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| ID | Type | Description | Link |
|---|---|---|---|
| R21HD088005 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
| Society for Pediatric Dermatology | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A - Antibiotics Indicated | Other | 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. |
|
| Group B - antibiotics not indicated | Other | 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. |
|
| Group CI/randomized to antibiotics | Other | 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. |
|
| Group CII/randomized to no antibiotics | Other |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Antibiotic | Drug | Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Until discharge from the NICU, up to 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Until discharge from the NICU, up to 1 year |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Josef Neu, MD | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida | Gainesville | Florida | 32610 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39373498 | Derived | Ojeda A, Akinsuyi O, McKinley KL, Xhumari J, Triplett EW, Neu J, Roesch LFW. Increased antibiotic resistance in preterm neonates under early antibiotic use. mSphere. 2024 Oct 29;9(10):e0028624. doi: 10.1128/msphere.00286-24. Epub 2024 Oct 7. | |
| 37308133 | Derived | Singh NK, Will L, Al-Mulaabed S, Ruoss L, Li N, de La Cruz D, Gurka M, Neu J. Antibiotics Use and Its Effects on the Establishment of Feeding Tolerance in Preterm Neonates. Am J Perinatol. 2024 May;41(S 01):e2248-e2253. doi: 10.1055/a-2108-1960. Epub 2023 Jun 12. |
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98 infants were enrolled in the study and were included in the arms of the study to receive intervention.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group B: Antibiotics Not Indicated | Infant not receiving antibiotics secondary to asymptomatic and delivered to mom's without high perinatal infectious risk factors. |
| FG001 | Group A: Antibiotics Indicated | Infants delivered to high infectious risk mothers or infants with symptoms out of proportion to what is expected for gestational age. |
| FG002 | Group CI/Randomized to Antibiotics | Infants in Group CI/antibiotics were randomized to antibiotics. Infants were eligible for randomization if they were delivered to moms with low perinatal infectious risk factor AND they had symptoms as expected for gestation. |
| FG003 | Group CII/Randomized to no Antibiotics | Group CII/no antibiotics. Infant in group CII were randomized to no antibiotics. Infants were eligible for randomization if they were delivered to moms with low perinatal infectious risk factor AND they had symptoms as expected for gestation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
x2 test or ANOVA
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| ID | Title | Description |
|---|---|---|
| BG000 | Group A/Antibiotics Indicated | 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. Antibiotic: Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion. Gastric fluid: Microbiome and inflammatory mediators will be evaluated using gastric aspirate. Breast milk: Microbiome, and inflammatory mediators will be evaluated using mother's breast milk. Stool samples: Microbiome will be evaluated using infant's stool. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Posted | Number | adverse events composite outcome | Until discharge from the NICU, up to 1 year |
|
20 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group A: Antibiotics Indicated | Infants delivered to high infectious risk mothers or infants with symptoms out of proportion to what is expected for gestational age. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| early onset sepsis | Infections and infestations | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| late onset sepsis | Infections and infestations | Non-systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Josef Neu | University of Florida | 352-733-0111 | neuj@peds.ufl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 8, 2018 | Feb 7, 2021 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Nov 7, 2018 | May 1, 2024 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D020345 | Enterocolitis, Necrotizing |
| D016470 | Bacteremia |
| D001997 | Bronchopulmonary Dysplasia |
| D007969 | Leukomalacia, Periventricular |
| ID | Term |
|---|---|
| D004760 | Enterocolitis |
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
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| ID | Term |
|---|---|
| D000900 | Anti-Bacterial Agents |
| D000667 | Ampicillin |
| D005839 | Gentamicins |
| D002439 | Cefotaxime |
| D008895 | Milk, Human |
| ID | Term |
|---|---|
| D000890 | Anti-Infective Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
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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.
|
| Gastric fluid | Other | Microbiome evaluated using gastric aspirate. |
|
|
| Breast milk | Other | Microbiome will be evaluated using mother's breast milk. |
|
| Stool samples | Other | Microbiome will be evaluated using infant's stool. |
|
| Antibiotics | Drug | Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion. |
|
|
| 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. | 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 | 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 | until discharge from the NICU, up to one year. |
| Length of Stay. | length of stay in NICU in days. | Average days +/- standard deviation of hospitalization, up to 15 weeks |
| 33479274 | Derived | 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. |
| BG001 | Group B/Antibiotics Not Indicated | 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. Gastric fluid: Microbiome will be evaluated using gastric aspirate. Breast milk: Microbiome, metabolome, and inflammatory mediators will be evaluated using mother's breast milk. Stool samples: Microbiome will be evaluated using infant's stool. |
| BG002 | 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. Gastric fluid: Microbiome will be evaluated using gastric aspirate. Breast milk: Microbiome will be evaluated using mother's breast milk. Stool samples: Microbiome will be evaluated using infant's stool. Antibiotics - Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion. |
| BG003 | 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. Gastric fluid: Microbiome will be evaluated using gastric aspirate. Breast milk: Microbiome will be evaluated using mother's breast milk. Stool samples: Microbiome will be evaluated using infant's stool. |
| BG004 | Total | Total of all reporting groups |
| gestation age in weeks |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| cesarean delivery | Count of Participants | Participants |
|
| singleton | Count of Participants | Participants |
|
| birth weight | Mean | Standard Deviation | grams |
|
| OG001 | Group B/Antibiotics Not Indicated | 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. Gastric fluid: Microbiome will be evaluated using gastric aspirate. Breast milk: Microbiome will be evaluated using mother's breast milk. Stool samples: Microbiome will be evaluated using infant's stool. |
| OG002 | 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. Gastric fluid: Microbiome will be evaluated using gastric aspirate. Breast milk: Microbiome will be evaluated using mother's breast milk. Stool samples: Microbiome will be evaluated using infant's stool. Antibiotics: Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion. |
| OG003 | 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. Gastric fluid: Microbiome will be evaluated using gastric aspirate. Breast milk: Microbiome will be evaluated using mother's breast milk. Stool samples: Microbiome will be evaluated using infant's stool. |
|
|
| Secondary | 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. | x2 test | Posted | Number | participants | Until discharge from the NICU, up to 1 year |
|
|
|
| Secondary | 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. | x2 test | Posted | Count of Participants | Participants | Until discharge from the NICU, up to 1 year |
|
|
|
| Secondary | 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 | x2 test | Posted | Count of Participants | Participants | Until discharge from the NICU, up to 1 year |
|
|
|
| Secondary | Number of Deaths | Enrolled subjects' medical record will be reviewed to determine the number of death prior to discharge from neonatal intensive care unit | x2 test | Posted | Count of Participants | Participants | until discharge from the NICU, up to one year. |
|
|
|
| Secondary | Length of Stay. | length of stay in NICU in days. | Posted | Mean | Standard Deviation | days | Average days +/- standard deviation of hospitalization, up to 15 weeks |
|
|
|
| 5 |
| 32 |
| 0 |
| 32 |
| 6 |
| 32 |
| EG001 | Group B: Antibiotics Not Indicated | Infant not receiving antibiotics secondary to asymptomatic and delivered to mom's without high perinatal infectious risk factors. | 0 | 11 | 0 | 11 | 0 | 11 |
| EG002 | Group CI/Randomized to Antibiotics | Infants in Group CI/antibiotics were randomized to antibiotics. Infants were eligible for randomization if they were delivered to moms with low perinatal infectious risk factor AND they had symptoms as expected for gestation. | 4 | 28 | 0 | 28 | 5 | 28 |
| EG003 | Group CII/Randomized to no Antibiotics | Group CII/no antibiotics. Infant in group CII were randomized to no antibiotics. Infants were eligible for randomization if they were delivered to moms with low perinatal infectious risk factor AND they had symptoms as expected for gestation. | 5 | 27 | 1 | 27 | 4 | 27 |
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| D007410 |
| Intestinal Diseases |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D018805 | Sepsis |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D055397 | Ventilator-Induced Lung Injury |
| D055370 | Lung Injury |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D007235 | Infant, Premature, Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D004678 | Encephalomalacia |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010400 |
| Penicillin G |
| D010406 | Penicillins |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013457 | Sulfur Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D002505 | Cephacetrile |
| D002511 | Cephalosporins |
| D013843 | Thiazines |
| D008892 | Milk |
| D001628 | Beverages |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D003611 | Dairy Products |
| D005502 | Food |
| D019602 | Food and Beverages |
| Male |
|