Antibiotic "Dysbiosis" in Preterm Infants

NCT ID: NCT02784821

Last Updated: 2024-06-05

Study Results

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Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

98 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-01-16

Study Completion Date

2019-09-11

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Enterocolitis, Necrotizing Bacteremia Bronchopulmonary Dysplasia Intraventricular Hemorrhage Periventricular Leukomalacia Chronic Lung Disease Ileal Perforation

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type OTHER

Antibiotic

Intervention Type DRUG

Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.

Gastric fluid

Intervention Type OTHER

Microbiome evaluated using gastric aspirate.

Breast milk

Intervention Type OTHER

Microbiome will be evaluated using mother's breast milk.

Stool samples

Intervention Type OTHER

Microbiome will be evaluated using infant's stool.

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.

Group Type OTHER

Gastric fluid

Intervention Type OTHER

Microbiome evaluated using gastric aspirate.

Breast milk

Intervention Type OTHER

Microbiome will be evaluated using mother's breast milk.

Stool samples

Intervention Type OTHER

Microbiome will be evaluated using infant's stool.

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.

Group Type OTHER

Gastric fluid

Intervention Type OTHER

Microbiome evaluated using gastric aspirate.

Breast milk

Intervention Type OTHER

Microbiome will be evaluated using mother's breast milk.

Stool samples

Intervention Type OTHER

Microbiome will be evaluated using infant's stool.

Antibiotics

Intervention Type DRUG

Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.

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.

Group Type OTHER

Gastric fluid

Intervention Type OTHER

Microbiome evaluated using gastric aspirate.

Breast milk

Intervention Type OTHER

Microbiome will be evaluated using mother's breast milk.

Stool samples

Intervention Type OTHER

Microbiome will be evaluated using infant's stool.

Interventions

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Antibiotic

Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.

Intervention Type DRUG

Gastric fluid

Microbiome evaluated using gastric aspirate.

Intervention Type OTHER

Breast milk

Microbiome will be evaluated using mother's breast milk.

Intervention Type OTHER

Stool samples

Microbiome will be evaluated using infant's stool.

Intervention Type OTHER

Antibiotics

Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.

Intervention Type DRUG

Other Intervention Names

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Ampicillin or Gentamicin or Cefotaxime Gastric aspirate Ampicillin or Gentamicin or Cefotaxime

Eligibility Criteria

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Inclusion Criteria

* All infants less than 33 weeks gestation.

Exclusion Criteria

* Infants who are non-viable at birth.
Minimum Eligible Age

23 Weeks

Maximum Eligible Age

33 Weeks

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role collaborator

Society for Pediatric Dermatology

OTHER

Sponsor Role collaborator

University of Florida

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Josef Neu, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

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University of Florida

Gainesville, Florida, United States

Site Status

Countries

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United States

References

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Ojeda A, Akinsuyi O, McKinley KL, Xhumari J, Triplett EW, Neu J, Roesch LFW. Increased antibiotic resistance in preterm neonates under early antibiotic use. mSphere. 2024 Oct 29;9(10):e0028624. doi: 10.1128/msphere.00286-24. Epub 2024 Oct 7.

Reference Type DERIVED
PMID: 39373498 (View on PubMed)

Singh NK, Will L, Al-Mulaabed S, Ruoss L, Li N, de La Cruz D, Gurka M, Neu J. Antibiotics Use and Its Effects on the Establishment of Feeding Tolerance in Preterm Neonates. Am J Perinatol. 2024 May;41(S 01):e2248-e2253. doi: 10.1055/a-2108-1960. Epub 2023 Jun 12.

Reference Type DERIVED
PMID: 37308133 (View on PubMed)

Russell JT, Lauren Ruoss J, de la Cruz D, Li N, Bazacliu C, Patton L, McKinley KL, Garrett TJ, Polin RA, Triplett EW, Neu J. Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants. Sci Rep. 2021 Jan 21;11(1):1943. doi: 10.1038/s41598-021-80982-6.

Reference Type DERIVED
PMID: 33479274 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

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R21HD088005

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB201501045-N

Identifier Type: -

Identifier Source: org_study_id

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