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

Best Pharmaceuticals for Children Act—Pediatric Trials Network

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective To evaluate the relationship between ampicillin dosing, exposure, and seizures. Study design 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. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR. Results We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95% CI 1.03, 1.17) and AUC24 (OR 1.11, 95% CI 1.05, 1.18) were associated with increased odds of seizures. Conclusions In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.

Original languageEnglish (US)
Pages (from-to)125-129.e1
JournalJournal of Pediatrics
Volume178
DOIs
StatePublished - Nov 1 2016

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Electronic Health Records
Ampicillin
Seizures
Pharmacokinetics
Newborn Infant
Neonatal Intensive Care Units
Birth Weight
Gestational Age
Observational Studies
Cohort Studies
Logistic Models
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health

Cite this

Best Pharmaceuticals for Children Act—Pediatric Trials Network. / Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates. In: Journal of Pediatrics. 2016 ; Vol. 178. pp. 125-129.e1.
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title = "Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates",
abstract = "Objective To evaluate the relationship between ampicillin dosing, exposure, and seizures. Study design 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. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR. Results We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95{\%} CI 1.03, 1.17) and AUC24 (OR 1.11, 95{\%} CI 1.05, 1.18) were associated with increased odds of seizures. Conclusions In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.",
author = "{Best Pharmaceuticals for Children Act—Pediatric Trials Network} and Hornik, {Christoph P.} and Benjamin, {Daniel K.} and Smith, {P. Brian} and Pencina, {Michael J.} and Tremoulet, {Adriana H.} and Capparelli, {Edmund V.} and Ericson, {Jessica E.} and Clark, {Reese H.} and Michael Cohen-Wolkowiez",
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Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates. / Best Pharmaceuticals for Children Act—Pediatric Trials Network.

In: Journal of Pediatrics, Vol. 178, 01.11.2016, p. 125-129.e1.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates

AU - Best Pharmaceuticals for Children Act—Pediatric Trials Network

AU - Hornik, Christoph P.

AU - Benjamin, Daniel K.

AU - Smith, P. Brian

AU - Pencina, Michael J.

AU - Tremoulet, Adriana H.

AU - Capparelli, Edmund V.

AU - Ericson, Jessica E.

AU - Clark, Reese H.

AU - Cohen-Wolkowiez, Michael

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Objective To evaluate the relationship between ampicillin dosing, exposure, and seizures. Study design 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. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR. Results We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95% CI 1.03, 1.17) and AUC24 (OR 1.11, 95% CI 1.05, 1.18) were associated with increased odds of seizures. Conclusions In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.

AB - Objective To evaluate the relationship between ampicillin dosing, exposure, and seizures. Study design 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. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR. Results We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95% CI 1.03, 1.17) and AUC24 (OR 1.11, 95% CI 1.05, 1.18) were associated with increased odds of seizures. Conclusions In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.

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DO - 10.1016/j.jpeds.2016.07.011

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