# Metronidazole exposure–response and safety in infants

## TL;DR

The study evaluated metronidazole dosing in infants and found it effective and safe for treating intra-abdominal infections.

## Contribution

This study provides evidence supporting current metronidazole dosing in infants based on exposure-response and safety data.

## Key findings

- Nearly 100% of pharmacodynamic targets for metronidazole were met in infants.
- No significant safety events were linked to metronidazole exposure in treated infants.

## Abstract

The nitroimidazole antibiotic, metronidazole, is frequently prescribed to
infants with serious intra-abdominal infections, and multiple dosing
recommendations exist. We sought to evaluate the extent to which
metronidazole doses and associated exposures achieved desired efficacy and
safety in infants enrolled in the Antibiotic Safety in Infants with
Complicated Intra-abdominal Infections (SCAMP) trial (NCT01994993). SCAMP
participants received intravenous metronidazole as part of multimodal
antimicrobial therapy. Participants received a 15 mg/kg loading dose and a
7.5 mg/kg maintenance dose at 24 h. A subsequent 7.5 mg/kg maintenance dose
was administered every 12 h for participants of postmenstrual age (PMA) 23
to <34 weeks; 8 h for PMA 34–40 weeks; and 6 h for PMA
>40 weeks. We evaluated associations between simulated metronidazole
exposures and pre-specified surrogate pharmacodynamic targets and clinical
outcomes of efficacy and safety. Nearly 100% of pharmacodynamic targets were
met. Infants with therapeutic success (a composite efficacy outcome, defined
as the absence of death, negative bacterial blood cultures, and presumptive
clinical cure at 30 days) had higher Cmin,ss,
Cmax,ss, AUC00–24,ss, and
AUCcum compared with infants without therapeutic success.
However, the relationships between these exposure measures and therapeutic
success were not significant in logistic regression analysis adjusting for
gestational age. Despite generally high simulated exposures, no
relationships were observed between exposures and prespecified safety events
(necrotizing enterocolitis, intestinal strictures, intestinal perforation,
positive blood culture, seizures, death, and intraventricular hemorrhage).
Findings support metronidazole dosing as administered in term and preterm
infants in the SCAMP trial.