CompletedNCT02784821Updated Jun 5, 2024Results posted

Antibiotic "Dysbiosis" in Preterm Infants

A Phase 2 interventional study of Antibiotic and Gastric fluid in Enterocolitis, Necrotizing, Bacteremia and Bronchopulmonary Dysplasia, sponsored by University of Florida. Completed at 1 site in United States. Open to participants aged 23 Weeks to 33 Weeks. Per ClinicalTrials.gov, last updated 2024-06-05.

Sponsored by University of Florida · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 98
Allocation: Randomized
Ages: 23 Weeks to 33 Weeks
Sex: All

Study 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.

Read the 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.

Conditions studied

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

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In context

Enterocolitis, Necrotizing

228 studies on the registry are indexed under Enterocolitis, Necrotizing; 44 are open to participants now.

This study's enrollment of 98 is close to the median of 103 across 127 interventional studies indexed under Enterocolitis, Necrotizing.

Browse Enterocolitis, Necrotizing studies →

Lead sponsor

University of Florida is the lead sponsor of 1,287 studies on the registry; 199 are open to participants now.

Of its 180 completed or terminated interventional studies of FDA-regulated products, 143 (79%) have results posted.

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Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 23 Weeks to 33 Weeks
Sexes eligible: All
Accepts healthy volunteers: No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

All infants less than 33 weeks gestation.

Exclusion criteria

Exclusion Criteria:

Infants who are non-viable at birth.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 98 participants (actual)

Study arms

Other
Group A - Antibiotics Indicated
These neonates have a clinical indication to receive antibiotics such as symptoms out of expected for gestation OR delivered to moms with high perinatal infectious risks. The standard of care antibiotics include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Drug: Antibiotic · Other: Gastric fluid · Other: Breast milk · Other: Stool samples
Other
Group B - antibiotics not indicated
These neonates are asymptomatic AND are delivered to moms with low perinatal infectious risk factors. 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.
Other: Gastric fluid · Other: Breast milk · Other: Stool samples
Other
Group CI/randomized to antibiotics
This group will be randomized to receive standard of care antibiotics which include Ampicillin and Gentamicin or Cefotaxime. Study interventions will include the collection of samples for the following: breast milk, gastric fluid and stool samples for analysis of the microbiome.
Other: Gastric fluid · Other: Breast milk · Other: Stool samples · Drug: Antibiotics
Other
Group CII/randomized to no 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.
Other: Gastric fluid · Other: Breast milk · Other: Stool samples

Interventions

DrugAntibiotic
Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion.
Also known as: Ampicillin or Gentamicin or Cefotaxime
OtherGastric fluid
Microbiome evaluated using gastric aspirate.
Also known as: Gastric aspirate
OtherBreast milk
Microbiome will be evaluated using mother's breast milk.
OtherStool samples
Microbiome will be evaluated using infant's stool.
DrugAntibiotics
Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.
Also known as: Ampicillin or Gentamicin or Cefotaxime

What researchers measure

Primary outcomes

Number of Events 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 number of patients with the composite outcome and the association between antibiotic administration and the components of the composite outcome
Time frame: Until discharge from the NICU, up to 1 year

Secondary outcomes

Number of Participants With Late Onset Sepsis
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed bacteremia after the first week of life (late onset sepsis) and the association between antibiotic administration and the development of late onset sepsis.
Time frame: Until discharge from the NICU, up to 1 year
Number of Participants With Bronchopulmonary Dysplasia (BPD)
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed BPD and the association between antibiotic administration and diagnosis of BPD.
Time frame: Until discharge from the NICU, up to 1 year
Number of Participants With Necrotizing Enterocolitis (NEC)
Enrolled subjects' medical record will be reviewed to determine the number of patients who developed NEC and the association between antibiotic administration and necrotizing enterocolitis
Time frame: Until discharge from the NICU, up to 1 year
Number of Deaths
Enrolled subjects' medical record will be reviewed to determine the number of death prior to discharge from neonatal intensive care unit
Time frame: until discharge from the NICU, up to one year.
Length of Stay.
length of stay in NICU in days.
Time frame: Average days +/- standard deviation of hospitalization, up to 15 weeks

Results

Posted Jun 5, 2024

Limitations and caveats

Limitations of our study are a small n, infants enrolled at the peri-viable and high risk gestation (high risk for mortality and serious adverse events), and high number of infants changed from group CII/no antibiotics to receive antibiotics in the first 48hours of life.

Participant flow

The study protocol was approved by the University of Florida IRB in September 2016. Enrollment occurred between January 2017 and January 2019. The study was paused for a full IRB review secondary to adverse outcomes and resumed when the incident of adverse outcomes was similar to the national standard. Actual enrollment was 98 infants.

Participant flow — Overall Study
Milestone	Group B: Antibiotics Not Indicated	Group A: Antibiotics Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
Started	11	32	28	27
Completed	11	27	24	22
Not completed	0	5	4	5
Withdrew: Death	0	5	4	5

Outcome measures

PrimaryNumber of Events 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 number of patients with the composite outcome and the association between antibiotic administration and the components of the composite outcome

Time frame:: Until discharge from the NICU, up to 1 year
Reported as:: Number · adverse events composite outcome

Number of Events of Composite Morbidities and Mortality, Including Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS), Bronchopulmonary Dysplasia (BPD) and Death
adverse events composite outcome	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/ Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
Number of Events of Composite Morbidities and Mortality, Including Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS), Bronchopulmonary Dysplasia (BPD) and Death	19	1	9	14

SecondaryNumber of Participants With Late Onset Sepsis

Enrolled subjects' medical record will be reviewed to determine the number of patients who developed bacteremia after the first week of life (late onset sepsis) and the association between antibiotic administration and the development of late onset sepsis.

Time frame:: Until discharge from the NICU, up to 1 year
Reported as:: Number · participants

Number of Participants With Late Onset Sepsis
participants	Group A: Antibiotics Indicated	Group B: Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
Number of Participants With Late Onset Sepsis	6	0	5	4

SecondaryNumber of Participants With Bronchopulmonary Dysplasia (BPD)

Enrolled subjects' medical record will be reviewed to determine the number of patients who developed BPD and the association between antibiotic administration and diagnosis of BPD.

Time frame:: Until discharge from the NICU, up to 1 year
Reported as:: Count of participants · Participants

Number of Participants With Bronchopulmonary Dysplasia (BPD)
Participants	Group A: Antibiotics Indicated	Group B: Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
Number of Participants With Bronchopulmonary Dysplasia (BPD)	12	1	3	8

SecondaryNumber of Participants With Necrotizing Enterocolitis (NEC)

Enrolled subjects' medical record will be reviewed to determine the number of patients who developed NEC and the association between antibiotic administration and necrotizing enterocolitis

Time frame:: Until discharge from the NICU, up to 1 year
Reported as:: Count of participants · Participants

Number of Participants With Necrotizing Enterocolitis (NEC)
Participants	Group A: Antibiotics Indicated	Group B: Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
Number of Participants With Necrotizing Enterocolitis (NEC)	1	0	2	1

SecondaryNumber of Deaths

Enrolled subjects' medical record will be reviewed to determine the number of death prior to discharge from neonatal intensive care unit

Time frame:: until discharge from the NICU, up to one year.
Reported as:: Count of participants · Participants

Number of Deaths
Participants	Group A: Antibiotics Indicated	Group B: Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
Number of Deaths	5	0	4	5

SecondaryLength of Stay.

length of stay in NICU in days.

Time frame:: Average days +/- standard deviation of hospitalization, up to 15 weeks
Reported as:: Mean · days

Length of Stay.
days	Group B: Antibiotics Not Indicated	Group A: Antibiotics Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
Length of Stay.	26.5 ± 19.7	64.5 ± 40.5	53.9 ± 30	61.6 ± 40.1

Adverse events

Collected over 20 months. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Group A: Antibiotics Indicated	5/32 (15.6%)	0/32 (0%)	6/32 (18.8%)
Group B: Antibiotics Not Indicated	0/11 (0%)	0/11 (0%)	0/11 (0%)
Group CI/Randomized to Antibiotics	4/28 (14.3%)	0/28 (0%)	5/28 (17.9%)
Group CII/Randomized to no Antibiotics	5/27 (18.5%)	1/27 (3.7%)	4/27 (14.8%)

Most frequent serious events

Most frequent serious events
Event	Group A: Antibiotics Indicated	Group B: Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
early onset sepsisInfections and infestations	0/32	0/11	0/28	1/27

Most frequent other events

Most frequent other events
Event	Group A: Antibiotics Indicated	Group B: Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics
late onset sepsisInfections and infestations	6/32	0/11	5/28	4/27

Baseline characteristics

x2 test or ANOVA

Age, Continuous
Age, Continuous(gestation age in weeks)	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics	Total
Gestational age	28.2 ± 2.9	32.1 ± 1	29.2 ± 2.5	28.8 ± 2.8	29.1 ± 2.8

Sex: Female, Male
Sex: Female, Male(Participants)	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics	Total
Female	16	7	15	10	48
Male	16	4	13	17	50

Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics	Total
Count of participants	—	—	—	—	0

Region of Enrollment
Region of Enrollment(participants)	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics	Total
United States	32	11	28	27	98

cesarean delivery
cesarean delivery(Participants)	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics	Total
Count of participants	19	3	17	19	58

singleton
singleton(Participants)	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics	Total
Count of participants	24	10	20	21	75

birth weight
birth weight(grams)	Group A/Antibiotics Indicated	Group B/Antibiotics Not Indicated	Group CI/Randomized to Antibiotics	Group CII/Randomized to no Antibiotics	Total
Mean	1138 ± 446	1900 ± 417	1234 ± 424	1098 ± 384	1240 ± 479

Study locations

1 site

University of Florida
Gainesville, Florida 32610, United States

References and documents

Publications

Russell JT, Lauren Ruoss J, de la Cruz D, Li N, Bazacliu C, Patton L, McKinley KL, Garrett TJ, Polin RA, Triplett EW, Neu J. Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants. Sci Rep. 2021 Jan 21;11(1):1943. doi: 10.1038/s41598-021-80982-6. PubMed 33479274 ↗

Study documents

Protocol and statistical analysis plan ↗ · May 8, 2018
Informed consent form ↗ · Nov 7, 2018

PDFs hosted by the registry, ClinicalTrials.gov.

Individual participant data

Plan to share: No

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reached

Ran from Jan 2017 to primary completion in Sep 2019, 31 months.

Results were first posted in Jun 2024, 4 years 8 months after primary completion.

How these figures are worked out, and which studies are left out of them.

Registered: May 3, 2016
First posted: May 27, 2016
StartActual: Jan 16, 2017
Primary completionActual: Sep 11, 2019
CompletionActual: Sep 11, 2019
Results first posted: Jun 5, 2024
Last update: Jun 5, 2024

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Jun 5, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02784821
Lead sponsor: University of Florida
Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Society for Pediatric Dermatology
Responsible party: Sponsor
First posted: May 27, 2016
Start date: Jan 16, 2017
Primary completion: Sep 11, 2019
Completion: Sep 11, 2019
Results posted: Jun 5, 2024
Last update: Jun 5, 2024

Study contacts

Josef Neu, MD

principal investigator · University of Florida

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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