Antibiotic "Dysbiosis" in Preterm Infants

Bronchopulmonary Dysplasia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02784821
• Other study ID #: IRB201501045-N
• Secondary ID: R21HD088005
• Status: Completed
• Phase: Phase 2
• Start date: January 16, 2017
• Est. completion date: September 11, 2019

Study information

• Verified date: April 2020
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 186
• Est. completion date: September 11, 2019
• Est. primary completion date: September 11, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 23 Weeks to 33 Weeks

Eligibility

Inclusion Criteria:

• All infants less than 33 weeks gestation.

Exclusion Criteria:

• Infants who are non-viable at birth.

Related Conditions & MeSH terms

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

Intervention

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

Other:
• Gastric fluid
Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.
• Breast milk
Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk.
• 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.

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida

Sponsors (3)

Lead Sponsor	Collaborator
University of Florida	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Society for Pediatric Dermatology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rates of composite morbidities and mortality, including necrotizing enterocolitis(NEC), late onset sepsis (LOS), bronchopulmonary dysplasia (BPD) and death	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	Rates of bacteremia	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
Secondary	Microbiota 16s ribosomal ribonucleic acid (rRNA) metagenomic sequencing	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
Secondary	Microbial diversity analysis	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
Secondary	Calprotectin (microgram per gram) levels in stool	Calprotectin levels will be analyzed using an ELISA kit.	Until discharge from the NICU, up to 1 year
Secondary	Metabolomic analysis (microMol per gram) in gastric aspirate, stool, and breast milk	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
Secondary	S1000A12 (microgram per gram) in stool	S1000A12 levels will be analyzed using an ELISA kit.	Until discharge from the NICU, up to 1 year
Secondary	Intraleukin-6 (micrograms per gram) in stool	Intraleukin-6 values will be assessed using multiplex technologies.	Until discharge from the NICU, up to 1 year
Secondary	Intraleukin-8 (micrograms per gram) in stool	Intraleukin-8 values will be assessed using multiplex technologies.	Until discharge from the NICU, up to 1 year
Secondary	Intraleukin-10 (micrograms per gram) in stool	Intraleukin-10 values will be assessed using multiplex technologies.	Until discharge from the NICU, up to 1 year
Secondary	Rates of bronchopulmonary dysplasia (BPD)	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
Secondary	Rates of spontaneous ileal perforation	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
Secondary	Rates of intraventricular hemorrhage	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
Secondary	Rates of necrotizing enterocolitis (NEC)	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
Secondary	Rates of retinopathy of prematurity	Enrolled subjects' medical record will be reviewed to determine the association	Until discharge from the NICU, up to 1 year
Secondary	Rates of periventricular leukomalacia	Enrolled subjects' medical record will be reviewed to determine the association	Until discharge from the NICU, up to 1 year