Neonatal Sepsis - early onset

1. Early Onset Neonatal Sepsis-
Questions and Controversies
Dr. Arun George
PG Registrar, Paediatrics

2. 1. Introduction
2. Definitions
3. Epidemiology
4. Microbiology
5. Risk Factors
6. Clinical Presentation
7. Evaluation
8. Management
9. Questions and Controversies

4. 1.
INTRODUCTION
Important cause of morbidity
and mortality
Incidence– low
Potential for serious adverse
outcomes
Low threshold for evaluation
and treatment

5. WHO 2011

6. 2. DEFINITIONS
• Neonatal Sepsis- Clinical syndrome in an infant 28 days of life or younger manifested by
systemic signs of infection and isolation of a bacterial pathogen from the blood stream
Early-onset
• Before 7 days of life
• Birth hospitalization
• Vertical transmission
• Ascending infection from maternal
GI/GU tract bacteria
• Bacteremia or sepsis
Ref: Fanaroff and Martin’s textbook

7. 3. EPIDEMIOLOGY
Overall world incidence of early-onset sepsis is 1
to 5/1000 live births (WHO 2015)
• Incidence has decreased due to a reduction in GBS sepsis,
due to the use of intrapartum antibiotic prophylaxis (IAP)
Late-onset sepsis has remained stable (CDC
2015)

8. 4. MICROBIOLOGY
GBS and E. coli are the most common
causes: 2/3 of early-onset, GI/GU tract
Listeria monocytogenes: rare
Staphylococcus aureus: emerging
pathogen, skin involvement
Enterococcus: preterm infants
GBS
Gram negatives
Microbiology of Neonatal Early-onset
Sepsis
Gram negatives
16%
Gram positives
38% GBS
22% E. coli
Gram positives
E. coli
24%

10. Microbiology
DeNIS study, Lancet 2016 (Delhi Neonatal Infection Study – AIIMS, VMMC, MAMC)

11. CMC EXPERIENCE :

12. Impact of GBS Intrapartum Antibiotic
Prophylaxis
Center for Disease Control and Prevention’s Active Bacterial Core Surveillance Report,
2015
Early-onset GBS infection rate in the US declined by 80% - from 0.6/1000 live births in
2000 to 0.25/1000 live births in 2013
Late-onset GBS infection rates remained stable at 0.29/1000 live births

14. Risk factors5. RISK FACTORS

15. • Meconium staining is not a consistent risk factor.

16. • There have been successful attempts to devise a sepsis risk calculator
based on a multivariate model nested case control study by Puopolo
et al

17. Rate of sepsis according to gestational
age.
Karen M. Puopolo et al. Pediatrics 2011;128:e1155-
e1163
©2011 by American Academy of Pediatrics
Dotted line- overall sepsis
frequency in the base
population
Red line – local regression
(lowess) smooth of the
relationship of gestational
age to sepsis rate

18. Rate of sepsis according to highest maternal intrapartum
temperature.
Karen M. Puopolo et al. Pediatrics 2011;128:e1155-
e1163
©2011 by American Academy of Pediatrics

19. Rate of sepsis according to duration of ROM. ROM was measured to the nearest 0.1 hour and took on
values from 0 to 226.4 (inclusive); ROM times of >50 hours were rare, and times between 30 and
50 hours were sparse.
Karen M. Puopolo et al. Pediatrics 2011;128:e1155-
e1163
©2011 by American Academy of Pediatrics

20. A study from PGI to assess risk of EOS in preterm neonates

22. 6.CLINICAL PRESENTATION
Wide range from subtle to shock.
Can occur in infants with an initially
reassuring status.
Temperature instability and respiratory
distress are the most common.
Term newborns without risk factors
with symptoms that improve over the
first 6 hours usually do not have sepsis

23. Neurologic
• Lethargy
• Poor tone
• Poor feeding
• Irritability
• Seizures
Temperature instability
• Term: febrile
• Preterm: hypothermic
Respiratory/Cardiovascular
• 85% have respiratory
symptoms
• Tachypnea
• 38% have apnea
• Tachycardia
• Poor perfusion
Fetal and Delivery Room
Distress
• Meconium stained fluid
• Apgar score <6

24. 7. EVALUATION
Diagnosis Modalities-
• Blood culture – Gold Standard
• Sepsis screen
• Radiology
• Lumbar Puncture
• Urine R/M, Culture
• RBS, Arterial blood gases, PT/
aPTT
• Advanced Diagnostic Methods

25. Blood culture
• Gold standard
• A positive blood culture with sensitivityof
the isolated organism is the best guide to
antimicrobial therapy
• Cultures should be collected only from a
fresh venepuncture site.

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

27. CRP
 Non specific marker of inflammation and tissue necrosis
 Normal concentrations in neonates - variable
 Detectable increased CRP value-within 6 to 18 hours,
Peak CRP -- 8 to 60 hours afteronset
 Half-life is 5 to 7 hours.
 Decreases promptly in the presenceof appropriate therapy

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

29. 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 havean elevated
CRP up to 10 times the normal concentration.
CRP has a low positivepredictivevalueand should not
be used alone todiagnosesepsis.

30. 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 by60
hours.
 Upper limit > 0.2.
 Limitation- many noninfectious processes, including
prolonged induction with oxytocin, stressful labor,
and even prolonged crying, are associated with
increasedI:T ratios.

32. Micro-ESR :
Positive Value (mm in firsthour)- 3+ age in days (in the first week)
Limitation
- increased in noninfectious (anemia, hyperglobulinemia)
- superficial infectionsand
-noninfectious processes, including asphyxia, aspiration pneumonia,
and respiratory distresssyndrome
-Values vary inversely with thehaematocrit.

33. •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 detectingsepsis.
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

34. A practical sepsis screen

35. Reference ranges for total neutrophil values in very low birthweightneonates
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, 19

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

37. Advanced Diagnostic Methods
 Cytokine measurement – IL-6, IL-8, IL-10, IL- 1b,
G-CSF, TNF-ἀ,
 IgM
 Polymerase chain reaction(PCR)
 DNA microarray technology
Kale A, Bonde V (2014) Neonatal
Sepsis: An Update. Iranian Journal of
Neonatology IJN 4(4): 39-51.

38. Immunoassay
 CD64
 Mannose-binding lectin
 Amniotic fluid MRscore
 ApoSAA
 Gene expressionprofiling

40. Role of Procalcitonin
 ProCT becomes detectablewithin 2 to 4 hours aftera
triggering event and peaks by 12 to 24hours.
 ProCT secretion parallels -closely the severity of the
inflammatoryinsult, with higher levels associated with
moreseverediseaseand declining levels with resolution of
illness.
 In theabsence of an ongoing stimulus, ProCT iseliminated
with a half-life of 24 to 35 hours, making it suitable for
serial monitoring.

41.  ProCT level of >2.0 ng/mL ---predicts sepsisand
>10 ng/mL ---septicshock.
>20 ng/mL --- guardedprognosis.
 higher the ProCT level ---- worse the prognosis.
 When sepsis has been successfully treated, ProCTlevels
should fall with a half-life of 24 to35 hours.

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

43. 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

44. PCR
Sensitivity
Specificity
positive predictivevalue
negative predictivevalue
96%
99.4%
88.9%
99.8%

45. Bio-markers
Cytokines IL-1ß, IL-6, IL-8, and TNF
 Major mediators of the systemic response to infection
 Studies have shown thatcombined useof IL-8 and CRP
as part of the workup for bacterial infection reduces
unnecessary antibiotictreatment
Surface neutrophil
 CD11 has been shown to be an excellent marker of
early infection thatcorrelates well with CRP but peaks
earlier.

46. Lumbar Puncture
Indication :
 In EOS - a positive bloodculture or clinical picture
consistent withsepticaemia.

47. Interpretation of CSF findings

48. DIAGNOSIS
• Diagnosis of neonatal sepsis- established only by a positive blood
culture.
• Ongoing research - validated risk stratification strategies - predictive
ability to detect neonatal sepsis.

49. • Culture-proven sepsis: Blood culture- diagnostic of sepsis when a
bacterial pathogen is isolated.
• Probable sepsis — Clinical course (eg, ongoing temperature
instability; ongoing respiratory, cardiocirculatory, or neurologic
symptoms not explained by other conditions; or ongoing laboratory
abnormalities suggestive of sepsis [ie, cerebrospinal fluid (CSF)
pleocytosis, elevated ratio of immature to total neutrophil counts, or
elevated C-reactive protein]).

50. • Infection unlikely — Infants with mild and/or transient symptoms
(ie, fever alone or other symptoms that quickly resolve) who remain
well-appearing with normal laboratory values and negative cultures at
48 hours are unlikely to have sepsis.
• Empiric antibiotic therapy should be discontinued after 48 hours in
these neonates

51. Management
• Aggressive supportive care
• Antimicrobial therapy
• Adjuvant therapies.

52. Supportive Care
a. Thermo-neutral environment- prevention of hypo or hyperthermia.
b. Maintenance of normoglycemic status (45 to 120 mg/dl).
c. Maintenance of Oxygen saturation (91 to 94%).

53. d. Maintenance of tissue perfusion and blood pressure using
colloids and inotropes.
e. Maintenance of adequate nutrition by enteral feeding if
not feasible by parenteral nutrition.
f. Blood products to normalize the coagulation
abnormalities, correction of anemia and thrombocytopenia.

54. Antimicrobial Therapy
• Choice of antimicrobial drug- based on predominant pathogen and
antibiotic sensitivity pattern.
• Indications for Starting Antibiotics
a. Presence of >3 risk factors for early onset sepsis.
b. Presence of foul smelling liquor.
c. presence of 2 antenatal risk factor and a positive septic
screen and `
d. Strong clinical suspicion of sepsis.

55. Duration of Antibiotic Therapy
a. Clinical sepsis (Based on clinical suspicion and/or sepsis
screen positivity):7-10 days.
b. Culture positive sepsis (not meningitis), UTI -14 days.
c. Meningitis-2 weeks after sterilization of CSF culture or
for a minimum of 2 weeks for gram positive meningitis and 3
weeks for gram negative meningitis, whichever is longer.
d. Bone and joint infection-4-6 weeks.

56. Adjuvant Therapies
• Intravenous Immunoglobulin:
little evidence.
• 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.
INIS Collaborative Group, Brocklehurst P, Farrell B, King A, Juszczak E, et al. (2011) Treatment of neonatal sepsis with intravenous immune
globulin. New England Journal of Medicine 365(13): 1201-1211.
Sadana S, Mathur NB, Thakur A (1997) Exchange transfusion in septic neonates with sclerema: effect on immunoglobulin and complement
levels. Indian Pediatr 34(1): 20-25.

57. • Granulocyte Colony Stimulating Factor:
insufficient evidence
• Other Therapies: Melatonin, zinc, pentoxyfyllin, probiotics has
been studied with inconsistent results .
Carr R, Modi N, Doré CJ (2003) G-CSF and GM-CSF for treating or preventing neonatal infections.
Cochrane Database Syst Rev 3: CD003066.

58. The incidence of early GBS infection was reduced with IAP
compared to no treatment (risk ratio (RR) 0.17, 95%
confidence interval (CI) 0.04 to 0.74, three trials, 488 infants; risk
difference -0.04, 95% CI -0.07 to -0.01; number needed to treat
to benefit 25, 95% CI.
EVIDENCE FOR INTRAPARTUM ANTIBIOTICS IN GBS
COLONIZATION

59. EVIDENCE FOR INTRAPARTUM ANTIBIOTICS IN
PPROM
Erythromycin in pPROM - reduction in childhood disability
- prolongation of pregnancy, reductions in neonatal treatment
with surfactant, decreases in oxygen dependence at 28 days of
age and older, fewer major cerebral abnormalities on
ultrasonography before discharge, and fewer positive blood
cultures.

60. Neither antibiotic had a significant effect on the overall level of behavioural
difficulties experienced, on specific medical conditions, or on the proportions of
children achieving each level in reading, writing, or mathematics at key stage one.
The prescription of antibiotics for women with preterm rupture of
the membranes seems to have little effect on the health of children
at 7 years of age.
EVIDENCE FOR INTRAPARTUM ANTIBIOTICS
IN PPROM – CHILDHOOD FOLLOW UP

61. None of the trial antibiotics was associated with a lower rate of the
composite primary outcome than placebo (erythromycin 90 [5·6%], co-
amoxiclav 76 [5·0%], both antibiotics 91 [5·9%], vs placebo 78 [5·0%]).
However, antibiotic prescription was associated with a lower occurrence of
maternal infection.
Antibiotics should not be routinely prescribed for women in spontaneous
preterm labour without evidence of clinical infection.
EVIDENCE FOR INTRAPARTUM ANTIBIOTICS IN
SPL

62. EVIDENCE FOR INTRAPARTUM ANTIBIOTICS IN
SPL- CHILDHOOD FOLLOW UP
More children whose mothers had received erythromycin or co-amoxiclav
developed cerebral palsy than did those born to mothers who received no
erythromycin or no
co-amoxiclav, respectively (erythromycin: 53 [3·3%] of 1611 vs 27 [1·7%] of
1562, 1·93, 1·21–3·09; co-amoxiclav: 50 [3·2%] of 1587 vs 30 [1·9%] of 1586,
1·69, 1·07–2·67). The number needed to harm with erythromycin was 64 (95%
CI 37–209) and with co-amoxiclav 79 (42–591).
The prescription of erythromycin for women in
spontaneous preterm labour with intact membranes was
associated with an increase in functional impairment
among their children at 7 years of age.

65. Prevention of Early onset sepsis GBS disease :

66. 2010 GBS Guidelines:
Algorithm for Selecting IAP Regimens

67. References
• Cloherty and Stark's Manual of Neonatal Care 8th edition
• Avery's Neonatology: Pathophysiology and Management of the
Newborn
• Neows telegram group
• Clinical features, evaluation, and diagnosis of sepsis in term and late
preterm infants - UpToDate