Preterm infants are born at less than 37 weeks of pregnancy. Sometimes a break or tear in the fluid filled bag that surrounds and protects the infant during pregnancy leads to an untimely birth. This state puts the infant at risk of serious condition called sepsis. Sepsis is a condition in which body responds inappropriately to an infection. Sepsis may progress to septic shock which can result in the loss of life. Doctors give antibiotics to treat sepsis. The goal of this research study is to find out: 1. Among neonates at risk of early-onset neonatal sepsis, whether a policy of administering antibiotics selectively to a subset of at-risk infants who later develop signs of sepsis is not inferior to administering antibiotics to all at-risk infants in the 1st week of life. 2. To find out if infants receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) require fewer antibiotic courses of 48 hours duration or more in the 1st week of life. 3. To find out whether infants receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) are significantly different with respect to a wide range of secondary outcomes (listed under "Outcomes").
Sepsis is the major cause of neonatal mortality and early-onset neonatal sepsis (EONS) accounts for more than two-thirds of all cases of neonatal sepsis. Prolonged rupture of membranes (PROM) and preterm premature rupture of membranes (pPROM) are important risk factors of EONS. There is equipoise in the published literature whether antibiotics must be immediately initiated among all preterm neonates (\<35 weeks gestation) delivered following PROM or pPROM who are asymptomatic at birth or whether antibiotics can be selectively administered if and when the at-risk neonates become symptomatic. Among neonates \<35 weeks gestation born with PROM \>18 hours or pPROM and who are either asymptomatic or have no symptoms of sepsis at 4 hrs postnatally (P), is selectively administering antibiotics to neonates who later develop clinical sepsis \[I\] compared to administering antibiotics pre-emptively to all at-risk neonates \[C\] non-inferior with respect to the composite outcome of "mortality and/or culture-positive sepsis and/or severe sepsis" \[O\] within 7 days after enrolment \[T\] by an absolute margin of 7% \[E\] in a randomized controlled trial (S)? The trial will also have a superiority outcome: "need for antibiotic treatment lasting greater than 48 hours within 7 days after enrolment". The absolute superiority margin will be 50%. The main objectives are as follows: 1. To determine whether antibiotics administered selectively to at-risk preterm neonates \[\<35 weeks gestation with prolonged rupture of membranes (PROM) or preterm premature rupture of membranes (pPROM)\] when they develop signs of sepsis compared to administering antibiotics from birth to all at-risk neonates is non-inferior with respect to the primary outcome of "mortality or any episode of culture-positive sepsis or severe sepsis" in the 1st week of life 2. To determine whether neonates receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) are superior with respect to the co-primary outcome of fewer antibiotic courses of 48 hours duration or more in the 1st week of life 3. To determine whether neonates receiving selective antibiotics (as above) compared to those receiving antibiotics from birth (as above) are significantly different with respect to a wide range of secondary outcomes (listed under "Outcomes")
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
1,500
In experimental arm, intravenous antibiotics as per the written down empirical antibody policy of the unit will be administered selectively to those newborn infants who later develop clinical signs of sepsis according to a predefined repertory of clinical signs. In active comparator arm, intravenous antibiotics as per the written down empirical antibody policy of the unit will be administered pre-emptively to all newborn infants from enrollment even if they do not have any clinical signs of sepsis at enrollment
Post Graduate Institute of Medical Education and Research (PGIMER)
Chandigarh, India
Composite of all-cause mortality and/or any episode of culture-positive sepsis and/or severe sepsis* within the 1st 7 days after randomization
Either mortality due to any cause and/or an episode of culture-positive sepsis and/or severe sepsis. These outcomes will be measured within the "1st 7 days after randomization", which for all practical purposes, is equivalent to the "1st 7 days of life" since participants will be randomized at about 4 hours of life. Hence, the duration expressed after randomization and of life will be used interchangeably for this outcome and other outcomes.
Time frame: Within 1st 7 days after randomization
Need for intravenous antibiotics for ≥ 48 hours within the 1st 7 days after randomization
Requirement for intravenous antibiotic courses whose duration is ≥ 48 hours with the onset of the course within the first 7 days after randomization. For all practical purposes, this would be equivalent to the 1st 7 days of life since participants will be randomized at about 4 hours of life.
Time frame: Within 1st 7 days after randomization
All-cause Mortality within 1st 7 days after randomization
Mortality due to any cause
Time frame: During 1st 7 days after randomization
Blood culture-positive sepsis of any severity within 1st 7 days after randomization
Blood culture proven septicemia
Time frame: Within 1st 7 days after randomization
Episode of severe sepsis within 1st 7 days after randomization
Any episode of severe sepsis during 1st 7 days after randomization. Severe sepsis be defined as clinical signs of sepsis AND either a positive blood culture or laboratory evidence of sepsis (either CRP OR Procalcitonin above the age-appropriate cut-off value OR any two of the CBC parameters outside the age-appropriate ranges OR chest x-ray suggestive of pneumonia) AND one or more of the following indices of severity \[Need for intubation and mechanical ventilation, Need for inotropes \>10 mic/kg/min dopamine or \>10 mic/kg/min dobutamine or adrenaline \> 0.05 mic/kg/min, Need for exchange transfusion, Need for platelet concentrates or FFP, Meningitis (defined as either CSF culture positive or Gram stain positive or Cell count \>25/microlitre or glucose \<25 mg/dl or protein \>180 mg/dl)\]
Time frame: Within 1st 7 days after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis within 1st 72 hours after randomization
Either mortality and/or blood culture-positive sepsis and/or severe sepsis
Time frame: Within first 72 hour after randomization
Individual components of composite outcome within 1st 72 hours after randomization
Separately mortality, blood culture-positive sepsis or severe sepsis
Time frame: Within 1st 72 hours after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis during hospital stay
Either mortality due to any cause and/or blood culture-positive sepsis and/or severe sepsis during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days
Time frame: During hospital stay upto 100 days after randomization
Individual components of composite outcome during hospital stay
Separately mortality, blood culture-positive sepsis or severe sepsis during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days
Time frame: During hospital stay upto 100 days after randomization
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during hospital stay
Necrotizing enterocolitis stage II-III by modified Bell's staging criteria during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days after randomization
Time frame: During hospital stay upto 100 days after randomization
Composite of mortality/blood culture positive sepsis/severe sepsis during 1st 30 days after randomization
Either all-cause mortality and/or blood culture-positive sepsis and/or severe sepsis during the 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Individual components of composite outcome during 1st 30 days
Separately, all-cause mortality, blood culture-positive sepsis or severe sepsis during the 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria
Necrotizing enterocolitis, stage II-III by modified Bell's staging criteria during the 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Sepsis-related mortality within 1st 72 hours after randomization
Mortality due to sepsis within 1st 72 hours. The decision of the treating team will be recorded for attributing mortality to sepsis.
Time frame: Within 1st 72 hours after randomization
Sepsis-related mortality within 7 day after randomization
Mortality due to sepsis within 7 days after randomization. The decision of the treating team will be recorded for attributing mortality to sepsis.
Time frame: Within 7 days after randomization
Sepsis-related mortality during hospital stay after randomization
Mortality due to sepsis during hospital stay. The decision of the treating team will be recorded for attributing mortality to sepsis.
Time frame: During hospital stay upto 100 days after randomization
Sepsis-related mortality during 1st 30 days after randomization
Mortality due to sepsis during 1st 30 days after randomization
Time frame: During 1st 30 days after randomization
Clinical sepsis within 1st 72 hours after randomization
Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) within 1st 72 hours
Time frame: Within 1st 72 hours after randomization
Clinical sepsis within 7 days after randomization
Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) within 7 days
Time frame: Within 7 days after randomization
Clinical sepsis during hospital stay
Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) during hospital stay, with maximum duration of observation during hospital stay being capped at 100 days after randomization
Time frame: During hospital stay upto 100 days
Clinical sepsis within 1st 30 days after randomization
Episodes of clinical EONS (as per definition from a repertoire of clinical signs with normal lab parameters) within 1st 30 days of life
Time frame: During 1st 30 days after randomization
Episode of Probable EONS within 72 hours after randomization
Episode of Probable EONS \[as per definition from a repertoire of clinical signs, AND with abnormal age-appropriate values of one or more of TLC, ANC, CRP, PCT, chest x-ray suggestive of pneumonia AND with sterile blood culture\]
Time frame: Within 72 hours after randomization
Episode of Probable EONS within 7 days after randomization
Episode of Probable EONS \[as per definition from a repertoire of clinical signs, AND with abnormal age-appropriate values of one or more of TLC, ANC, CRP, PCT, chest x-ray suggestive of pneumonia AND with sterile blood culture\]
Time frame: Within 7 days after randomization
Episode of asymptomatic proven EONS within 72 hours after randomization
Episode of asymptomatic proven EONS \[asymptomatic but baseline blood culture positive with non-contaminant organism\]
Time frame: Within 72 hours after randomization
Need for sepsis workup during 1st 72 hours after randomization
\["Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture\] during 1st 72 hours of life
Time frame: During 1st 72 hours after randomization
Need for sepsis workup during 1st 7 days after randomization
"Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture during 1st 7 days of life
Time frame: During 1st 7 days after randomization
Need for sepsis workup during 1st 30 days after randomization
"Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture during 1st 30 days of life
Time frame: During 1st 30 days after randomization
Need for sepsis workup during hospital stay
"Sepsis workup" defined as one or more of CBC, CRP, Procalcitonin, blood culture during hospital stay, with the period of observation during hospital stay being capped at 100 days
Time frame: During hospital stay upto 100 days
Cumulative duration of antibiotic therapy during 1st 7 days after randomization
Cumulative duration of antibiotic therapy during the 1st 7 days, which may include the sum of the durations of multiple courses of antibiotics, either in continuation or discontinuous. If any course of antibiotics continues beyond the 1st 7 days after randomization, only that portion of the antibiotic course would be included until the 1st 7 days after randomization.
Time frame: During 1st 7 days after randomization
Cumulative duration of antibiotic therapy during 1st 72 hrs after randomization
Cumulative measure of antibiotics therapy during the 1st 72 hours
Time frame: During 1st 72 hours after randomization
Cumulative duration of antibiotic therapy during hospital stay
Cumulative measure of antibiotics therapy during hospital stay, with the period of observation during hospital stay capped at 100 days
Time frame: During hospital stay upto 100 days after randomization
Duration of hospitalization
Full length of hospital stay, with the period capped at 100 days
Time frame: Upto 100 days
Episodes of healthcare associated infection during hospital stay.
Defined as any episode of culture positive sepsis with onset after 72 hours of life or any episode of culture-positive sepsis if baseline blood culture was sterile, with the period of observation during hospital stay capped at 100 days
Time frame: From after 72 hours until 100 days during hospital stay
Adverse effects until day 30 after randomization
Adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Time frame: During 30 days after randomization
Serious adverse effects until day 30 after randomization
Serious adverse effects will be recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Time frame: During 30 days after randomization
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