K et al. (2014) Advances in pediatric pharmacology, therapeutics, and toxicology. Adv Pediatr 61:7-31

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