1. Management of Neonatal Sepsis
Niki Kosmetatos, MD
Anthony Piazza, MD
Ira Adams-Chapman, MD
J. Devn Cornish, MD
Emory University
Department of Pediatrics
Note: Dr. Cornish does not have any financial relationships to disclose nor will he discuss any non-approved drug or device uses.

2. Babies and Bacteria… Gram positive bacteria (anthrax)
Gram negative bacteria
(pseudomonas)

3. …Don’t mix!

4. Incidence Mortality Meningitis Sepsis 13-69% world wide
13-15% of all neonatal deaths (US) (8th cause)
Meningitis
/1000 live births (US /1000)
Mortality 13-59%; US 4% of all neonatal deaths
Sepsis
1-21/1000 world wide; US,1-2/1000 live births
Culture proven 2/1000 (3-8% of infants evaluated for sepsis); 10-20/1000 VLBW
Prematures <1000 g 26/ g /1000

5. Predisposing Factors General Host Factors
Prematurity (OR 25 if < 1,000 gms)
Race – GBS sepsis blacks>whites (x4)
Sex – sepsis & meningitis more common in males, esp. gram negative infections
Birth asphyxia, meconium staining, stress
Breaks in skin & mucous membrane integrity (e.g. omphalocoele, meningomyelocoele)
Environmental exposure
Procedures (e.g. lines, ET-tubes)

6. Predisposing Factors Maternal/Obstetrical Factors
General – socioeconomic status, poor prenatal care, vaginal flora, maternal substance abuse, known exposures, prematurity, twins
Maternal infections –chorioamnionitis (1-10% of pregnancies), fever (>38° C/100.4° F), sustained fetal tachycardia, venereal diseases, UTI/bacteriuria, foul smelling lochia, GBS+ (OR 204), other infections
Obstetrical manipulation – amniocentesis, amnioinfusion, prolonged labor, fetal monitoring, digital exams, previa/abruption?
Premature & Prolonged ROM, preterm labor

7. Predisposing Factors Overall sepsis rate 2/1000 Maternal Fever 4/1000
PROM /1000
Fever & PROM 87/1000

8. Preterm Labor/PROM Prematurity (~10%) 15-25% due to maternal infection
>18-24h term; >12-18h preterm
Bacterial infection
 synthesis of PG
Macrophage TNF/IL stimulate PG synthesis, cytokine release**
Release of collagenase & elastase  ROM
+ Amniotic fluid cultures 15% (with intact membranes)

9. SEPSIS ORGANISMS (all babies) Note: 73% G+ and 27% G-
Group B strep (most common G+) 41%
Other strep %
Coliforms (E. coli most common G-) 17%
Staph aureus %
Listeria %
Nosocomial infections
Candida
Note: 73% G+ and 27% G-

10. SEPSIS ORGANISMS (VLBW) Note: 45% G+ and 53% G-
Group B strep (most common G+) 12%
Other strep %
Coliforms (E. coli most common G-) 41%
CONS %
Listeria %
Nosocomial infections
Candida %
Note: 45% G+ and 53% G-
Source: Stoll et al Ped Inf Dis 2005, 24:635

11. Routes of Infection Transplacental/Hematogenous Ascending/Birth Canal
Aspiration
Device Associated Infection
Nosocomial
Epidemic

12. Transplacental/Hematogenous
Organisms (Not just “TORCHS”)
Toxoplasmosis Parvovirus
Rubella Gonorrhea
Cytomegalovirus Mumps
Herpes* TB
Syphilis Varicella
Acute Viruses HIV
Coxsackie Polio
Adenovirus GBS
Echo Malaria
Enterovirus Lyme

13. Ascending/Birth Canal
Organisms - GI/GU flora, Cervical/Blood
E. Coli Herpes
GBS Candida
Chlamydia HIV
Ureaplasma Mycoplasma
Listeria Hepatitis
Enterococcus Anaerobes
Gonorrhea Syphilis
HPV

14. Nosocomial Organisms – Skin Flora, Equipment/Environment MRSA
Staphylococcus – Coagulase neg & pos
MRSA
Klebsiella
Pseudomonas
Proteus
Enterobacter
Serratia
Rotavirus
Clostridium – C dificile
Fungi

15. Infection Timing Onset Early Onset 1st 24 hrs 85 % 24-48 hrs 5%
Late Onset days

16. Symptoms Non-specific/Common
Respiratory distress (90%) - RR, apnea (55%), hypoxia/vent need (36%), flaring/grunting
Temperature instability, feeding problems
Lethargy-irritability (23%)
Gastrointestinal – poor feeding, vomiting, abdominal distention, ileus, diarrhea
Color—Jaundice, pallor, mottling
Hypo- or hyperglycemia
Cardiovascular – Hypotension (5%), hypoperfusion, tachycardia
Metabolic acidosis NICHD data

17. Symptoms Less common Meningitis symptoms Seizures DIC Petechiae
Hepatosplenomegaly
Sclerema
Meningitis symptoms
Irritability, lethargy, poorly responsive
Changes in muscle tone, etc.

18. Evaluation Non-specific Specific – Cultures, stains
CBC/diff, platelets – ANC, I/T ratio
Radiographs
CRP
Fluid analysis – LP, U/A
Glucose, lytes, gases
Specific – Cultures, stains
Other – immunoassays, PCR, DNA microarray

19. Results “Trigger Points”
CBC
WBC <5.0, abs neutro <1,750, bands >2.0
I/T ratio > 0.2*
Platelets < 100,000
CRP > 1.0 mg/dl
CSF > 20 WBC’s with few or no RBC’s
Radiographs: infiltrates on CXR, ileus on KUB, periosteal elevation, etc.

20. Treatment Prevention – vaccines, GBS prophylaxis, HAND-WASHING
Supportive – respiratory, metabolic, thermal, nutrition, monitoring drug levels/toxicity
Specific – antimicrobials, immune globulins
Non-specific – IVIG, NO inhibitors & inflammatory mediators

21. Neonatal Sepsis: the special case of Group B Strep Sepsis

22. Mother to Infant Transmission
GBS colonized mother (20-30% in US)
50%
50%
Non-colonized newborn
Colonized newborn
98% 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.
Early-onset sepsis, pneumonia, meningitis
Asymptomatic

23. GBS SEPSIS RISK FACTORS Previous GBS-infected baby
Gestational age <37 wks
Maternal disease (esp. GBS UTI)
Ruptured membranes > 18 hours
Location of delivery (e.g., home)
Infant/Fetal symptommatology
Clinical suspicion
Note: incidence has fallen 80% since CDC prevention guidelines were published in 1996

24. Mothers in labor or with ROM should be treated if:
Chorioamnionitis
History of previous GBS+ baby
Mother GBS+ or GBS-UTI this preg.
Mother’s GBS status unknown and:
< 37 wks gestation
ROM ≥ 18 hrs
Maternal temp ≥ 38o (100.4oF)

25. Rate of Early- and Late-onset GBS Disease in the 1990s, U.S.
Group B Strep Association formed
1st ACOG & AAP
statements
CDC draft
guidelines published
Consensus
guidelines
RATE OF EARLY- AND LATE-ONSET GBS DISEASE IN THE 1990s, U.S.
More important than changes in policies are changes in disease incidence.
This slide shows a graph plotting the incidence of early-and late-onset GBS disease in the ABCs areas from 1989 to 2000.
Late-onset disease is represented by the blue line in this graph.
Even with the implementation of guidelines recommending GBS prophylaxis, late-onset disease rates remain stable during the 1990s at approximately 0.3 cases per 1000 live births.
The white line represents early-onset disease.
The incidence of early-onset GBS disease in the United States since 1993 has declined 70% (from 1.7 cases per 1000 live births in 1993 to 0.45 cases per 1000 live births in 1999) , coinciding with increased prevention activities.
As of 2000, the graph shows that the rates have plateaued at 0.5 cases per 1000 live births.
This graph was originally published by Schrag in New England Journal of Medicine, 2000, 342:
Schrag, New Engl J Med : 15-20

26. GBS SEPSIS INFANTS TO BE SCREENED Maternal “chorioamnionitis”
Maternal illness (i.e. UTI, pneumonia)
Maternal peripartum fever > 38o (100.4oF)
Prolonged ROM ≥ 18 hrs (≥ 12 hrs preterm)
Mother GBS+ with inadequate treatment (< 4 hrs)
No screening necessary if C-section delivery with intact membranes

27. GBS SEPSIS INFANTS TO BE SCREENED Prolonged labor (> 20 hrs)
Home or contaminated delivery
“Chocolate-colored”/foul smelling amniotic fluid
Persistent fetal tachycardia
SYMPTOMATIC INFANT
treat immediately (in DR if possible)

28. GBS SEPSIS SEPSIS SCREEN CBC with differential Platelet count
Blood culture x 1-2 (ideally 1 ml)
Chest X-ray &/or LP if symptommatic
Close observation and frequent clinical evaluation
Role of CRP

29. Algorithm for Neonate whose Mother Received Intrapartum Antibiotics
Maternal antibiotics
for suspected
chorioamnionitis?
Duration of IAP
before delivery
< 4 hours #
Full diagnostic evaluation *
Empiric therapy++
Limited evaluation$ &
Observe ≥ 48 hours
If sepsis is suspected, full
diagnostic evaluation and
empiric therapy ++
Gestational age
<35 weeks?
No evaluation
No therapy
Observe ≥ 48 hours**
Maternal Rx for GBS?
Signs of neonatal sepsis?
YES
YES
YES NO NO NO
* CBC, blood cx, & CXR if resp sx. If ill consider LP.
++ Duration of therapy may be 48 hrs if no sx.
$ CBC with differential and blood culture
# Applies only to penicillin, Ampicillin, or cefazolin.
** If healthy & ≥ 38 wks & mother got ≥ 4 hours IAP, may D/C at 24 hrs.

30. Immediate Antibiotics Blood Culture Positive
Careful Observation
&
Immediate Antibiotics
Careful Observation pending review of screen
Symptomatic INFANT
Maternal intrapartum fever > 38.6o
“Chocolate” or foul smelling fluid
Ill mother
Fetal tachycardia
Home delivery
Maternal fever < 38.6o
PROM
Mat GBS with < 2 dose abx
(-) Screen (+) Screen (-) Screen (+) Screen
d/c abx; careful obs and monit bld cx until d/c
Cont abx until bld cx neg for 48o if asympt. Use clini-cal judgement for cessation of abx if pt is/was sympt
Careful obs and monit bld cx until d/c
Initiate abx & cont until bl cx (-) for 48o. Clinical judgement for cessation of abx if pt sympt
Blood Culture Positive
Initiate, resume or continue abx therapy and treat for 7-10 days for gram pos organism or longer if gram neg organism cultured. LP may be performed at the discretion of attending, especially in seriously symptomatic pt

31. SEPSIS SIGNS and SYMPTOMS temp instability • lethargy
poor feeding/residuals • resp distress
glucose instability • poor perfusion
hypotension • bloody stools
abdominal distention • bilious emesis
apnea • tachycardia
skin/joint findings

32. LABORATORY EVALUATION
SEPSIS
LABORATORY EVALUATION
Provide added value when results are normal
high negative predictive value
low positive predictive value
abnl results could be due to other reasons and not infection
IT < 0.3, ANC > 1,500 (normal) do not start abx, or d/c abx if started, if pt remains clinically stable
IT > 0.3, ANC < 1,500 consider initiation of abx pending bld cx in “at-risk” pt who was not already begun on antibiotics for other factors

33. LABORATORY EVALUATION
SEPSIS
LABORATORY EVALUATION
Positive screen
total WBC < 5,000 – I/T > 0.3
ANC < 1,500 – platelets < 100,000
Additional work-up
CXR, urine cx, and LP as clinically indicated
CRP
no added value for diagnosis of early onset sepsis
best for negative predicative value or when used serially
not to be used to decide about rx, duration of rx or need for LP
positive results for a single value obtained at 24 hrs ranges > mg/dL

34. SEPSIS TREATMENT Review protocol Antibiotics Symptomatic management
Ampicillin 100 mg/kg/dose IV q 12 hours
Gentamicin 4 mg/kg/dose IV q 24 hours
IM route may be used in asymptomatic pt on whom abx are initiated for maternal risk factors or to avoid delays when there is difficulty obtaining IV
For meningitis: Ampicillin mg/kg/d
Symptomatic management
respiratory, cardiovascular, fluid support

35. Prognosis Fatality rate 2-4 times higher in LBW than in term neonates
Overall mortality rate 15-40%
Survival less likely if also granulocytopenic (I:T > 0.80 correlates with death and may justify granulocyte transfusion).

36. Infection and Outcome Leviton, et al, Ped Res 1999
1078 infants <1500 grams and/or <32 wks
Infants with IUI were more likely to have PVL
Chorioamnionitis was associated with a 4-fold increased risk of CP (17% vs. 3%)
Nelson, et al reported increased cytokine response in population based study of term but not preterm infants

37. Infection and ND Outcome
IUI and postnatal infection both appear to increase the risk for adverse ND outcome
Role of inflammatory mediators/SIRS in brain injury in the preterm infant
Pressure passive CNS circulation
Direct cytotoxicity to the developing brain
Inherent vulnerability of the oligodendrocyte precursor

38. Postnatal Infection and ND Outcome: PDI < 70
Infection Groups Compared to Uninfected by Logistic Regression
Clinical Infection (N=1415)
Sepsis Alone (N=1740)
Sepsis+NEC (N=252)
Sepsis+Meningitis (N=152)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Adjusted Odds Ratios and 95% CIs
Stoll, JAMA 2004

39. Postnatal Infection and ND Outcome: Cerebral Palsy
Infection Groups Compared to Uninfected by Logistic Regression
Clinical Infection (N=1415)
Sepsis Alone (N=1740)
Sepsis+NEC (N=252)
Sepsis+Meningitis (N=152)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Adjusted Odds Ratios and 95% CIs
Stoll, JAMA 2004

40. Late Onset Infection Majority of ELBW infants will develop
late onset sepsis
Significant associated morbidity and mortality
CONS still the most common pathogen
Gram-negative pathogens increasing in prevelance and are associated with higher mortality rate

41. Neonatal Infection and Outcome
Increased risk of adverse ND outcome in ELBW infants with LOS
Increased risk of poor growth at 18 months AA in ELBW with LOS
Poor outcome associated with NEC
?Role of cytokines and inflammatory mediators in CNS

42. Prevention of Nosocomial Infections
HANDWASHING
Universal precautions
Limit use devices and catheters
Minimize catheter manipulation
Nursery design
Meticulous skin care
Education

43. Thank You!!