Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates.
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.
['Hornik|Christoph P|CP|', 'Benjamin|Daniel K|DK|', 'Smith|P Brian|PB|', 'Pencina|Michael J|MJ|', 'Tremoulet|Adriana H|AH|', 'Capparelli|Edmund V|EV|', 'Ericson|Jessica E|JE|', 'Clark|Reese H|RH|', 'Cohen-Wolkowiez|Michael|M|', '|||']
D000667:Ampicillin D000900:Anti-Bacterial Agents 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
ampicillin exposure seizure dosing infants