Transcript Document

Neonatal sepsis
early vs. late
maternal vs. nosocomial vs. community acquired
modes of vertical trasmission
Overview of neonatal immune system
Manifestations of neonatal sepsis
Differential diagnosis
Maternal screening for STD
Diagnostic work up for neonatal sepsis
Treatment duration
Antibiotics (dose – interval)
Modes of transmission
1- transplacental
2- transvaginal
3- ascending
4- breast milk
Chronology
Early onset <7days→(sepsis- pneumonia)
Late onset>7days→(meningitis- local infections )
Late late onset>1month
Source
Maternal (vertical)
Hospital (nosocomial)
Community
Early onset sepsis Presents during the first week, usually during
the first 72h of life . The clinical presentation is respiratory
distress and pneumonia. Three common pathogens are GBS –
E coli – Listeria monocytogen. UTI is not common.
Late onset sepsis Presentation is after the first week. Pathogens
are the same as early onset sepsis. Presentation with
meningitis is more common than early onset sepsis.
Nosocomial infection The CDC-NNIS system defines a
nosocomial infection as a localized or systemic condition (1)
that results from an adverse reaction to the presence of an
infectious agent or it’s toxin and (2) that was not present or
incubating at the time of admission to the hospital. (a)
Pathogens are different from early and late onset sepsis and
include klebsiella – pseudomona – enterobacter – CONS –
staphylococcus aureus – stenotrophomonas – acintobacter –
candida – enterococcus…
Characteristics of Neonatal Sepsis
Early Onset (<7 Days)
Intrapartum
complications
Often present
Late Onset
7 Days to 3Months
Usually absent
Late, Late Onset
(>3 Months)
Varies
Transmission
Vertical; organism often
acquired from mother’s
genital tract
Vertical or through
Postnatal
environment
Usually postnatal
environment
Clinical
manifestations
Fulminant course ;
multisystem involvement
pneumonia common
Insidious or acute,
focal infection,
meningitis common
insidious
Case fatality rate
5-20%
5%
low
Overview of neonatal immune system
Immunoglobulin
In premature infants, cord IgG levels are directly proportional to gestational age.
Studies of type-specific IgG antibodies to GBS have shown that the ratio of cord to
maternal serum concentrations is 1.0, 0.5, and 0.3 at term, 32 wk, and 28 wk of
gestation, respectively.
Complement
Full-term newborn infants have slightly diminished classical pathway complement
activity and moderately diminished alternative pathway activity. Premature
infants have lower levels of complement components and less complement activity than
full-term newborns do.
Monocyte – macrophage system
The number of circulating monocytes in neonatal blood is normal, but the mass or
function of macrophages in the reticuloendothelial system is diminished,
particularly in preterm infants. In both term and preterm infants, chemotaxis of
monocytes is impaired.
Natural killer cells
neonatal NK cells have decreased cytotoxic activity and ADCC in comparison to adult
cells. The diminished cytotoxicity against herpes simplex virus (HSV)-infected cells
may predispose to disseminated HSV infection in newborn.
Neutrophils
Quantitative and qualitative deficiencies of the phagocyte system contribute
to the newborns' susceptibility to infection. Neutrophil migration
(chemotaxis) is abnormal at birth in both term and preterm infants.
Neonatal neutrophils have decreased adhesion, aggregation, and
deformability, all of which may delay the response to infection.
The number of circulating neutrophils is elevated after birth in both term and
preterm infants, with a peak at 12 hr that returns to normal by 22 hr.
Band neutrophils constitute less than 15% in normal newborns and may
increase in newborns with infection and other stress responses such as
asphyxia.
Neutropenia is frequently observed in preterm infants and those with
intrauterine growth restriction; it increases the risk for sepsis.
The neutrophil storage pool in newborn infants is 20-30% of that in adults and
is more likely to be depleted in the face of infection. Mortality is increased
when sepsis is associated with severe sepsis-induced neutropenia and bone
marrow depletion.
Granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage
colony-stimulating factor (GM-CSF) are cytokines that play important roles
in the proliferation, differentiation, functional activation, and survival of
phagocytes.
Placental transport of antibodies
The transport of IgG is an active placental process, and the
neonates serum IgG concentration at birth is 5% to 10% higher
than that of the mother.
Elevated levels of IgM or IgA in cord blood usually indicate that
the infant has been exposed to antigen in utero and has
synthesized antibody itself.
The concentration of IgG falls postnatally (because of the
catabolism of maternal IgG) and reaches a nadir (physiologic
hypogammaglobulinemia) at approximately 3 to 4 months of
age.
BACTERIAL SEPSIS
Neonates with bacterial sepsis may have either nonspecific
signs and symptoms or focal signs of infection , including
temperature instability, hypotension,
poor perfusion with pallor and mottled skin,
metabolic acidosis, tachycardia or bradycardia, apnea,
respiratory distress, grunting, cyanosis, irritability, lethargy,
seizures, feeding intolerance, abdominal distention,
jaundice, petechiae, purpura, and bleeding.
BACTERIAL SEPSIS
The initial manifestation may involve only limited symptomatology
and only 1 system, such as apnea alone or tachypnea with
retractions or tachycardia, or it may be an acute catastrophic
manifestation with multiorgan dysfunction.
Infants should be reevaluated over time to determine whether the
symptoms have progressed from mild to severe.
Later complications of sepsis include
respiratory failure, pulmonary hypertension, cardiac failure,
shock, renal failure, liver dysfunction, cerebral edema or
thrombosis, adrenal hemorrhage and/or insufficiency, bone
marrow dysfunction (neutropenia, thrombocytopenia ,anemia),
and disseminated intravascular coagulopathy (DIC).
BACTERIAL SEPSIS
A variety of noninfectious conditions can occur together with
neonatal infection or can make the diagnosis of infection more
difficult.
Respiratory distress syndrome (RDS) secondary to surfactant
deficiency can coexist with bacterial pneumonia.
Because bacterial sepsis can be rapidly progressive, the physician
must be alert to the signs and symptoms of possible infection
and initiate diagnostic evaluation and empirical therapy in a
timely manner. The differential diagnosis of many of the signs
and symptoms that suggest infection is extensive; these
noninfectious disorders must also be considered.
SIRS
The clinical manifestations of infection depend on the virulence of the
infecting organism and the body's inflammatory response.
The term systemic inflammatory response syndrome (SIRS) is most
frequently used to describe this unique process of infection and the
subsequent systemic response.
In addition to infection, SIRS may result from trauma, hemorrhagic
shock, other causes of ischemia, and pancreatitis.
Patients with SIRS have a spectrum of clinical symptoms that
represent progressive stages of the pathologic process. In adults,
SIRS is defined by the presence of 2 or more of the following:
(1) fever or hypothermia, (2) tachycardia, (3) tachypnea, and (4)
abnormal WBC count or an increase in immature forms.
TNF→ increased vascular permeability
TNF + IL1→ fever + vasodilation
Arachidonic acid metabolites →fever, tachypnea, V/Q
abnormalities, lactic acidosis
Nitric oxide →hypotention
Myocardial depressant factors→ myocardial
depression
SIRS
In neonates and pediatric patients, SIRS is manifested as
temperature instability,
respiratory dysfunction (altered gas exchange, hypoxemia,
acute respiratory distress syndrome [ARDS],
cardiac dysfunction (tachycardia, delayed capillary refill,
hypotension), and
perfusion abnormalities (oliguria, metabolic acidosis).
Increased vascular permeability results in capillary leak into
peripheral tissues and the lungs, with resultant pulmonary
and peripheral edema. DIC results in the more severely
affected cases. The cascade of escalating tissue injury may
lead to multisystem organ failure and death.
Sepsis signs in body systems
Fever
T instability
Not doing well
Poor feeding
edema
Abdominal
distention
Diarrhea
Vomiting
hepatomegaly
Pallor
Mottling
Cold clammy skin
Tachycardia
Hypotension
bradycardia
Irritability
Lethargy
Tremor
Seizure
Hypotonia
hyporeflexia
Apnea
Cyanosis
Tachypnea
Retraction
Nasal flaring
grunting
Jaundice
Splenomegaly
Pallor
Petechia
Purpura
Bleeding
Oliguria
Irregular respiration
High pitch cry
Full fontanel
FEVER
Only about 50% of infected newborn infants have a
temperature higher than 37.8 (axillary).
Fever in newborn infants does not always signify
infection; it may be caused by increased ambient
temperature, isolette or radiant warmer malfunction,
dehydration, central nervous system (CNS) disorders,
hyperthyroidism, familial dysautonomia, or ectodermal
dysplasia.
RASH
Cutaneous manifestations of infection include
impetigo,
cellulitis, mastitis, omphalitis, and subcutaneous
abscesses.
Ecthyma gangrenosum is indicative of infection with
Pseudomonas species.
The presence of small salmon-pink papules
suggests L. monocytogenes infection.
A vesicular rash
is consistent with herpesvirus infection.
Ecthyma gangrenosum
OMPHALITIS
Omphalitis is a neonatal infection resulting from
inadequate care of the umbilical cord, which continues to be a
problem, particularly in developing countries. The umbilical
stump is colonized by bacteria from the maternal genital tract
and the environment. The necrotic tissue of the
umbilical cord is an excellent medium for bacterial growth.
Omphalitis may remain a localized infection or may spread to
the abdominal wall, the peritoneum, the umbilical or portal
vessels, or the liver.
Abdominal wall cellulitis or necrotizing fasciitis
with associated sepsis and a high mortality rate may develop in infants
with omphalitis.
Prompt diagnosis and treatment is necessary to avoid serious
complications.

TETANUS
Neonatal tetanus is a serious neonatal
infection in developing countries. It results from unclean delivery and
unhygienic management of the umbilical cord in an infant born to a
mother who has not been immunized against tetanus.
The surveillance case definition of neonatal tetanus requires the
ability of a newborn to suck at birth and for the 1st few days of
life, followed by an inability to suck starting between 3 and 10
days of age, difficulty swallowing, spasms, stiffness, seizures, and
death.
Bronchopneumonia, presumably resulting from aspiration,
is a common complication and cause of death. Neonatal tetanus
is a preventable disease. It can be prevented by immunizing
mothers before or during pregnancy and by ensuring a clean
delivery, sterile cutting of the umbilical cord, and proper cord
care after birth.
Pneumonia
Pneumonia
Signs of pneumonia on physical examination, such as dullness to
percussion, change in breath sounds, and the presence of rales
or rhonchi, are very difficult to appreciate in a neonate.
X-rays of the chest may reveal new infiltrates or an effusion, but
if the neonate has underlying RDS or BPD, it is very difficult to
determine whether the radiographic changes represent a new
process or worsening of the underlying disease.
Bacterial pneumonia
The progression of neonatal
pneumonia can be variable.
Fulminant infection is most
commonly associated with
pyogenic organisms such as
GBS. Onset may be during the
1st hours or days of life, with
the infant often manifesting
rapidly progressive circulatory
collapse and respiratory
failure. With early-onset
pneumonia, the clinical course
and radiographs of the chest
may be indistinguishable from
severe RDS.
Afebrile pneumonia syndrome
In contrast to the rapid progression
of pneumonia when caused by
pyogenic organisms, older infants
with community-acquired
infection often have an indolent
course. The onset is usually
preceded by upper respiratory
tract symptoms or conjunctivitis.
A nonproductive cough ensues,
and the degree of respiratory
compromise is variable. Fever is
usually absent, and radiographic
examination of the chest shows
focal or diffuse interstitial
pneumonitis. This infection has
been called the "afebrile
pneumonia syndrome" and is
generally caused by C. trachomatis,
CMV, Ureaplasma urealyticum, or
one of the respiratory viruses.
Although Pneumocystis carinii was
implicated in the original
description of this syndrome, its
etiologic role is now in doubt,
except in newborns infected with
HIV.
SCREENING
Sexually transmitted infections (STls)
that infect a pregnant woman are of particular
concern to the fetus and newborn because of the
possibility for intrauterine or perinatal
transmission.
All pregnant women and their partners should be
queried about a history of STls.Women should also
be counseled about the need for timely diagnosis
and therapy for infections during pregnancy.
SCREENING
The CDC recommends the following screening tests and appropriate treatment of
infected mothers: (1) All pregnant women should be offered voluntary and
confidential HIV testing at the 1st prenatal visit. For women at high risk of infection
during pregnancy (multiple sexual partners or STls during pregnancy, intravenous
drug use), repeat testing in the 3rd trimester is recommended. (2) A serologic test
for syphilis should be performed on all pregnant women at the 1st prenatal visit.
Repeat screening early in the 3rd trimester and again at delivery is recommended
for women who had positive serology in the 1st trimester and for those at high risk
for infection during pregnancy. (3) A serologic test for hepatitis B surface antigen
(HBsAg) should be performed at the 1st prenatal visit and repeated late in
pregnancy in those who are initially negative but at high risk for infection. (4) A
maternal genital culture for C. trachomatis should be performed at the 1st prenatal
visit.Young women (under 25 yr) and those at increased risk for infection (new or
multiple partners during pregnancy) should be retested during the 3rd trimester. (5)
A maternal genital culture for Neisseria gonorrhoeae should be performed at the 1st
prenatal visit for women at risk and for those who live in areas with a high
prevalence of gonorrhea. Repeat testing in the 3rd trimester is recommended for
those at continued risk. (6) Evaluation for bacterial vaginosis should be considered
at the 1st prenatal visit for asymptomatic women at high risk for preterm labor. (7)
The CDC has recommended universal screening for rectovaginal GBS colonization
of all pregnant women at 35-37 wk gestation and a screening-based approach to
selective intrapartum antibiotic prophylaxis against GBS.
SCREENING
1-HIV
2- Syphilis
3- hepatitis B
4- C. trachomatis
5- Neisseria gonorrhoea
6- Bacterial vaginosis
7- GBS
Diagnostic workup
Bacterial infection is diagnosed by isolating the
etiologic agent from a normally sterile body site
(blood, CSF, urine, joint fluid).
Obtaining 2 blood culture specimens by venipuncture
from different sites avoids confusion caused by skin
contamination and increases the likelihood of
bacterial detection. (size of sample=0.5-1cc)
Samples should be obtained from an umbilical
catheter only at the time of initial insertion.
Although the total WBC count and differential and
the ratio of immature to total neutrophils have
limitations in sensitivity and specificity,
an immature-to-total neutrophil ratio of >0.2 suggests
bacterial infection.
Neutropenia is more common than neutrophilia
in severe neonatal sepsis, but neutropenia also occurs
in association with maternal hypertension,
preeclampsia, and intrauterine growth restriction.
Thrombocytopenia is a nonspecific indicator of
infection.
Tests to demonstrate an inflammatory
response include:
C-reactive protein, procalcitonin, haptoglobin,
GCSF - fibrinogen,
inflammatory cytokines (including IL-6, IL-8,IL10
and TNF-a),
and cell surface markers like CD64.
When the clinical findings suggest an acute infection
and the site of infection is unclear, additional studies
should be performed, including blood cultures,
lumbar puncture, urine examination, and a chest xray.
(Urine should be collected by catheterization or suprapubic
aspiration;)
urine culture for bacteria can be omitted in
suspected early-onset infections because
hematogenous spread to the urinary tract is rare at
this point.
When the clinical findings suggest an acute infection, the
examination of the “buffy coat” with Gram or methylene blue stain
may demonstrate intracellular pathogens.
Demonstration of bacteria and inflammatory cells in Gram-stained
gastric aspirates on the 1st day of life may reflect maternal
amnionitis, which is a risk factor for early-onset infection.
Stains of endotracheal secretions in infants with early-onset
pneumonia may demonstrate intracellular bacteria, and cultures
may reveal either pathogens or upper respiratory tract flora.
Careful examination of the placenta
can be helpful in the diagnosis of both chronic and acute
intrauterine Infections.
Diagnostic evaluation is indicated for asymptomatic infants born to
mothers with chorioamnionitis.
The probability of neonatal infection correlates with the degree of
prematurity and bacterial contamination of the amniotic fluid.
In an asymptomatic term infant whose mother has chorioamnionitis, 2
blood cultures should be performed and presumptive treatment
initiated.
Maternal chorioamnionitis=
Fever + leukocytosis + uterine tenderness + foul smelling
amniotic fluid
There is controversy over
whether
a lumbar puncture is necessary for
all term infants with suspected
early-onset sepsis.
LP indications
1- positive blood culture
2- seizure
3- drowsiness/unconsciousness
4- pneumonia
5- apnea
CSF normal values:
Normal, un infected infants from 0-4 wk of age may
have
elevated CSF protein levels of 85 ± 45 mg/ dL,
glucose of 45 ± 10 mg/ dL,
and
elevated CSF leukocyte counts of 11 ± 10 with the
90th percentile being 22.
During the neonatal period presence of RBC in CSF
(up to 800 in first day and 50 in the end of neonatal
period ) can be considered a normal finding.
Gram stain of CSF yields a positive result in most patients with
bacterial meningitis. The leukocyte count is usually elevated,
with a predominance of neutrophils (>70-90%); the number
is often >1,000 but may be <100 in infants with neutropenia
or early in the disease. Microorganisms are recovered from
most patients who have not been pretreated with antibiotics.
Bacteria have also been isolated from CSF that did not have
an abnormal number of cells (<25) or an abnormal protein
level (<200 mg/dL), thus underscoring the importance of
performing a culture and Gram stain on all CSF specimens.
Contamination of CSF by bacteremia after traumatic lumbar
puncture may occur rarely.
Culture negative meningitis
may be seen with antibiotic pretreatment, brain abscess, or
infection with Mycobacterium hominis, U. urealyticum, Bactericides
fragilis, enterovirus, or HSV. Head ultrasonography or, more
often, CT with contrast enhancementmay be helpful in
diagnosing ventriculitis and brain abscess.
Head circumference chart is mandatory in neonatal meningitis.
All the neonates should be reexamined for CSF (analysis and culture) 3-4 days
after starting the treatment, to find out whether the antibiotic treatment
has been effective or not in eradication of infection. The antibiotic regimen
may be changed accordingly if necessary.
A final examination on CSF should be done as well near the end of therapy,
before discontinuation of antibiotics.
Therapy for meningitis is continued for a minimum of 2 weeks after
sterilization of CSF cultures. This equates to 14 days of therapy for
meningitis caused by gram positive organisms and a minimum of 21 days of
therapy for meningitis caused by gram negative pathogens. (a)
Treatment for candida meningitis is with amphotericin B and flucytosine for a
period of 3 to 6 weeks. (a)
Dexamethasone is not used in neonatal meningitis.
Complications of neonatal meningitis: the acute complications include
communicating and noncommunicating hydrocephalus, subdural effusion,
ventriculitis, and blindness. (a)
Immature/total
The I:T ratio has been investigated as an early predictor of
sepsis. The maximal I:T ratio in uninfected neonates is 0.16 in
the first 24hrs, decreasing to 0.12 by 60 hrs. the upper limit
of normal for neonates of 32 weeks gestation or less is slightly
higher, at 0.2.
Prolonged induction with oxytocin
Stressful labor
Prolonged crying
IVIG
Meta-analysis of studies of IVIG for the treatment
of neonates with sepsis has shown a significant
decrease in the mortality rate compared with
standard therapies.
Dose: 200mg/kg/dose over 2hr
GCSF
10 mcg/kg sc 1-3doses
1- CBC – diff – ESR – CRP – BC – PT – ABG – UA – UC – SC
CSF analysis & culture – ETT culture – clot for electrolytes
2- CXR
3- antibiotics
4- IVIG if indicated
5- G- CSF if indicated
6- exchange transfusion if indicated
7- acyclovir if indicated
8- amphotericin – B if indicated
9- hyperglycemia management
10- duration of antibiotic 10days if started for a positive BC or 7days after
improvement if AB is started based on clinical indication.
11- chart head circumference in meningitis to detect hydrocephalus.
12- repeat LP after 3-4 days of AB treatment to decide whether the current
antibiotics are appropriate or should be changed.
13- always make sure of normal CSF profile before discontinuing the AB
therapy ( repeat LP near the end of treatment period).
ESR
First 2 weeks of life:
3 + age in days
Beyond 2 weeks of life:
the maximum rate varies between 10 and 20
mm per hour.
CRP
Normal concentrations in neonates are
1mg/dl or lower.
An increasing CRP value is usually
detectable within 6 – 18 hours,
and the peak CRP is seen at 8 – 60 hours
after onset of the inflammatory process.
Is antibiotic therapy mandatory
for all neonates who receive
intravenous fluid?
AB
route
W<1200
0-4w
W1200-2000
0-7days
W1200-2000
>7days
W>2000
0-7days
W>2000
>7days
Ampicillin
IM
IV
50 q12h
25q12h
50q12h
25q12h
50q8h
25q8h
50q8h
25q8h
50q6h
25q6h
Amikacin
IM
IV
7.5q12h
7.5q12h
7.5q8h
10q12h
10q8h
Cefotaxime
IM
IV
50q12h
50q12h
50q8h
50q12h
50q8h
Ceftazidime
IM
IV
50q12h
50q12h
50q8h
50q8h
50q8h
Vancomycin
IV
15q24h
10q12h
10q12h
10q8h
10q8h
metronidazol
e
IV
PO
7.5q48h
7.5q24h
7.5q12h
7.5q12h
15q12h
Imipenem
IM
IV
-
20q12h
20q12h
20q12h
20q8h
Ciprofloxacin
IV
-
-
10-20q24h
-
20-30q12h
Cephalothin
IV
20q12h
20q12h
20q8h
20q8h
20q6h
Ceftriaxone
IM
50q24h
50q24h
50q24h
50q24h
75q24h