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 Retrospective observational cohort study of electronic health record (EHR) data combined with pharmacokinetic model derived drug exposure predictions. EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. 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 her 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/day (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 [Odds ratio (OR) = 1.10, (95% confidence interval (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.

Use of Population Pharmacokinetics and Electronic Health Records to Assess Piperacillin–Tazobactam Safety in Infants

“…5 We did not observe a statistically significant relationship between piperacillin exposure and seizures, which could be due in part to the much smaller sample size in this study (746) compared to the published study (131,723 infants). 5 Also, the median age of first exposure was only 1 day for ampicillin (compared to 10.5 days for piperacillin-tazobactam) and serum creatinine measurements are considered less reliable in the first few days of life. 5,17 Alternatively, piperacillin could be less likely to cause seizures than ampicillin because of slight differences in chemical structure and central nervous system penetration.…”

“…5 The authors noted that the prevalence of seizure was lower on days when infants received optimal dosing, per recommendations from another published study 16 , compared to days when infants received higher or lower dosing. 5 We did not observe a statistically significant relationship between piperacillin exposure and seizures, which could be due in part to the much smaller sample size in this study (746) compared to the published study (131,723 infants). 5 Also, the median age of first exposure was only 1 day for ampicillin (compared to 10.5 days for piperacillin-tazobactam) and serum creatinine measurements are considered less reliable in the first few days of life.…”

“…5 In particular, a daily Cmax ss > 140 μg/mL was associated with a 1.76 fold increased odds of seizures (95% CI 1.35, 2.30). 5 The authors noted that the prevalence of seizure was lower on days when infants received optimal dosing, per recommendations from another published study 16 , compared to days when infants received higher or lower dosing.…”

“…5 In particular, a daily Cmax ss > 140 μg/mL was associated with a 1.76 fold increased odds of seizures (95% CI 1.35, 2.30). 5 The authors noted that the prevalence of seizure was lower on days when infants received optimal dosing, per recommendations from another published study 16 , compared to days when infants received higher or lower dosing. 5 We did not observe a statistically significant relationship between piperacillin exposure and seizures, which could be due in part to the much smaller sample size in this study (746) compared to the published study (131,723 infants).…”

“…A recent study confirmed the utility of using EHR data and pharmacokinetic modeling to assess the safety of ampicillin and seizure risks in neonates. 5 Although this approach was cost-effective and minimized risk by using simulated PK concentrations and routinely collected safety data, it might not be generalizable so the relationship between exposure and safety must be evaluated for other drugs.…”