Study Population

Respiratory Support for Very Low Birth Weight Infants Receiving Dexamethasone

Posted on by Kayla Korzekwinski

The Journal of Pediatrics • April 2017

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Virkud YV, Hornik CP, Benjamin DK, Laughon MM, Clark RH, Greenberg RG, Smith PB.

To assess how neonatal intensive care units followed the American Academy of Pediatrics guidelines for use of dexamethasone in preterm infants by evaluating respiratory support at the time of dexamethasone administration. This is an observational study of infants discharged from one of 290 neonatal intensive care units from 2003 to 2010. The cohort included very low birth weight (<1500 g birth weight) infants born at ≤32 weeks gestational age. The main outcome was respiratory support at time of exposure to dexamethasone.

Pharmacokinetics of Clindamycin in Obese and Nonobese Children

Posted on by Kayla Korzekwinski

Antimicrobial Agents and Chemotherapy • March 2017

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Smith MJ, Gonzalez D, Goldman JL, Yogev R, Sullivan JE, Reed MD, Anand R, Martz K, Berezny K, Benjamin DK Jr, Smith PB, Cohen-Wolkowiez M, Watt K; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size.

Risk factors for group B streptococcal disease in neonates of mothers with negative antenatal testing

Posted on by Kayla Korzekwinski

Journal of Perinatology • February 2017

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Parente V, Clark RH, Ku L, Fennell C, Johnson M, Morris E, Romaine A, Benjamin DK, Smith PB, Greenberg R

The aim of this study was to identify risk factors for early-onset group B Streptococcus (EOGBS) disease in neonates of mothers with negative antenatal screening. Maternal age <18 years and black race were the strongest predictors of EOGBS. Further research investigating contributors to the discordance between screening results and neonatal outcomes in these populations is needed.

Metronidazole Metabolism in Neonates and the Interplay Between Ontogeny and Genetic Variation

Posted on by Kayla Korzekwinski

The Journal of Clinical Pharmacology • February 2017

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Wang LA, Gonzalez D, Leeder JS, Tyndale RF, Pearce RE, Benjamin DK Jr, Kearns GL, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee.

Metronidazole is commonly used to treat intra-abdominal infections in neonates. The parent drug is converted to 5 metabolites, with 2-hydroxy-metronidazole being the most clinically significant, as it possesses 30–65% of the antimicrobial activity of the parent compound. In vitro studies have demonstrated that cytochrome P450 2A6 (CYP2A6) is the primary catalyst responsible for metronidazole hydroxylation. This enzyme is initially expressed at low levels at birth, with expression increasing over the course of the first year of life to reach adult levels. CYP2A6 is known to be a highly polymorphic gene with more than 45 variant alleles that result in inactive to ultra-rapid metabolizer phenotypes. Additionally, certain allelic variants such as CYP2A6*17 have amino acid changes that alter metabolism for some but not other substrates, resulting in different metabolizing phenotypes for the same genotype. The role of genetic variation on variable metronidazole metabolism in neonates has not been previously described, nor has the effect of CYP2A6*17 on metronidazole been characterized. As such, the objective of this study was to evaluate the effect of CYP2A6 genetic variation on the pharmacokinetics of metronidazole in a small cohort of preterm neonates.

Safety of Enalapril in Infants Admitted to the Neonatal Intensive Care Unit

Posted on by Kayla Korzekwinski

Pediatric Cardiology • January 2017

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Ku LC, Zimmerman K, Benjamin DK, Clark RH, Hornik CP, Smith PB; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.

Enalapril is used to treat hypertension and congestive heart failure in infants. However, enalapril is not labeled for neonates, and safety data in infants are sparse. To evaluate the safety of enalapril in young infants, we conducted a retrospective cohort study of infants who were exposed to enalapril in the first 120 days of life and were cared for in 348 neonatal intensive care units from 1997 to 2012.

Safety of High-dose Acyclovir in Infants With Suspected and Confirmed Neonatal Herpes Simplex Virus Infections

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The Pediatric Infectious Disease Journal • December 2016

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Ericson JE, Gostelow M, Autmizguine J, Hornik CP, Clark RH, Benjamin DK Jr, Smith PB; Pediatric Trials Network Executive Committee and Investigators.

Acyclovir is used to treat herpes simplex virus disease in infants. Treatment with high-dose acyclovir, 60 mg/kg/d, is recommended; however, the safety of this dosage has not been assessed in the past 15 years, and this dosage is not currently approved for infants by the US Food and Drug Administration. We included infants with neonatal herpes simplex virus disease treated with ≥14 days of intravenous acyclovir starting in the first 120 days of life admitted to 1 of 42 neonatal intensive care units managed by the Pediatrix Medical Group between 2002 and 2012.

Use of Reflux Medications in Premature Infants After Hospital Discharge

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Pediatrics • December 2016

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Smith PB

Medications are frequently used to treat gastroesophageal reflux (GER) in premature infants. However, diagnostic modalities for GER are poor and clinical diagnosis is highly variable. Despite the frequent use of GER medications in premature infants, short- or long-term benefits of GER medications in this population are undocumented. Studies in premature infants have failed to show a correlation between apnea, bradycardia, or respiratory symptoms typically thought to be due to GER. This study sought to fill these information gaps.

Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants

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JAMA Pediatrics • December 2016

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Ericson JE, Popoola VO, Smith PB, Benjamin DK, Benjamin DK Jr, Clark RH, Milstone AM
Staphylococcus aureus is a frequent cause of infection in hospitalized infants. These infections are associated with increased mortality and morbidity, and longer hospital stays, but data on the burden of S. aureus disease in hospitalized infants are limited. This study compared demographics and mortality of infants with invasive methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA), determined the annual proportion of S. aureus infections that were MRSA, and compared the risk of death following an invasive MRSA infection to the risk following an invasive MSSA infection.

Pharmacologic studies in vulnerable populations – using the pediatric experience

Posted on by Kayla Korzekwinski

Seminars in Perinatology • November 2016

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Zimmerman K, Gonzalez D, Swamy GK, Cohen-Wolkowiez M
Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women.

Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure-Response Relationships in Renal Transplant Patients

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Therapeutic Drug Monitoring • October 2016

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Zimmerman K, Wu H, Greenberg R, Hill K, Patel U, Ku L, Gonzalez D, Hornik C, Melloni C, Cohen-Wolkowiez M

Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined. Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function.