The following is the summary of “Exposure-response Relationships of Metronidazole in Infants: Integration of Electronic Health Record Data With Population Pharmacokinetic Modeling-derived Exposure Simulation” published in the January 2023 issue of Pediatric Infectious Disease by Jane, et al. 

Metronidazole is often used to prevent surgical site infections and treat intra-abdominal infections in infants, albeit the dosage and length of treatment might vary widely. However, the incidence of seizures in babies and its correlation with metronidazole dose and duration of exposure remain unknown. Researchers looked at the Pediatrix Clinical Data Warehouse for newborns who were treated with metronidazole in a neonatal critical care unit at least once between 1997 and 2018. To estimate multivariable correlations between metronidazole dose, exposure factors, and seizure occurrence, investigators used a preexisting population pharmacokinetic model to simulate exposure parameters.

A total of 31 newborns had an epileptic episode after receiving one of the 19,367 intravenous metronidazole doses given to 1,546 infants. Median (interquartile values) length of metronidazole exposure was greater in infants who experienced seizures than in those who did not (11 days [6, 15] vs. 7 days [4, 11], P=0.01). In addition, the risks of having a seizure rose with the number of days on metronidazole (OR = 1.06, 95% CI: 1.02-1.10) and with an increase in the cumulative area under the plasma concentration-time curve (OR=1.27, 95% CI: 1.11-1.45) for each standard deviation. 

The probabilities of having a seizure was reduced at higher maximum plasma concentrations in the simulations (OR=0.88, 95% CI: 0.81-0.96). There may be an association between newborn metronidazole exposure over longer periods of time and higher cumulative exposure and an increased risk of infant seizures. Study group were able to detect an extremely uncommon side effect of metronidazole by using a large observational dataset, but more research is needed to confirm this result and better characterize the dose- and exposure-safety connections of this drug.