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

Clinical Infectious Diseases • August 2016.

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.

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.

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Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

Antimicrobial Agents and Chemotherapy • April 2016.

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.

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.

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

Journal of Neonatal and Perinatal Medicine • November 2014.

Sampson MR, Bloom BT, Arrieta A, Capparelli E, Benjamin DK Jr, Smith PB, Kearns GL, van den Anker J, Cohen-Wolkowiez M.

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.

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Medication use in the neonatal intensive care unit

American Journal of Perinatology • October 2014.

Hsieh EM, Hornik CP, Clark RH, Laughon MM, Benjamin DK Jr, Smith PB; Best Pharmaceuticals for Children Act—Pediatric Trials Network.

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.

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

Clinical Pharmacology and Therapeutics • September 2014.

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.

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.

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