Metronidazole exposure-response and safety in 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 C_min,ss, C_max,ss, AUC0_0-24,ss, and AUC_cum 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.