Clinical Trial: Antibiotic "Dysbiosis" in Preterm Infants

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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.


Detailed Summary:

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 necrotizing enterocolitis, late onset sepsis, BPD, and mortality.


Sponsor: University of Florida

Current Primary Outcome: 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


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.


Original Secondary Outcome: Same as current

Information By: University of Florida

Dates:
Date Received: May 3, 2016
Date Started: January 2017
Date Completion: December 2018
Last Updated: February 2, 2017
Last Verified: February 2017