1. Neonatal Sepsis

2. Objectives
Differentiate between the evaluation of a symptomatic newborn and the assessment of risk factors in an asymptomatic infant at risk for sepsis
Review obstetric risk factors for neonatal sepsis in an asymptomatic newborn
Review diagnostic tools for evaluation of sepsis in an asymptomatic newborn

3. Symptomatic infants
Symptomatic infants require prompt diagnostic testing and institution of antibiotic therapy given the rapidity of deterioration and the high likelihood of successful treatment in infants with true bacteremia.
The need for clinical judgment in this decision-making process precludes the use of an algorithm or protocol.

4. Symptoms of Neonatal Sepsis
Respiratory distress/grunting
Lethargy
Irritability
Hypothermia
Hypoglycemia
Hypotonia
Acidosis
Apnea
Cyanotic spells
Poor perfusion

5. Evaluation of the Symptomatic Infant
CBC with manual differential-WBC corrected for NRBCs
Blood culture
A significant number of infants with meningitis will have a negative blood culture. A lumbar puncture may be considered if:
the infant has specific symptoms of meningitis
symptoms more suggestive of sepsis than MAS or RDS
the blood culture is positive
Urine culture is not indicated
Tracheal aspirate/gastric cultures may be useful in the first 12 hours of life. A positive culture may be found in 44% of infants with clinical pneumonia and a negative blood culture.

6. Group B Streptococcus Gram positive, beta hemolytic bacteria
Common colonizer of human gastrointestinal and genitourinary tracts
Recognized as causing disease in humans in the 1930s
Causes serious disease in young infants, pregnant women and older adults
Emerged as most common cause of sepsis and meningitis in infants <3 months in the 1970s
Group B Streptococcus
Group B Streptococcus is a gram positive, beta hemolytic bacteria.
It is a common colonizer of the human gastrointestinal and genitourinary tracts.
It was first recognized as causing disease in humans in the 1930s.
It can cause serious disease in young infants, pregnant women and older adults.
It emerged as the most common cause of sepsis and meningitis in young infants in the 1970s

7. GBS Disease in Infants Before Prevention Efforts
Early-onset: 0-6 days of life
Late onset: 7-89 days of life
GBS Disease In Infants Before Prevention Efforts
This slide shows the distribution of infant GBS disease by age of onset.
The data are taken from a study that was summarized in a review by Schuchat and published in Clin Micro Rev in 1998, Volume 11, pages The data represent cases detected in the 1980s, before prevention efforts.
Among infants under 90 days of age, the risk of GBS disease was not evenly distributed.
The graph shows that 77.5% of GBS cases in infants were among those less than 1 week old.
Cases occurring within the first week of life are called early-onset disease. Cases in infants 7-89 days of life are called late-onset.
A Schuchat. Clin Micro Rev 1998;11:

8. Mother to Infant Transmission of GBS
GBS colonized mother
Non-colonized newborn
50%
Colonized newborn
Asymptomatic
98%
Early-onset sepsis, pneumonia, meningitis 2%
MATERNAL-TO-INFANT TRANSMISSION
Most Group B Streptococcal Disease cases among newborns result from mother-to-infant transmission during labor and delivery.
Many women are asymptomatically colonized by group B streptococcus in the genital and gastrointestinal tracts.
Colonization is not altered by or dependent on pregnancy.
About half the infants born to colonized mothers are themselves colonized on the skin and mucosal surfaces as a result of passage through the birth canal or as a result of GBS ascending into the amniotic fluid.
The majority of colonized infants, 98%, are asymptomatic.
About 2% will develop early-onset disease, presenting with sepsis, pneumonia or meningitis in the first few days of life.

9. Rate of Early- and Late-Onset GBS, 1990-2008
Early-onset GBS
Late-onset GBS
RATE OF EARLY- AND LATE-ONSET GBS DISEASE , U.S.
This graph plots the incidence of early-and late-onset GBS disease in the ABCs areas from 1989 to 2008.
The yellow line represents late-onset disease in this graph.
Even with the implementation of guidelines recommending GBS prophylaxis, late-onset GBS disease rates have remained stable since 1990 at approximately 0.3 cases per 1,000 live births.
The white line represents early-onset disease.
The incidence of early-onset GBS disease in the United States since 1993 has declined 84% (from 1.7 cases per 1,000 live births in 1993 to 0.28 cases per 1,000 live births in 2008) , coinciding with increased prevention activities.
These data are from Active Bacterial Core surveillance, part of the CDC’s Emerging Infections Program.
Before national prevention policy
Transition
Universal screening
Source: Active Bacterial Core surveillance / Emerging Infections Program

10. Antibiotics for IAP Penicillin the first-line agent for IAP
Dosage: 5 million IU IV then million IU IV every 4 hours
Revised dose ( million IU) consistent with available penicillin formulations
Ampicillin an acceptable alternative
Antibiotics for intrapartum antibiotic prophylaxis
Penicillin is the first-line agent for IAP.
Recommended dose is 5 million IU IV then million IU IV every 4 hours
Revised dose to be consistent with commercially available penicillin formulations and avoid need for pharmacies to specially mix doses
Ampicillin is an acceptable alternative.

11. Data on Antibiotics for Intrapartum GBS Prophylaxis
Data from clinical trials, observational studies, and pharmacokinetics studies indicate that penicillin and ampicillin given as intrapartum prophylaxis are effective in preventing early-onset GBS disease.
Data from observational and pharmacokinetics studies indicate that cefazolin is probably effective as GBS intrapartum prophylaxis.
In contrast, there are no similar data available for clindamycin, erythromycin, or vancomycin.

12. Antibiotics for IAP in Women Allergic to Penicillin
Cefazolin best option for a woman allergic to penicillin but not at high risk for anaphylaxis
Drugs with less evidence for effectiveness (e.g. clindamycin, vancomycin) only for women at high risk of anaphylaxis
High risk for anaphylaxis defined as history of anaphylaxis, angioedema, respiratory distress or urticaria following penicillin
Erythromycin no longer included as option
Antibiotics for intrapartum antibiotic prophylaxis in penicillin-allergic women
Ampicillin is an acceptable alternative.
For women who are allergic to penicillin, cefazolin is the best option for a woman who is not at high risk for anaphylaxis
Drugs with less evidence for effectiveness as GBS IAP, such as clindamycin and vancomycin, should only be used if a woman has a high risk of anaphylaxis to penicillin
High risk for anaphylaxis is defined as a history of anaphylaxis, angioedema, respiratory distress, or urticaria following administration of a penicillin or a cephalosporin.
Erythromycin is no longer included as an option in the 2010 GBS gudielines

13. Newborn Management in the 2010 GBS Guidelines
This section will cover newborn management in the 2010 GBS guidelines.

14. This slide shows an algorithm for the secondary prevention of early-onset GBS disease among newborns.

15. Diagnosing Chorioamnionitis (2010 CDC Guidelines)
On the basis of signs and symptoms:
fever (which might be low-grade)
uterine tenderness
fetal tachycardia
maternal tachycardia
foul-smelling or purulent amniotic fluid
Fever alone in labor may be used as a sign of chorioamnionitis and hence indication for antibiotic treatment

16. Infants Born to Mothers with Chorioamnionitis Show Symptoms Quickly
In Manroe’s 1977 study all 45 infants had clinical signs of sepsis by 14 hours
Time to onset of symptoms is not delayed by maternal antibiotics: CDC surveillance (GBS)
208 no abx 60 min prior to delivery; median illness 2 hours of life range hours
33 got abx > 60 min prior to delivery; median illness 0 hours of life range 0-19

17. Risk Factors in Asymptomatic Infants and Likelihood of Proven Sepsis
PROM >18 hours 1%
Maternal + GBS (preprophylaxis era) %
Maternal + GBS (in prophylaxis era) %
Maternal + GBS + PROM, fever or preterm 4-7%
Chorioamnionitis %*
+GBS and chorioamnionitis %
PROM + preterm %
PROM + low Apgar score 3-4%
Prematurity. The risk of sepsis from any cause starts and continues to rise at any gestation < 36 weeks.
*Escobar, Pediatrics, 2000

18. Informal Poll of Neonatologists
25% would start antibiotics for asymptomatic chorioamnionitis without other evidence
75% wanted screening tests first

19. Screening Tests Gerdes, Ped Clin 2004; Gerdes and Polin, Ped Inf Dis J, 1987
Adjunctive test
Sensitivity (%)
PPV (%)
NPV (%)
ANC <= 1750
38-96
20-77
96-99
I/T >= 0.2
90-100
11-51
99-100
I/T >= 0.25 45 6 98
I/T >= 0.3 35 7
CRP > 1.0 mg/dL
70-93
7-43
*WBC <= 5000
100 27
* 2/3 tests positive

20. CRP-Benitz Pediatrics 1998
Two CRP levels <1 mg/dL obtained 24 hours apart, 8 to 48 hours after presentation, indicate that bacterial infection is unlikely.
The sensitivity of a normal CRP at the initial evaluation is not sufficient to justify withholding antibiotic therapy.
CRP elevation begins 4-6 hours after the onset of sepsis (or other stimulus) and peaks at hours.
The positive predictive value of elevated CRP levels is low.

21. Blood Cultures Aren’t Perfect
Fastidious organisms, maternal antibiotic treatment and small volumes (<1ml) decrease sensitivity
Contamination with skin organisms
Molecular methods may eventually improve detection in less time

22. I:T Manroe J Peds, 1977
Purpose was to differentiate “wet lung” from GBS pneumonia
No sensitivities or predictive values were calculated
Upper limits of normal for I:T ratios were “designated”

23. Likelihood Ratios (LR)
Combine sensitivity and specificity
(probability that person with disease has positive test) sensitivity (probability that person without disease has positive test) 1-specificity
A person with disease A is “___” more times likely to have a positive test than someone without the disease

24. Bayes Theorem
“Pre-test probability” is estimated based on personal experience, prevalence data, published reports, etc.
The test is used to modify pre-test probability to “post-test probability”
Post-test odds= pre-test odds x LR

25. Fagan’s Nomogram

26. Maternal Risk Factor Assessment Using a Multivariate Model (Puopolo et al, Pediatrics, Nov 2011)
34 weeks and up, 350 cases (culture-confirmed bacterial sepsis at <72 hours) from 608,014 births
Combining cutoff methods (ROM>x, T>x, GA<x) flags 17% of population at risk but only identifies 47% of sepsis cases

27. Maternal Variables and Risk for sepsis: Pre-test Probability
37-40wk
ref
GBS -
REF
34-36wk
2.56
GBS +
1.14
41wk-
1.62
GBS -/UNK
ROM < 12hr
1.38 hr
3.65
No intrapartum abx
Ref hr
2.81
Any antibiotic
1.91
24 hr-
14.8
GBS IAP
1.77
<100.5
Broad spectrum abx
6.25
4.53
Abx < 4 hr prior to del
20.08
Abx > 4 hr prior to del
.34
102.5-
103.37

29. Interpretation of CBCs in Newborns at Risk for Sepsis (Newman et al, Pediatrics, 2010)
67, week and up infants, 245 positive blood cultures
GBS 56%(decreasing over time)
Ecoli 22%
Enterococcus 4%
Other 18%

30. LR for WBC, ANC, I/T Test <1 hour 1-3.99 hours 4+ hours
WBC x 103/ul LR
0.4.99
n/a
27.6
80.5
5-9.99
1.4
2.4
6.4
1.1
0.65
1.0
0.73
0.64
0.41
20-
1.2
0.77
0.16
ANC x 103/ul
0-0.99
7.5
33.5
115
1-1.99
2.3
9.3
51.7
2-4.99 1
6.9
0.89
0.92
10-
0.93
0.55
0.31
I/T
0-0.14
0.45
0.46
0.25
1.3
2.9
3.1
4.8
3.3
8.8
0.6-
6.1
8.4
10.7
LR for WBC, ANC, I/T

31. Case 1:
38 week infant, asymptomatic, mother diagnosed with chorioamnionitis
Temp 101.5, GBS+ antibiotics >4 hours prior, ampicillin. ROM 28 hours
What is pretest risk based on experience?
Based on Escobar’s paper? (0.23%)

32. Case 1: Additional Risk Based on Screening
CBC WBC count 22.5K (LR1.2, .77, .06)
I/T ratio of 0.3 (LR 1.4, 2.9, 3.1)
ANC 6000 (LR .89, .82, .64)

33. Fagan’s Nomogram

34. Case 2:
38 week infant, asymptomatic, mother diagnosed with chorioamnionitis
Temp 103, GBS+ antibiotics >4 hours prior, ampicillin. ROM 24 hours
What is pretest risk based on experience?
Based on Escobar’s paper? (2.21%)

35. Case 2: Additional Risk Based on Screening
CBC WBC count 4K (N/A, 27, 80)
I/T ratio of .6 (LR 6, 8.4, 10.7)
ANC 750 (LR 7.5, 33.5, 115)

36. Fagan’s Nomogram

37. Case 3:
40 week infant, asymptomatic, mother diagnosed with chorioamnionitis (no question)
No prenatal information
What is pretest risk based on experience? (5%?)

38. Case 3: Additional Risk Based on Screening
CBC WBC count 4K (N/A, 27, 80)
I/T ratio of .6 (LR 6, 8.4, 10.7)
ANC 750 (LR 7.5, 33.5, 115)

39. Fagan’s Nomogram 5% baseline risk
I/T ratio .3
I/T ratio .6
ANC < 1000

40. Fagan’s Nomogram 1% baseline risk
I/T ratio .3
I/T ratio .6
ANC < 1000