Red Book updated with fluconazole dosing information from PTN study

The American Academy of Pediatrics (AAP) has updated the 2018 edition of the Red Book to include fluconazole dosing information determined by a Pediatric Trials Network (PTN) study. The Red Book is the leading resource on pediatric infectious disease, providing the most up-to-date information on a wide variety of diseases that doctors see in children.

The updates include dosing information for the treatment of Cryptococcus neoformans and Cryptococcus gattii infections, as well as Cryptococcal meningitis in children. The updates, which can be viewed on Red Book Online, will enable doctors to provide a safer, more accurate dose of the antifungal drug fluconazole to treat these diseases in children.

The changes were based on a study conducted from 2008 to 2011 in collaboration with PTN that analyzed safety data on the use of fluconazole to treat infections caused by the Candida yeast. While Candida and Cryptococcus yeasts are not the same, they are treated similarly enough to allow dosing information for one to apply to the other. The study examined data from nearly 800 infants in three randomized trials.

The research was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Antimicrobial Agents and Chemotherapy • August 2016.

Momper JD, Capparelli EV, Wade KC, Kantak A, Dhanireddy R, Cummings JJ, Nedrelow JH, Hudak ML, Mundakel GT, Natarajan G, Gao J, Laughon M, Smith PB, Benjamin DK Jr.

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly.

Access article on PubMed.

Fluconazole Prophylaxis for the Prevention of Candidiasis in Premature Infants: A Meta-analysis Using Patient-level Data

Clinical Infectious Diseases • August 2016.

Ericson JE, Kaufman DA, Kicklighter SD, Bhatia J, Testoni D, Gao J, Smith PB, Prather KO, Benjamin DK Jr; Fluconazole Prophylaxis Study Team on behalf of the Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee.

Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States.

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Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation

Antimicrobial Agents and Chemotherapy • June 2015.

Watt KM, Gonzalez D, Benjamin DK Jr, Brouwer KL, Wade KC, Capparelli E, Barrett J, Cohen-Wolkowiez M.

Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis.

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Editorial commentary: Fluconazole therapeutic drug monitoring in children with cancer: not today

Clinical Infectious Disease • December 2014.

Cohen-Wolkowiez M, Benjamin DK Jr.

This editorial focuses on insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children.

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

JAMA • June 2014.

Benjamin DK Jr, 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.

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. 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.

Access article on PubMed.

The fluconazole prophylaxis study locks its database

The PTN team behind the Safety of Fluconazole Prophylaxis in Infants study successfully locked the Benjamin study database last week. To evaluate the safety of fluconazole, the team is gathering randomized trial datasets from several thought leaders to perform a data meta-analysis—the Benjamin study comprises the first of these datasets. The PTN will examine safety data from these earlier randomized controlled trials of fluconazole prophylaxis to prevent candidiasis in very low birth weight and extremely low birth weight infants. Infants born <28 weeks gestational age are susceptible to this disease, which can lead to death or neurodevelopmental impairment.

The Benjamin study was a phase 3, randomized, blinded, multicenter, placebo-controlled trial comparing the efficacy of fluconazole administration to placebo for the prevention of neonatal candidiasis in infants <750 grams birth weight. The primary purpose of the trial was to evaluate death or candidiasis at study day 49 and to determine the safety and efficacy of fluconazole in this context.

The PTN team will analyze this and the other datasets to study primary safety outcomes, including gastrointestinal events, adverse events, serious adverse events, and laboratory values. By cultivating a better understanding of the potential safety issues involved with treating low birth weight infants with fluconazole, we hope to use the drug to better prevent the devastating results of candidiasis in this vulnerable population.