Rifampin Pharmacokinetics and Safety in Preterm and Term Infants

Antimicrobial Agents and Chemotherapy • May 2019.

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.

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.

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National Survey of Neonatal Intensive Care Unit Medication Safety Practices

American Journal of Perinatology • November 2018.

Greenberg RG, Smith PB, Bose C, Clark RH, Cotten CM, DeRienzo C.

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.

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

Early Human Development • October 2018.

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.

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.

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

Therapeutic Drug Monitoring • February 2018.

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.

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.

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A Weight Estimation Strategy for Preterm and Full-Term Infants

Global Pediatric Health • December 2017.

Abdel-Rahman SM, Paul IM, Delmore P, James L, Fearn L, Atz A, Poindexter B, Al-Uzri A, Lewandowski A, Harper B, Smith PB.

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.

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

Annals of Human Biology • December 2017.

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.

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.

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

The Pediatric Infectious Disease Journal • September 2017.

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.

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.

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

American Journal of Perinatology • April 2017.

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.

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.

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Respiratory Support for Very Low Birth Weight Infants Receiving Dexamethasone

The Journal of Pediatrics • April 2017.

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.

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

The Journal of Clinical Pharmacology • February 2017.

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.

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