Project Details

Perioperative Tissue Penetration of Antimicrobials in Infants

Sarah Commander, MD

Summary

BACKGROUND: Antibiotic concentrations in the intestines depend upon uptake from the blood stream into the intestinal wall and local metabolism, both of which are complex and understudied processes involving intestinal perfusion, endothelial integrity, and expression and function of metabolizing enzymes and transporters. Both processes are affected by pathophysiologic alterations of complicated intra-abdominal infections (cIAI) and by infant growth and maturation and remain incompletely understood. GAP: This study aims to define the pharmacokinetic (PK) properties of a commonly used antibiotic to treat cIAI, metronidazole, in the intestinal wall tissue of healthy infants undergoing intestinal surgery to optimize intestinal wall penetration of antibiotics in infants. HYPOTHESIS: Intestinal wall penetration and metabolism of metronidazole in infants will vary with age and require optimization of current dosing regimens to achieve adequate target tissue penetration. METHODS: This study is an open-label pilot PK study to concomitantly measure antibiotic concentrations in the plasma and the intestinal wall of infants without cIAI undergoing intestinal operations. RESULTS: A total of 21 infants were enrolled in this study with 16 males and 5 females with a median age of 3.0 months and median weight of 3.5 kg at the time of surgery. The median gestational age and birth weight were 35 weeks and 2.0 kg, respectively with 10 children born at less than 34 weeks. Nineteen baseline plasma samples were collected prior to metronidazole administration. Additional plasma samples were collected starting at 0 minutes after metronidazole administration and at 30-minute intervals until the end of surgery for a total of 110 plasma samples. Metronidazole concentration peaked a 0-minute time point and 2-hydroxymetronidazole peaked at the 3-4-hour time point. Median metronidazole plasma and tissue concentrations were significantly above target pharmacodynamic concentration of 8 mg/L IMPACT: Intestinal antibiotic concentrations in infants are unknown, which poses significant risk of under treatment with cIAI, where mortality can approach 30%. This report provides preliminary efficacy data for metronidazole administration in children with cIAI, ultimately supporting the optimization of current dosing regimens. PK analysis will be done using computing concentration ratios between plasma and tissue and performing nonlinear mixed effects modeling for dosing simulations as part of this ongoing analysis. This pilot study will inform the design of future studies in a cIAI population and help establish an efficient platform to broadly study tissue distribution of medications in infants by leveraging intraoperative biospecimen collection and PK modeling.