Early Onset Neonatal Sepsis questions and controversies

1. EONS- QUESTIONS
AND
CONTROVERSIES
Dr Arun George

2. Questions ???
■ Who should be
evaluated?
■ Who should receive
empiric antibiotics?

3. What’s the big concern with starting antibiotics?
■ 4-fold increase in late initiation of breast feeding
■ 2-fold increase in non-medically indicated formula supplementation

6. ■ NICE guidelines - classified the
clinical symptoms as just
indicators or red flags.

7. ■ AAP's hierarchical classification of clinical
signs

10. ■ Repeated tests or
repeated examination
have a role in predicting
early sepsis

11. ■ Incidence of sepsis inWELLAPPEARING LATE PRETERM andTERM infants with risk
factors is very low(2.7%-5.6%). 80-100% of infants with positive blood culture for a
pathogenic organism exhibit clinical signs.
■ If repeated clinical monitoring is resorted to, monitoring is required for at least 12
hours (at 0, 1 and 2 hours and then 2-hourly for 10 hours) - NICE Guidelines. It can be
done by a doctor or a neonatal nurse too

12. ■ Even in babies given antibiotics because of risk factors for infection or clinical indicators of
possible infection consider stopping the antibiotics at 36 hours if the baby's clinical condition is
reassuring with no clinical indicators of possible infection

13. AAP 2012 guidelines for chorioamnionitis

14. AAP 2012 guidelines for PPROM

17. Role of adjuvant therapies:
Recent advances in Paediatrics – Suraj Gupte

18. Exchange transfusion
 Sadana et al. have evaluated the role of double volume
exchange transfusion in septic neonates with scleremaand
demonstrated a 50% reduction in sepsis related
mortality in the treatedgroup.

19. Intravenous Immunoglobulin (IVIG):
 Endogenous immunoglobulin synthesis does not begin until 24 weeks of life:
thus, young infants rely on in-utero maternally acquired immunoglobulins for
protection against systemicinfection.
 The placental transfer of these protective antibodies, however, does not
occur until week 32of gestation
 and post-natally IgG levels decrease due to reduced production in
newborns
 Therefore, investigators have proposed the use of intravenous
immunoglobulins (IVIG) to preventand treat neonatal sepsis in this
population.

20.  Meta-analyses of trials of intravenous immune globulin for suspected
or proven neonatal sepsis suggest a reduced rate of death from any cause,
but thetrials have been small and have varied inquality.
 The INIS(International Neonatal Immunotherapy Study)Collaborative
Group*(N Engl J Med 2011;365:1201-11)
 At 113 hospitals in nine countries, enrolled 3493 infants( from 2001 to 2007) receiving
antibiotics for suspected or proven serious infection and randomly assigned them to
receive two infusionsof eitherpolyvalent IgG immuneglobulin or matching placebo
48 hoursapart.
 Therewas nosignificant difference in the ratesof the primaryoutcome or in the
ratesof secondary outcomes, including the incidence of subsequent sepsis
episodes. In follow-up of 2-year-old infants, there were no significant differences in
the rates of major or nonmajor disability or of adverseevents.

21. Therapy with intravenous
immune globulin had no effect
on the outcomes of suspected
or proven neonatal sepsis.
The INIS(International Neonatal ImmunotherapyStudy)Collaborative
Group*(N Engl J Med 2011;365:1201-11)

22. Myeloid colony stimulating factor (GM-CSF & G-CSF):
 Thesearecytokines thatstimulatethe productionof bone marrow
neutrophils.
 As premature infants -- limited numberand functionof neutrophils
 investigators haveevaluated the useof these factors in the prevention
and adjuvant treatment of neonatalsepsis.
 A systematicreview(Combinationof five studies ) examined theeffect
of adjuvant G-CSF or GM-CSF on 14 and 28-day overall mortality in
neonates with suspected or documented sepsis. Analysis showed a
reduction inall-cause mortalityin treated infants .

23.  Colony stimulating factors are a safe treatment
modality in older patients; however, the current
evidence suggests a multi-center randomized
clinical trial demonstrating clinical efficacy of CSF
is needed prior to universal recommendation of
this therapy in thenursery.

24. Probiotics
 Lactobacillus and Bifidobacterium sp., the
most frequently used probiotic supplements,
 live microbial species that under physiologic
conditionscolonize thegastrointestinal tractof
healthy individuals.
 Investigators have hypothesized that probiotic
supplements may protect high-risk infants in the
nursery from developing necrotizingenterocolitis
(NEC) and sepsis.

25.  A randomized controlled trial in VLBW infantsof a
mixed probiotic supplement(Lactobacillusacidophilus
and Bifidobacterium infantis) to prevent NEC and
mortality was conducted. The probiotic preparation
was given twice daily to breast-fed infants until NICU
discharge.
 Although the study was not powered to detect
differences in sepsis rates, culture-proven
systemic infectionwas loweramong infants in
thestudygroup thancontrols

26.  Honeycutt etal.
- Theyevaluated the useof onecapsuleof
Lactobacillus rhamnosus strain GG (10 ×109
cells/capsule) administered daily for the duration of
hospitalization in the reduction of the incidence of
nosocomial infections;
-theproductdid not reduce the
incidenceof nosocomial infections
 Lactobacillus GG sepsis has been documented in
the immunocompromised host

27. Therefore until larger randomized
controlled-trialsare conducted, the
routine use of probiotics to prevent
invasive bacterial and fungal
infections in neonates is not
recommended.

28. Lactoferrin
 Lactoferrin is an iron-binding glycoprotein. Ithas
broad-spectrum antimicrobialactivity.
 A multicenter, randomized, placebo controlled trial
involving VLBW infants who received daily orally
administered Bovine lactoferrin alone (n=99, dose =
100 mg/day), in combination with Lactobacillus GG
(n=99, dose = 106 CFU/day), or placebo (n=104) for 30–
45 days show that the incidence of culture-proven
sepsis was lower in the groups that received
lactoferrin.
 Final and completeresults from this studyare
pending.

29. Glutamine
 Glutamine -- mostabundant aminoacid in plasmaand
human milk.
 Studies in immunocompromised adults have suggested
that intravenous parenteral nutrition supplementedwith
glutaminedecreases the risk of sepsis and mortality.
 A recently published Cochrane systematic review examined
the effect of enteral or parenteral glutamine
supplementation on the incidence of culture-proven
invasive infection from 5 clinical trials (n= 2,240). The
meta-analysis did not reveal a statistically significant
difference between the glutamine supplemented and
control groups (RR 1.01; 95% CI 0.91, 1.13).

30. Recombinant human protein C
 Activated protein C is an endogenouscompound that
promotes anticoagulation and modulatesthe
inflammatory response.
 During severe systemic infections, the levels and degree of
protein C activation aredecreased;
 In one study, decreased activityof activated protein C was
associated with increase mortality among neonates with
sepsis.
 The largest randomized controlled-trial of recombinant
activated protein C in children (n=477);approximately6%
young infants) failed to show an improvement in the
clinical score used at the primary outcome and in the 28-
day mortalitywhen thedrug was compared to placebo

31.  Immunotherapy used as an adjuvant for the
prevention and treatment of neonatal sepsis holds
promise; however, for most of these therapies testedto
date, clinical trials have failed to demonstrate a
significant effect in neonatal outcomes. Some of these
studiesare limited by the studydesign, sample
size, and outcome evaluation and therefore, trials
specifically designed towards the neonatalpopulation
and appropriately powered to detect treatment
differences are necessary prior to universal
recommendation of these therapies in thenursery.

33. Summarising evidence
■ Restrict evaluation and use of antibiotics
■ Know the red flags / clinical indicators of sepsis
■ Sepsis risk calculator is an useful tool
■ Well appearing at risk late preterm / term neonates even with chorioamnionitis can be safely monitored clinically
■ Serial physical examination is as good as or better than most lab tests, but ensure its done q2h for atleast 12 hours.
■ Commonly used laboratory tests have a limited positive predictive accuracy and should never be used as a rationale to
continue treatment in an otherwise healthy term infant at 48 to 72 hours of life
■ Even if antibiotics started, if the clinical condition is reassuring at 36 hours, stop antibiotics