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Perioperative Tissue Penetration of Antimicrobials in Infants

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ClinicalTrials.gov Identifier: NCT04299867
Recruitment Status : Recruiting
First Posted : March 9, 2020
Last Update Posted : September 25, 2020
Sponsor:
Information provided by (Responsible Party):
Duke University

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.

Condition or disease Intervention/treatment
Bowel Dysfunction 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.

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Study Type : Observational
Estimated Enrollment : 20 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Perioperative Tissue Penetration of Antimicrobials in Infants
Actual Study Start Date : July 15, 2020
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

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.





Primary Outcome Measures :
  1. Pharmacokinetic Clearance [ Time Frame: Day of Surgery + 12 hours ]
  2. Pharmacokinetic Half-life [ Time Frame: Day of Surgery + 12 hours ]
  3. Pharmacokinetic Volume of Distribution [ Time Frame: Day of Surgery + 12 hours ]
  4. Pharmacokinetic Area under the curve [ Time Frame: Day of Surgery + 12 hours ]

Secondary Outcome Measures :
  1. CYP2A6 quantification [ Time Frame: Day of Surgery + 12 hours ]
  2. Ratio of Metronidazole to 2-hydroxymetronidazole concentration [ Time Frame: Day of Surgery + 12 hours ]
  3. Ratio of Metronidazole in plasma/intestine [ Time Frame: Day of Surgery + 12 hours ]
  4. Ratio of 2-hydroxymetronidazole concentration in plasma/intestine [ Time Frame: Day of Surgery + 12 hours ]

Biospecimen Retention:   Samples Without DNA
Plasma samples Intestinal tissue


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 2 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Children < 2 years of age undergoing intestinal surgery
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04299867


Contacts
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Contact: Christoph Hornik, MD 919-684-8111 christoph.hornik@duke.edu
Contact: Sarah J Commander, MD 919-684-8111 sarah.commander@duke.edu

Locations
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United States, North Carolina
Duke University Health System Recruiting
Durham, North Carolina, United States, 27710
Contact: Sarah J Commander, MD    919-684-8111    sarah.commander@duke.edu   
Contact: Stacy S Murray    919-684-7983    stacy.murray@duke.edu   
Principal Investigator: Christoph Hornik, MD         
Sponsors and Collaborators
Duke University
Investigators
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Principal Investigator: Christoph Hornik, MD Duke University
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Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT04299867    
Other Study ID Numbers: Pro00103890
First Posted: March 9, 2020    Key Record Dates
Last Update Posted: September 25, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Aggregate data and results will be shared in publication

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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
Additional relevant MeSH terms:
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Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Metronidazole
Anti-Infective Agents
Anti-Bacterial Agents
Antiprotozoal Agents
Antiparasitic Agents