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Neonatal Infections

Catherine M. Bendel, M.D.


Associate Professor of Pediatrics
Director, Neonatal-Perinatal Medicine Fellowship Program

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
Figure 1.1 Antibodies (anti- foreign bodies) are produced by host while 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

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

NormalVLBWneonates

Mouzinho et al, Pediatr 94:76, 1994

NormalVLBWneonates

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

QuickTime and a
TIFF (Uncompressed) decompressor
are needed to see this picture.

JL Rowen, Sem Perinatal 27:406-413, 2003

QuickTime and a
TIFF (Uncompressed) decompressor
are needed to see this picture.

Epidemiology

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
< 5 days old
Obstetrical
complications
Prematurity
Perinatal acquisition
High mortality, 5-50%

Late Onset Neonatal


Sepsis (LONS)
Sepsis or meningitis
5 days to 3 months old
Perinatal or postnatal
acquisition
Lower mortality, 2-6%

Neonatal Infections
Sepsis
Meningitis
Pneumonia
Otitis Media
Diarrheal Disease
UTI
Osteomyelitis
Suppurative Arthritis
Conjunctivitis
Orbital Cellulitis
Cellulitis - - Omphalitis

Bacterial / Viral / Fungal

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
Feigen&Cherry,FifthEdition,2004

Incidence of Neonatal
Group B Streptoccal Sepsis
5-35% Pregnant women colonized
1/100-200 colonized women will have an
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.
2.5

Group B Strep
1st ACOG & AAP
Association
statements
formed
CDC draft

2
1.5

guidelines published
Consensus
guidelines

1
0.5
0
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Early-onset
Schrag, New Engl J Med 2000 342: 15-20

Late-onset

Rate of Early-Onset Disease by Race


1993-1998

2.5

Black

2
1.5

White

1
0.5
0
1993

Healthy People 2010


1994

Schrag, New Engl J Med 2000 342: 15-20

1995

1996

1997

1998

Current Estimates of Annual GBS


Early-Onset Disease in the U.S.
(2001 provisional, from ABCs/EIP Network)
~4,400 cases prevented per year
1720 cases still occurring annually
70 - 90 deaths
Remains leading infectious cause of neonatal
morbidity and mortality

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 EarlyOnset Sepsis Cases, Full-Term Infants, ABCs,
Selected Counties CA and GA, 1998-2000
Sensitive

Resistant

9
8
7
6
5
4
3
2
1
0
1998
N=22, p=0.52, linear trend

Hyde et al, Pediatrics 2002;110(4):690-5.

1999

2000

Ampicillin Susceptibility of E. coli from EarlyOnset Sepsis Cases Preterm Infants, ABCs,
Selected Counties CA and GA, 1998-2000
Sensitive

Resistant

20
15
10
5
0
1998
N=37, p=0.02, linear trend

Hyde et al, Pediatrics 2002;110(4):690-5.

1999

2000

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

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)

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
--timing of the sample important
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, culturenegative neonates > 35 weeks GA had
1 or more abnormal WBC values

Early Onset Neonatal Sepsis:


C-Reactive Protein

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:


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(fromfirstnegativeculture)
Uncomplicated sepsis
Meningitis

10 - 14 days
14 days minimum

Treatment of E. Coli Infections


Ampicillin and an Aminoglycoside IV
With confirmation of diagnosis /sensitivities:
- drop Amp
- substitute a third generation cephalosporin

Duration(fromfirstnegativeculture)
Uncomplicated sepsis
Meningitis

10 -14 days
21 days minimum

Treatment of Listeria
Monocytogenes Infections
Ampicillin and an Aminoglycoside IV
Duration(fromfirstnegativeculture)
Uncomplicatedsepsis

1014days

Meningitis

14daysminimum

Early Onset Neonatal Sepsis:


C-Reactive Protein

Pediatrics, 1997, 99:216-221

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.

Early Onset Neonatal Sepsis:


Treatment & CRP

Exposure to antibiotics during labor did not change the


clinical spectrum of disease or onset of clinical signs of
infection within 24 hours of birth for term infants with
EOGBS infection.
Normal CRP values at 24 hours of age supported these
observations.

Pediatrics, 2000, 106:244-250

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, 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%)
Impossible to distinguish 1o vs 2o

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

4. Onset 1-4 weeks of age


5. Clinical overlap exists
6. 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 >48 hours of age
Skin vesicles, urine, stool, blood and CSF

PCR - diagnostic method of choice - best on CSF, other fluids possible


CSF pleocytosis (especially monos) and elevated protein
Coagulopathy/DIC, thrombocytopenia, severe liver dysfunction
EEG

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 Herpes: Number of Patients and


Outcome by Body Site Involved in Infants
with a Pre-Mortem Diagnosis and Not
Treated with Antivirals*
TypeofInfection

Patients(%)Death(%)

OutcomeinInfant(%)Normal(%)
Sequelae

Disseminated
withoutCNSinvolvement
withCNSinvolvement

38(16)
78(33)

87
71

3
15

10
14

Localized
CNS
skin
eye
mouth

61(26)
39(17)
13(5)
4(2)

37
10
0
0

51
26
31
0

12
64
69
100

2(1)

100

235(100)

49

25

26

Asymptomatic
TOTAL

*ModifiedfromNahmiasetal.

265

Primarysevereneurologicsequelae.
Noapparentsequelaefromavailablefollowupinformation.

Feigen&Cherry,FifthEdition,2004

Neonatal Nosocomial Infections

Risk Factors for Neonatal


Nosocomial Sepsis

Prematurity
ELBW > VLBW
Increased LOS
Abdominal surgery / NEC
Hyperalimentaion / Intralipids
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 Infections
Sepsis
Meningitis
Pneumonia
Otitis Media
Diarrheal Disease
UTI
Osteomyelitis
Suppurative Arthritis
Conjunctivitis
Orbital Cellulitis
Cellulitis - - Omphalitis

Bacterial / Viral / Fungal


Multi-organ involvement common

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(fromfirstnegativeculture):
Rule out sepsis
Pneumonia
Sepsis
Meningitis

48 - 72 hours
5 - 7 days
10 -14 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

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
VancomycinIV
(Rifampinifdifficulttoclear)
Duration(fromfirstnegativeculture)
Uncomplicatedsepsis

1014days

Meningitis

1421days

Removalofindwellingintravascularcatheters

Treatment of Gram-Negative Infections

AminoglycosideIV+something(basedonsensitivities)
Duration(fromfirstnegativeculture)
Uncomplicatedsepsis

1014days

Meningitis

1421days

Removalofindwellingintravascularcatheters

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

Thanks for all your


excellent care on the
NICU!

Indications for GBS


Intrapartum Prophylaxis

AAP Redbook, 2006 Report of the Committee on Infectious Diseases

Empiric management of the


infant after maternal IAP

AAP Redbook, 2006 Report of the Committee on Infectious Diseases

Common Manifestations of
Viral Infections in the Newborn Infant
Specific Features (acute)
Hyper- or hypothermia
General: irritability, lethargy, jitters, poor feeding, vomiting
CNS: seizures, hyper- or hypotonia, full fontanelle,
meningitis, encephalitis
Skin: icterus, petechiae, purpura, vesicle, maculopapular
rash
Eye: conjunctivitis, keratitis
Heart: myocarditis, hypotension
Abdomen: hepatosplenomegaly, hepatitis
Lung: pneumonitis, respiratory distress, cyanosis

Feigen & Cherry, Fifth Edition, 2004

Early Onset Neonatal Sepsis:


Enteroviral infections
Diagnosis:
Culture of stool, rectum pharynx best
Culture of urine, blood and CSF may be positive
Culture of mother may be diagnostic
PCR more rapid, but less specific

Therapy: supportive only

Time/Mode of Acquisition of Viral Agent


TimePrenatalPerinatalPostnatal
ModeTransplacental
BirthCanalorAscending
Contact
Mother
Maternal
colonized
viremia,
invagina
Nosocomial
amnioitis
orGItract
orhorizontal
Implications+ symptoms
+ symptoms
transmission
CMV
Rubella
HerpesII
EBV
Echo
Coxsackie
HTLVIII
Influenza
HepatitisB
Varicella
Adeno
Rotavirus
RSV
Parainfluenza type3
Rhinovirus

+
+
+
++
+(rare)

+
+
+
+
+

+
+
+

+
+
+
+
+
+
+
+
+
+
+
+
+
+
+