Publications test

Included here are publications by faculty members intimately involved with the Pediatric Trials Network, many of which stem from studies conducted by the network. Some of the publications are accessible to the public; others require a subscription to the journal in which the article was published. If you are unable to view an article, ask your physician if he or she can access the article. View PTN’s publications policy.

Condition
  • All ()
  • Bronchopulmonary dysplasia ()
  • Candidiasis ()
  • Chylothorax ()
  • Complicated intra-abdominal infections ()
  • Congenital hyperinsulinism ()
  • Congestive heart failure ()
  • Gastrointestinal bleeding ()
  • GERD ()
  • Hemangioma ()
  • Herpes Simplex Virus (HSV) ()
  • Hypertension ()
  • Hypoglycemia ()
  • Infections ()
  • Necrotizing enterocolitis ()
  • Neutropenia ()
  • Retinopathy of Prematurity (ROP) ()
Population
  • All ()
  • Adolescents ()
  • Children (2-11 years) ()
  • Infants ()
  • Neonates ()
  • Pregnant or Breastfeeding Women ()
Drug Class
  • All ()
  • ACE inhibitors ()
  • Anesthetics ()
  • Antiarrhythmics ()
  • Antibacterials ()
  • Antidiarrheals ()
  • Antiepileptics ()
  • Antifungals ()
  • Antihypoglycemics ()
  • Antineoplastics ()
  • Antivirals ()
  • Beta blockers ()
  • Corticosteroids ()
  • Diuretics ()
  • Immunosuppressives ()
  • Proton pump inhibitors ()
  • Sedatives ()
  • Vasodilators ()

Rifampin Pharmacokinetics and Safety in Preterm and Term Infants

Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA). We enrolled 27 infants; the median (range) gestational age was 26 weeks (23 to 41 weeks), and the median PNA was 10 days (0 to 84 days). We collected 102 plasma PK samples from 22 of the infants and analyzed safety data from all 27 infants. We analyzed the data using a population PK approach.
Smith PB, Cotten CM, Hudak ML, Sullivan JE, Poindexter BB, Cohen-Wolkowiez M, Boakye-Agyeman F, Lewandowski A, Anand R, Benjamin DK Jr, Laughon MM; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.
Antimicrobial Agents and Chemotherapy, May 2019
AntibacterialsInfantsInfectionsNeonatesPrematurityPublicationsRifampin

Systemic Timolol Exposure Following Topical Application to Infantile Hemangiomas

Off-label ophthalmic timolol has been rapidly adopted for treatment of infantile hemangioma since topical application of beta-blockers was presumed to have an improved safety profile compared to oral administration. We examined timolol plasma concentrations in children receiving ophthalmic preparations applied to skin hemangiomas.
Drolet BA, Boakye-Agyeman F, Harper B, Holland K, Lewandowski A, Stefanko N, Melloni C; Pediatric Trials Network Steering Committee.
Journal of the American Academy of Dermatology, February 2019
Beta blockersHemangiomaInfantsPublicationsTimolol

National Survey of Neonatal Intensive Care Unit Medication Safety Practices

We conducted a detailed survey to identify medication safety practices among a large network of United States neonatal intensive care units (NICUs). We created a 53-question survey to assess 300 U.S. NICU's demographics, medication safety practices, adverse drug event (ADE) reporting, and ADE response plans.
Greenberg RG, Smith PB, Bose C, Clark RH, Cotten CM, DeRienzo C.
American Journal of Perinatology, November 2018
InfantsNeonatesNICUPublications

Prevalence and safety of diazoxide in the neonatal intensive care unit

Diazoxide is used to treat infants with persistent hypoglycemia, but the prevalence of its use and adverse effects are not well described. We report demographic and clinical characteristics of infants treated with diazoxide in neonatal intensive care units (NICUs). Retrospective cohort study of infants 24-41 weeks' gestation admitted to 392 NICUs from 1997-2016, comparing characteristics between hypoglycemic infants exposed/not exposed to diazoxide.
Gray KD, Dudash K, Escobar C, Freel C, Harrison T, McMillan C, Puia-Dumitrescu M, Cotten CM, Benjamin R, Clark RH, Benjamin DK Jr, Greenberg RG; Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee.
Journal of Perinatology, November 2018
AntihypoglycemicsDiazoxideHypoglycemiaInfantsNICUPublications

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice.
Ku LC, Hornik CP, Beechinor RJ, Chamberlain JM, Guptill JT, Harper B, Capparelli EV, Martz K, Anand R, Cohen-Wolkowiez M, Gonzalez D; Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee.
CPT Pharmacometrics & Systems Pharmacology, November 2018
AdolescentsAntiepilepticsChildren (2-11 years)DiazepamInfantsPublicationsSedativesSeizuresStatus epilepticus

A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents

Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers.
Shakhnovich V, Brian Smith P, Guptill JT, James LP, Collier DN, Wu H, Livingston CE, Zhao J, Kearns GL, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act–Pediatric Trials Network.
Pediatric Drugs, October 2018
AdolescentsChildren (2-11 years)GERDObesityPantoprazoleProton pump inhibitorsPublications

Prolonged furosemide exposure and risk of abnormal newborn hearing screen in premature infants

At very high doses, furosemide is linked to ototoxicity in adults, but little is known about the risk of hearing loss in premature infants exposed to furosemide. Our aim was to evaluate the association between prolonged furosemide exposure and abnormal hearing screening in premature infants.
Wang LA, Smith PB, Laughon M, Goldberg RN, Ku LC, Zimmerman KO, Balevic S, Clark RH, Benjamin DK, Greenberg RG; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.
Early Human Development, October 2018
Bronchopulmonary dysplasiaDiureticsFurosemideHearingInfantsNeonatesPrematurityPublications

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature.
Dallefeld SH, Atz AM, Yogev R, Sullivan JE, Al-Uzri A, Mendley SR, Laughon M, Hornik CP, Melloni C, Harper B, Lewandowski A, Mitchell J, Wu H, Green TP, Cohen-Wolkowiez M.
Journal of Pharmacokinetics and Pharmacodynamics, June 2018
AmiodaroneAntiarrhythmicsInfantsPublicationsVentricular fibrillationVentricular tachycardia

Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children

Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown.
Hornik CP, Gonzalez D, van den Anker J, Atz AM, Yogev R, Poindexter BB, Ng KC, Delmore P, Harper BL, Melloni C, Lewandowski A, Gelber C, Cohen-Wolkowiez M, Lee JH; Pediatric Trial Network Steering Committee.
The Journal of Clinical Pharmacology, April 2018
AdolescentsAnesthesiaChildren (2-11 years)InfantsKetaminePublicationsSedatives

Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures

To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula.
Shakhnovich V, Smith PB, Guptill JT, James LP, Collier DN, Wu H, Livingston CE, Zhao J, Kearns GL; Best Pharmaceuticals for Children Act – Pediatric Trials Network.
The Journal of Pediatrics, February 2018
AdolescentsChildren (2-11 years)GERDObesityPantoprazoleProton pump inhibitorsPublications

Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates

Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. An open-label, multicenter, opportunistic, prospective study was conducted in neonates.
Le J, Poindexter B, Sullivan JE, Laughon M, Delmore P, Blackford M, Yogev R, James LP, Melloni C, Harper B, Mitchell J, Benjamin DK Jr, Boakye-Agyeman F, Cohen-Wolkowiez M.
Therapeutic Drug Monitoring, February 2018
AmpicillinAntibacterialsInfectionsNeonatesPublications

A Weight Estimation Strategy for Preterm and Full-Term Infants

Weight is the foremost marker of health outcomes in infants; however, the majority of community workers and health care providers in remote, resource-constrained settings have limited access to functional scales. This study develops and validates a simple weight estimation strategy for infants that addresses the limitations of current approaches.
Abdel-Rahman SM, Paul IM, Delmore P, James L, Fearn L, Atz A, Poindexter B, Al-Uzri A, Lewandowski A, Harper B, Smith PB.
Global Pediatric Health, December 2017
DevicesInfantsNeonatesPrematurityPublicationsWeight estimation

Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children.
Autmizguine J, Melloni C, Hornik CP, Dallefeld S, Harper B, Yogev R, Sullivan JE, Atz AM, Al-Uzri A, Mendley S, Poindexter B, Mitchell J, Lewandowski A, Delmore P, Cohen-Wolkowiez M, Gonzalez D; the Pediatric Trials Network Steering Committee.
Antimicrobial Agents and Chemotherapy, December 2017
AdolescentsAntibacterialsChildren (2-11 years)InfantsInfectionsPublicationsSulfamethoxazoleTrimethoprim

An anthropometric survey of US pre-term and full-term neonates

Anthropometric data prove valuable for screening and monitoring various medical conditions. In young infants, however, only weight, length and head circumference are represented in publicly accessible databases. Our aim was to characterise length and circumferential measures in pre-term and full-term infants up to 90 days post-natal.
Abdel-Rahman SM, Paul IM, Delmore P, James L, Fearn L, Atz AM, Poindexter BB, Al-Uzri A, Lewandowski A, Harper BL, Smith PB; Best Pharmaceuticals for Children Act – Pediatric Trials Network.
Annals of Human Biology, December 2017
Anthropometric dataDevicesInfantsNeonatesPrematurityPublications

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin-Tazobactam Safety in Infants

Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012.
Salerno S, Hornik CP, Cohen-Wolkowiez M, Smith PB, Ku LC, Kelly MS, Clark R, Gonzalez D; Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee.
The Pediatric Infectious Disease Journal, September 2017
AntibacterialsInfectionsNeonatesPiperacillin-TazobactamPublications

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE.
Gonzalez D, Chamberlain JM, Guptill JT, Cohen-Wolkowiez M, Harper B, Zhao J, Capparelli EV; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.
Clinical Pharmacokinetics, August 2017
AdolescentsChildren (2-11 years)InfantsLorazepamPublicationsSedativesSeizuresStatus epilepticus

Effectiveness of Granulocyte Colony-Stimulating Factor in Hospitalized Infants with Neutropenia

The objective of this study was to determine the time to hematologic recovery and the incidence of secondary sepsis and mortality among neutropenic infants treated or not treated with granulocyte colony-stimulating factor (G-CSF). We identified all neutropenic infants discharged from 348 neonatal intensive care units from 1997 to 2012. Neutropenia was defined as an absolute neutrophil count ≤ 1,500/µL for ≥ 1 day during the first 120 days of life.
Lee JA, Sauer B, Tuminski W, Cheong J, Fitz-Henley J 2nd, Mayers M, Ezuma-Igwe C, Arnold C, Hornik CP, Clark RH, Benjamin DK Jr, Smith PB, Ericson JE; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.
American Journal of Perinatology, April 2017
InfantsNeonatesNeutropeniaPublications

Respiratory Support for Very Low Birth Weight Infants Receiving Dexamethasone

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.
Virkud YV, Hornik CP, Benjamin DK, Laughon MM, Clark RH, Greenberg RG, Smith PB.
The Journal of Pediatrics, April 2017
CorticosteroidsDexamethasoneInfantsLow birth weightNeonatesPublicationsRespiratory support

Pharmacokinetics of Clindamycin in Obese and Nonobese Children

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.
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.
Antimicrobial Agents and Chemotherapy, March 2017
AdolescentsAntibacterialsChildren (2-11 years)ClindamycinInfantsInfectionsObesityPublications

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

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.
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.
The Journal of Clinical Pharmacology, February 2017
AntibacterialsInfectionsMetronidazoleNeonatesPrematurityPublications

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

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.
Ku LC, Zimmerman K, Benjamin DK, Clark RH, Hornik CP, Smith PB; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee.
Pediatric Cardiology, January 2017
ACE inhibitorsCongestive heart failureEnalaprilHypertensionInfantsNeonatesPublications

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

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.
Ericson JE, Gostelow M, Autmizguine J, Hornik CP, Clark RH, Benjamin DK Jr, Smith PB; Pediatric Trials Network Executive Committee and Investigators.
The Pediatric Infectious Disease Journal, December 2016
AcyclovirAntiviralsHerpes Simplex Virus (HSV)InfantsPublications

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

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.
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.
Antimicrobial Agents and Chemotherapy, August 2016
AntifungalsCandidiasisFluconazoleInfantsLow birth weightNeonatesPublications

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

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.
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.
Clinical Infectious Diseases, August 2016
AntifungalsCandidiasisFluconazoleInfantsNeonatesPrematurityPublications

Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates

This was a retrospective observational cohort study of electronic health record (EHR) data combined with pharmacokinetic model derived drug exposure predictions. We used the EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. We included all infants 24-41 weeks gestational age, 500-5400 g birth weight, first exposed to ampicillin prior to 25 days postnatal age. In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.
Hornik CP, Benjamin DK Jr, Smith PB, Pencina MJ, Tremoulet AH, Capparelli EV, Ericson JE, Clark RH, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act—Pediatric Trials Network.
Journal of Pediatrics, August 2016
AmpicillinAntibacterialsInfectionsNeonatesPublications

Safety of histamine-2 receptor blockers in hospitalized VLBW infants

Histamine-2 receptor (H2) blockers are often used in very low birth weight infants despite lack of population specific efficacy and safety data. We sought to describe safety and temporal trends in histamine-2 receptor (H2) blocker use in hospitalized very low birth weight (VLBW) infants.
Romaine A, Ye D, Ao Z, Fang F, Johnson O, Blake T, Benjamin DK Jr, Cotten CM, Testoni D, Clark RH, Chu VH, Smith PB, Hornik CP; Best Pharmaceuticals for Children Act – Pediatric Trials Network.
Early Human Development, August 2016
InfantsLow birth weightPublications

Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials.
Gonzalez D, Delmore P, Bloom BT, Cotten CM, Poindexter BB, McGowan E, Shattuck K, Bradford KK, Smith PB, Cohen-Wolkowiez M, Morris M, Yin W, Benjamin DK Jr, Laughon MM.
Antimicrobial Agents and Chemotherapy, April 2016
AntibacterialsClindamycinInfantsInfectionsNeonatesPrematurityPublications

Optimizing operational efficiencies in early phase trials: The Pediatric Trials Network experience

Performing drug trials in pediatrics is challenging. In support of the Best Pharmaceuticals for Children Act, the Eunice Kennedy Shriver National Institute of Child Health and Human Development funded the formation of the Pediatric Trials Network (PTN) in 2010. Since its inception, the PTN has developed strategies to increase both efficiency and safety of pediatric drug trials.
England A, Wade K, Smith PB, Berezny K, Laughon M; Best Pharmaceuticals for Children Act — Pediatric Trials Network Administrative Core Committee.
Contemporary Clinical Trials, March 2016
Operational efficiencyPublicationsTrial design

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia; however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU.
Estepp JH, Melloni C, Thornburg CD, Wiczling P, Rogers Z, Rothman JA, Green NS, Liem R, Brandow AM, Crary SE, Howard TH, Morris MH, Lewandowski A, Garg U, Jusko WJ, Neville KA; Best Pharmaceuticals for Children Act-Pediatric Trials Network Administrative Core Committee.
Journal of Clinical Pharmacology, March 2016
AdolescentsAntineoplasticsChildren (2-11 years)HydroxyureaPublicationsSickle cell anemia

Sildenafil and retinopathy of prematurity risk in very low birth weight infants

We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003–2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil prior to first eye exam to three non-exposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression.
Samiee-Zafarghandy S, van den Anker JN, Laughon MM, Clark RH, Smith PB, Hornik CP; Pharmaceuticals for Children Act – Pediatric Trials Network Administrative Core Committee.
American Journal of Perinatology, February 2016
AntihypoglycemicsInfantsLow birth weightPublicationsRetinopathy of Prematurity (ROP)SildenafilVasodilators

Gaps in Drug Dosing for Obese Children: A Systematic Review of Commonly Prescribed Emergency Care Medications

Approximately 1 of 6 children in the United States is obese. This has important implications for drug dosing and safety because pharmacokinetic (PK) changes are known to occur in obesity due to altered body composition and physiologic mechanisms. Inappropriate drug dosing in an emergency setting can limit therapeutic efficacy and increase drug-related toxic effects for obese children.
Rowe S, Siegel D, Benjamin DK Jr; Best Pharmaceuticals for Children Act – Pediatric Trials Network Administrative Core Committee.
Clinical Therapy, September 2015
AdolescentsChildren (2-11 years)Emergency careObesityPublications

Cefepime and Ceftazidime Safety in Hospitalized Infants

Cefepime and ceftazidime are cephalosporins used for the treatment of serious Gram-negative infections. These cephalosporins are used off-label in the setting of minimal safety data for young infants. We identified all infants discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012 who were exposed to either cefepime or ceftazidime in the first 120 days of life. We reported clinical and laboratory adverse events occurring in infants exposed to cefepime or ceftazidime and used multivariable logistic regression to compare the odds of seizures and death between the 2 groups.
Arnold CJ, Ericson J, Cho N, Tian J, Wilson S, Chu VH, Hornik CP, Clark RH, Benjamin DK Jr, Smith PB; Best Pharmaceuticals for Children Act--Pediatric Trials Network Administrative Core Committee.
The Pediatric Infectious Disease Journal, August 2015
AntibacterialsCefepimeCeftazidimeInfantsInfectionsNeonatesPublications

Use and Safety of Erythromycin and Metoclopramide in Hospitalized Infants

Prokinetic medications are used in premature infants to promote motility and decrease time to full enteral feeding. Erythromycin and metoclopramide are the most commonly used prokinetic medications in the neonatal intensive care unit (NICU), but their safety profile is not well defined. We conducted a large retrospective cohort study using data from 348 NICUs managed by the Pediatrix Medical Group. All of the infants exposed to ≥1 dose of erythromycin, metoclopramide, or both, from a cohort of 8,87,910 infants discharged between 1997 and 2012 were included.
Ericson JE, Arnold C, Cheeseman J, Cho J, Kaneko S, Wilson E, Clark RH, Benjamin DK Jr, Chu V, Smith PB, Hornik CP; Best Pharmaceuticals for Children Act–Pediatric Trials Network Administrative Core Committee.
Journal of Pediatric Gastroenterology and Nutrition, August 2015
AntibacterialsErythromycinInfantsInfectionsMetoclopramideNeonatesPublications

Drug Dosing and Pharmacokinetics in Children With Obesity: A Systematic Review

Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown. We searched the MEDLINE, Cochrane, and EMBASE databases (January 1, 1970-December 31, 2012) and included studies if they contained data on drug clearance, volume of distribution, or drug concentration in obese children (aged ≤18 years).
Harskamp-van Ginkel MW, Hill KD, Becker KC, Testoni D, Cohen-Wolkowiez M, Gonzalez D, Barrett JS, Benjamin DK Jr, Siegel DA, Banks P, Watt KM; Best Pharmaceuticals for Children Act–Pediatric Trials Network Administrative Core Committee.
JAMA Peds, July 2015
AdolescentsChildren (2-11 years)Drug dispositionObesityPublications

Safety of octreotide in hospitalized infants

Octreotide is used off-label in infants for treatment of chylothorax, congenital hyperinsulinism, and gastrointestinal bleeding. The safety profile of octreotide in hospitalized infants has not been described; we sought to fill this information gap. We identified all infants exposed to at least 1 dose of octreotide from a cohort of 887,855 infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012.
Testoni D, Hornik CP, Neely ML, Yang Q, McMahon AW, Clark RH, Smith PB; Best Pharmaceuticals for Children Act — Pediatric Trials Network Administrative Core Committee.
Early Human Development, July 2015
AntidiarrhealsChylothoraxCongenital hyperinsulinismGastrointestinal bleedingInfantsNeonatesOctreotidePublications

Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection

Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options--including angiotensin-converting enzyme inhibitors--are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state.
Trachtman H, Frymoyer A, Lewandowski A, Greenbaum LA, Feig DI, Gipson DS, Warady BA, Goebel JW, Schwartz GJ, Lewis K, Anand R, Patel UD; Best Pharmaceuticals for Children Act-Pediatric Trials Network Administrative Core Committee.
Clinical Pharmacology Therapy, July 2015
ACE inhibitorsAdolescentsChildren (2-11 years)HypertensionKidney transplantLisinoprilPublications

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

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.
Watt KM, Gonzalez D, Benjamin DK Jr, Brouwer KL, Wade KC, Capparelli E, Barrett J, Cohen-Wolkowiez M.
Antimicrobial Agents and Chemotherapy, June 2015
AdolescentsAntifungalsCandidiasisChildren (2-11 years)FluconazoleInfantsPublications

Rifampin use and safety in hospitalized infants

This study aims to examine the use and safety of rifampin in hospitalized infants. Observational study of clinical and laboratory adverse events among infants exposed to rifampin from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Overall, 2,500 infants received 4,279 courses of rifampin; mean gestational age was 27 weeks (5th, 95th percentile; 23, 36) and mean birth weight was 1,125 g (515; 2,830). Thrombocytopenia (121/1,000 infant days) and conjugated hyperbilirubinemia (25/1,000 infant days) were the most common laboratory adverse events.
Arnold CJ, Ericson J, Kohman J, Corey KL, Oh M, Onabanjo J, Hornik CP, Clark RH, Benjamin DK Jr, Smith PB, Chu VH; Best Pharmaceuticals for Children Act–Pediatric Trials Network Administrative Core Committee.
American Journal of Perinatology, May 2015
AntibacterialsInfantsInfectionsNeonatesPublicationsRifampin

Simultaneous determination of trimethoprim and sulfamethoxazole in dried plasma and urine spots

Trimethoprim-sulfamethoxazole (TMP-SMX) is an antimicrobial drug combination commonly prescribed in children and adults. The study objectives were to validate and apply an HPLC-MS/MS method to quantify TMP-SMX in dried plasma spots (DPS) and dried urine spots (DUS), and perform a comparability analysis with liquid matrices. For TMP the validated range was 100-50,000 ng/ml for DPS and 500-250,000 ng/ml for DUS; for SMX, the validated range was 1000-500,000 ng/ml for both DPS and DUS. Good agreement was noted between DPS/DUS and liquid plasma and urine samples for TMP, while only modest agreement was observed for SMX in both matrices.
Gonzalez D, Melloni C, Poindexter BB, Yogev R, Atz AM, Sullivan JE, Mendley SR, Delmore P, Delinsky A, Zimmerman K, Lewandowski A, Harper B, Lewis KC, Benjamin DK Jr, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act--Pediatric Trials Network Administrative Core Committee.
Bioanalysis, May 2015
AntibacterialsPublicationsSulfamethoxazoleTrimethoprim

Anaerobic antimicrobial therapy after necrotizing enterocolitis in VLBW infants

To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants. We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical).
Autmizguine J, Hornik CP, Benjamin DK Jr, Laughon MM, Clark RH, Cotten CM, Cohen-Wolkowiez M, Benjamin DK, Smith PB; Best Pharmaceuticals for Children Act—Pediatric Trials Network Administrative Core Committee.
Pediatrics, January 2015
AntibacterialsClindamycinInfantsLow birth weightMeropenemMetronidazoleNecrotizing enterocolitisPiperacillin-TazobactamPublications

Safety of milrinone use in neonatal intensive care units

Milrinone use in the neonatal intensive care unit has increased over the last 10 years despite a paucity of published safety data in infants. We sought to determine the safety of milrinone therapy among infants in the neonatal intensive care unit. We conducted a retrospective data analysis, identifying all infants who were exposed to milrinone and discharged from 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997-2010.
Samiee-Zafarghandy S, Raman SR, van den Anker JN, McHutchison K, Hornik CP, Clark RH, Smith PB; Best Pharmaceuticals for Children Act—Pediatric Trials Network Administrative Core Committee.
Early Human Development, January 2015
InfantsMilrinoneNeonatesPublicationsVasodilators

Intestinal Fatty-Acid Binding Protein and Metronidazole Response in Premature Infants

In premature infants with suspected intra-abdominal infection, biomarkers for treatment response to antimicrobial therapy are lacking. Intestinal fatty acid-binding protein (I-FABP) is specific to the enterocyte and is released in response to intestinal mucosal injury. I-FABP has not been evaluated as a surrogate marker of disease response to antimicrobial therapy. We examined the relationship between metronidazole exposure and urinary I-FABP concentrations in premature infants with suspected intra-abdominal infection.
Sampson MR, Bloom BT, Arrieta A, Capparelli E, Benjamin DK Jr, Smith PB, Kearns GL, van den Anker J, Cohen-Wolkowiez M.
Journal of Neonatal and Perinatal Medicine, November 2014
AntibacterialsInfantsInfectionsMetronidazoleNeonatesPrematurityPublications

Medication use in the neonatal intensive care unit

The aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time. We performed a retrospective review (2005-2010) of a large prospectively collected administrative database.
Hsieh EM, Hornik CP, Clark RH, Laughon MM, Benjamin DK Jr, Smith PB; Best Pharmaceuticals for Children Act—Pediatric Trials Network.
American Journal of Perinatology, October 2014
InfantsNeonatesNICUPrematurityPublications

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents

Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care.
Gonzalez D, Melloni C, Yogev R, Poindexter BB, Mendley SR, Delmore P, Sullivan JE, Autmizguine J, Lewandowski A, Harper B, Watt KM, Lewis KC, Capparelli EV, Benjamin DK Jr, Cohen-Wolkowiez M; Best Pharmaceuticals for Children Act – Pediatric Trials Network Administrative Core Committee.
Clinical Pharmacology and Therapeutics, September 2014
AdolescentsAntibacterialsChildren (2-11 years)ClindamycinInfantsInfectionsPrematurityPublications

Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design

Although ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (≤ 34 or >34 weeks) and postnatal age (PNA) (≤ 7 or >7 days).
Tremoulet A, Le J, Poindexter B, Sullivan JE, Laughon M, Delmore P, Salgado A, Ian-U Chong S, Melloni C, Gao J, Benjamin DK Jr, Capparelli EV, Cohen-Wolkowiez M; Administrative Core Committee of the Best Pharmaceuticals for Children Act-Pediatric Trials Network.
Antimicrobial Agents and Chemotherapy, June 2014
AmpicillinAntibacterialsInfectionsNeonatesPublications

Pharmacokinetics of Antimicrobials in Obese Children

Childhood obesity is common and results in substantial morbidity. The most commonly prescribed drugs in obese children are antibiotics. However, physiological changes associated with childhood obesity can alter antibiotic pharmacokinetics and optimal body size measures to guide dosing in this population are ill defined.
Sampson M, Cohen-Wolkowiez M, Benjamin D Jr, Capparelli E, Watt K.
GaBI Journal, June 2014
AdolescentsAntibacterialsChildren (2-11 years)ObesityPublications

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

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.
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.
JAMA, June 2014
AntifungalsCandidiasisFluconazoleInfantsPrematurityPublications

Population pharmacokinetics of intravenous acyclovir in preterm and term infants

Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population. We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis.
Sampson MR, Bloom BT, Lenfestey RW, Harper B, Kashuba AD, Anand R, Benjamin DK Jr, Capparelli E, Cohen-Wolkowiez M, Smith PB; Best Pharmaceuticals for Children Act–Pediatric Trials Network.
The Pediatric Infectious Disease Journal, December 2013
AcyclovirAntiviralsHerpes Simplex Virus (HSV)InfantsNeonatesPrematurityPublications

Comparative effectiveness of 3 surfactant preparations in premature infants

To compare effectiveness of 3 surfactant preparations (beractant, calfactant, and poractant alfa) in premature infants for preventing 3 outcomes: (1) air leak syndromes; (2) death; and (3) bronchopulmonary dysplasia (BPD) or death (composite outcome).
Trembath A, Hornik CP, Clark R, Smith PB, Daniels J, Laughon M; Best Pharmaceuticals for Children Act—Pediatric Trials Network.
Journal of Pediatrics, October 2013
Bronchopulmonary dysplasiaInfantsPrematurityPublicationsSurfactant

Adverse events associated with meropenem versus imipenem/cilastatin therapy in a large retrospective cohort of hospitalized infants

Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin. We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010.
Hornik CP, Herring AH, Benjamin DK Jr, Capparelli EV, Kearns GL, van den Anker J, Cohen-Wolkowiez M, Clark RH, Smith PB; Best Pharmaceuticals for Children Act-Pediatric Trials Network
The Pediatric Infectious Disease Journal, July 2013
AntibacterialsComplicated intra-abdominal infectionsInfantsMeropenemPublications

Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants

Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM).
Cohen-Wolkowiez M, Sampson M, Bloom BT, Arrieta A, Wynn JL, Martz K, Harper B, Kearns GL, Capparelli EV, Siegel D, Benjamin DK Jr, Smith PB; Best Pharmaceuticals for Children Act–Pediatric Trials Network.
The Pediatric Infectious Disease Journal, July 2013
AntibacterialsInfantsInfectionsMetronidazolePrematurityPublications

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections

Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections. Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively.
Cohen-Wolkowiez M, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Randolph DA, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Rich W, Brozanski BS, van den Anker J, Blumer J, Laughon M, Watt KM, Kearns GL, Capparelli EV, Martz K, Berezny K, Benjamin DK Jr, Smith PB; Meropenem Study Team.
Clinical Infectious Disease, December 2012
AntibacterialsComplicated intra-abdominal infectionsInfantsMeropenemNeonatesPrematurityPublications

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied.
Smith PB, Cohen-Wolkowiez M, Castro LM, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Bhatt-Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Brozanski BS, Sanchez P, van den Anker J, Blumer J, Kearns GL, Capparelli EV, Anand R, Benjamin DK Jr; Meropenem Study Team.
The Pediatric Infectious Disease Journal, October 2011
AntibacterialsComplicated intra-abdominal infectionsInfantsMeropenemNeonatesPrematurityPublications