Neonatal Infections
Mesfin Woldesenbet, MD
Jimma University, Jimma, Ethiopia
Houston, Texas
July, 2012
Questions?
• Why are infants,
especially premies,
more susceptible to
infections?
• What are the clinical
manifestations of
neonatal infections?
• Bacterial?
• HSV?
• How to prevent
infections?
• Antibiotics indications,
contraindications,
cautions, resistance,
etc.
• How to interpret labs?
• Any precautions with
lines?
Objectives
• To briefly review neonatal immunology and why
neonates are so susceptible to infections
• To review the epidemiology, clinical presentation,
diagnosis and treatment of the most common
bacterial and HSV neonatal infections.
• To review modes of infection prevention.
• To differentiate between preterm and term infants
in all these areas
“Prematurity is an infectious disease.”
- James Todd, M.D.
Why are infants,
especially premies, more
susceptible to
infections?
Neonatal Immune System
• All neonates relatively immunocompromised
• Immature and Ineffective:
– Antibodies
– Complement
– Neutrophils
– Skin / mucosal barriers
Antibody
Antibodies
Infectious agent
Immunity
Antibodies (anti- foreign bodies) are produced by host white cells on
contact with the invading micro-organism which is acting as an antigen
(e.g. generates antibodies). The individual may then be immune to
further attacks.
(Modified From: Roitt, I: Essential Immunology, 4th edition, Blackwell Scientific Publications, 1980)
Antibodies
Infectious agent
x
x
Immunity
No contact with infectious agents = no antibody production
Maternal Transfer of Antibodies
• Antibody transfer
increases with GA
• Most during 3rd
trimester
• No guarantee
maternal antibodies
present to the
infecting organism
Remington and Klein, Sixth Edition, 2006
Complement
Neutrophils
Neonatal Neutrophils
• Immature
–
–
–
–
 Chemotaxis
 Deformability
 Phagocytosis
 Storage pool
• Adults 14-fold >
circulating pool
• Neonates only 2-fold
Manroe et al, J Pediatr, 1979
“Normal” VLBW neonates
Mouzinho et al, Pediatr 94:76, 1994
Neonatal Barriers to
Infection
Neonatal Anatomic Barriers
• Immature skin and mucosal surfaces
– layers
– junctions between cells
– secretory IgA
• Umbilical cord
• Breaches - catheters, tape
Invasive Fungal Dermatitis in a VLBW
infant
JL Rowen, Sem Perinatal 27:406-413, 2003
Epidemiology
Incidence
•
Mortality
–
–
•
Meningitis
–
–
•
13-69% world wide
13-15% of all neonatal deaths (US)
0.4-2.8/1000 live births (US 0.2-0.4/1000)
Mortality 13-59%; US 4% of all neonatal deaths
Sepsis
–
–
–
1-21/1000 world wide; US1-8/1000 live births
Culture proven 2/1000 (3-8% of infants evaluated
for sepsis)
Premature
<1000 g
26/1000
1000- 2000 g
8-9/1000
Neonatal Sepsis: Incidence
• 2/1000 live births with culture proven sepsis
– Bacterial / Viral / Fungal
– 80% infants develop bacterial sepsis
– 20% infants perinatally acquired viral infections
– ~ 25% of infected infants have meningitis
• Higher rate with preterm birth
– 26/1000 preterm infants with BW < 1000g
– 8-9/1000 preterm infants with BW 1000-2000g
Remington and Klein, Sixth Edition, 2006
Neonatal Bacterial Sepsis:
Disease Patterns
• Early Onset Neonatal
Sepsis (EONS)
– Fulminant, multi-system
illness
– < 7 days old
– Obstetrical complications
– Prematurity
– Perinatal acquisition
– High mortality, 5-50%
• Late Onset Neonatal Sepsis
(LONS)
– Sepsis and/or meningitis
– 7 days to 3 months old
– Perinatal or postnatal
acquisition
– Lower mortality, 2-6%
Infection
Timing
• Onset
– Early Onset
– Late Onset
1st 24 hrs
24-48 hrs
7-90 days
85 %
5%
Etiologic Agents of Neonatal Sepsis
Frequency(%)
 Group B Streptococci
 Escherichia coli
Streptococcus viridans
Staphylococcus aureus
Enterococcus spp
Coagulase-negative staphylococci
Klebsiella pneumoniae
Pseudomonas spp
Serratia marcescans
Others
*Schuchat et al, Pediatrics 105: 21-26, 2000
40
17
7
6
6
5
4
3
2
10
Etiologic Agents of Neonatal Meningitis
Gram Positive Bacteria;
Frequency (%)
 Group B Streptococci
Listeria monocytogenes
Miscellaneous gram-positives
53
7
6
Gram Negative Bacteria:
 Escherichia coli
Klebsiella species
Haemophilus influenzae
Miscellaneous gram-negatives
19
8
1
8
Anaerobes
3
Feigen & Cherry, Fifth Edition, 2004
Incidence of Neonatal
Group B Streptoccal Sepsis
• 5-35% Pregnant women colonized
• 1/100-200 colonized women
• infant with early onset disease
• 1-7/1000 live births in 1993
• 0.44/1000 live births in 1999
Remington and Klein, Sixth Edition, 2006
Rate of Early- and Late-onset GBS Disease in
the 1990s, U.S.
Group B Strep
Association
formed
Schrag, New Engl J Med 2000 342: 15-20
1st ACOG & AAP
statements
CDC draft
guidelines published
Consensus
guidelines
What do we know about trends in
“other pathogens”?
• Most studies: stable rates of ‘other’ sepsis
• Concerns for increased rates of E. coli, all gram negatives,
or amp-R infections
• Population-based (multicenter) studies find stable rates of
total non-GBS and E. coli
• One multicenter study of very LBW infants found a
decrease in GBS by 4.2 /1,000, but an increase in E coli
rates of 3.6/1,000 (Stoll et al, NEJM, 2002, 347:240-7)
• % of E. coli sepsis w/ amp resistance may be increasing
• Increases restricted to low birth weight or preterm
deliveries
Ampicillin Susceptibility of E. coli from Early-Onset
Sepsis Cases, Full-Term Infants, ABCs, Selected
Counties CA and GA, 1998-2000
N=22, p=0.52, linear trend
Hyde et al, Pediatrics 2002;110(4):690-5.
Ampicillin Susceptibility of E. coli from Early-Onset
Sepsis Cases Preterm Infants, ABCs, Selected Counties
CA and GA, 1998-2000
N=37, p=0.02, linear trend
Hyde et al, Pediatrics 2002;110(4):690-5.
Susceptibility of GBS:
ABC/EIP Isolates, 1995-2000
• 1280 isolates from MN, GA, NY, OR (1173 invasive,
107 colonizing):
–
All susceptible to penicillin, ampicillin, cefotaxime and
vancomycin
–
19% erythromycin resistance
–
11% clindamycin resistance
Risk Factors for Early Onset Neonatal
Sepsis
• Primary (significant)
 Prematurity or low birth weight
– Preterm labor
– Premature or prolonged rupture of membranes
 Maternal fever / chorioamnionitis
– Fetal hypoxia
– Traumatic delivery
• Secondary
– Male
– Lower socioeconomic status
– African-American race
Remington and Klein, Sixth Edition, 2006
Factors associated with early-onset GBS
disease: multivariable analysis
Characteristic
Adjusted RR (95% CI)
GBS screening
0.46 (0.36-0.60)
Prolonged ROM (> 18 h)
1.41 (0.97-2.06)
Pre-term delivery
1.50 (1.07-2.10)
Black race
1.87 (1.45-2.43)
Maternal age <20 y
2.22 (1.59-3.11)
Previous GBS infant
5.54 (1.71-17.94)
Intrapartum fever
5.36 (3.60-7.99)
Schrag et al, NEJM 2002, 347:233-9
Predisposing Factors
Overall sepsis rate
8/1000
Maternal Fever
4/1000
PROM
10-13/1000
Fever & PROM
87/1000
Early Onset Neonatal Sepsis:
Risk Factors - Maternal Fever
• Maternal fever is a significant risk factor for
EONS and may add in the identification of
infected but initially asymptomatic infant.
• 5.36 = adjusted RR
• 25% of asymptomatic infants, with culture
positive sepsis, had maternal fever as the ONLY
criteria for evaluation.
Chen et al, J of Perinatal, 2002, 22:653-657
Early Onset Neonatal Sepsis:
Presentation and Diagnosis
Early Onset Neonatal Sepsis:
Signs/Symptoms
?
Early Onset Neonatal Sepsis:
Signs/Symptoms
Strongly suggestive
hypoglycemia / hyperglycemia
hypotension
metabolic acidosis
apnea
shock
DIC
hepatosplenomegaly
bulging fontanelle
seizures
petechiae
hematochezia
respiratory distress
Early Onset Neonatal Sepsis:
Signs/Symptoms
Nonspecific
lethargy, irritability
temperature instability -- hypothermia or fever
poor feeding
cyanosis
tachycardia
abdominal distention
jaundice
tachypnea
Early Onset Neonatal Sepsis:
Signs/Symptoms - Fever
• The infant with sepsis may have an elevated,
depressed or normal temperature.
• Fever is seen in up to 50% of infected infants.
• Fever is more common in term infants, while
hypothermia is more common in preterm infants
• A single elevated temperature reading or fever as
an isolated finding is infrequently associated with
sepsis.
• Persistent fever for greater than 1 hour is more
frequently associated with infection.
• Fever occurs more frequently with LONS or with
viral, rather than bacterial, sepsis.
Klein, Sem in Perinat, 5:3-8
Early Onset Neonatal Sepsis:
Laboratory Evaluation
•  Cultures 
• Chest Radiograph
• Complete Blood Cell Count
• Glucose
• Bilirubin
• Liver Function Tests
• Coagulation studies
• C-reactive Protein (CRP)
RDS vs. GBS pneumonia???
Early Onset Neonatal Sepsis:
Cultures -- Who and Which?
• Blood culture -- indicated in ALL infants with
suspected sepsis. Repeat cultures indicated if
initial culture positive.
• Urine culture -- low yield in EONS
– + in 1.6% EONS compared to 7.47% LONS
Klein, Sem in Perinat, 5:3-8
Early Onset Neonatal Sepsis:
Cultures -- Who and Which?
• CSF culture -- should always be considered
Meningitis frequently accompanies sepsis
- 50-85% meningitis cases have + blood culture
- Yield reportedly low if respiratory distress is the
only major sign of infection
- Specific signs & symptoms occur in less than
50% of infants with meningitis
- Using “selective criteria” for obtaining CSF may
result in missed or delayed diagnosis in up to
37% of infants with meningitis
Wiswell et al, Pediatrics, 1995
Laboratory Diagnosis of
Neonatal Meningitis
CSF - - > 32 WBC/mm3
> 60% PMN
glucose < 50% - 75% of serum
protein > 150 mg/dl
organisms on gram stain
Early Onset Neonatal Sepsis:
Complete Blood Cell Counts
• Is the CBC helpful as an indicator of early onset
neonatal sepsis?
– Thrombocytopenia frequently associated with
sepsis
– WBC may be high, low or “normal
– Persistent low WBC more predictive of sepsis
than elevated WBC (ANC < 1200)
– I:T quotient unreliable
Early Onset Neonatal Sepsis:
Complete Blood Cell Counts
Early Onset Neonatal Sepsis:
Complete Blood Cell Counts
• Single or serial neutrophil values DO NOT
assist in the diagnosis of EONS or
determining the duration of therapy
• 99% of asymptomatic, culture-negative
neonates > 35 weeks GA had 1 or more
“abnormal” WBC values
Early Onset Neonatal Sepsis:
C-Reactive Protein
• Measure of inflammation -- NOT specific for infection
• Elevated CRP, > 10 mg/L (>1 mg/dl), highly associated
with sepsis --- but NOT diagnostic
• Limited by lack of “normal” reference values for <24
hours old or preterm infants
• Trend with multiple samplings correlates with infection
as takes time to rise -- two samples ~24 hours apart
useful
• Potentially useful when maternal antibiotics given pretreatment interferes with cultures
Early Onset Neonatal Sepsis:
C-reactive Protein
• CRP levels <10mg/L, determined >24 hours after beginning
therapy correctly identified 99% of infants not needing
further therapy.
• May be useful in determining end-point for “rule-out
sepsis” evaluations, especially with maternal antibiotic
treatment.
• CRP-guided determination of length of therapy, shortened
the treatment course for most infected infants without
increasing the rate of relapse.
• Limitations: no studies evaluating meningitis or infections
other than bacterial sepsis.
Treatment
• Prevention – vaccines, GBS prophylaxis, HANDWASHING
• Supportive – respiratory, metabolic, thermal,
nutrition, monitoring drug levels/toxicity
• Specific – antimicrobials, immune globulins
• Non-specific – IVIG, NO inhibitors &
inflammatory mediators
Early Onset Neonatal Sepsis:
Empiric Treatment
Initial:
Ampicillin and Gentamicin IV
(Cefotaxime discouraged)
Duration:
“Rule out sepsis”
Pneumonia
Sepsis
Meningitis
48 - 72 hours
5 - 7 days
7 - 10 days
14 - 21 days
Primarily determined by etiologic organism cultured
Secondarily determined by clinical course/response
?CRP-guided determination of duration?
Remington and Klein, Sixth Edition, 2006
Early Onset Neonatal Sepsis:
Supportive Therapy
•
•
•
•
•
•
Ventilation
BP support - fluids, Dopamine/Dobutamine/HCTZ
TPN
FFP - clotting factors, C3, antibodies
G-CSF - stimulate WBC production/release
Steroids not indicated as anti-inflammatory
Remington and Klein, Sixth Edition, 2006
Treatment of GBS Infections
Initial
- Ampicillin and Gentamycin IV
(Gent synergy for first 3 days)
- May switch to Penicillin G IV
(with confirmation of diagnosis/sensitivities)
Duration (from first negative culture)
Uncomplicated sepsis
10 - 14 days
Meningitis
14 days minimum
Indications for GBS Intrapartum
Prophylaxis
AAP Redbook, 2006 Report of the Committee on Infectious Diseases
Algorithm for Neonate whose Mother Received Intrapartum Antibiotics
Maternal Rx
for GBS?
Maternal antibiotics
for suspected
chorioamnionitis?
Signs of neonatal
sepsis?
Gestational age
<35 weeks?
Duration of IAP
before delivery
< 4 hours #
No evaluation
No therapy
Observe ≥ 48 hours**
Full diagnostic evaluation
*
Empiric therapy++
Limited evaluation$ &
Observe ≥ 48 hours
If sepsis is suspected, full
diagnostic evaluation and
empiric therapy ++
* 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.
Treatment of E. Coli Infections
Ampicillin and an Aminoglycoside IV
With confirmation of diagnosis /sensitivities:
- drop Amp
- substitute a third generation cephalosporin
Duration (from first negative culture)
Uncomplicated sepsis
10 -14 days
Meningitis
21 days minimum
Treatment of Listeria
Monocytogenes Infections
Ampicillin and an Aminoglycoside IV
Duration (from first negative culture)
Uncomplicated sepsis
10 -14 days
Meningitis
14 days minimum
Prognosis
Neonatal Sepsis
Mortality 20 - 30% overall - highest in premature infants
Morbidity ?? 25% ??
Neonatal Bacterial Meningitis
Mortality 15 - 30% - - 5% if infant survives the first 24 hr
Morbidity up to 50%
30 - 35% mild to moderate neurologic sequelae
5 - 10% severe neurologic impairment
Early Onset Neonatal Sepsis:
Prognosis - Prematurity
Organism
Mortality for
BW <1500g
Mortality for
BW 1500-2500g
Mortality for
BW >2500g
Group B
Streptococci
73%
20%
10%
Escherichia coli
73%
42%
13%
Staphylococcus
aureus
44%
15%
5%
Other
67%
33%
13%
Total
67%
28%
10%
Remington and Klein, Sixth Edition, 2006
Early Onset Neonatal Sepsis:
Summary
• GBS is still the predominant organism isolated in EONS
• Our efforts at IAP have reduced, but not eliminated,
early onset GBS sepsis
• Obstetrical risk factors, including premature/near-term
delivery and maternal intrapartum fever, help to identify
the infants at highest risk for EONS
• Ancillary laboratory evaluations, including the CRP
value, may assist in determination of the most
appropriate length of therapy
Late Onset Neonatal Sepsis
Late Onset Neonatal Sepsis
• Perinatal acquisition with later onset
–
–
–
–
Term or preterm
Bacterial: GBS, Chlamydia
Viral: HSV, CMV, HepB, HIV
Fungal: Candida
• Nosocomial acquisition
– Health care associated infections
– Preterm or sick term infant
Late Onset GBS
• Transmission - Perinatally or postnatally -- intrapartum
prophylaxis or neonatal treatment of early onset disease
does not decrease risk of late onset disease
• Symptoms - 7days - 3 months. Typically 3-4 weeks old.
Occult bacteremia or meningitis most common. However,
focal infections (pneumonia, UTI, cellulitis, osteomylelitis,
septic arthritis) may occur.
• Diagnosis - Culture of blood, CSF, sputum, urine, abscess
or other body fluid.
• Treatment - Penicillin, as with early onset disease.
Herpes Simplex Virus (HSV)
• Incidence
•
•
•
•
•
•
1/3000-20,000 live births
1/200 pregnant women
> 75% asymptomatic
Enveloped DS-DNA
75% HSV II
HSVI
• Transmission
• 5-8% transplacental (congenital)
• 85-90% perinatally
• Primary infection (risk 30-50%)
• Secondary infection (risk <5%
• 5-10% postnatally
• Parent, caregiver
• Usually non-genital - hand,
mouth
• Nosocomial spread from other
infants via hands of health care
professionals
HSV Specific Symptoms
1. Disseminated Disease
• Multi-organ involvement
• Sepsis syndrome, DIC
• Liver, CNS, lung predominance
• Severe liver & CNS dysfunction common
• Wide temp variations characteristic
2. Localized Central Nervous System Disease
• Seizures common
3. Disease localized to the skin, eye and mouth
• Vesicles, cloudy cornea. conjunctivitis, ulcers
• Onset 1-4 weeks of age
• Clinical overlap exists
• Skin lesions absent or appear late with
disseminated/CNS disease
HSV Diagnosis
• High index of suspicion
– History
– Age (1-4 weeks)
– Sepsis Syndrome unresponsive to antibiotic therapy
• PE - classic vesicular lesions
• Culture - readily grows within 1-3 days
– Mouth, nasopharynx, conjunctivae rectum – swabs after 2448 hours of age
– Skin vesicles, urine, stool, blood and CSF
 PCR - diagnostic method of choice - best on CSF, other fluids
– CSF pleocytosis (especially monos) and elevated protein
– Coagulopathy/DIC, thrombocytopenia, liver dysfunction
– EEG
Imaging
• Classic CT/MRI temporal lobe lesion
but may have many
presentations to
include hydrocephalus
HSV Therapy - Prognosis
• Acyclovir IV
– 21 days for disseminated or CNS
– 14 days for skin, eye and mouth
• Mimimal toxicity - primarily liver - large volume IV
• Decreases mortality with disseminated disease from
~75% to 25-40%
• Decreases morbidity from 90% to 65%
• Improvements in both mortality and morbidity
dependent upon early initiation of Acyclovir
Neonatal Nosocomial
Infections
Risk Factors for Neonatal
Nosocomial Sepsis
•
•
•
•
•
•
•
Prematurity
ELBW > VLBW
Increased LOS
Abdominal surgery / NEC
Hyperalimentaion / Intralipids / IV fluid
Neutropenia, Thrombocytopenia
Catheters
– UAC, UVC, ETT, Foley, CT, Peritoneal drains, etc
Umbilical Arterial and Venous
Catheters
• Life-saving tools on the NICU
• Necessary evil
• Increased of infections
– Minimally at 7 days
– Significantly at 10-14 days or when clot present
• UVC > UAC
– Stasis, hyperal/IL, thrombin formation
Umbilical Arterial and Venous
Catheters
• Require strict protocols regarding use and
care to reduce infection rates
• Remove:
– when no longer needed
– when evidence of infection or clot formation
• Replace when required >14 days
– PICC / broviac / percutaneous a-line
Neonatal Nosocomial Infections: Microbiology
• Skin flora
Coagulase negative Staphylococcus
Candida spp
• Methicillin-resistant Staphylococcus aureus
– Source: infant, care-givers, parents
• Gram-negative bacteria
Enterococcus spp, Enterobacter spp, E. coli
• Pseudomonas spp, Klebsiella spp, Seratia spp
– Source:
• Infant GI tract
• Person-to-person transmission from Nursery
personnel
• Nursery environmental sites: sinks, multiple use
solutions, countertops, respiratory therapy
equipment…
Late Onset Neonatal Sepsis:
Empiric Treatment
Initial:
Vancomycin and Aminoglycoside IV
(Cefotaxime discouraged)
Duration (from first negative culture):
“Rule out sepsis” 48 - 72 hours
Pneumonia
5 - 7 days
Sepsis
10 -14 days
Meningitis
14 - 21 days
Primarily determined by etiologic organism cultured
Secondarily determined by clinical course/response
?CRP-guided determination of duration?
Remington and Klein, Sixth Edition, 2006
Concerns for Antibioticresistant organisms
• Vancomycin- resistant
enterococcus (VRE)
– Theoretic risk on
NICU
–  risk with multiple
course of vanco
– Strict contact
isolation
• Methicillin-resistant
Staphylococcus aureus
(MRSA)
– Real risk on NICU
– Community /
maternal acquired
– Vanco use required
– Strict contact
isolation
Treatment of Coagulase Negative
Staphylococcal Infections
Vancomycin IV
(± Rifampin if difficult to clear)
Duration (from first negative culture)
Uncomplicated sepsis
10 -14 days
Meningitis
14 - 21 days
Removal of indwelling intravascular catheters
Treatment of Gram-Negative Infections
Aminoglycoside IV + Cefotaxime or Cefepime
Duration (from first negative culture)
Uncomplicated sepsis
10 -14 days
Meningitis
14 - 21 days
Removal of indwelling intravascular catheters
Prognosis
Dependent upon organism and early initiation of
appropriate therapy
LOS increased in all cases
Morbidity also variable dependent upon organ
involvement - worse with meningitis
Gentamicin
PMA
(weeks)
Postnatal Age
( Days)
Dose
Interval
(mg/kg/dose) (hours)
≤ 29*
0-7
8-28
≥ 29
5
4
4
48
36
24
30-34
0-7
≥8
4.5
4
36
24
≥ 35
ALL
4
24
* Significant asphyxia, use of indomethaci
Do Gentamicin level around the 3rd dose