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.
  
  
  METHODS
  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 Cmaxssand AUC24were 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.
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; Department of Pediatrics, Duke University School of Medicine, Durham, NC. Electronic address: christoph.hornik@duke.edu.
authors: Christoph P
authors: CP
authors: Hornik
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors: Daniel K
authors: DK
authors: Benjamin
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors: P Brian
authors: PB
authors: Smith
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors: Michael J
authors: MJ
authors: Pencina
authors: Department of Pediatrics, University of California, San Diego, La Jolla, CA.
authors: Adriana H
authors: AH
authors: Tremoulet
authors: Deparment of Biostatistics and Bioinformatics, Duke University, Durham, NC; Skaggs School of Pharmacy, University of California, San Diego, La Jolla, CA.
authors: Edmund V
authors: EV
authors: Capparelli
authors: Department of Pediatrics, Penn State University, Hershey, PA.
authors: Jessica E
authors: JE
authors: Ericson
authors: Pediatrix-Obstetrix Center for Research and Education, Sunrise, FL.
authors: Reese H
authors: RH
authors: Clark
authors: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors: Michael
authors: M
authors: Cohen-Wolkowiez
mesh_terms: D000667:Ampicillin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D015331:Cohort Studies; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D012189:Retrospective Studies; D018570:Risk Assessment; D012640:Seizures / Q000139:chemically induced / Q000453:epidemiology*
chemical_list: D000900:Anti-Bacterial Agents; D000667:Ampicillin
keywords: ampicillin; dosing; exposure; infants; seizure