Clinical trial NCT02784821
Conditions: Enterocolitis, Necrotizing Bacteremia Bronchopulmonary Dysplasia Intraventricular Hemorrhage Periventricular Leukomalacia Chronic Lung Disease Ileal Perforation
Sponsor: University of Florida
Start date: 2017-01-16; Completion date: 2019-09-11
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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 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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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.
Interventions: intervention 1: Antibiotic intervention 2: Gastric fluid intervention 3: Breast milk intervention 4: Stool samples intervention 5: Antibiotics
Intervention descriptions: intervention 1: Babies that are assigned to antibiotics receive therapy based on the clinical team's discretion. intervention 2: Microbiome evaluated using gastric aspirate. intervention 3: Microbiome will be evaluated using mother's breast milk. intervention 4: Microbiome will be evaluated using infant's stool. intervention 5: Babies that are randomized to antibiotics receive therapy based on the clinical team's discretion.

Protocol documents:
Prot_SAP_001.pdf: 
 
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Cover Letter: 
Routine Early Antibiotic use in SymptOmatic preterm Neonates (REASON): a prospective randomized controlled trial.  
Protocol without Statistical Analysis Plan 
NCT02784821 
 


 
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Antibiotic Effects on the Developing Microbiome, Metabolome and Morbidities in Preterm Neonates 
 
SPECIFIC AIMS  
This research challenges existing dogma for pre-emptive antibiotic use in preterm infants immediately after birth. Antibiotic use, especially when 
repeated, induces a perturbation (“dysbiosis”) in gut microbiota that may not recover to the basal state.1-3 Antibiotic use increases the risk of 
subsequent disease and adverse outcomes. 4-8 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. 9-11 A 
majority of preterm very low birthweight (VLBW) infants are exposed to antibiotics. 12Surveys 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,12,13 which is consistent with our data from 3 University of Florida 
Hospitals, where we routinely do blood cultures after birth, but could find only 9 of nearly 900 infants less than 1,250 grams over a 5 year period 
whose cultures were positive. When cultures are done on cord blood with increased volumes of blood, there is a higher yield of positive cultures, but 
these are largely Ureaplasma urealyticum and Mycoplasma hominis14, mircoorganisms that are not that are not sensitive to the usual routine 
antimicrobial regimens provided right after birth. 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.15 Based on 
this review, 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.  
Our 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. We propose a randomized trial of pre-emptive antibiotics versus no-pre-emptive antibiotics in preterms born at <33 
weeks’ gestation.  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. We 
will take advantage of the unique expertise of our team and facilities to achieve the following aims: 
Aim 1. In a prospective, randomized pilot study, test the effects of pre-emptive postnatal antibiotics on the microbiome, metabolome and 
inflammatory responses in the neonate during the NICU course. We hypothesize that antibiotic use results in alterations in the microbial ecology of 
the intestinal microbiome that lasts well beyond discontinuance of antibiotic use and that this in turn results in altered fecal metabolic and 
inflammatory profiles that are associated with a higher incidence of adverse outcomes (Aim 2) while these infants are in the neonatal intensive care 
unit. .  
Aim 2. In this same prospective, randomized pilot study, test the effects of pre-emptive postnatal antibiotics on adverse outcomes in the neonate 
while in the NICU. We hypothesize that higher antibiotic use will not be associated with decreased early onset sepsis and will be associated with 
increased adverse outcomes including necrotizing enterocolitis, late onset sepsis and mortality. 


 
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Impact: Here we will provide new data on the functional consequences of the widespread use of antibiotics in care of infants born preterm using 
novel multi-omic and systems biology approaches that will provide a better understanding of how these relate to common morbidities in the NICU. 
Fulfilling the aims of this research should stimulate multicenter trials that could ultimately lead to beneficial changes in perinatal and neonatal 
intensive care. 
I. 
SIGNIFICANCE 
The use of routine antibiotics during pregnancy in order to avoid adverse maternal and neonatal outcomes is widespread despite a relative lack of 
evidence for efficacy.16  One exception to this has been intrapartum antimicrobial prophylaxis for Group B-Streptococcal disease. 17 There are no 
studies showing efficacy of postpartum prophylaxis against early onset sepsis. Antibiotics are by far the most common drugs given to neonates in the 
neonatal intensive care unit (NICU).12  The cost of these practices in terms of antibiotic-induced harm has only recently been questioned.18-22 In the 
preterm neonate, the rationale to routinely and pre-emptively give these antibiotics shortly after birth is speculative rather than evidence based and 
includes the immature immune system of these infants, the possibility that preterm delivery may have been caused by infection in the mother, that the 
immaturity-related respiratory distress cannot be readily distinguished from infectious pneumonia and that antibiotic use is safe.  This may be 
incorrect. The average length of treatment of this “standard of care” practice is between 5-7 days.4,13 Recent studies have shown an association 
between duration of early antibiotic use with increased odds of developing NEC, 4,5a disease with extremely high mortality and morbidity.23 We 24-
26and others27,28 have shown that NEC and late onset sepsis (LOS) are preceded by an intestinal dysbiosis, which may partially be due to antibiotic 
usage. There has also been a trend toward resistant microbes causing late onset sepsis in infants treated with an early course of antibiotics and the gut 
is a major source of entry into the bloodstream for microorganisms via translocation.28 It has been shown that the intestinal microbiome is 
significantly affected by the early use of antibiotics, and that this effect often persists after discontinuation of the antibiotic.2,19,21,29 It is very 
concerning that infants who receive 5-7 days of antibiotics in their first week had increased relative abundance of Enterobacteriacae and low 
diversity in the second and third weeks after birth.29 These infants also experienced more NEC, sepsis and death than those not exposed. 29 
 
These studies beg for a systematic study of the antibiotic effects on the microbiomes and metabolomes of the infant along with the effects on 
morbidity to better understand the consequences of these practices.  We hypothesize 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 adverse outcomes. 
Since the rationale for this possible abuse of antibiotics is based on tradition and fear rather than evidence, equipoise amongst neonatologists for a 
large randomized trial is currently lacking:  better evidence to support and guide such a trial is clearly needed. We propose that a systems biology 
approach utilizing “multi-omic” data will begin to fill a major gap in our knowledge of the consequences of antibiotic use in these infants that will 
lead to changes in practice. The data gathered in this pilot study will clarify the consequences of such widespread antibiotic use, and will be highly 
significant for lending credence for a larger trial which could lead to a paradigm shift in clinical neonatology. Our long-term goal is the 
development of regimes of antibiotic use (and perhaps microbial therapeutic measures) that provide protection against infection while maintaining 
gut health through a diverse microbiome.   
 
 
 
  


 
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II. INNOVATION 
• First randomized study of the effects of withholding pre-emptive antibiotics from preterm infants. 
• First comprehensive evaluation of the microbiome, metabolome and inflammatory response in relation to adverse outcomes in neonates 
exposed to routine versus non-preemptive antibiotics.  
• Development and use of novel bioinformatics tools that link clinical complex clinical metadata to the microbiome and metabolomes of 
preterm infants and their mothers. 
III. APPROACH 
 
 
Rationale. We previously showed that providing maternal antibiotics resulted in a lower microbial diversity of meconium in preterm infants born 
less than 32 week’s gestation. 30 Preterm infants whose meconium microbes are less diverse have a greater association with late onset sepsis. 31 A 
single dose of intrapartum antibiotics in another study resulted in significant shifts of the microbiota in the infants most evident at 30 days after 
birth.19  A recent study in mice elegantly showed that antepartum antibiotics can alter the offspring’s postnatal intestinal microbiota, decrease 
neutrophil and macrophage production via an interleukin-17 mediated mechanism, which in turn contributed to increased susceptibility of antibiotic-
exposed neonatal mice to Escherichia coli K1 and Klebsiella pneumoniae sepsis.10 A recent Cochrane review included a total of 14 studies 
randomizing 7,837 women. An increase in neonatal deaths was shown for infants of women receiving prophylactic antibiotics when compared with 
placebo. Comparing any antibiotics with placebo, a marginally non-statistically significant increase was shown in any functional impairment.32 In 
addition to the dysbiosis-inducing effects that antibiotics can cause in the pregnant mother, routine antibiotic use in the preterm infant requires further 
investigation. 
 Dysbiosis consists of one or a combination of several types: loss of keystone bacteria, loss of diversity, shifts in metabolic components and/or a 
bloom of pathogens that increases systemic inflammation. Preliminary studies by our group using Shannon Diversity Index on fecal samples obtained 
from infants less than 33 week’s gestational age show that those infants who received no antibiotics had considerably higher diversity at 6 weeks’ 
post-birth compared to those infants who received ampicillin and gentamicin for only 1 week or longer. This suggests a major effect of postnatal 
antibiotics on the microbiota and begs further studies evaluating the effects of  pre-emptively used antibiotics on preventing sepsis and their 
potentially detrimental effects using a “meta-biome” approach 33 
Patients and samples.  
All studies will be done at University of Florida Children’s neonatal intensive care unit (NICU) under an institutional review board (IRB) approved 
protocol. Mothers will undergo usual clinical care as per obstetrics. We plan to enroll 185maternal subjects and 185 neonatal subjects (approximately 
half of those available) during the course of the first year of this study. Informed consent will be obtained prior to delivery or within the first hours 
after birth.  
Aim 1. In a prospective, randomized pilot study, test the effects of pre-emptive postnatal antibiotics on 
the microbiome, metabolome and inflammatory responses in the neonate during the NICU course.  


 
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A telephonic consent will be utilized when mothers are not available to be consented in person. This includes consenting mothers of neonatal subjects 
that are born in an outside facility and then transferred to UFHealth Shands’ NICU. Most often, the mother is not transferred with the infant and in 
such cases, the mother will be contacted at the outside facility for consent.   
 
Subject to availability, we will be collecting a cutaneous microbiome sample within 24 hours of collecting a stool sample. This addition will allow 
for comparisons between the development of the microbiome in both the skin and gut within the same subject. It will also allow us to explore the 
impact of antibiotic exposure on cutaneous microbial diversity and adverse outcomes including sepsis. Skin swabs are collected using sterile 
technique. A cotton tip applicator will be rubbed on the subject’s forearm, or other area of skin easily accessible, in a circular motion for 20 seconds 
and placed in a sterile transport tube. Additional swabs will be collected at each time point to include a control “air” swab and an isolette/crib swab.  
The air swab will be opened and allowed to rest on the sterile field during the procedures and then place into a sterile transport tube.  The crib swab 
will be opened and the cotton tip applicator will be rubbed on the inside of the isolette on the same side as the subject’s forearm that is used for the 
study.  All three swabs will be moistened with 2-3 drops of sterile saline (sodium chloride) prior to collection. 
 
In the event of adverse outcomes, cultured pathogenic organisms will be compared to microbial profiles of the skin and intestine to explore which site 
was likely breached. The skin swabs will be collected within 24 hours of stool sample collection. 
 
Maternal diet can affect the fetal microbiome. We would like to gather information about the mother’s typical diet. We will provide the mothers an 
optional dietary recall form. As available, infant meconium and subsequent fecal samples (at least once a week), gastric fluid (from an existing 
standard of care gastric tube), and one breast milk sample (obtained in the first week after birth from mothers who choose to breast feed) will be 
collected and analyzed using techniques described in the approach section of the application. Fecal samples and skin swabs will be placed in -80-
degree C freezers as soon as possible.  
 
In terms of the rationale for obtaining the breast milk samples, the NICU at the Shands Hospital only provides human milk to babies born <33 weeks 
gestation in the first few weeks after birth. This can consist of milk from babies' own mothers or donor milk that is bought from a milk bank. Donor 
milk is pasteurized and should not contain live microbes, whereas babies' own mothers milk is known to contain cultivable microbes that may have a 
beneficial effect on the baby's developing gastrointestinal tract via alteration of the intestinal microbiome. In this study we have the opportunity to 
track whether the microbes from the mother's milk may be found in the infant GI tract and whether providing baby's own mothers milk versus donor 
milk may be a confounding factor that alters the microbial profile of the babies receiving antibiotics or not receiving the antibiotics. We will thus do 
16S sequencing analysis on the microbial profile of both donor and breast milk samples provided to the infants.  
Valuable information can be obtained from all groups of babies <33 weeks’ gestation, so all will be enrolled and have their microbiome, 
metabolome, inflammatory mediators and clinical outcomes analyzed. All of the individual groups will be categorized in intent to treat or not treat. 
Clinicians need to have the option to change treatment based on safety concerns for the patients.  
Our overarching goal is to establish the effects of early antibiotic use on the infant intestinal microbial ecology as well as the effects on intestinal 
microbial metabolite and inflammatory marker production and subsequent morbidities. Extensive metadata from both mothers and infants for the 


 
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newly derived samples will be transferred from our hospital EPIC electronic hospital record system into the REDCAP System. An enrollment log 
linking the subject’s name with their unique identifier will be kept in a password-protected, UF server. All other subject PHI will be transferred from 
directly from EPIC to REDCap. In order for our data to be able to interface with data sets being used for similar studies, we will utilize a newly 
developed standardized template for clinical studies in preterm birth. 
Subjects will be de-identified by assigning the mother and the neonate(s) dyad a unique identifier.  REDCap will assign neonatal subjects a subject 
number upon group assignment in REDCap. Maternal subjects will use the same subject number but will be linked to the neonate’s ID. 
After samples are collected, they will be labelled with the above mentioned identifier and kept in a freezer in the PI’s lab. This lab is locked. 
 
 
Covariates for the mother include: 
• Antibiotic use, type of antibiotic, and duration of therapy 
• Length of rupture of amniotic membranes 
• Prior or current infections 
• C-section versus vaginal delivery 
• Other drug use such as antacids or steroids  
• Dietary history 
• Body habitus 
• Placental pathology reports 
 
Covariates for the neonate include: 
• Feeding type (baby’s own mothers’ milk, donor milk, formula, fortification) 
• Morbidities (retinopathy of prematurity (ROP), chronic lung disease (CLD), bronchopulmonary dysplasia (BPD), necrotizing Enterocolitis 
(NEC), spontaneous ileal perforations (SIP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), sepsis after the first 
three days of life, sepsis before the first 3 days of life, death) 
• Length of time on parenteral nutrition 
• Duration of use of central arterial or venous catheters 
• Growth velocities 
• Complete blood count, blood culture, C-reactive protein results,  
• Antibiotic use, type of antibiotic, and duration of therapy 
• Date of birth 
• Gestational age 
 
Additional Covariates for the skin microbiome include: 


 
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• Location of swab collection (left arm, right arm),  
• Time of last meal/feeding 
• Time of last bath 
• Type of last bath including soap/wipe details (if recorded) 
• Topical medications and lotions applied  
• Time of last handling/kangaroo care 
• Time of last 2 diaper changes 
• Type of bed (isolette, crib, etc) 
• Start/stop dates of isolette humidity 
 
 
 
Randomization: 
We hypothesize that antibiotics will affect the microbial taxonomy, metabolic and inflammatory milieu of the developing gastrointestinal tract, and 
that non-pre-emptive use will not result in increased sepsis. We will have 3 groups to compare: the antibiotic-indicated group, the antibiotic not 
indicated group, and  the  randomized group, which will consist of 2 arms, subjects randomized to antibiotic therapy and those randomized to 
withhold antibiotic therapy 
 
The “Antibiotic Indicated Group” is one that we cannot justify randomizing because they are highly likely to be septic. This would represent about 
15% of the patients in our NICU as per our recent survey over the past 2 years. Guidelines for treating patients will be derived from newly published 
review based on a recent NIH workshop. As an example, if the mother has a temperature >39 degrees C. and if there are other symptoms such as fetal 
tachycardia, purulent fluid from the cervical os, maternal white blood cell count >15,000 in the absence of corticosteroids, the infant will be treated 
with antibiotics.   
The “Antibiotics Not Indicated Group” comprises babies who are at extremely low risk. This would represent about 20% of patients <33 weeks’ 
gestational age admitted to our NICU as per a recent survey over the past 2 years. These infants are ‘asymptomatic” showing no significant signs of 
respiratory distress or having other risk factors.  
Most of the infants who are “symptomatic” with respiratory distress requiring respiratory support over this time in our NICU were started on pre-
emptive antibiotic therapy.  This represents approximately 65% of the infants in our NICU over the past 2 years and is the group that will be 
randomized into “receive antibiotics” or “do not receive antibiotic” arms.  Group allocation will not be blinded. Standard open label UF Clinical 
Research Center methodology will be used for randomization.  Respiratory distress, apnea and bradycardia, feeding intolerance or other factors 
clearly associated with prematurity will not be exclusion criteria. The intent will be that no baby randomized to receive antibiotics (ampicillin and 
gentamicin) will be treated for more than 48 hours.  If the baby is allocated to the no antibiotic group and shows symptoms of deterioration along 


 
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with lab values (e.g., increasing CRP, abnormal CBC) that could be consistent with sepsis, the clinician can choose to “bail out” and initiate 
antibiotics.   
It is strongly suggested that all of these enrolled infants have blood cultures, complete blood counts and C-reactive proteins done shortly after birth as 
per routine care in our NICU.  Infants whose blood cultures are positive at any time will have intravenous antibiotics initiated as per clinical team 
discretion.  
 
 
The following scheme will be used for patient enrollment:  
 
 
 
Schedule of events: 
 
Prenatally: 
ICF is obtained from mother. This will be our primary means to obtain consent.  
0-6 Hours after birth:  
Babies <33 weeks 
gestation 
Antibiotics Indicated 
Antibiotics not indicated 
Randomized into 
Antibiotic Yes or No 
Groups 
Informed Consent: 
Samples collected as 
below.  


 
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Informed consent obtained if not done prenatally and mother is able to give informed consent 
• Infant is assigned to group A, B, or C based on obstetrical history and clinical appearance of subject. Subjects assigned to group C will be 
randomized to pre-emptive antibiotics or no pre-emptive antibiotics 
• Obtain gastric aspirate from standard of care gastric decompression tube, if gastric fluid is present 
1-3 days after birth: 
• Collect meconium sample, if available 
• Obtain 3ml of breast milk or donor milk if available 
• Collect skin swab 
      
Every week until neonate’s discharge: 
• Collect stool samples, if available 
• Collect skin swabs..  
 
Approximately 60% of the mothers delivering babies who are born <33 weeks’ gestation at UF receive prenatal antibiotics and 80 % of these infants 
begin to receive antibiotics starting in the first 12 hours after birth. The usual postnatal antibiotic regimen (>95%) in consists of intravenously 
administered ampicillin and gentamicin. In order for our data to be able to interface with data sets being used for similar studies, we will utilize a 
newly developed standardized template for clinical studies in preterm birth34.   
 
Inclusion Criteria: Valuable information can be obtained from all groups of babies <33 weeks’ gestation, so all consented neonatal subjects will have 
their microbiome, metabolome, inflammatory mediators and clinical covariates analyzed. All of the individual groups will be categorized in intent to 
treat or not treat. Clinicians need to have the option to change treatment based on safety concerns for the patients.  
Exclusion Criteria: The only exclusions will be those from whom we are not able to obtain informed consent and those infants likely considered to be 
non-viable. Respiratory distress, apnea and bradycardia, feeding intolerance or other factors clearly associated with prematurity will not be exclusion 
criteria. 
It will be strongly suggested that all enrolled infants will have blood cultures, complete blood counts and C-reactive proteins done shortly after birth 
as per routine care in our NICU.  Infants in the “Antibiotics Not Indicated Group” and those “symptomatic” infants randomized to “do not receive 
antibiotics” whose blood cultures are positive at any time will have intravenous antibiotics initiated as per clinical team discretion.  
For additional clarification on the length of time the antibiotics will be provided and the risks and benefits of the antibiotics, please note the 
following: 
a) Statistics from the literature suggest that the average number of days preterm babies undergo treatment with antibiotics after birth is 5-7 days. This 
varies tremendously between different NICUs, with many trying to limit antibiotic use to 48 hours and in some cases 24-48 hours. In our protocol, 
the group that will likely undergo this length of treatment (5-7 days) is the first group where the suspicion for early onset sepsis is very high. 


 
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However, in the group that is randomized, the length of time the babies randomized to receive antibiotics will be treated is projected to 48 hours. This 
48 hour course is consistent with current practice in our NICU when the level of suspicion is actually low, but the babies are still given a course of 
antibiotics pre-emptively until cultures can be read and the results returned to the physician. Thus, the randomized group will actually not be 
undergoing an alternative treatment.  
b) The risks of the antibiotics include: 1) the emergence of resistant microbes that may be much more difficult to treat;2) a higher risk of adverse 
outcomes such as increased necrotizing enterocolitis, late onset sepsis with more resistant organisms; 3) antibiotic induced metabolic alterations and 
epigenetic effects that may lead to diseases such as obesity in later life. The risk of not giving the antibiotic is that the baby may be harboring 
microbes that could cause an infection that is not being treated. We do not know whether the risks outweigh the benefits and that is the purpose of 
this study.  
c) Occasionally a regimen of antibiotics other than ampicillin and gentamicin is chosen, usually for suspicion of renal failure risk or an infection that 
may be incurred by a microbe that is not sensitive to ampicillin and/or gentamicin. This occurs relatively seldom, and we will only use babies who 
receive this regimen in the randomized part of the study. 
Risks: 
The are no risks to the mothers who are enrolled in this study. 
There is a potential risk that a neonate who is randomized to not receive antibiotics or in the “antibiotic not indicated group” could develop an 
infection. The primary medical team has the option to “bail out” of the randomization and initiate antibiotic therapy if the neonate shows signs of 
clinical deterioration along with corresponding lab values that support a presumptive diagnosis of sepsis (increasing C reactive protein, abnormal 
complete blood count values). Infants randomized to not receive antibiotics will receive a standard of care sepsis rule-out (CBC with differential, 
CRP, and blood cultures).  
Benefits: 
There are no benefits to the mothers who are enrolled in this study. 
Potential benefits for the neonate are decreased rates of late onset sepsis, NEC, death. 
Expected outcomes, potential pitfalls, and alternative strategies. We hypothesize that antibiotics will affect the microbial taxonomy, metabolic 
and inflammatory milieu of the developing gastrointestinal tract. We anticipate that non-pre-emptive use will not result in increased sepsis (non-
inferiority). As in our previous research that related the development of the microbiome to NEC, sepsis, and preterm birth, we will evaluate microbial 
taxonomy25,35-38, as well as more sophisticated metagenomics, metabolomics and inflammatory mediators (see below). We are well poised to analyze 
multi-omics data with our collaborator, Dr. Ana Conesa, who has specific expertise in multi-omic systems. We anticipate finding significant and 
lasting differences in the microbiome, metabolome and host inflammatory response related to antibiotic usage. For example, along with 
altered microbiota at 30 days after birth, we will find altered metabolites with antibiotic treatment. We are cognizant that these studies are not 
designed to determine specific mechanisms of disease pathogenesis, but instead, they are likely to provide robust associations in human preterm 
infants that will provide critical information for future studies of mechanisms as well as data that will provide strong impetus for prospective clinical 
trials to evaluate the necessity for the current widespread use of antibiotics.  
 


 
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. 
Aim 2 Test the effects of pre-emptive postnatal antibiotics on adverse outcomes in the 
neonate while in the NICU. We hypothesize that higher antibiotic use will not be associated 
with decreased early onset sepsis and will be associated with increased adverse outcomes 
including necrotizing enterocolitis, late onset sepsis, BPD, and mortality. 


 
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Rationale. Currently there are no studies correlating the developing microbiome, metabolome and inflammatory responses to subsequent adverse 
outcomes in the neonate in a prospective controlled manner. For aim 2, subjects enrolled in the Aim 1 studies will be followed in terms of their 
clinical status. The incidence of early onset sepsis (culture proven and suspected) will be evaluated and compared among and between the groups. 
Multivariable logistic regression will be conducted to determine independent relationships between initial empirical antibiotic therapy and study 
outcomes that control for birth weight, gestational age, race, prolonged premature rupture of membranes, days on mechanical ventilation, and the 
amount of breast milk received in the first 14 days after birth. 
Expected outcomes, potential pitfalls, and alternative strategies. We anticipate there will be an increase in adverse outcomes that correspond to 
perturbations in the microbiome, metabolome and inflammatory markers in the group receiving antibiotics. There are several confounding factors 
including maternal antibiotics, mode of delivery, gestational age, and length of rupture of membranes that will be taken into account using multiple 
regressions.  
Specific Methodologies 
Microbiota 16s rRNA, metagenomic sequencing, and analyses.  DNA, RNA and protein extraction, 16S rRNA amplication and sequencing, 16S 
rRNA analyses, metagenomic sequencing and genome assembly will be done as described previously. 39 In our previous work where certain bacteria 
were negatively correlated with gestational age 24, we found that a single bacterial genus would dominate the microbiome (>50% of the population).  
If we see several samples dominated by a single genus, we will mine these samples for whole genomes using PacBio sequencing to get a broader 
view of their physiology as we have done in the past. 39,40 Where shotgun metagenomics are needed for other, more complex samples, either PacBio 
or Illumina sequencing will be done and the data analyzed using MG-RAST.41 Dr. Triplett’s lab is highly capable of culturing difficult to culture 
microbes, if needed.  
Basic diversity indices (Chao1, Shannon) & ordination methods (DCA with adonis).  Microbial diversity is assessed using Chao1, Shannon, and 
ordination methods implemented using the 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. 
 
Inflammatory markers. Inflammatory markers will be analyzed by Dr. Nan Li using a combination of multiplex technologies using the BioRad 
Bio-Plex platform to obtain the comparative data from meconium samples. The markers evaluated include common markers of intestinal 
inflammation including calprotectin and S100A12, in addition to other markers such as IL-6, TNF, IL-10 and other cytokines and chemokines that 
may play a role in the inflammatory and/or anti-inflammatory process. These assays will be done on the stools of the babies. The data will be 
analyzed using direct comparisons of the 4 groups of infants using analysis of Variance and subsequent individual comparisons. 
 
Metabolomics. The microbiome plays a prominent role in human metabolism because microbes produce harmful and beneficial small molecules 
such as vitamins, polyphenols, cholesterol and short chain fatty acids43.  These analyses will be conducted at the CTSI Southeast Center for 


 
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Integrated Metabolomics at the University of Florida: http://secim.ufl.edu/. Metabolites in stool as biomarkers of microbial-host metabolism and 
breast milk samples will be identified by state-of-the-art NMR and MS.  
Data integration.   
Since this research will also include a clinical trial, DHHS regulations to protect humans from research risks will be undertaken. This will include 
parental informed consent, IRB approval, and registration with ClinicalTrials.gov.  
Safety: It is strongly suggested that all subjects have infection-screening labs done soon after delivery as per NICU standard of care to include CBC 
with differential, blood cultures, and C-reactive protein. Final determination about screening labs will be left to the judgment of the primary medical 
team. Subjects who are randomized to Group C, no antibiotics, have a small risk of developing an early onset infection. Adverse events for the study 
will include septicemia and death. 
Common morbidities which will be recorded are NEC, SIP, IVH/PVL, ROP, CLD, BPD, and rates of sepsis. 
DSMB is in place. The DSMB will meet after of 20 and 50 subjects have attained  32 weeks corrected age or discharge or earlier if there is any 
suggestion of greater than usual number of adverse events in patients enrolled in the study.  
Conflict of interest: 
The principal investigator and co-investigators have no conflicts of interest in this study. 
     
 
Summary: At the end of this 2 year project, we will have effectively challenged existing dogma that nearly all preterm infants require at least a short 
course of intravenous antibiotics. We will have a better understanding of the risks versus benefits of early pre-emptive antibiotic use in preterm 
infants. We will have a better understanding of the effects of antibiotics routinely given to pregnant women and preterm infants on the developing 
intestinal and human milk microbiome, metabolome and inflammatory status. It is anticipated that correlations to common morbidities such as late 
onset sepsis and necrotizing enterocolitis will be found. These will provide targets for future mechanistic based studies of causality. A greater 
justification for larger randomized trials may also result. 
 
 
 
 
 


 
201501045 revision 5/8/18 
 
References 
1. 
Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA 
sequencing. PLoS Biol 2008;6:e280. 
2. 
Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc 
Natl Acad Sci U S A 2011;108 Suppl 1:4554-61. 
3. 
Fouhy F, Guinane CM, Hussey S, et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following 
parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother 2012;56:5811-20. 
4. 
Cotten CM, Taylor S, Stoll B, et al. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing 
enterocolitis and death for extremely low birth weight infants. Pediatrics 2009;123:58-66. 
5. 
Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr 
2011;159:392-7. 
6. 
Blaser M. Antibiotic overuse: Stop the killing of beneficial bacteria. Nature 2011;476:393-4. 
7. 
Tripathi N, Cotten CM, Smith PB. Antibiotic use and misuse in the neonatal intensive care unit. Clin Perinatol 2012;39:61-8. 
8. 
Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature 
infants. J Pediatr 2011;159:720-5. 
9. 
Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012;489:231-41. 
10. 
Deshmukh HS, Liu Y, Menkiti OR, et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal 
mice. Nat Med 2014;20:524-30. 
11. 
Lamouse-Smith ES, Tzeng A, Starnbach MN. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ 
free mice. PLoS One 2011;6:e27662. 
12. 
Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: data from a large national data set. 
Pediatrics 2006;117:1979-87. 
13. 
Stoll BJ, Gordon T, Korones SB, et al. Early-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human 
Development Neonatal Research Network. J Pediatr 1996;129:72-80. 
14. 
Goldenberg RL, Andrews WW, Goepfert AR, et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma 
hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 2008;198:43 e1-5. 
15. 
Schulman J, Dimand RJ, Lee HC, Duenas GV, Bennett MV, Gould JB. Neonatal intensive care unit antibiotic use. Pediatrics 2015;135:826-33. 
16. 
Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P, Ota E. Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy 
outcomes and morbidity. The Cochrane database of systematic reviews 2015;1:CD002250. 
17. 
Schrag SJ, Verani JR. Intrapartum antibiotic prophylaxis for the prevention of perinatal group B streptococcal disease: experience in the United States 
and implications for a potential group B streptococcal vaccine. Vaccine 2013;31 Suppl 4:D20-6. 
18. 
Dardas M, Gill SR, Grier A, et al. The impact of postnatal antibiotics on the preterm intestinal microbiome. Pediatr Res 2014;76:150-8. 
19. 
Arboleya S, Sanchez B, Milani C, et al. Intestinal microbiota development in preterm neonates and effect of perinatal antibiotics. J Pediatr 2015;166:538-
44. 
20. 
Fricke WF. The more the merrier? Reduced fecal microbiota diversity in preterm infants treated with antibiotics. J Pediatr 2014;165:8-10. 


 
201501045 revision 5/8/18 
 
21. 
DiGiulio DB. Prematurity and perinatal antibiotics: a tale of two factors influencing development of the neonatal gut microbiota. J Pediatr 2015;166:515-
7. 
22. 
Tzialla C, Borghesi A, Serra G, Stronati M, Corsello G. Antimicrobial therapy in neonatal intensive care unit. Italian journal of pediatrics 2015;41:27. 
23. 
Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;364:255-64. 
24. 
Torrazza RM, Ukhanova M, Wang X, et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One 
2013;8:e83304. 
25. 
Mai V, Torrazza RM, Ukhanova M, et al. Distortions in development of intestinal microbiota associated with late onset sepsis in preterm infants. PLoS 
One 2013;8:e52876. 
26. 
Mai V, Young CM, Ukhanova M, et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 2011;6:e20647. 
27. 
Wang Y, Hoenig JD, Malin KJ, et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. 
ISME J 2009;3:944-54. 
28. 
Carl MA, Ndao IM, Springman AC, et al. Sepsis from the gut: the enteric habitat of bacteria that cause late-onset neonatal bloodstream infections. Clin 
Infect Dis 2014;58:1211-8. 
29. 
Greenwood C, Morrow AL, Lagomarcino AJ, et al. Early Empiric Antibiotic Use in Preterm Infants Is Associated with Lower Bacterial Diversity and Higher 
Relative Abundance of Enterobacter. J Pediatr 2014. 
30. 
Mshvildadze M, Neu J, Schuster J, Theriaque D, Li N, Mai V. Intestinal microbial ecology in premature infants assessed with non-culture-based 
techniques. J Pediatr 2010;156:20-5. 
31. 
Madan JC, Farzan SF, Hibberd PL, Karagas MR. Normal neonatal microbiome variation in relation to environmental factors, infection and allergy. Curr 
Opin Pediatr 2012;24:753-9. 
32. 
Flenady V, Hawley G, Stock OM, Kenyon S, Badawi N. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. The Cochrane 
database of systematic reviews 2013;12:CD000246. 
33. 
Fritz JV, Desai MS, Shah P, Schneider JG, Wilmes P. From meta-omics to causality: experimental models for human microbiome research. Microbiome 
2013;1:14. 
34. 
Myatt L, Eschenbach DA, Lye SJ, et al. A standardized template for clinical studies in preterm birth. Reprod Sci 2012;19:474-82. 
35. 
Mshvildadze M, Neu J, Schuster J, Theriaque D, Li N, Mai V. Microbial Ecology of the premature infant using non Culture ased techniques. 2009. 
36. 
Mai V, Young CM, Ukhanova M, et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 2011;6:e20647. 
37. 
Murgas Torrazza R, Neu J. The developing intestinal microbiome and its relationship to health and disease in the neonate. J Perinatol 2011;31:S29-34. 
38. 
Ardissone AN, de la Cruz DM, Davis-Richardson AG, et al. Meconium microbiome analysis identifies bacteria correlated with premature birth. PLoS One 
2014;9:e90784. 
39. 
Davis-Richardson AG, Ardissone AN, Dias R, et al. Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for 
type 1 diabetes. Frontiers in microbiology 2014;5:678. 
40. 
Leonard MT, Davis-Richardson AG, Ardissone AN, et al. The methylome of the gut microbiome: disparate Dam methylation patterns in intestinal 
Bacteroides dorei. Frontiers in microbiology 2014;5:361. 
41. 
Meyer F, Paarmann D, D'Souza M, et al. The metagenomics RAST server - a public resource for the automatic phylogenetic and functional analysis of 
metagenomes. BMC bioinformatics 2008;9:386. 
42. 
McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PloS one 2013;8:e61217. 
43. 
Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science 2012;336:1262-7. 


 
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ICF_002.pdf: 
IRB Project #: IRB201501045
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IRB Version: 10/19/2011
PI Version: 11/6/2018
INFORMED CONSENT FORM
to Participate in Research, and
AUTHORIZATION 
to Collect, Use, and Disclose Protected 
Health Information (PHI)
INTRODUCTION
Name of person seeking your consent:
Place of employment & position: 
Please read this form which describes the study in some detail. A member of the research 
team will describe this study to you and answer all of your questions.  Your participation is 
entirely voluntary.  If you choose to participate you can change your mind at any time and 
withdraw from the study.  You will not be penalized in any way or lose any benefits to which 
you would otherwise be entitled if you choose not to participate in this study or to withdraw.  
If you have questions about your rights as a research subject, please call the University of 
Florida Institutional Review Board (IRB) office at (352) 273-9600.   
GENERAL INFORMATION ABOUT THIS STUDY
1. Name of Participant ("Study Subject")
___________________________________________________________________ 
2.
What is the Title of this research study?
Antibiotic Effects on the Developing Microbiome, Metabolome and Morbidities in 
Preterm Neonates
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3.
Who do you call if you have questions about this research study?
Principal Investigator: Josef Neu, MD 352 273 8985 or 352 265 0033
Co-investigators:  Catalina Bazacliu, MD 352 273 8985 or 352 265 0033
                             Diomel de la Cruz, MD 352 273 8985 or 325 265 0033
                             Lauren Ruoss, MD 352 273 8985 or 352 265 0033                            
Other research staff: Sue Sinnamon, BSN  352-294-8642                                  
4.  Who is paying for this research study? 
The sponsors of this study are The University of Florida, the Children’s Miracle 
Network, the National Institutes of Health, and the Society for Pediatric Dermatology.
 5. In general, what do you need to know about this Research Study?
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
to which you are entitled. If you have questions about your rights as a research 
subject, please call the University of Florida Institutional Review Board (IRB) office at 
(352) 273-9600.    
a) In general, what is the purpose of the research, how long will you be involved?           
The purpose of this research is to evaluate the risks and benefits of current 
antibiotic use in babies born less than 33 weeks of gestation. Researchers want 
to know the best way to prevent infection in preterm babies and also keep their 
bowels healthy. The majority of preterm very low birth weight (VLBW) infants are 
exposed to antibiotics, despite data showing that proven blood infections in these 
infants at birth is only between 1-2 of 100 babies born. Neonatal Intensive Care 
Units (NICUs) in the US have different reasons to give antibiotics to preterm 
babies, but (NICUs) around the country have very similar rates of infections and 
other problems that are common with preterm babies. Mothers who choose to 
participate in this study will have information collected from the chart and babies 
will be enrolled until discharge.
           
         
.
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b) What is involved with your participation, and what are the procedures to be 
followed in the research?
If your baby needs a gastric tube, researchers will collect less than a teaspoon of 
stomach fluid, if available. If your baby does not need a gastric tube, no stomach 
fluid will be collected and no gastric tube will be placed. Every week after your 
baby is born, research staff will attempt to collect stool from your baby’s diapers. 
In addition, staff will attempt to collect a skin swab by rubbing a cotton swab on 
your baby’s forearm or other area of skin that is easily accessible. If you choose 
to breastfeed your baby, about a teaspoonful of breast milk will be collected after 
your baby is fed. From the babies chart, we will collect information about the 
baby’s diet, feeds, bathing, episodes of holding, the type/humidification of bed, 
soaps, lotions, types of IV’s/fluids, measurements, lab values and certain problems 
that preterm babies may develop. Your baby will be included in one of three 
groups: Babies that definitely need antibiotics, Babies that do not need antibiotics, 
and Babies that might or might not need antibiotics.
c) What are the likely risks or discomforts to you?
The risk of not giving antibiotics is that the baby may have bacteria that could 
cause an infection. The risks of receiving antibiotics that are not needed are not 
known. We do not know whether the risks outweigh the benefits. Researchers 
will take appropriate steps to protect any information they collect about you and 
your baby. There is a slight risk that information could be revealed accidentally.  
Participation in more than one research study may further increase the risks to 
you.
d) What are the likely benefits to you or to others from the research? 
Your baby may have healthier intestines and develop fewer infections as he or 
she stays in the NICU.   Our goal is to find out if giving routine antibiotics to 
babies who do not have infections causes more health problems like bowel 
infections and other infections that happen after the first week of life.
e) What are the appropriate alternative procedures or courses of treatment, if any, 
that might be helpful to you?
You may choose not to participate in this study.
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Additional and more detailed information is provided within the remainder of this 
Informed Consent form, please read before deciding if you wish to participate in this 
study.
Why is this research study being done? 
The majority of preterm very low birth weight (VLBW) infants are exposed to 
antibiotics, despite data showing that proven blood infections in these infants at birth 
is only between 1-2 of 100 babies born. Neonatal Intensive Care Units (NICUs) in the 
US have different reasons to give antibiotics to preterm babies, but (NICUs) around 
the country have very similar rates of infections and other problems that are common 
with preterm babies.
There are “good” bacteria in the bowels that are needed to help with digestion and 
fight infections. In preterm babies, these “good” bacteria are also needed to help the 
baby’s immune system develop. Some studies have suggested that early, 
unnecessary antibiotic use makes preterm babies less able to fight infections later. 
Antibiotics kill “good” bacteria. When the bacteria that should normally live in the 
intestine are reduced or killed, harmful bacteria may take their place inside the 
bowels. These harmful bacteria can cause a potentially deadly infection in the bowel 
called necrotizing enterocolitis or NEC. Harmful bacteria can also leave the bowel and 
enter the baby’s blood. Bacteria in the blood can make the baby very sick and cause 
long term problems. Many harmful bacteria can also cause inflammation in the brain 
tissue of preterm babies. Some studies have shown that preterm babies who have a 
bacterial blood infection while in the NICU have a higher risk of developing cerebral 
palsy when they are older.
There is some data that babies who received no antibiotics had considerably healthier 
intestinal environments at 6 weeks after birth compared to those infants who received 
antibiotics for 1 week or longer.
The purpose of this research is to evaluate the risks and benefits of current antibiotic 
use in babies born less than 33 weeks of gestation. Researchers want to know the 
best way to prevent infection in preterm babies and also keep their bowels healthy.
You are being asked to be in this research study because 
Your baby is less than 33 weeks gestational age and:
  Needs antibiotics because he or she has a high risk of getting an infection
OR
  Does not need antibiotics because he or she is at low risk of getting an infection
OR
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  Would normally be treated with antibiotics because he or she is having trouble 
breathing
A description of this clinical trial is available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you. 
 At most, the Web site will include a summary of the results. You can search this Web 
site at any time. 
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY?
6.  What will be done as part of your normal clinical care (even if you did not      
participate in this research study)? 
Your baby will receive standard NICU care. Your baby’s doctor will monitor him or her 
for common but serious problems that are associated with babies who are born early. 
Preterm babies are at risk for these problems, but not all babies all develop them. The 
earlier a baby is born, the more chance that he or she will have some of these 
problems.
•
Necrotizing Enterocolitis (NEC), which is a serious and sometimes deadly 
bowel infection. You baby will be monitored very closely to make sure he or 
she is digesting milk and that his or her bowels are not becoming inflamed.
•
Spontaneous ileal perforation (SIP), which is when the baby’s bowel develops 
a small hole near where the small bowel connects to the large bowel. SIP is 
not necessarily linked to having an inflamed bowel.
•
Bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD), which 
can be caused from the need to have a breathing tube and or breathing 
machine because they baby’s lungs are immature.  Babies with BPD 
sometimes need a ventilator even after they go home. Babies with CLD 
sometimes need extra oxygen after they go home. Your baby will be given the 
least amount of breathing help that he or she needs to reduce the amount of 
time a ventilator or oxygen is needed.
•
Retinopathy of prematurity (ROP) which is an eye problem that is specific to 
preterm babies. ROP causes the blood vessels in the back of the eye to grow 
in areas where they shouldn’t. This can cause vision problems or blindness. 
Depending on how early your baby is born, he or she will have eye exams 
done to watch the growth of the blood vessels in the eyes.
•
Infections. Because the immune systems of preterm babies do not work well, 
preterm babies are risk of infection in the blood, in the urine, and in the spinal 
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fluid. Your baby will be monitored closely for early signs that an infection might 
be starting.

Intraventricular hemorrhages (IVH) can happen when the very fragile blood 
vessels in the preterm baby’s brain rupture. Sometimes this bleeding is minor 
and goes away as the baby grows. Other times the bleeding is severe and can 
cause long term changes in the brain tissue, called periventricular 
leukomalacia (PVL).
7.  What will be done only because you are in this research study?  

Many preterm babies are too small to eat by mouth and need a gastric tube to 
be placed into their nose or mouth for feeding. This tube goes to the stomach. 
This tube can be used to feed your baby or to remove extra stomach fluid that 
sometimes builds up. If your baby needs a gastric tube, researchers will collect 
less than a teaspoon of stomach fluid, if available. If your baby does not need 
a gastric tube, no stomach fluid will be collected and no gastric tube will be 
placed.

Researchers will attempt to collect the first stool your baby passes. This is 
called meconium.

Every week after your baby is born, research staff will attempt to collect stool 
from your baby’s diapers. In addition, staff will attempt to collect a skin swab by 
rubbing a cotton swab on your baby’s forearm or other area of skin that is 
easily accessible. 

If you choose to breastfeed your baby, your preterm baby may not be able to   
feed directly from your breast at first. Mothers of preterm babies who provide 
breast milk, use a breast pump to help remove milk from the breast. This 
breast milk is then collected and given to the baby. If you choose to participate 
in this study, about a teaspoonful of this collected milk will be collected. We will 
only collect breast milk if you have milk left over after your baby is fed.

There are bacteria in all mother’s breast milk.  Researchers would like to see 
what type of bacteria are in your breast milk. This will be done in order to see 
whether the potentially good microbes from your milk are getting into the 
baby’s intestine. We will compare this to the bacteria in the stool of the babies 
fed donor milk. In order to determine if other factors cause a healthy intestinal 
environment, all babies who enroll in this study will have information collected 
from the mother including: method of delivery, the time from when the 
mother’s water broke until birth, mother’s medication use, mother’s infections, 
an optional diet history, mother’s height and weight, and a copy of the 
placenta pathology report that is normally done after the baby’s birth.

We will collect information about the baby’s diet (baby’s own mothers’ milk, 
donor breast milk, formula, breast milk fortification) from the baby’s chart. Also, 
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from the baby’s chart we will collect the timing of feeding, bathing information, 
diaper change times, episodes of holding or kangaroo care. We will document 
what type of specialized beds the baby may use and how long the baby 
received humidification in the isolette. If there is any documentation in the 
baby’s chart about soaps, lotions, or medical creams used, we will document 
that also. We will document which arm or area of the body was swabbed for 
the skin sample.

Also, while the baby is the NICU, we will collect information from his or her 
chart about certain problems that preterm babies may develop. These include:

Necrotizing Enterocolitis (NEC)

Spontaneous ileal perforation (SIP)

Bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD)

Retinopathy of prematurity (ROP)

Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL

Infections before the baby is 3 days old and infections that happen after the 
baby is 3 days old
These conditions are commonly seen in premature infants and may be decreased or 
increased depending on whether we treat with antibiotics. 

We will collect information from your baby’s chart about what type of IVs are 
used and how long IV fluids were given, how well your baby grows including 
weight, length and head growth, and lab values used to decide if a baby has 
an infection.
If you have any questions now or at any time during the study, please contact one of 
the research team members listed in question 3 of this form.
Groups:
Your baby will be included in one of 3 groups: 

the Antibiotic-indicated group(babies that definitely need antibiotics)

the Antibiotic not indicated group(babies that do not need antibiotics)

and two randomized groups (babies that might or might not need antibiotics). 
Babies that definitely need antibiotics: Babies in the “Antibiotic Indicated Group” 
have a diagnosed infection either from the mother or the baby. These babies will 
receive routine antibiotics for as long as the doctors caring for your baby decide. 
The antibiotics that are usually used are ampicillin and gentamicin, however, if the 
baby has a bacteria that is not killed with ampicillin and gentamicin, the baby’s 
doctor will choose another antibiotic for that bacteria. Some babies show signs of 
decreased blood flow to their kidneys. Gentamicin can be difficult for the body to use 
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if the kidneys are not working well. If your baby needs to be started on antibiotics 
and s/he has signs of decreased blood flow to the kidneys, your doctor will choose 
another antibiotic to be given along with ampicillin.
Babies that do not need antibiotics: Babies in the “Antibiotics Not Indicated 
Group” are babies who are at extremely low risk of having an infection. Sometimes 
babies are delivered early because of health problems with the mother.  If your 
baby’s doctor believes that your baby should not receive antibiotics, because s/he is 
doing very well, your baby will not receive antibiotics right after birth. If your baby is 
in the “Antibiotics Not Indicated Group” and shows signs and symptoms of infection, 
your baby’s doctor may still choose to start antibiotics. The antibiotics that are 
usually used are ampicillin and gentamicin. Some babies show signs of decreased 
blood flow to their kidneys. Gentamicin can be difficult for the body to use if the 
kidneys are not working well. If your baby needs to be started on antibiotics and 
s/he has signs of decreased blood flow to the kidneys, your doctor will choose 
another antibiotic to be given along with ampicillin. 
Babies that might or might not need antibiotics: Nationwide, most babies born 
prematurely receive antibiotics after birth even if there is not a diagnosed infection in 
the mother or baby. These are babies who the doctors are not sure whether they 
should be receiving antibiotics or not, but in the past have received antibiotics for at 
least 2 days. We are finding that these antibiotics may actually cause harm, like 
NEC and infections that may happen later in the baby’s NICU stay.  
Babies in the “might need antibiotics group” will either receive routine antibiotics or 
will not receive routine antibiotics. This decision will be made randomly, like “flipping 
a coin” where the chance of receiving the antibiotic or not is 50%. If your baby is 
placed in the group that receives antibiotics, s/he will receive ampicillin and 
gentamicin. Some babies show signs of decreased blood flow to their kidneys. 
Gentamicin can be difficult for the body to use if the kidneys are not working well. If 
your baby is in the group of babies that receives antibiotics and s/he has signs of 
decreased blood flow to the kidneys, your doctor will choose another antibiotic to be 
given along with ampicillin.
If your baby is placed in the group that does not receive antibiotics, his/her doctor 
will still be able to start antibiotics if s/he starts showing signs that an infection may 
be developing. This will be left to the judgment of your baby’s doctor. 
Information collected on all babies in the study:  It is strongly suggested to the 
baby’s medical team that all of the enrolled infants have blood cultures, complete 
blood counts and C-reactive proteins done shortly after birth as per routine care in 
our NICU Infants whose blood cultures are positive at any time or begin to show 
signs of infection will have intravenous antibiotics started.
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We know that antibiotics kill “good” and “bad” bacteria. In some babies, once the 
“good” bacteria are killed, they don’t come back even after antibiotic treatment 
stops. This can allow the “bad” bacteria to grow in large numbers in the baby’s body. 
Not all of these “bad” bacteria are easy to kill with antibiotics and can become 
resistant to antibiotics. 
By collecting and comparing gastric fluid, skin swabs and stool from babies in this 
study and collecting and comparing breast milk from these babies’ mothers, 
researchers are trying to figure out if giving unneeded antibiotics causes long-term 
changes to preterm babies’ immune systems. Specific things the researchers will 
look at are:

Whether or not antibiotics increase the levels of “bad” bacteria in the baby’s 
body

Whether or not antibiotics allow “bad” bacteria to cause NEC in the bowels

Whether or not antibiotics, permanently reduce “good” bacteria and cause 
infections after the first week of life

Whether or not antibiotics change how the intestines and immune system 
digest nutrients

Whether or not antibiotics change how well the baby grows. Sometimes if 
preterm babies do not grow well after birth, they have a harder time weaning 
off the ventilator or oxygen. The longer the baby needs a breathing machine 
or oxygen, the more risk that s/he will develop BPD, CLD, or ROP.
The following scheme will be used for patient enrollment:
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Babies <33 weeks 
gestation
Antibiotics Indicated
Antibiotics not indicated
Randomized into 
Antibiotic Yes or No 
Groups
Informed Consent: 
Samples collected as 
below. 
Tests done only for research purposes will not be evaluated or used to diagnose or 
treat any of your medical problems. This/these test(s) may need to be repeated if 
required for your medical care in the future
Once this research study is completed, any information that could identify you might 
be removed from any identifiable private information or identifiable biospecimens 
collected and that, after such removal, the information or biospecimens could be used 
for future research studies or distributed to another investigator for future research 
studies without additional informed consent from you or your legally authorized 
representative
If you have any questions now or at any time during the study, please contact one of 
the research team members listed in question 3 of this form.
8. How long will you be in this research study?
Mothers who choose to participate in this study will have information collected 
including: method of delivery, the time from when the mother’s water broke until 
birth, mother’s medication use, mother’s infections, an optional mother’s diet history, 
mother’s height and weight, and a copy of the placenta pathology report that is 
normally done after the baby’s birth. Most of this information will be collected shortly 
after the baby’s birth. Sometimes the placental pathology report takes a few days to 
be completed. After this report is filed and the other information above is collected, 
researchers will no longer need to get information from the mother.
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Babies enrolled in this study will have stool and skin swabs collected at least once a 
week until they are discharged from the hospital. Researchers will collect information 
from the baby’s chart until hospital discharge.    
9.
How many people are expected to take part in this research study?
220 babies and 220 mothers. 
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND 
WHAT ARE YOUR OPTIONS?
10.What are the possible discomforts and risks from taking part in this research    
study?
The risk of not giving antibiotics is that the baby may have bacteria that could cause 
an infection. By not giving antibiotics, the infection could get worse and make the 
baby very sick or die. We do not know whether the risks outweigh the benefits and 
that is the purpose of this study. 
The risks of receiving antibiotics that are not needed are not known, however some 
studies are showing that there may be an increased risk of NEC and infections that 
occur later in the baby’s NICU stay. Understanding what problems unnecessary 
antibiotics cause is the purpose of this study. 
Researchers will take appropriate steps to protect any information they collect about 
you.  However, there is a slight risk that information about you could be revealed 
inappropriately or accidentally.  Depending on the nature of the information, such a 
release could upset or embarrass you, or possibly affect your insurability or 
employability.  Questions 17-21 in this form discuss what information about you will 
be collected, used, protected, and shared.
This study may include risks that are unknown at this time.
Participation in more than one research study or project may further increase the risks 
to you.  If you are already enrolled in another research study, please inform one of the 
research team members listed in question 3 of this form or the person reviewing this 
consent with you before enrolling in this or any other research study or project.
Throughout the study, the researchers will notify you of new information that may 
become available and might affect your decision to remain in the study. 
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If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the research team members listed in question 
3 in this form.
11a. What are the potential benefits to you for taking part in this research study?
Your baby may have healthier intestines and develop fewer infections as he or she 
stays in the NICU. Researchers hope that if your baby can avoid getting infections 
while in the NICU, that he or she will grow faster and go home sooner.
11b. How could others possibly benefit from this study?
Our goal is to find out if giving routine antibiotics to babies who do not have infections 
causes more health problems like bowel infections and other infections that happen 
after the first week of life. We hope that our study will help reduce these problems 
from happening to other preterm babies.
11c. How could the researchers benefit from this study?
In general, presenting research results helps the career of a scientist. Therefore, the 
Principal Investigator listed in question 3 of this form may benefit if the results of this 
study are presented at scientific meetings or in scientific journals.
12.What other choices do you have if you do not want to be in this study? 
You can decide not to participate in this study.
13a. Can you withdraw from this study?
You are free to withdraw your consent and to stop participating in this study at any 
time.  If you do withdraw your consent, you will not be penalized in any way and you 
will not lose any benefits to which you are entitled.  
If you decide to withdraw your consent to participate in this study for any reason, 
please contact one of the research team members listed in question 3 of this form.  
They will tell you how to stop your participation safely.
If you have any questions regarding your rights as a research subject, please call the 
Institutional Review Board (IRB) office at (352) 273-9600.
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13b.If you withdraw, can information about you still be used and/or collected?
If you decide to withdraw from the study, the data collected prior to withdrawal will not 
be used.
13c. Can the Principal Investigator withdraw you from this study? 
You may be withdrawn from the study without your consent for the following reasons:

There is no foreseen medical reason for the principal investigator to withdraw 
babies from this study. However, if there is any reason to believe that the study 
is harmful to your baby, or if samples cannot be collected for any reason, the 
principal investigator may decide to withdraw your baby from the study. 
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE?
14. If you choose to take part in this research study, will it cost you anything?
Study Services 
The Sponsor will pay for all services required as part of your participation in this study 
as described above in the question “What Will Be Done Only Because You Are In 
This Research Study”. If you receive a bill for these services, please contact Josef 
Neu, MD at 352-273-8985 or Kelly Curry, MSN at 352-273-8979
Items/Services Not Paid for by the Sponsor 
The cost of antibiotics and the gastric tube placement (if applicable) will be billed to 
you or your insurance company. You will be responsible for paying any deductible, 
co-insurance, or co-payments for these items/services and for any non-covered or 
out-of-network items/services. 
Any other medical services you receive would have been provided to you even if you 
were not in this study. These services will be billed to you or your insurance company 
in the usual manner. You will be responsible for paying any deductible, co-insurance, 
co-payments, for those services, and for any non-covered or out-of-network services. 
15. Will you be paid for taking part in this study?
No.
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16. What if your baby is injured because of the study?  
If you are injured as a direct result of your participation in this study, only the 
professional services that you receive from any University of Florida Health Science 
Center healthcare provider will be provided without charge.  These healthcare 
providers include physicians, physician assistants, nurse practitioners, dentists or 
psychologists. Any other expenses, including Shands hospital expenses, will be billed 
to you or your insurance provider. 
You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
research-related injuries. Please contact your insurance company for additional 
information. 
The Principal Investigator will determine whether your injury is related to your 
participation in this study. 
No additional compensation is routinely offered. The Principal Investigator and others 
involved in this study may be University of Florida employees. As employees of the 
University, they are protected under state law, which limits financial recovery for 
negligence.
Please contact one of the research team members listed in question 3 of this form if 
you experience an injury or have questions about any discomforts that you 
experience while participating in this study.
17. How will your health information be collected, used and shared?
If you agree to participate in this study, the Principal Investigator will create, collect, 
and use private information about you and your health. This information is called 
protected health information or PHI. In order to do this, the Principal Investigator 
needs your authorization  The following section describes what PHI will be collected, 
used and shared, how it will be collected, used, and shared, who will collect, use or 
share it, who will have access to it, how it will be secured, and what your rights are to 
revoke this authorization. 
Your protected health information may be collected, used, and shared with others to 
determine if you can participate in the study, and then as part of your participation in 
the study.  This information can be gathered from you or your past, current or future 
health records, from procedures such as physical examinations, x-rays, blood or urine 
tests or from other procedures or tests.  This information will be created by receiving 
study treatments or participating in study procedures, or from your study visits and 
telephone calls.  More specifically, the following information may be collected, used, 
and shared with others: 
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
Method of delivery (vaginal or Caesarean Section)

Maternal infections during pregnancy

Maternal health history including a diet history

Maternal medication use during pregnancy and time of delivery. 

Your baby’s lab values including blood cultures, complete blood counts, and C-
reactive protein levels.

Your baby’s diet (breast milk or formula)

Information collected from stomach fluid, breast milk, skin swabs, and stool 
samples, and the placental pathology report that will be done after birth

Your baby’s growth will be monitored which will include weight, length and 
head circumference. 
This information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices. 
Some of the information collected could be included in a "limited data set" to be used 
for other research purposes.  If so, the limited data set will only include information 
that does not directly identify you.  For example, the limited data set cannot include 
your name, address, telephone number, social security number, photographs, or 
other codes that link you to the information in the limited data set.  If limited data sets 
are created and used, agreements between the parties creating and receiving the 
limited data set are required in order to protect your identity and confidentiality and 
privacy.
18. For what study-related purposes will your protected health information be 
collected, used, and shared with others?
Your PHI may be collected, used, and shared with others to make sure you can 
participate in the research, through your participation in the research, and to evaluate 
the results of the research study.  

Information collected from the mother’s chart that is important for study 
purpose includes use of antibiotics or other medications, weight changes 
during pregnancy, and factors related to delivery that may have an effect on 
baby’s chances to develop infections after birth.
Once this information is collected, it becomes part of the research record for this 
study.
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19. Who will be allowed to collect, use, and share your protected health 
information?
Only certain people have the legal right to collect, use and share your research 
records, and they will protect the privacy and security of these records to the extent 
the law allows. These people include:

the study Principal Investigator (listed in question 3 of this form) and research 
staff associated with this project.

other professionals at the University of Florida or Shands Hospital that provide 
study-related treatment or procedures.

the University of Florida Institutional Review Board (IRB; an IRB is a group of 
people who are responsible for looking after the rights and welfare of people 
taking part in research).  
20. Once collected or used, who may your protected health information be shared 
with?
Your PHI may be shared with:

the study sponsor (listed in Question 4 of this form).

United States governmental agencies who are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health 
and Human Services, and the Office of Human Research Protections
.

Government agencies who are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments.
Otherwise, your research records will not be released without your permission unless 
required by law or a court order. It is possible that once this information is shared with 
authorized persons, it could be shared by the persons or agencies who receive it and 
it would no longer be protected by the federal medical privacy law.  
21.  If you agree to take part in this research study, how long will your protected 
health information be used and shared with others?
Your PHI will be used and shared with others until the end of the study.  
You are not required to sign this consent and authorization or allow researchers to 
collect, use and share your PHI. Your refusal to sign will not affect your treatment, 
payment, enrollment, or eligibility for any benefits outside this research study. 
However, you cannot participate in this research unless you allow the collection, use 
and sharing of your protected health information by signing this consent and 
authorization.
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You have the right to review and copy your protected health information.  However, 
we can make this available only after the study is finished.
You can revoke your authorization at any time before, during, or after your 
participation in this study.  If you revoke it, no new information will be collected about 
you.  However, information that was already collected may still be used and shared 
with others if the researchers have relied on it to complete the research.  You can 
revoke your authorization by giving a written request with your signature on it to the 
Principal Investigator.
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SIGNATURES
As an investigator or the investigator’s representative, I have explained to the 
participant the purpose, the procedures, the possible benefits, and the risks of this 
research study; the alternative to being in the study; and how the participant’s protected 
health information will be collected, used, and shared with others:
Signature of Person Obtaining Consent and Authorization
Date
Consenting Adults.  You have been informed about this study’s purpose, procedures, 
possible benefits, and risks; the alternatives to being in the study; and how your protected 
health information will be collected, used and shared with others.  You have received a 
copy of this Form.  You have been given the opportunity to ask questions before you sign, 
and you have been told that you can ask other questions at any time.  
Adult Consenting for Self.  By signing this form, you voluntarily agree to participate in 
this study. You hereby authorize the collection, use and sharing of your protected health 
information as described in sections 17-21 above.  By signing this form, you are not 
waiving any of your legal rights. 
_____________________________________________     
_____________________
Signature of Adult Consenting & Authorizing for Self         
Date
Parent/Adult Legally Representing the Subject.  By signing this form, you voluntarily 
give your permission for the person named below to participate in this study.  You hereby 
authorize the collection, use and sharing of protected health information for the person 
named below as described in sections 17-21 above.  You are not waiving any legal rights 
for yourself or the person you are legally representing.  After your signature, please print 
your name and your relationship to the subject.
____________________________________________ 
_____________________
Consent & Authorization Signature 
Date
of Parent/Legal Representative
________________________________     ___________________________________
Print:  Name of Legal Representative 
Print:  Relationship to Participant:  
______________________________________________
Print:  Name of Subject:  
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