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

Background: Piperacillin, in combination with tazobactam, is frequently used in infants for treating nosocomial infections, although safety data in this population are limited. Electronic health record (EHR) data can be used to evaluate drug safety in infants, but measures of drug exposure are lacking. Methods: To relate simulated piperacillin exposure with adverse events (AEs) in infants using EHR data, we identified infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. Using a previously published population pharmacokinetic model in the target population, we simulated piperacillin steady state area under the concentration versus time curve from zero to t (AUC ss, 0t) and steady state maximal drug concentration (Cmax ss). Next, we used multivariable logistic regression to evaluate the association between simulated AUC ss, 0-t and Cmax ss with clinical AEs (seizure and rash) and laboratory AEs controlling for gestational age. The odds ratios (95% confidence intervals) comparing the third versus the first tertiles for AUC ss, 0-t and Cmax ss were reported. Results: We identified 746 infants with a median (interquartile range) gestational age of 30 weeks (26-33) and postnatal age of 11 days (6-25). The median ( interquartile range) piperacillin dose was 225 mg/kg/d (176-300). No significant associations were found between simulated piperacillin exposure (AUC ss, 0-t and Cmax ss) and clinical and laboratory AEs. Conclusions: We found no associations between predicted piperacillin exposures and the occurrence of AEs. This study confirms the feasibility of using population pharmacokinetics and EHR to relate drug exposure with safety.