Neonatal Infectious diseases: Evaluation of Neonatal Sepsis

1. Andres Camacho-Gonzalez,
Paul W Spearman, Barbara J Stoll
Pediatr Clin N Am 60 (2013) 367-389

2.  Neonatal sepsis-most feared & serious
complication among VLBW infants.
 Divided into Early onset sepsis (EOS) & Late
onset sepsis (LOS).
 EOS-onset in the first week of life – infections
occuring in the first 72 hrs , caused by
maternal intra partum transmission of
invasive organisms.

3. SOURCE RISK FACTORS
EARLY ONSET NEONATAL SEPSIS Maternal Group B Streptococcal
colonization
Chorioamnionitis
Premature rupture of membranes
Prolonged rupture of membranes
(>18 hr)
Maternal urinary tract infection
Multiple pregnancies
Preterm delivery

4. SOURCE RISK FACTOR
LATE ONSET NEONATAL SEPSIS Breakage of natural barriers (skin,
mucosa)
Prolonged catheter use
Invasive procedures (endotracheal
intubation)
Necrotizing enterocolitis
Prolonged antibiotic use
H2 receptor blocker use or PPI use
NEONATAL Prematurity
Decreased passage of maternal
immunoglobulin & antibodies.
Immature function of immune
system

5.  LOS-infections occuring after 1week & attributed
to pathogens acquired postnatally.
 United states-intra partum antibiotic prophylaxis
(IAP) to reduce vertical transmission of Group B
Streptococcus (GBS) infections in high risk
women –decline in EOS GBS infection.
 NICHD & NRN study, incidence of EOS -0.98
cases per 1000 live births.
 Studies have shown increase in EOS by E.coli
among VLBW preterm infants.

6.  E.coli-severe infections & meningitis –leading
cause of sepsis related mortality among VLBW
infants-24.5 %
 GBS & E.coli-70 % of EOS in neotal period.
 LOS- common in preterm VLBW infants.
 NICHD & NRN -21% VLBW infants <1500 g
developed blood culture confirmed LOS with
rates inversely related to geststional age (GA).
 58 %-22 wks GA , 20 %-28 wks GA

7.  VLBW preterm infants –risk for LOS –
prolonged hospitalization, catheters,
endotracheal tubes & other invasive
procedures.
 Several studies LOS rates-1.87-5.42 % with
decreasing rates as birth weight increases.
 Coagulase negative Staphylococci (CoNS) -
emerged as commonly isolated pathogen –
VLBW infants with LOS.

8.  Development of immune system –changes
that occur in first year of life.
 Preterm infants-relatively
immunocompromised –immaturity of immune
system & decreased passage of maternal
antibodies.

9. INNATE IMMUNE SYSTEM
 Immediate immunological response without prior
exposure to specific pathogen.
 Neonatal cells-decreased ability to produce
inflammatory cytokines & proinflammatory responses
that activate adaptive immune system.
 Reduction in cytokine –decreased activation of natural
killer cells.
 Increased susceptibility to bacterial & viral infections.

10.  ADAPTIVE IMMUNE SYSTEM
 Designed to eliminate specific pathogens.
 Decreased cytotoxic function, immaturity, decreased
memory –increases risk of infections .
 Transplacental passage of maternal IgG-inversely
related to gestational age.
 Term infants protected against most vacccine
preventable neonatal infections
 Preterm –lack adequate humoral protection.

11.  Preterm –IgA, IgG, cytokines,& anti bacterial
peptides in human milk compromised.
 Lack of IgA decrease neonate ability to
respond to pathogens.
COMPLEMENT
 Complement levels increase with increasing
gestational age.
 Reduced complement levels-associated with
deficient opsonization & impaired bacterial
killing.

12. EARLY ONSET SEPSIS
 Group B Streptococcus
 Escherichia coli
 Listeria monocytogenes
 Streptococcus pyogenes, streptococcus
viridans, streptococcus pneumoniae
 Enterococci
 Haemophilus influenza.

13.  LATE ONSET SEPSIS
 Coagulase negative Staphylococcus
 Staphylococcus aureus
 Enterococci
 Gram negative rods-(E.coli, Klebsiella,
Pseudomonas, Enterobacter)
 Candida

14.  GROUP B STREPTOCOCCUS (GBS)
 Most common organism assoc. with EOS
 Gram positive encapsulated bacteria-10
serotypes.
 Serotype 3 –most common 54 %
 Colonize gastrointestinal & genital tracts.
 Infants –signs of respiratory distress &
cardiovascular instability, meningitis.

15. ESCHERICHIA COLI
 Gram negative rod –colonizes maternal
urogenital & GI tract.
 Second most common cause of neonatal
sepsis in term & most common in VLBW
neonates.
 Neonatal sepsis, meningitis,
thrombocytopenia & death in first days of life.

16. LISTERIA MONOCYTOGENES
 Facultative anaerobic, gram positive bacteria
 Pregnant women 17 % higher risk –
spontaneous abortion & stillbirth.
 Respiratory distress, sepsis, meningitis.
 Granulomatous rash-granulomatosis
infantisepticum.
 Serotypes 1,2,4
 Higher risk in mothers-consumed raw milk or
unpasteurized milk products.

17. EOS-OTHER BACTERIAL AGENTS
 Streptococci (Streptococcus pyogenes,
viridans, S.pneumoniae)
 Enterococci
 Staphylococci
 H.influenza
 Group A Streptococcus (S.pyogenes)-
pneumonia & empyema (42 %), toxic shock
syndrome (17 %)

18.  CoNS & STAPHYLOCOCCUS AUREUS
 CoNS:22 %-55 % LOS infections –VLBW infants
 S.aureus-4 %-8 %
 Colonizes human skin & mucous membranes.
 Formation of biofilms-protect bacteria from
antibiotic penetration & helps to evade
immune system.
 MRSA : 28% staphylococcal infections in
preterm neonates.

19. GRAM NEGATIVE ORGANISMS
 E.coli, Klebsiella, Pseudomonas, Enterobacter,
Citrobacter, Serratia.
 49 %-69 % of deaths
 Transmission-hands of health care workers,
colonization of GI tract, contamination of
TPN, bladder catheterization.
 Pseudomonas-highest mortality
 Citrobacter-brain abscess.

20. CANDIDA INFECTIONS
 3rd leading cause of LOS in premature infants.
 Risk factors-low birth weight, broad
spectrum antibiotics, male gender, lack of
enteral feedings.
 Candida albicans, Candida parapsilosis
 Higher mortality rates & neuro developmental
delay.

21. SEPSIS / MENINGITIS Temperature instability
Respiratory distress
Apnea
Jaundice & feeding intolerance
Bulging fontanel
Seizures
Skin lesions-staphylococci, listeria,
candida

22.  Blood culture-gold standard for diagnosis of
neonatal sepsis.
 Rate of positivity low-intra partum
administration of antibiotics & limitations of
blood volume per culture obtained in
neonates.
 Blood, C.S.F, urine culture (after 3rd day)
 CXR-respiratory symptoms.
 Disseminated herpes-surface cultures from
conjunctiva, mouth, skin & anus.

23.  Maternal & exposure history , complete physical
examination, skin & catheter insertion sites.
COMPLETE BLOOD COUNT
 WBC count does not accurately predict infection
in neonates.
 Multicentre study of blood culture & CBC in
neonates of 293 NICU-low WBC & absolute
neutrophil count & high immature to total
neutrophil ratio –assoc. with increasing infection.

24. CRP
 Seriel measurement of CRP in first 24-48 hrs
 Normal CRP-99 % negative predictive value.
 PROM, maternal fever, PIH, prenatal steroid
use, fetal distress-cause elevation of CRP.
 Gestational age influences CRP kinetics-
preterm neonates –lower & shorter response.

25.  PROCALCITONIN (PCT)
 Tissue release of Procalcitonin increases with
infection.
 Useful for detection of EOS.
 Auriti & colleagues in a multicentre study of
762 neonates –increase in PCT level in
neonates with sepsis.
 Further studies needed to clarify use of PCT

26. MANNOSE BINDING LECTIN (MBL)
 Plasma protein produced by liver –important
role in immune defense.
 MBL-activates complement system pathway –
increases opsonozation & enhance
phagocytosis.
 Lower level of MBL-sepsis.
 Needs further study

27. CYTOKINE PROFILE
 IL-6, IL-8, IL-10, TNF-alpha.
 IL-6, IL-8 increase very rapidly with bacterial
invasion-but normalise within first 24 hrs.
 Ratio of IL-10 & TNF-alpha –diagnosis of LOS
in VLBW neonates.

28.  NEUTROPHIL CD64 & NEUTROPHIL/
MONOCYTE CD11 B
 Cell surface antigens –production increases
after activation of leukocytes by bacteria.
 Cost & processing time –barriers for the use.

29.  MOLECULAR TECHNIQUES FOR EARLY
DETECTION OF NEONATAL SEPSIS
 Real time PCR
 Meta analysis study done by Pammi –Blood
culture studies found to be superior.
 HSV PCR-gold standard for HSV encephalitis.

30. GENOMICS & PROTEOMICS
 Genomics targets genes that are upregulated
with infection.
 Proteomics analyzes structure, function &
interactions of proteins produced by
particular gene.
 Identification of sepsis & necrotizing
enterocolitis.
 Further studies needed.

31. PREVENTION
 Maternal prenatal care-prevention of EO GBS
sepsis.
 Universal GBS screening for all pregnant
women-35-37 weeks gestation.
 Early recognition of chorio amnionitis &
antimicrobial therapy for mother.
 Intrapartum prophylaxis with penicillin,
ampicillin, cefazolin 4hrs before delivery.

32. ANTIBIOTIC DOSE
PENICILLIN G 5 Million units iv as initial dose
followed by 2.5 million units every
4 hrs until delivery.
AMPICILLIN 2 g iv as initial dose followed by 1
gm iv every 4 hrs until delivery
CEFAZOLIN 2 gm iv as initial dose followed by
1 gm iv every 8 hrs until delivery

33. Reduce hospital acquired late onset infections
 Hand washing, infection control
 Proper placement & management of central
catheters.
 Alcohol based products for hand hygiene.

34. PREVENTION STRATEGY NOTES
• INTRAVENOUS IMMUNOGLOBULIN No proven efficacy for prevention of
neonatal sepsis
• ANTI STAPHYLOCOCCAL
MONOCLONAL ANTIBODIES
Monoclonal antibodies against
capsular polysaccharide antigen &
clumping factor A –no effect in
prevention of sepsis.
Anti lipoteichoic acid antibodies
(Pagibaximab)-have an effect.
• GRANULOCYTE MACROPHAGE
COLONY STIMULATING FACTOR
(GM-CSF)
No proven efficacy of neonatal sepsis
• GLUTAMINE No proven efficacy of neonatal sepsis
• PROBIOTICS No proven efficacy of neonatal
sepsis. Useful as prevention of
Necrotizing enterocolitis.

35. PREVENTION STRATEGY NOTES
• LACTOFERIN Glycoprotein in human milk.
Immuno regulatory properties-
increases cytokine prod. in gut &
assoc. lymphoid tissue.
Small studies show reduction of
both fungal & bacterial infections.
Large studies needed.
• FLUCONAZOLE Efficacious in prevention of
candida species in VLBW infants.
No neuro developmental
outcomes.
Fluconazole resistant strains.

36.  Indiscriminate antibiotic use-multidrug resistant
organisms-disseminated candida, necrotizing
enterocolitis, vancomycin resistant
enterococcus, beta lactamase producing
organisms (E.coli, klebsiella, enterobacter )
 Ampicillin & Gentamicin –empiric Rx. for
suspected early onset neonatal sepsis.
 Ampicillin resistant E.coli-3rd gen.
cephalosporin.
 LOS-Vancomycin –VLBW infants at risk for CoNS

37.  Amphotericin & Fluconazole-antifungal drug
of choice in neonatal candidiasis.
 Newer antifungals-Echinocandins (Micafungin
Caspofungin, Anidulafungin )
 Micafungin-most studied drug-higher doses
for CNS penetration.

38. • Empiric initiation of antibiotics Use when bacterial infections are
likely & discontinue when they have
not been identified.
• Switch antibiotics based on
susceptibility
Change antibiotic agents to those
with narrowest spectrum.
• Define duration of antibiotic
therapy
Establish final duration of antibiotic
based on disease process.

39. CLINICAL PRESENTATION DURATION OF ANTIBIOTIC
THERAPY
Early onset sepsis without meningitis 10 days
Late onset sepsis without meningitis 10-14 days
Meningitis-Early onset or Late onset
sepsis
14-21 days
Gram negative rod Meningitis 21 days

40.  Neonatal sepsis-continues to be significant cause
of mortality & morbidity in term & preterm
infants.
 Intrapartum antibiotic prophylaxis –decrease in
GBS neonatal sepsis.
 GBS & E.coli-common causes of EOS.
 CONS-common cause of LOS in VLBW neonates.
 Seriel CRP & immature : total neutrophil count
provide best negative predictive value for
neonatal sepsis.

41.  Newer biomarkers-Real time PCR –early
detection of neonatal sepsis-further study
needed.
 Fluconazole prophylaxis in VLBW neonates-
repeated efficacy in multiple trial studies.
 Antistaphylococcal monoclonal antibodies &
lactoferrin-early promise to prevent neonatal
sepsis-needs larger studies.