Antibiotic "Dysbiosis" in Preterm Infants
Condition: Enterocolitis, Necrotizing; Bacteremia; Bronchopulmonary Dysplasia; Intraventricular Hemorrhage; Periventricular Leukomalacia; Chronic Lung Disease; Ileal Perforation
MeSH terms: Bacteremia; Enterocolitis; Enterocolitis, Necrotizing; Lung Diseases; Bronchopulmonary Dysplasia; Leukomalacia, Periventricular; Hemorrhage
Study type: Interventional
Phase: Phase 2

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 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.
    

Intervention name(s): Antibiotic; Gastric fluid; Breast milk; Stool samples; Antibiotics - pre-emptive
Intervention type(s): Drug; Other; Other; Other; Drug
Intervention description(s): Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.; Microbiome, metabolome, and inflammatory mediators will be evaluated using gastric aspirate.; 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 intervention name(s): Ampicillin or Gentamicin or Cefotaxime; Gastric aspirate; Ampicillin or Gentamicin or Cefotaxime
Intervention MeSH terms: Anti-Bacterial Agents; Gentamicins; Ampicillin; Cefotaxime; Cefoxitin; Antibiotics, Antitubercular
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment