Antibiotic "Dysbiosis" in Preterm Infants

June 3, 2024 updated by: University of Florida

Antibiotic Effects on the Developing Microbiome, Metabolome and Morbidities in Preterm Neonates

Prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities, including necrotizing enterocolitis (NEC), late-onset sepsis, bronchopulmonary dysplasia (BPD), and mortality.

The hypothesis is that early and prolonged antibiotic use in preterm neonates has significant consequences on the developing intestinal microbiome, metabolome and host response, predisposing the neonate to various major morbidities. It is possible that the effect of this widespread antibiotic use outweighs the potential benefits. This study will randomize preterm infants born at less than 33 weeks gestation to either pre-emptive antibiotics or no-pre-emptive antibiotics.

The purpose of this research is to evaluate the risks and benefits of current practice to determine optimal levels of antibiotic use that protects the babies from infection with minimal effect on the microbiome and subsequent adverse outcomes related to overuse of antibiotics.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

A majority of preterm very low birthweight (VLBW) infants are exposed to antibiotics. Surveys from large databases in the US show that the rate of culture proven bacteremia in these infants at birth is only between 1-2 percent.

Antibiotic use, especially when repeated, induces a perturbation ("dysbiosis") in gut microbiota that may not recover to the basal state. Antibiotic use increases the risk of subsequent disease and adverse outcomes. The dependence of the developing immune system on the intestinal microbiota is supported by emerging evidence from studies in animals demonstrating decreased resistance to subsequent disease with early exposure to antibiotics.

A retrospective review of 50,0261 neonates across 127 neonatal intensive care units (NICUs) from California showed a forty-fold variation in NICU antibiotic prescribing practice with similar burdens of proven infection and mortality. A large number of preterm infants are thus subjected to a potentially harmful course of antibiotics that provides no clear benefit. There remains a major gap in our understanding of antibiotic-related intestinal microbial dysbiosis and how this may result in disease.

There will be two aims. In the first aim, a prospective, randomized pilot study, will test the effects of pre-emptive postnatal antibiotics on the microbiome, metabolome and inflammatory responses in the neonate during the NICU course. The second aim will assess the effects of pre-emptive postnatal antibiotics on adverse outcomes in the neonate while in the NICU. The hypothesis is that higher antibiotic use will not be associated with decreased early onset sepsis and in fact, will be associated with increased adverse outcomes including retinopathy of prematurity, necrotizing enterocolitis, spontaneous ileal perforation, late onset sepsis, chronic lung disease, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, and mortality.

Study Type

Interventional

Enrollment (Actual)

98

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Gainesville, Florida, United States, 32610
        • University of Florida

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 months to 7 months (Child)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • All infants less than 33 weeks gestation.

Exclusion Criteria:

  • Infants who are non-viable at birth.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Group A - Antibiotics Indicated

These neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks.

The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime.

Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Drug: Antibiotic
Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.
Other Names:
  • Ampicillin or Gentamicin or Cefotaxime
Other: Gastric fluid
Microbiome evaluated using gastric aspirate.
Other Names:
  • Gastric aspirate
Other: Breast milk
Microbiome will be evaluated using mother's breast milk.
Other: Stool samples
Microbiome will be evaluated using infant's stool.
Other: Group B - antibiotics not indicated

These neonates are asymptomatic AND are delivered to moms with low perinatal infectious risk factors.

Antibiotics is not indicated for this group as standard of care.

Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Other: Gastric fluid
Microbiome evaluated using gastric aspirate.
Other Names:
  • Gastric aspirate
Other: Breast milk
Microbiome will be evaluated using mother's breast milk.
Other: Stool samples
Microbiome will be evaluated using infant's stool.
Other: Group CI/randomized to antibiotics

This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime.

Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Other: Gastric fluid
Microbiome evaluated using gastric aspirate.
Other Names:
  • Gastric aspirate
Other: Breast milk
Microbiome will be evaluated using mother's breast milk.
Other: Stool samples
Microbiome will be evaluated using infant's stool.
Drug: Antibiotics
Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.
Other Names:
  • Ampicillin or Gentamicin or Cefotaxime
Other: Group CII/randomized to no antibiotics

This group will be randomized not to receive standard of care antibiotics.

Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Other: Gastric fluid
Microbiome evaluated using gastric aspirate.
Other Names:
  • Gastric aspirate
Other: Breast milk
Microbiome will be evaluated using mother's breast milk.
Other: Stool samples
Microbiome will be evaluated using infant's stool.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Events of Composite Morbidities and Mortality, Including Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS), Bronchopulmonary Dysplasia (BPD) and Death
Time Frame: Until discharge from the NICU, up to 1 year
Enrolled subjects' medical record will be reviewed to determine the number of patients with the composite outcome and the association between antibiotic administration and the components of the composite outcome
Until discharge from the NICU, up to 1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Late Onset Sepsis
Time Frame: Until discharge from the NICU, up to 1 year
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed bacteremia after the first week of life (late onset sepsis) and the association between antibiotic administration and the development of late onset sepsis.
Until discharge from the NICU, up to 1 year
Number of Participants With Bronchopulmonary Dysplasia (BPD)
Time Frame: Until discharge from the NICU, up to 1 year
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed BPD and the association between antibiotic administration and diagnosis of BPD.
Until discharge from the NICU, up to 1 year
Number of Participants With Necrotizing Enterocolitis (NEC)
Time Frame: Until discharge from the NICU, up to 1 year
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed NEC and the association between antibiotic administration and necrotizing enterocolitis
Until discharge from the NICU, up to 1 year
Number of Deaths
Time Frame: until discharge from the NICU, up to one year.
Enrolled subjects' medical record will be reviewed to determine the number of death prior to discharge from neonatal intensive care unit
until discharge from the NICU, up to one year.
Length of Stay.
Time Frame: Average days +/- standard deviation of hospitalization, up to 15 weeks
length of stay in NICU in days.
Average days +/- standard deviation of hospitalization, up to 15 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Florida

Collaborators

Society for Pediatric Dermatology
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

  • Principal Investigator: Josef Neu, MD, University of Florida

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 16, 2017

Primary Completion (Actual)

September 11, 2019

Study Completion (Actual)

September 11, 2019

Study Registration Dates

First Submitted

May 3, 2016

First Submitted That Met QC Criteria

May 24, 2016

First Posted (Estimated)

May 27, 2016

Study Record Updates

Last Update Posted (Actual)

June 5, 2024

Last Update Submitted That Met QC Criteria

June 3, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB201501045-N
  • R21HD088005 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe