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Trial record 9 of 47 for:    necrotizing enterocolitis | NIH

Antibiotic "Dysbiosis" in Preterm Infants

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ClinicalTrials.gov Identifier: NCT02784821
Recruitment Status : Recruiting
First Posted : May 27, 2016
Last Update Posted : September 12, 2018
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Society for Pediatric Dermatology
Information provided by (Responsible Party):
University of Florida

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Enterocolitis, Necrotizing Bacteremia Bronchopulmonary Dysplasia Intraventricular Hemorrhage Periventricular Leukomalacia Chronic Lung Disease Retinopathy of Prematurity Ileal Perforation Drug: Antibiotic Other: Gastric fluid Other: Breast milk Other: Stool samples Drug: Antibiotics - pre-emptive Other: Skin swabs Phase 2

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  (Clinical Trial)
Estimated Enrollment : 420 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Antibiotic Effects on the Developing Microbiome, Metabolome and Morbidities in Preterm Neonates
Study Start Date : January 2017
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Antibiotics Control

These neonates have a clinical indication to receive antibiotics, such as maternal chorioamnionitis with fetal tachycardia. The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime and as part of standard of care blood tests such as complete blood cell counts, blood cultures, and C-reactive proteins will be performed.

Study interventions will include the collection of samples for the following: breast milk, gastric fluid, skin swabs and stool samples for analysis of the microbiome and metabolome.

Drug: Antibiotic
Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.
Other Name: Ampicillin or Gentamicin or Cefotaxime

Other: Gastric fluid
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Name: Gastric aspirate

Other: Breast milk
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.

Other: Stool samples
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.

Other: Skin swabs
The neonate's microbiome will be evaluated using infant's skin swab.

No Antibiotics Control

These neonates show no signs of respiratory distress(RDS) or have no indications of maternal chorioamnionitis. 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, skin swabs and stool samples for analysis of the microbiome and metabolome, along with standard of care complete blood counts, blood cultures, and C-reactive proteins.

Other: Gastric fluid
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Name: Gastric aspirate

Other: Breast milk
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.

Other: Stool samples
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.

Other: Skin swabs
The neonate's microbiome will be evaluated using infant's skin swab.

Randomized to pre-emptive antibiotics

This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime. Standard of care blood tests such as complete blood cell counts, blood cultures, and C-reactive proteins will be performed.

Study interventions will include the collection of samples for the following: breast milk, gastric fluid, skin swabs and stool samples for analysis of the microbiome and metabolome.

Other: Gastric fluid
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Name: Gastric aspirate

Other: Breast milk
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.

Other: Stool samples
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.

Drug: Antibiotics - pre-emptive
Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.
Other Name: Ampicillin or Gentamicin or Cefotaxime

Other: Skin swabs
The neonate's microbiome will be evaluated using infant's skin swab.

Randomized to no pre-emptive 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, skin swabs and stool samples for analysis of the microbiome and metabolome, along with standard of care complete blood counts, blood cultures, and C-reactive proteins.
Other: Gastric fluid
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Name: Gastric aspirate

Other: Breast milk
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.

Other: Stool samples
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.

Other: Skin swabs
The neonate's microbiome will be evaluated using infant's skin swab.




Primary Outcome Measures :
  1. Rates of necrotizing enterocolitis(NEC) [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and NEC


Secondary Outcome Measures :
  1. Rates of bacteremia [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and the development of bacteremia after the first week of life.

  2. Microbiota 16s ribosomal ribonucleic acid (rRNA) metagenomic sequencing [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Pacific BioSciences or Illumina sequencing will be done and the data analyzed using metagenomics Rapid Annotation using Subsystem Technology (MG-RAST).

  3. Microbial diversity analysis [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Microbial diversity is assessed using Chao1, Shannon, and ordination methods implemented using a software program called phyloseq package in R.42 Chao1 estimates the species richness for each sample, while the Shannon Index scores richness and abundance, though is not sufficient in assessing overall microbiome differences. Detrended Correspondence Analysis (DCA), a multivariate statistical method, will be applied to detect overall microbiome differences. Adonis methods were used to attribute additional variables' contribution to microbial variance.

  4. Calprotectin (microgram per gram) levels in stool [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Calprotectin levels will be analyzed using an ELISA kit.

  5. Metabolomic analysis (microMol per gram) in gastric aspirate, stool, and breast milk [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Metabolites as biomarkers of microbial-host metabolism will be identified by nuclear magnetic resonance and mass spectrometry. Levels of vitamins(microMol per gram), polyphenols(microMol per gram), cholesterol (microMol per gram), and short chain fatty acids(microMol per gram) will be measured.

  6. S1000A12 (microgram per gram) in stool [ Time Frame: Until discharge from the NICU, up to 1 year ]
    S1000A12 levels will be analyzed using an ELISA kit.

  7. Intraleukin-6 (micrograms per gram) in stool [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Intraleukin-6 values will be assessed using multiplex technologies.

  8. Intraleukin-8 (micrograms per gram) in stool [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Intraleukin-8 values will be assessed using multiplex technologies.

  9. Intraleukin-10 (micrograms per gram) in stool [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Intraleukin-10 values will be assessed using multiplex technologies.

  10. Rates of retinopathy of prematurity (ROP) [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and ROP

  11. Rates of chronic lung disease [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and chronic lung disease

  12. Rates of bronchopulmonary dysplasia (BPD) [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and diagnosis of BPD.

  13. Rates of spontaneous ileal perforation [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and spontaneous ileal perforation

  14. Rates of intraventricular hemorrhage [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and intraventricular hemorrhage

  15. Rates of periventricular leukomalacia [ Time Frame: Until discharge from the NICU, up to 1 year ]
    Enrolled subjects' medical record will be reviewed to determine the association between antibiotic administration and periventricular leukomalacia



Information from the National Library of Medicine

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Ages Eligible for Study:   23 Weeks to 33 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All infants less than 33 weeks gestation.

Exclusion Criteria:

  • Infants who are non-viable at birth.

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): NCT02784821


Contacts
Contact: Kelly Curry, MSN 352 273 8979 hernack1@ufl.edu

Locations
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Josef Neu, MD    352-273-8985    neu@ufl.edu   
Sponsors and Collaborators
University of Florida
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Society for Pediatric Dermatology
Investigators
Principal Investigator: Josef Neu, MD University of Florida

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02784821     History of Changes
Other Study ID Numbers: IRB201501045-N
R21HD088005 ( U.S. NIH Grant/Contract )
First Posted: May 27, 2016    Key Record Dates
Last Update Posted: September 12, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Enterocolitis
Enterocolitis, Necrotizing
Hemorrhage
Lung Diseases
Bacteremia
Bronchopulmonary Dysplasia
Retinopathy of Prematurity
Cerebral Hemorrhage
Leukomalacia, Periventricular
Pathologic Processes
Respiratory Tract Diseases
Bacterial Infections
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Ventilator-Induced Lung Injury
Lung Injury
Infant, Premature, Diseases
Infant, Newborn, Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Retinal Diseases
Eye Diseases
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases