Perioperative Tissue Penetration of Antimicrobials in Infants

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. Metronidazole will be given at standard of care intravenous loading dose of 30 mg/kg 15 minutes prior to incision, with a maximum dose of 2g. Intraoperative plasma samples will be obtained from pre-existing vascular access catheters at end of bolus, 30, 60, 90 minutes, at time of intestinal excision, and at the end of the case in ethylenediaminetetraacetic acid microcontainers, exceeding no more than 5mL total.

Study Overview

• Status: Completed
• Conditions: Bowel Dysfunction
• Intervention / Treatment: Procedure: Bowel Surgery with Metronidazole

Detailed Description

This is a single center pilot pharmacokinetic (PK) study to concomitantly measure antibiotic concentrations in the plasma and the intestinal wall of healthy infants undergoing intestinal surgery.

Metronidazole will be given at standard of care intravenous loading dose of 30 mg/kg 15 minutes prior to incision, with a maximum dose of 2g. Exact time, dose, and infusion rate and duration will be recorded. The use of a loading dose will allow characterization of plasma and tissue PK after a single dose that would be expected with steady state dosing, thus increasing the translatability of the investigator's findings to cIAI treatment.

Intraoperative plasma samples will be obtained from pre-existing vascular access catheters at end of bolus, 30, 60, 90 minutes, at time of intestinal excision, and at the end of the case in ethylenediaminetetraacetic acid microcontainers, exceeding no more than 5mL total. At the time of intestinal excision, the surgeon will cut at least 250mg of intestine from the specimen, ensuring all layers of bowel are included. This sample will be placed in a sterile, dry container. All samples will be processed and stored in a -80°C freezer within 1 hour of acquisition. Samples will be batched and shipped to a central commercial laboratory (OpAns Analytical Solutions LLC, Durham, NC) for concentration measurement of metronidazole and its primary metabolite 2-hydroxymetronidazole using a HPLC/MS/MS plasma assay previously developed and validated per FDA guidance. This assay will be modified and validated for tissue concentration measurement utilizing porcine intestinal tissue and run over three mediums to ensure correct measurement. The samples will also be used to quantify CYP2A6 protein levels using commercially available enzyme-linked immunosorbent assay kits.

• Study Type: Observational
• Enrollment (Actual): 23

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Children < 2 years of age undergoing intestinal surgery

Description

Inclusion Criteria:

1. Age 0 to 2 years at enrollment
2. Written informed consent provided by a parent or legal guardian
3. Scheduled to undergo elective intestinal operation for the removal of non-infected bowel
4. Sufficient intravascular access to complete the study procedures

Exclusion Criteria:

1. Prior treatment with metronidazole for any dose during the 72 hours prior to study drug administration.
2. Patients with active inflammatory or infectious conditions of the bowel such as inflammatory bowel disease, Hirschprung's disease in the portion of bowel to be excised, diverticular disease, cancerous or pre-cancerous lesions, colitis, enteritis, ulcerative disease, Meckel's diverticulum, celiac disease, and irritable bowel syndrome.
3. Renal dysfunction defined as serum creatinine >2 mg/dL at enrollment
4. Receiving any extracorporeal life support including extracorporeal membrane oxygenation, ventricular assist devices, and renal replacement therapy at enrollment
5. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the participant or the quality of the data.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
< 34 weeks gestational age; Metronidazole will be given per standard of care prior to incision. Intraoperative plasma samples will be obtained from pre-existing vascular access catheters at end of bolus, 30, 60, 90 minutes, at time of intestinal excision(s), and at the end of the case in ethylenediaminetetraacetic acid microcontainers, exceeding no more than approximately 5 mL total. At the time of intestinal excision, the surgeon will cut at least 500 mg of intestine from the specimen, ensuring all layers of bowel are included. If more than one intestinal sample is taken during the surgery, such as in the case of multiple strictures removed, each sample will be obtained and labeled appropriately.	Procedure: Bowel Surgery with Metronidazole; Metronidazole will be given per standard of care prior to incision. Intraoperative plasma samples will be obtained from pre-existing vascular access catheters at end of bolus, 30, 60, 90 minutes, at time of intestinal excision(s), and at the end of the case in ethylenediaminetetraacetic acid microcontainers, exceeding no more than approximately 5 mL total. At the time of intestinal excision, the surgeon will cut at least 500 mg of intestine from the specimen, ensuring all layers of bowel are included. If more than one intestinal sample is taken during the surgery, such as in the case of multiple strictures removed, each sample will be obtained and labeled appropriately.
34 weeks gestational age; Metronidazole will be given per standard of care prior to incision. Intraoperative plasma samples will be obtained from pre-existing vascular access catheters at end of bolus, 30, 60, 90 minutes, at time of intestinal excision(s), and at the end of the case in ethylenediaminetetraacetic acid microcontainers, exceeding no more than approximately 5 mL total. At the time of intestinal excision, the surgeon will cut at least 500 mg of intestine from the specimen, ensuring all layers of bowel are included. If more than one intestinal sample is taken during the surgery, such as in the case of multiple strictures removed, each sample will be obtained and labeled appropriately.	Procedure: Bowel Surgery with Metronidazole; Metronidazole will be given per standard of care prior to incision. Intraoperative plasma samples will be obtained from pre-existing vascular access catheters at end of bolus, 30, 60, 90 minutes, at time of intestinal excision(s), and at the end of the case in ethylenediaminetetraacetic acid microcontainers, exceeding no more than approximately 5 mL total. At the time of intestinal excision, the surgeon will cut at least 500 mg of intestine from the specimen, ensuring all layers of bowel are included. If more than one intestinal sample is taken during the surgery, such as in the case of multiple strictures removed, each sample will be obtained and labeled appropriately.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic Clearance	Day of Surgery + 12 hours
Pharmacokinetic Half-life	Day of Surgery + 12 hours
Pharmacokinetic Volume of Distribution	Day of Surgery + 12 hours
Pharmacokinetic Area under the curve	Day of Surgery + 12 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
CYP2A6 quantification	Day of Surgery + 12 hours
Ratio of Metronidazole to 2-hydroxymetronidazole concentration	Day of Surgery + 12 hours
Ratio of Metronidazole in plasma/intestine	Day of Surgery + 12 hours
Ratio of 2-hydroxymetronidazole concentration in plasma/intestine	Day of Surgery + 12 hours

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: christoph Hornik, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2020
• Primary Completion (Actual): March 26, 2022
• Study Completion (Actual): April 25, 2022

Study Registration Dates

• First Submitted: March 5, 2020
• First Submitted That Met QC Criteria: March 6, 2020
• First Posted (Actual): March 9, 2020

Study Record Updates

• Last Update Posted (Actual): July 28, 2022
• Last Update Submitted That Met QC Criteria: July 27, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole
• Other Study ID Numbers: Pro00103890

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Aggregate data and results will be shared in publication

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No