Metronidazole exposure–response and safety in infants

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 <i>C</i><sub>min,ss</sub>, <i>C</i><sub>max,ss</sub>, AUC0<sub>0-24,ss</sub>, and AUC<sub>cum</sub> 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.

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Journal
Antimicrobial Agents and Chemotherapy
Published
2025-09-19
DOI
https://doi.org/10.1128/aac.00377-25
Primary Topic
Antibiotics Pharmacokinetics and Efficacy
Type
article
Field-Weighted Citation Impact
0.00

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article

Metronidazole exposure–response and safety in infants

Hala Chaaban, Janice E. Sullivan, Andrea Trembath, Stephen J. Balevic et al.
Antimicrobial Agents and Chemotherapy
Antibiotics Pharmacokinetics and Efficacy
article

Metronidazole exposure–response and safety in infants

Hala Chaaban, Janice E. Sullivan, Andrea Trembath, Stephen J. Balevic, Ian M. Paul, Lily Chen, Fernando Moya, Zoë Sund, Rachel L. Randell, Michael Cohen‐Wolkowiez, Rakesh Chhabra, Jennifer Cermak, Leanne L. West, Rose Beci, Chi Dang Hornik, Matthew M. Laughon, Ravinder Anand, Matthew A. Saxonhouse, Kelly C. Wade, Gregory M. Sokol, Naveed Hussain, Gina Simone, Christiane E.L. Dammann, Phyllis Kennel, Gregory L. Kearns, Lawrence Taylor, Adrian Lavery, Kanecia Obie Zimmerman, Rachel G. Greenberg, Michael J. Smith, Daniel K. Benjamin, Joseph M. Bliss, Kathleen L. O’Connor, Cheryl Alderman, Jörn-Hendrik Weitkamp, Christoph P. Hornik, Catherine M. Bendel, Kylie Opel, L. Corbin Downey, Elizabeth Payne
article en

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 <i>C</i><sub>min,ss</sub>, <i>C</i><sub>max,ss</sub>, AUC0<sub>0-24,ss</sub>, and AUC<sub>cum</sub> 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.

Antimicrobial Agents and ChemotherapyVol. 69(11)
University of North Carolina at Chapel Hill (US), Tufts University (US), Atrium Health Wake Forest Baptist (US), Tufts Medical Center (US), Monroe Carell Jr. Children's Hospital (US), Children's Hospital of Orange County (US), Pennsylvania State University (US), Hackensack University Medical Center (US), Children's Hospital of Philadelphia (US), Duke University (US), University of Rochester Medical Center (US), Clinical Research Institute (US), Wichita Medical Research and Education Foundation (US), The Coordinating Center (US), Monroe Carell Jr. Children's Hospital (US), Connecticut Children's Medical Center (US), Duke Medical Center (US), Levine Children's Hospital (US), University of Minnesota Medical Center (US), University of Louisville Hospital (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), Hackensack Meridian Health (US), Indiana University School of Medicine, University of Oklahoma Health Sciences Center (US), Indiana University – Purdue University Indianapolis (US), Indiana University (US), The University of Texas at Austin (US), Vanderbilt University Medical Center (US)
Biogen, Children's Hospital of Philadelphia, Vanderbilt University, University of Pennsylvania, Tufts Medical Center, Cincinnati Children's Hospital Medical Center, University of Minnesota, University of Louisville, University of Oklahoma, Pennsylvania State University, East Carolina University, Loma Linda University, Indiana University Health, Wichita Medical Research and Education Foundation, University of Texas Health Science Center at Houston, Vanderbilt University Medical Center, Connecticut Children's Medical Center, National Institutes of Health, University of North Carolina at Chapel Hill, Penn State College of Medicine, National Heart, Lung, and Blood Institute, National Institute of Child Health and Human Development, Duke Clinical Research Institute
Openalex Percentile: Top 71%
Antibiotics Pharmacokinetics and Efficacy
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