This Mentored Patient-Oriented Research Career Development application will provide for a structured environment with expert mentorship that will enable Dr. Michael Cohen-Wolkowiez to develop as an independent clinical researcher. Although antibiotics are the most commonly used medications in hospitalized infants, dosing for infants is often extrapolated from data obtained in older children and adults. Piperacillin/tazobactam and metronidazole are two antimicrobials commonly used in the nursery for which few pharmacokinetic data are available in premature infants. Dr. Cohen-Wolkowiez will use an integrative approach to investigate the pharmacokinetics and pharmacodynamics of these two agents in premature infants. This approach will include: development of a multiplex antimicrobial assay to measure drug concentrations of five antimicrobials in one ultra-low-volume infant plasma sample;application of sparse sampling methodologies;advanced population PK/PD modeling;and use of clinical opportunities to collect samples. This application will capitalize on unique opportunities provided by the Pediatric Pharmacology Research Unit-funded trial, Antimicrobial PK in High-Risk Infants (PI: Benjamin). Dr. Cohen-Wolkowiez will also have access to the resources of the Duke Clinical Research Institute and the Eshelman School of Pharmacy at UNC (Kashuba, Pollack). The mentorship team assembled is uniquely qualified, and strengths include extensive clinical research experience;internationally recognized thought leadership in trial design, research methods, pharmacology, and PK/PD modeling;and a successful history of mentorship of junior faculty. Dr. Cohen-Wolkowiez's long-term goal is to advance public health by improving antibiotic safety and dosing in infants. This K23 application will provide him with the opportunity to develop a multiplex drug assay and to master PK/PD modeling and simulation techniques in addition to refining clinical trial methodologies to maximize information gained from the limited samples available in this vulnerable population. These skills will be developed through a combination of formal didactic training in pharmacology and biostatics, as well as through mentoring from nationally recognized experts in clinical trials and pediatric pharmacology.

Public Health Relevance

Relevance Statement Invasive infections in premature infants are common and often fatal. Therefore, physicians commonly prescribe antimicrobial agents to treat suspected or confirmed infections in this population. Appropriate dosing of most antimicrobial agents in infants is unknown and information obtained from older patients often has failed to accurately predict newborn drug disposition. This application will use a novel approach to investigate the pharmacokinetics and pharmacodynamics of antimicrobial agents commonly used in infants, using an ultra-low volume multiplex assay, scavenge sampling methodologies, and advanced PK-PD modeling.

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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Special Emphasis Panel (ZHD1-DSR-A (CM))
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Ren, Zhaoxia
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Duke University
Schools of Medicine
United States
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Autmizguine, Julie; Cohen-Wolkowiez, Michael; Ilowite, Norman et al. (2015) Rilonacept pharmacokinetics in children with systemic juvenile idiopathic arthritis. J Clin Pharmacol 55:39-44
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
Gonzalez, Daniel; Paul, Ian M; Benjamin Jr, Daniel K et al. (2014) Advances in pediatric pharmacology, therapeutics, and toxicology. Adv Pediatr 61:7-31
Cohen-Wolkowiez, Michael; Watt, Kevin M; Zhou, Chenguang et al. (2014) Developmental pharmacokinetics of piperacillin and tazobactam using plasma and dried blood spots from infants. Antimicrob Agents Chemother 58:2856-65
Gonzalez, D; Melloni, C; Yogev, R et al. (2014) Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents. Clin Pharmacol Ther 96:429-37
Beam, K S; Aliaga, S; Ahlfeld, S K et al. (2014) A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants. J Perinatol 34:705-10
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
Beam, Kristyn S; Laughon, Matthew M; Hornik, Christoph P et al. (2014) Predictors of positive cerebrospinal fluid cultures in infants with bacteremia. Pediatr Infect Dis J 33:360-5
Autmizguine, Julie; Guptill, Jeffrey T; Cohen-Wolkowiez, Michael et al. (2014) Pharmacokinetics and pharmacodynamics of antifungals in children: clinical implications. Drugs 74:891-909
Gostelow, Martyn; Gonzalez, Daniel; Smith, P Brian et al. (2014) Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants, children and adults. Expert Rev Clin Pharmacol 7:327-40

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