- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02784821
Antibiotic "Dysbiosis" in Preterm Infants
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
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Florida
-
Gainesville, Florida, United States, 32610
- University of Florida
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- All infants less than 33 weeks gestation.
Exclusion Criteria:
- Infants who are non-viable at birth.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: 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 and stool samples for analysis of the microbiome and metabolome. |
Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.
Other Names:
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Names:
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.
|
Other: 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 and stool samples for analysis of the microbiome and metabolome, along with standard of care complete blood counts, blood cultures, and C-reactive proteins. |
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Names:
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.
|
Other: 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 and stool samples for analysis of the microbiome and metabolome. |
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Names:
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.
Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.
Other Names:
|
Other: 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 and stool samples for analysis of the microbiome and metabolome, along with standard of care complete blood counts, blood cultures, and C-reactive proteins.
|
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
Other Names:
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.
Microbiome, metabolome, and inflammatory mediators will be evaluated using infant's stool.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rates 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 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 |
---|---|---|
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.
|
Until discharge from the NICU, up to 1 year
|
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).
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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.
|
Until discharge from the NICU, up to 1 year
|
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
|
Until discharge from the NICU, up to 1 year
|
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
|
Until discharge from the NICU, up to 1 year
|
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 intraventricular hemorrhage
|
Until discharge from the NICU, up to 1 year
|
Rates of retinopathy of prematurity
Time Frame: Until discharge from the NICU, up to 1 year
|
Enrolled subjects' medical record will be reviewed to determine the association
|
Until discharge from the NICU, up to 1 year
|
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
|
Until discharge from the NICU, up to 1 year
|
Collaborators and Investigators
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Cardiovascular Diseases
- Vascular Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Infections
- Respiratory Tract Diseases
- Systemic Inflammatory Response Syndrome
- Inflammation
- Gastrointestinal Diseases
- Infant, Newborn, Diseases
- Gastroenteritis
- Intestinal Diseases
- Bacterial Infections
- Bacterial Infections and Mycoses
- Sepsis
- Lung Injury
- Infant, Premature, Diseases
- Ventilator-Induced Lung Injury
- Encephalomalacia
- Lung Diseases
- Hemorrhage
- Bacteremia
- Enterocolitis
- Enterocolitis, Necrotizing
- Bronchopulmonary Dysplasia
- Leukomalacia, Periventricular
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Protein Synthesis Inhibitors
- Antitubercular Agents
- Ampicillin
- Anti-Bacterial Agents
- Antibiotics, Antitubercular
- Gentamicins
- Cefotaxime
- Cefoxitin
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)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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.
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