This Mentored-Patient Oriented Research Career proposal will provide for a structured environment with expert mentorship that will allow Dr. Brian Smith to develop into an independent clinical researcher. Antibiotics are the most commonly used medications in hospitalized infants;however, dosing for infants is often extrapolated from data obtained in older children and adults. Meropenem and cefazolin are two commonly used antimicrobials for which little PK data are available. Dr. Smith will use an integrative approach to efficiently investigate the PK of these two agents in infants. This approach will include: application of scavenge sampling methodologies, advanced PK-PD modeling, integration of standard of care laboratory monitoring into the trial design, and use of clinical opportunities to collect samples. This proposal will capitalize on the unique opportunities provided by an NICHD-funded trial, Meropenem Pediatric Off- Label Study (PI Benjamin). Dr. Smith will also have access to the resources provided through the Pediatric Pharmacology Research Unit (PPRU);this includes the involvement of Drs. Benjamin (PI North Carolina Collaborative PPRU), Capparelli (PI University of San Diego PPRU), and McCracken (PI University Texas Southwestern PPRU). The proposal also benefits from the infrastructure of the Duke Neonatal Perinatal Research Institute (Goldberg), the Duke Clinical Research Institute (Benjamin) and the School of Pharmacy at UNC (Thakker). The strengths of the mentorship team include extensive clinical research experience; internationally recognized thought leadership in trial design, research methods, and pharmacology;and a successful history of mentorship of junior faculty. Dr. Smith's long term goal is to develop a clinical trial group specializing in evaluating therapeutic agents in critically ill infants. This K23 proposal will allow him the opportunity to master PK/PD modeling and simulation techniques and to refine clinical trial methodologies in order to maximize information gained from the limited samples available in premature infants. These skills will be developed through a combination of formal didactic training in pharmacology and biostatics, and from mentorship from nationally recognized experts in clinical trials and pediatric pharmacology.

Public Health Relevance

Despite a neonatal medicine's long history of catastrophic adverse events resulting from inadequate study of drugs prior to their widespread use, the majority of antimicrobials used in infants have undergone insufficient study in infants. This proposal will use an integrative approach to efficiently investigate the PK of meropenem and cefazolin, two agents commonly used in infants, using the following methods: application of scavenge sampling methodologies, advanced PK-PD modeling, and use of clinical opportunities to collect samples.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
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Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Zajicek, Anne
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Duke University
Schools of Medicine
United States
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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
Cotten, C Michael; Murtha, Amy P; Goldberg, Ronald N et al. (2014) Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr 164:973-979.e1
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
Dobson, Nicole R; Patel, Ravi M; Smith, P Brian et al. (2014) Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr 164:992-998.e3
Mamikonian, Lara S; Mamo, Lisa B; Smith, P Brian et al. (2014) Cardiopulmonary bypass is associated with hemolysis and acute kidney injury in neonates, infants, and children*. Pediatr Crit Care Med 15:e111-9
Derienzo, Chris; Smith, P Brian; Tanaka, David et al. (2014) Feeding practices and other risk factors for developing transfusion-associated necrotizing enterocolitis. Early Hum Dev 90:237-40
Samiee-Zafarghandy, Samira; Smith, P Brian; van den Anker, Johannes N (2014) Safety of sildenafil in infants*. Pediatr Crit Care Med 15:362-8
Sampson, Mario R; Bloom, Barry T; Lenfestey, Robert W et al. (2014) Population pharmacokinetics of intravenous acyclovir in preterm and term infants. Pediatr Infect Dis J 33:42-9
Laughon, Matthew M; Avant, Debbie; Tripathi, Nidhi et al. (2014) Drug labeling and exposure in neonates. JAMA Pediatr 168:130-6

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