This document discusses recent advances in neonatal septicemia. It begins by defining neonatal septicemia and describing the types, including early onset sepsis within 72 hours of birth and late onset sepsis from 3-90 days of life. It then discusses the epidemiology, risk factors, clinical presentation and diagnostic evaluation. Key diagnostic tests discussed include blood cultures, sepsis screens, lumbar puncture and novel biomarkers. Management of neonatal septicemia includes supportive care and administration of empiric and targeted antibiotic therapy guided by culture results.

1. Recent Advances in
Neonatal Septicemia
Dr. Hemraj Soni
MBBS, DCH, DNB(Paediatrics)
Consultant Pediatrician & Neonatologist,
Imperial Hospital and Research Centre Jaipur

2. Definition
Neonatal septicemia is a clinical syndrome of
systemic illness accompanied by bacteremia
occurring in the first month of life.

3.  Includes -
meningitis, pneumonia, arthritis, osteomyelitis, and
urinary tract infections.
Superficial infections like conjunctivitis and oral
thrush are not included under neonatal sepsis.

4. Epidemiology
 About 1.6 million deaths every year worldwide.
 Responsible for about 30-50% of the total neonatal deaths
in developing countries
 Up to 20% of neonates develop sepsis and
approximately 1% die of sepsis related causes.

5. According to NNPD data (2002-03) , The commonest
primary cause of death was sepsis (37.6 %), followed by
prematurity and related complications in 19.3 % and
birth asphyxia in 18.5

6. Types of NNS
1. Early onset sepsis (EOS)
 often presents as a fulminant, multi-system illness
 within 72 hours of delivery (or in the first 7 days of life
according to Fanaroff )
 It is mainly due to bacteria acquired before and during
delivery

7. 2. Late onset sepsis (LOS)
 can present as either insidious or acute onset, focal
infection or meningitis.
 from 3 to 90 days of life
 due to bacteria acquired after delivery (nosocomial or
community sources)

8. 3. Very-late-onset sepsis-
 after 3 months of life
 affects premature infants VLBW / ELBW in the NICU.
 Often caused by Candida species or by commensal
organisms such as coagulase-negative staphylococci
(CONS).
(Fanaroff and martins text book)

9. LATE ONSET (≥7 DAYS TO 3
EARLY ONSET (<7 DAYS) VERY LATE ONSET (>3 MONTHS)
MONTHS)
Intrapartum complications Often present Usually absent Varies
Vertical; organism often acquired from Vertical or through postnatal
Transmission Usually postnatal environment
mother’s genital tract environment
Fulminant course, multisystem Insidious or acute, focal infection,
Clinical manifestations Insidious
involvement, pneumonia common meningitis common
Case-fatality rate 5%–20% 5% Low

10. Risc Factors-
Early onset sepsis
1. Low birth weight (<2500 grams) or prematurity
2. Febrile illness in the mother with evidence of bacterial
infection within 2 weeks prior to delivery.
3. Foul smelling and/or meconium stained liquor.
4. Rupture of membranes > 18 hours.
5. Single unclean or > 3 sterile vaginal examination(s) during
labor
6. Prolonged labor (sum of 1st and 2nd stage of labor > 24 hrs)
7. Perinatal asphyxia (Apgar score <4 at 1 minute)

11. Late onset sepsis
Nosocomial (hospital-acquired) ->
- low birth weight,
-prematurity,
- admission in intensive care unit,
- mechanical ventilation,
- invasive procedures,
- administration of parenteral fluids,
- use of stock solutions.
Community-acquired
- poor hygiene,
- poor cord care,
-bottle-feeding, and prelacteal feeds.

12. Micro-organisms in EOS
 GBS – leading cause of EOS in term infants.
 gram negative enteric bacilli --the leading cause of EOS in
preterm infants
E. Coli, Klebsiella, Pseudomonas, Enterobacter.
 Less common-
Listeria, Citrobacter, Staphylococcus, Enterococcus

13. Micro-organisms in LOS
 CONS- most common
 NICHD, Pediatrics 2002; 110 ->
- 50%- CONS
-22% - other G+ organism (Staph aureus,
Enterococcus, GBS)
-18%- gram negative ( E.coli, klebsiella,
pseudomonas )
-12%- Fungal (Candida albicans , C. parapsilosis)

14. Presentation-
Earliest signs: Often subtle and non-specific
 Hypothermia or fever (less common)
 Lethargy, poor cry, refusal to suck
 Poor perfusion, prolonged capillary refill time
 Hypotonia, absent neonatal reflexes
 Brady/tachycardia
 Respiratory distress, apnoea and gasping respiration
 Hypo/hyperglycaemia
 Metabolic acidosis

15. Specific features related to various
systems
CNS : Bulging anterior fontanelle, vacant stare, high-
pitched cry, excess irritability, stupor/coma, seizures, neck
retraction.
Cardiac: Hypotension, poor perfusion, shock
Gastrointestinal: Feed intolerance -
vomiting, abdominal distension, paralytic ileus, necrotizing
enterocolitis (NEC).

16. Hepatic: Hepatomegaly, direct hyperbilirubinaemia
(especially with UTI)
Renal: Acute renal failure
Haematological: Bleeding, petechiae, purpura
Skin changes: Multiple
pustules, abscess, sclerema, mottling, umbilical redness
and discharge

17. Perinatal infection risk score.

18. Suggested Intervention

19. Diagnosis Modalities-
 Blood culture – Gold Standard
 Sepsis screen
 Radiology
 Lumber Puncture
 Urine R/M, Culture
 RBS, Arterial blood gases, PT/ aPTT
 Advanced Diagnostic Methods

20. Advanced Diagnostic Methods
 CRP
 Procalcitonin
 Cytokine measurement – IL-6, IL-8, IL-10, IL- 1b,
G-CSF, TNF-ἀ,
 IgM
 Polymerase chain reaction (PCR)
 DNA microarray technology

21. Immunoassay
 Procalcitonin
 CD64
 Mannose-binding lectin
 Amniotic fluid MR score
 ApoSAA
 Gene expression profiling

22. Blood culture
 Gold standard
 Sould be performed in all cases of suspected sepsis prior to
starting antibiotics
 A positive blood culture with sensitivity of the isolated
organism is the best guide to antimicrobial therapy
 cultures should be collected only from a fresh veni-
puncture site.

23. Blood culture contd.
 The volume of blood - 0.5 ml venous blood in a pediatric
blood culture bottle or
1 ml in an adult blood culture bottle
 If catheter-associated sepsis is suspected, a culture should
be obtained through the catheter as well as through a
peripheral vein

24. Sepsis screen
Consists of 5 items:
1. C-reactive protein (CRP),
2. Total leukocyte count
3. Absolute neutrophil count (ANC)
4. Immature to total neutrophil ratio
(ITR)
5. Micro-erythrocyte sedimentation rate
(μ-ESR).

25. CRP
 Non specific marker of inflammation and tissue necrosis
 Normal concentrations in neonates are 1 mg/dL or lower.
 Detectable increased CRP value-within 6 to 18 hours,
Peak CRP -- 8 to 60 hours after onset
 Half-life is 5 to 7 hours.
 Decreases promptly in the presence of appropriate therapy

26.  Serial CRP at 12-hour intervals -- sensitivity of CRP in
detecting sepsis
 Quantitative CRP assayed by nephelometry is superior to
CRP by ELISA and semi-quantitative CRP by a latex
agglutination kit.
 Cut-off value for quantitative assay is 1 mg/dl.

27. Limitations-
 Infants with onset of infection in the first 12 hours of
life and with GBS infection may not have an elevated
CRP
 Noninfectious processes, including meconium
aspiration pneumonitis, asphyxia can have an elevated
CRP up to 10 times the normal concentration.
 CRP has a low positive predictive value and should not
be used alone to diagnose sepsis.

28. IT Ratio
= Immature neutrophils (band
forms, metamyelocytes, myelocytes)
Mature + immature neutrophils
 early predictor of sepsis.
 N value = 0.16 in first 24 hours, decreasing to 0.12 by 60
hours.
 Upper limit > 0.2.
 Limitation- many noninfectious processes, including
prolonged induction with oxytocin, stressful labor, and
even prolonged crying, are associated with increased I:T
ratios.

30. Micro-ESR :
 Positive Value (mm in first hour) > 3+ age in days (first week of life)
> 10 thereafter
 Limitation- increased in noninfectious (anemia, hyperglobulinemia)
-Values vary inversely with the hematocrit
- superficial infections and
-noninfectious processes, including asphyxia,
aspiration pneumonia, and respiratory distress syndrome.

31. Presence of two abnormal parameters in a screen is
associated with a sensitivity of 93-100%, specificity of
83%, positive and negative predictive values of 27% and
100% respectively in detecting sepsis.
Polinski C. The value of white blood cell count and differential in the prediction of neonatal
sepsis. Neonatal Netw 1996;15:13-23
Da Silva O, Ohlsson A, Kenyon C. Accuracy of leukocyte indices and C-reactive protein for
diagnosis of neonatal sepsis: a critical review. Pediatr Infect Dis J 1995;14:362-6

32. A practical sepsis screen

33. Reference ranges for total neutrophil values in very low birthweight neonates
from birth to 60 hours of life (A) and 61 hours to 28 days of life (B).
(From Mouzinho A et al:
Revised reference ranges for circulatingneutrophils in very-low-birth-weight neonates. Pediatrics 94:78, 199

34. The total neutrophil count reference range in the first 60 hours of life for a group of term neonates.
Points represent single values; numbers represent the number of values at the same point;
(From Manroe BL: The neonatal blood count in health and disease I: Reference values for
neutrophilic cells.
J Pediatr 95:91, 1979.)

35. Lumber Puncture
Indication :
 In EOS - a positive blood culture or clinical picture
consistent with septicemia.
 In late onset sepsis, LP should be done in all infants prior
to starting antibiotics

36. Interpretation of CSF findings
CSF - - > 32 WBC/mm3
> 60% PMN
glucose < 50% - 75% of serum
protein > 150 mg/dl
organisms on gram stain

37. Radiology:
 Chest x-ray
 Abdominal x-ray
 Neurosonogram and computed tomography (CT scan)

38. Urine analysis
 Indication for urine analysis- Neonates with LOS
-VLBW neonates
- urinary tract anomalies
- bladder catheterization
- visibly turbid urine
 Supra pubic aspiration is the ideal method

41. Role of Procalcitonin
 ProCT becomes detectable within 2 to 4 hours after a
triggering event and peaks by 12 to 24 hours.
 ProCT secretion parallels -closely the severity of the
inflammatory insult, with higher levels associated with
more severe disease and declining levels with resolution of
illness.
 In the absence of an ongoing stimulus, ProCT is eliminated
with a half-life of 24 to 35 hours, making it suitable for
serial monitoring.

42.  ProCT level of >2.0 ng/mL ---predicts sepsis and
>10 ng/mL ---septic shock.
>20 ng/mL --- guarded prognosis.
 higher the ProCT level -----worse the prognosis.
 When sepsis has been successfully treated, ProCT levels
should fall with a half-life of 24 to 35 hours.

43.  Identification of secondary septic events –
elevated noninfectious ProCT level, ProCT levels should
fall at a predictable pace in the absence of secondary
infection.
 Limitation - ProCT levels that are elevated in
noninfectious conditions like after cesearean
section, resuscitation at birth, perinatal steroid exposure
BUT should start falling within 48 hours . Persistent high
levels or secondary peaks suggest secondary infection.

44. The results show that the serum procalcitonin levels
seem to be significantly increased in proven sepsis
and decrease dramatically in all types of sepsis after
appropriate treatment.
Procalcitonin as a Marker of Neonatal Sepsis
Iranian Journal of Pediatrics, Volume 19 (Number 2), June 2009, Pages:
117122

45. Polymerase Chain Reaction
(PCR)
 Under investigation for bacterial and fungal
infection
 amplification of 16S rRNA,
 a gene universally present in bacteria but absent
in humans
 Results in 9 h of sample acquisition

46. PCR
 Sensitivity 96%
 Specificity 99.4%
 positive predictive value 88.9%
 negative predictive value 99.8%

47. Bio-markers
Cytokines IL-1ß, IL-6, IL-8, and TNF
 major mediators of the systemic response to infection
 Studies have shown that combined use of IL-8 and CRP
as part of the workup for bacterial infection reduces
unnecessary antibiotic treatment
Surface neutrophil
 CD11 has been shown to be an excellent marker of
early infection that correlates well with CRP but peaks
earlier.

48. Management – Supportive
Specific
 Antibiotics
 Exchange transfusion
 Intravenous immunoglobulins (IVIG)
 Myeloid colony stimulating factor (GM-CSF & G-CSF)
 Probiotics
 Lactoferrin
 Glutamine
 Recombinant human protein C

49. Indications for starting antibiotics
Indications in neonates at risk of EOS include any
one of the following:
 presence of >3 risk factors for early onset sepsis
 presence of foul smelling liquor
 presence of 2 antenatal risk factor and a positive septic
screen and
 strong clinical suspicion of sepsis.

50. Indications for starting antibiotics in LOS include:
 positive septic screen and/or
 strong clinical suspicion of sepsis.

51. Starting empirical antibiotics
Policy for community acquired sepsis
 Ampicillin + Gentamicin/Amikacin (empirical)
 Staphylococcus : Cloxacillin +
Gentamycin/Amikacin
 Meningitis: Add Cefotaxime

52. Policy for nosocomial sepsis
 It is not possible to suggest a single antibiotic policy
for use in all newborn units.
 Every newborn unit must have its own antibiotic
policy based on the local sensitivity patterns and the
profile of pathogens.
 Preferably choose Penicillin + Aminoglycoside
 BE Aware--Cephalosporins rapidly induce the
production of extended spectrum β-lactamases
(ESBL), cephalosporinases and fungal colonization.

53. Upgradation of empirical antibiotics
 No Expected clinical improvement with ongoing line
of antibiotics.
 At least 48-72 hours period of observation should be
allowed before declaring Failure.
 Current evidence does not support the use of serial
quantitative CRP as a guide for deciding whether or
not antibiotics should be upgraded empirically

54. Antibiotic therapy once culture report is
available
??whether the positive blood culture is a contaminant. --
growth in only one bottle (if two had been sent), ------
growth of non-pathogen organism
-- onset of growth beyond 96 hours in the absence of a
history of prior exposure of antibiotics in the previous
72 hours .

55. Rationale use of antibiotics:
 If the organism is sensitive to an antibiotic with a
narrower spectrum or lower cost, therapy must be
changed to such an antibiotic.
 If possible, a single sensitive antibiotic must be
used, the exception being Pseudomonas for which two
sensitive antibiotics must be used.

56. ORGANISM AND DRUGS
 GBS – ampicillin or penicillin
 E .coli –cefotaxime or ampicillin + gentamycin
 CONS –Vancomycin
 Klebsiella - cefotaxime or meropenam +gentamycin
 Enterococcus –ampicillin or vancomycin + gentamycin
 Listeria – ampicillin + gentamycin
 Psudomonas – ceftazidime or piperacillin-tazobactum
+ gentamycin
 Staph. Aureas – nafcillin
 MRSA - Vancomycin

57. Duration of antibiotics
 Culture positive sepsis: 10-14 days.

58. Culture negative sepsis:
If the blood culture is reported sterile at 48 hours, the
following guidelines must be adhered to:
 Asymptomatic neonate at risk of EOS: stop antibiotics
 Suspected EOS or LOS and the neonate becomes completely
asymptomatic over time: stop antibiotics
 Suspected EOS or LOS and the neonate have not improved
or have worsened: upgrade antibiotics as per the empiric
antibiotic policy.
 Simultaneously, alternative explanations for the clinical
signs must be actively sought for.

59. Meningitis(Culture, Gm stain+, CSF) :
 21-day course of parenteral antibiotics
 that cross uninflamed meninges.
 Anti-meningitic doses
 Only antibiotics with a proven in vitro sensitivity.

60. Quick review of Antibiotics--

61. Exchange transfusion
 Sadana et al. have evaluated the role of double volume
exchange transfusion in septic neonates with sclerema and
demonstrated a 50% reduction in sepsis related
mortality in the treated group.

62. 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 systemic infection.
 The placental transfer of these protective
antibodies, however, does not occur until week 32 of
gestation
 and post-natally IgG levels decrease due to reduced
production in newborns
 Therefore, investigators have proposed the use of
intravenous immunoglobulins (IVIG) to prevent and
treat neonatal sepsis in this population.

63.  Meta-analyses of trials of intravenous immune globulin
for suspected or proven neonatal sepsis suggest a
reduced rate of death from any cause, but the trials have
been small and have varied in quality.
 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
infusions of either polyvalent IgG immune globulin or matching
placebo 48 hours apart.
 There was no significant between-group difference in the rates of
the primary outcome in the rates of 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 adverse events.

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

65. Myeloid colony stimulating factor (GM-CSF & G-CSF):
 These are cytokines that stimulate the production of bone marrow
neutrophils.
 As premature infants -- limited number and function of neutrophils
 investigators have evaluated the use of these factors in the prevention
and adjuvant treatment of neonatal sepsis.
 A systematic review(Combination of five studies ) examined the effect
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 in all-cause mortality in treated infants .

66.  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 the nursery.

67. Probiotics
 Lactobacillus and Bi dobacterium sp., the most
frequently used probiotic supplements,
 live microbial species that under physiologic
conditions colonize the gastrointestinal tract of
healthy individuals.
 Investigators have hypothesized that probiotic
supplements may protect high-risk infants in the
nursery from developing necrotizing enterocolitis
(NEC) and sepsis.

68.  A randomized controlled trial in VLBW infants of a
mixed probiotic supplement(Lactobacillus acidophilus
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
infection was lower among infants in the study group
than controls

69.  Honeycutt et al.
- They evaluated the use of one capsule of Lactobacillus
rhamnosus strain GG (10 ×109 cells/capsule)
administered daily for the duration of hospitalization
in the reduction of the incidence of nosocomial
infections;
-the product did not reduce the incidence of
nosocomial infections
 Lactobacillus GG sepsis has been documented in the
immunocompromised host

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

71. Lactoferrin
 Lactoferrin is an iron-binding glycoprotein. It has
broad-spectrum antimicrobial activity.
 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 complete results from this study are
pending.

72. Glutamine
 Glutamine -- most abundant amino acid in plasma and
human milk.
 Studies in immunocompromised adults have suggested
that intravenous parenteral nutrition supplemented with
glutamine decreases 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).

73. Recombinant human protein C
 Activated protein C is an endogenous compound that
promotes anticoagulation and modulates the
inflammatory response.
 During severe systemic infections, the levels and degree of
protein C activation are decreased;
 In one study, decreased activity of 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);approximately 6%
young infants) failed to show an improvement in the
clinical score used at the primary outcome and in the 28-
day mortality when the drug was compared to placebo

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