Clinical trial NCT04299867: Perioperative Tissue Penetration of Antimicrobials in Infants
Official title: Perioperative Tissue Penetration of Antimicrobials in Infants
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Bowel Dysfunction
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2020-03-09
Enrollment: 23
Sex: ALL
Minimum age (years): 0
Maximum age (years): 2
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Children \< 2 years of age undergoing intestinal surgery

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Pharmacokinetic Clearance
timeFrame: Day of Surgery + 12 hours
measure: Pharmacokinetic Half-life
timeFrame: Day of Surgery + 12 hours
measure: Pharmacokinetic Volume of Distribution
timeFrame: Day of Surgery + 12 hours
measure: Pharmacokinetic Area under the curve
timeFrame: Day of Surgery + 12 hours
Secondary outcomes:
measure: CYP2A6 quantification
timeFrame: Day of Surgery + 12 hours
measure: Ratio of Metronidazole to 2-hydroxymetronidazole concentration
timeFrame: Day of Surgery + 12 hours
measure: Ratio of Metronidazole in plasma/intestine
timeFrame: Day of Surgery + 12 hours
measure: Ratio of 2-hydroxymetronidazole concentration in plasma/intestine
timeFrame: Day of Surgery + 12 hours
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
Study officials:
affiliation: Duke University
name: Christoph Hornik, MD
role: PRINCIPAL_INVESTIGATOR
References: