The most common etiology of infection-related death or neurodevelopmental impairment in neonates with birth weight less than 750 grams is invasive candidiasis. Invasive candidiasis is diagnosed by positive culture for Candida species 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 birth weight of less than 750 grams 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 less than 750 grams, 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 less than 750 grams, 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. This research will evaluate whether fluconazole decreases invasive infection from Candida in neonates less than 750 grams birth weight. The research will evaluate the efficacy, safety, and neurodevelopmental outcomes related to fluconazole use.

Public Health Relevance

This research will show that fluconazole decreases invasive infection from Candida in neonates <750 grams birthweight. The research will provide guidance as to the efficacy, safety, and neuro developmental outcomes related to fluconazole use.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
5R01FD003519-02
Application #
7690898
Study Section
Special Emphasis Panel (ZFD1-OPD-N (S1))
Program Officer
Needleman, Katherine
Project Start
2008-09-20
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Momper, Jeremiah D; Capparelli, Edmund V; Wade, Kelly C et al. (2016) Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams. Antimicrob Agents Chemother 60:5539-45
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
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
Sampson, Mr; Cohen-Wolkowiez, M; Benjamin Jr, Dk et al. (2013) Pharmacokinetics of Antimicrobials in Obese Children. GaBI J 2:76-81
Bauserman, Melissa S; Laughon, Matthew M; Hornik, Christoph P et al. (2013) Group B Streptococcus and Escherichia coli infections in the intensive care nursery in the era of intrapartum antibiotic prophylaxis. Pediatr Infect Dis J 32:208-12
Watt, Kevin; Manzoni, Paolo; Cohen-Wolkowiez, Michael et al. (2013) Triazole use in the nursery: fluconazole, voriconazole, posaconazole, and ravuconazole. Curr Drug Metab 14:193-202
Hornik, Christoph P; Herring, Amy H; Benjamin Jr, Daniel K et al. (2013) Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants. Pediatr Infect Dis J 32:748-53
Benjamin Jr, Daniel K; Deville, Jaime G; Azie, Nkechi et al. (2013) Safety and pharmacokinetic profiles of repeated-dose micafungin in children and adolescents treated for invasive candidiasis. Pediatr Infect Dis J 32:e419-25
Wynn, James L; Hansen, Nellie I; Das, Abhik et al. (2013) Early sepsis does not increase the risk of late sepsis in very low birth weight neonates. J Pediatr 162:942-8.e1-3
Lee, Jan Hau; Hornik, Christoph P; Benjamin Jr, Daniel K et al. (2013) Risk factors for invasive candidiasis in infants >1500 g birth weight. Pediatr Infect Dis J 32:222-6

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