Exposure-response Relationships of Metronidazole in Infants: Integration of Electronic Health Record Data With Population Pharmacokinetic Modeling-derived Exposure Simulation.

Abstract

Infants frequently receive metronidazole at variable doses and duration for surgical site infection prophylaxis and treatment of intra-abdominal infections. Seizures are a rare (but potentially devastating) side effect of metronidazole, yet the prevalence of seizures in infants, as well as the relationship with metronidazole dose and exposure, are unknown. We examined the Pediatrix Clinical Data Warehouse for infants in neonatal intensive care units from 1997 to 2018 who received at least 1 dose of metronidazole during their first 120 days of life. We used an existing population pharmacokinetic model to simulate exposure parameters, estimating multivariable associations between metronidazole dosing and exposure parameters, and the occurrence of seizure. There were 19,367 intravenous doses of metronidazole given to 1546 infants, and 31 experienced a seizure. Infants with a seizure had a longer median (interquartile values) duration of metronidazole exposure than those without (11 days [6, 15] vs. 7 [4, 11], P = 0.01). Each added day of metronidazole (OR = 1.06, 95% CI: 1.02-1.10), and each standard deviation increase in cumulative area under the plasma concentration-time curve (OR = 1.27, 95% CI: 1.11-1.45) were associated with increased odds of seizure. Higher simulated maximum plasma concentration was associated with lower odds of seizure (OR = 0.88, 95% CI: 0.81-0.96). Longer metronidazole exposure and higher cumulative exposure could be associated with increased odds of infant seizures. Using a large observational dataset allowed us to identify a rare adverse event, but prospective studies are needed to validate this finding and further characterize metronidazole dose- and exposure-safety relationships.