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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Anaerobic antimicrobial therapy after necrotizing enterocolitis in VLBW infants

Pediatrics • January 2015.

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.

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).

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

The Pediatric Infectious Disease Journal • July 2013.

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.

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).

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