Early neonatal sepsis

By
Mohamedbehairy
Neonatology specialist

Introduction
Sepsis has been a burden to humans for millions of years and will
continue to plague humans as long as microorganisms exist here
on the earth.
There have been many advances in prevention, assessment and
treatment of neonatal sepsis in the past few decades.
However, the morbidity and mortality associated with sepsis remains
high for susceptible neonates.
Neonatal sepsis is an important but underestimated problem around the
world.
Infection is an important cause of morbidity and mortality during the
neonatal period, despite the great improvements in intensive neonatal
care and the use of extended spectrum antimicrobial agents.

Definitions
Infection: The invasion and multiplication of microorganisms such as bacteria,
viruses, and parasites that are not normally present within the body. An infection
may cause no symptoms and be subclinical, or it may cause symptoms and be
clinically apparent. An infection may remain localized, or it may spread through the
blood or lymphatic vessels to become systemic .
SIRS: The systemic inflammatory response to a variety of clinical insults, manifested
by 2 or more of the following conditions:
 Temperature instability <35°C or >38.5°C .
 Respiratory dysfunction
. Tachypnea > 2 SD above the mean for age .
. Hypoxemia (PaO2 <70 mm Hg on room air) .
 Cardiac dysfunction
.Tachycardia > 2 SD above the mean for age .
.Delayed capillary refill >3 sec .
.Hypotension > 2 SD below the mean for age .

 Perfusion abnormalities ;
.Oliguria (urine output <0.5 mL/kg/hr)
. Lactic acidosis (elevated plasma lactate
and/or arterial pH <7.25)
. Altered mental status.
Bacteremia: The presence of a live bacteria in the bloodstream.
Toxemia: A condition in which the blood contains toxins produced by
a local source of infection or derived from the growth of
microorganisms.

Septicemia: is the body’s overwhelming and life-threatening response to
infection that can lead to tissue damage, organ failure, and death.
Neonatal Sepsis:
1. Probable (clinical) sepsis: It is found in an infant having a clinical picture suggestive
of septicemia, if any one of the following criteria are present:
. Existence of predisposing factors: Maternal fever, foul smelling liquor, prolonged
rupture of membranes (>24 hrs), or gastric polymorphs (>5 per high-power field).
.The septic screen would be positive due to the presence of two of the four
parameters namely;
.TLC (< 5000/mm),
. band to total polymorphonuclear cells ratio of >0.2,.
.absolute neutrophil count < 1800/ml,.
.C-reactive protein (CRP) >1mg/dl .
.micro ESR > 10 mm-first hour.
. Radiological evidence of pneumonia

2. Culture Positive (proven) Sepsis: In an infant having a clinical picture
suggestive of septicemia, pneumonia or meningitis, if either of the following
criteria are found:
-Isolation of pathogens from blood or CSF or urine or abscess (es)
-Pathological evidence of sepsis in the autopsy.
Typesofneonatalsepsis:
 Early onset; manifests within the first 72 hours after birth by the vertical
transfer of microorganisms existing in maternal passages.
 LATE onset; : manifests after the first 72 hours after birth up to 28 days, by the
vertical or horizontal transfer of microorganisms existing maternal
passages.
The primary cause of late sepsis is hospital infection.

HistoricalBackground
 In the 1930’s, group A β-haemolytic streptococci was the most frequent
cause of perinatal infections but it was controlled with the
introduction of the penicillin’s
 The 1940’s witnessed increased incidence of Gram-negative bacterial
infection, particularly that due to Escherichia coli and the 1950s that of
penicillinase producing Staphylococcus aureus which was controlled
with more potent antibiotics.
 The Gram-negative bacterial infection again became predominant in
the 1960s, giving way to the group B β-haemolytic streptococci in the
1970s.
 The group B β-haemolytic streptococci and enteric microorganism
have remained the most common infecting organisms in the United
States in the delivery setting, while there is preponderance of Gram-
negative organisms in the tropics.

 In the 1980s, Nosocomial infections became predominant in the
intensive care nursery.
 The risk of nosocomial infections is inversely proportional to the birth
weight.
 Very low birth weight (VLBW) and low birth weight (LBW) babies are
at increased risk of nosocomial infections.
 Intubation, indwelling catheters, parenteral nutrition, and antibiotic
induced overgrowth of resistant flora increases the risk of nosocomial
infections.
 Other contributing factors to nosocomial infections include lack of
strict adherence to aseptic procedures, like scrupulous hand washing
by neonatal intensive care unit personnel, and the presence of
contaminated equipment and cleansing solutions.

Epidemiology
Globally, sepsis is still one of the major causes of morbidity and mortality
in neonates, in spite of recent advances in health care units.
The incidence of neonatal septicemia varies widely between the
developed and developing countries. It also varies from one nursery to
another.
The characteristic of neonates studied also influences the incidence ,
Thus, the prevalence rate is 3-10 folds higher in preterm than in full-
term neonates.
Also, the incidence is higher in low birth weight (LBW) than normal
weight babies, and in males than females.
Other factors includes the levels of obstetric and nursery care available,
the presence of predisposing factors like; lack of good water supply,
poor socioeconomic status, delivery at home or unhygienic
environment.

The reported incidence of neonatal septicemia in developed countries
ranged between 0.95/1000 to 3/1000 live birth.
While in developing countries had an incidence of 9/1000 live births.
Epidemiological data from developed countries show important
differences not only in incidence but also in risk factors, bacteriological
agents, as well as morbidity and mortality from that of developing
countries.
Neonatal septicemia is higher in the preterm than term neonates because
the preterm neonate’s host defence, both specific (such as humoral and
cellular) and non-specific (such as skin, mucous membrane) are poorly
developed and not functioning optimally.

Burden of neonatal sepsis:
The most recent estimates suggest that neonatal mortality is
responsible for 41% of the total under age five mortality, or
approximately 3.1 million neonatal deaths per year.
Approximately 95% of these deaths occur in developing countries,
and most are attributable to preterm birth (28%), severe
infections (26%), and asphyxia (23%).
Three-quarters of neonatal deaths happen in the first week, and
the highest risk of death is on the first day of life.

Case-fatality rates for severe bacterial infections in developing countries
are high, in part due to late or inadequate administration of the
necessary antibiotics.
Deaths are often due to delays in the identification and treatment of
newborns with infection, specifically, under-recognition of illness, lack
of access to appropriate treatment and trained health workers to
administer it, delay in initiation of treatment, and inability to pay for
treatment by families, if warranted.

pathophysiology
Infections are a frequent and important cause of neonatal
and infant morbidity and mortality.
As many as 2% of fetuses are infected in utero, and up to 10%
of infants have infections in the 1st mo of life.
Neonatal infections are unique in several ways:
1. Infectious agents can be transmitted from the mother to
the fetus or newborn infant by various modes.
2. Newborn infants are less capable of responding to
infection because of one or more immunologic
deficiencies.
3. Co-existing conditions often complicate the diagnosis and
management of neonatal infections.

4. The clinical manifestations of newborn infections vary and include
subclinical infection, mild to severe manifestations of focal or systemic
infection, and, rarely, congenital syndromes resulting from in utero
infection.
5. The timing of exposure, inoculum size, immune status, and virulence
of the etiologic agent influence the expression of disease.
6. Maternal infection that is the source of transplacental fetal infection is
often undiagnosed during pregnancy because the mother was either
asymptomatic or had nonspecific signs and symptoms at the time of
acute infection.
7. A wide variety of etiologic agents infect the newborn, including
bacteria, viruses, fungi, protozoa, and mycoplasmas.
8. Immature, very low birthweight newborns have improved survival but
remain in the hospital for a long time in an environment that puts
them at continuous risk for acquired infections.

The organisms most frequently involved in early-onset neonatal sepsis of
term and preterm infants together are GBS and Escherichia coli,
which account for approximately 70% of infections combined.
Additional pathogens to consider, which account for the remaining
minority of cases, are other streptococci (most commonly viridans
group streptococci but also Streptococcus pneumoniae)
, Staphylococcus aureus, Enterococcus spp., Gram-negative enteric
bacilli such as Enterobacter spp., Haemophilus influenzae, and Listeria
monocytogenes.
When preterm and VLBW infants are considered separately, the burden
of disease attributable to E. coli and other Gram-negative rods is
increased, making Gram-negative sepsis the most common etiology of
EOS in this population.

In preterm infants, EOS was associated with higher rates of infections by
Gram-negative organisms about 55%, than by Gram-positive
organisms 38%, fungal pathogens such as Candida sp., about 5%, and
other unclassified organisms.
Viral infections, including herpes simplex virus (HSV), enteroviruses,
and, are also implicated in early-onset neonatal sepsis and must be
clinically differentiated from bacterial sepsis.
There are other viruses associated with congenital infections, such as
rubella virus, cytomegalovirus, and human immunodeficiency virus.
Additional seasonal viruses, including influenza virus, respiratory
syncytial virus (RSV), adenoviruses, rhinoviruses, and rotaviruses, have
been identified in hospitalized neonates, related primarily to
horizontal transmission.

However, these pathogens are not typically associated with an EOS
presentation.
Fungal pathogens are rarely associated with early-onset neonatal sepsis,
and Candida spp. are most likely, occurring primarily among VLBW
infant.
Candida infections may also present as congenital candidiasis that can
occur in term or preterm infants, with symptoms occurring at birth or
within the first 24 h of life .
Also there is a numerous host factors predispose the newborn infant to
sepsis.
These factors are especially prominent in the premature infant and
involve all levels of host defense, including cellular immunity, humoral
immunity, and barrier function.

Cellular immunity :
The neonatal neutrophil or polymorphonuclear (PMN) cell, which is vital for
effective killing of bacteria, is deficient in chemotaxis and killing capacity.
Decreased adherence to the endothelial lining of blood vessels reduces their
ability to marginate and leave the intravascular space to migrate into the
tissues.
Once in the tissues, they may fail to degranulate in response to chemotactic
factors. Also, neonatal PMNs are less deformable; therefore, they are less
able to move through the extracellular matrix of tissues to reach the site of
inflammation and infection.

The limited ability of neonatal PMNs for phagocytosis and killing
of bacteria is further impaired when the infant is clinically ill.
Lastly, neutrophil reserves are easily depleted because of the
diminished response of the bone marrow, especially in the
premature infant.
Neonatal monocyte concentrations are at adult levels; however,
macrophage chemotaxis is impaired and continues to exhibit
decreased function into early childhood. The absolute numbers
of macrophages are decreased in the lungs and are likely
decreased in the liver and spleen, as well. The chemotactic and
bacteriocidal activity and the antigen presentation by these cells
are also not fully competent at birth.

Cytokine production by macrophages is decreased, which may be
associated with a corresponding decrease in T-cell production.
Although T cells are found in early gestation in fetal circulation and
increase in number from birth to about age 6 months, these cells
represent an immature population, These naive cells do not proliferate
as readily as adult
T cells when activated and do not effectively produce the cytokines that
assist with B-cell stimulation and differentiation and
granulocyte/monocyte proliferation.
A delay occurs in the formation of antigen specific memory function
following primary infection, and the cytotoxic function of neonatal T
cells is 50-100% as effective as adult T cells.

At birth, neonates are deficient in memory T cells, As the neonate
is exposed to antigenic stimuli, the number of these memory T
cells will be increases.
Natural killer (NK) cells are found in small numbers in the
peripheral blood of neonates, These cells are also functionally
immature in that they produce far lower levels of interferon-
gamma upon primary stimulation than do adult NK cells.
This combination of findings may contribute to the severity of
infection in the neonatal period.

Humoral immunity:
The fetus has some preformed immunoglobulin present, primarily
acquired through nonspecific placental transfer from the mother. Most
of this transfer occurs in late gestation, such that lower levels are found
with increasing with maturity.
The neonate's ability to generate immunoglobulin in response to
antigenic stimulation is intact; however, the magnitude of the
response is initially decreased, but, rapidly rising with increasing
postnatal age.
The neonate is also capable of synthesizing immunoglobulin M (IgM)
in utero at 10 weeks' gestation; however, IgM levels are generally low at
birth, unless the infant was exposed to an infectious agent during the
pregnancy, thereby stimulating increased IgM production.

Immunoglobulin G (IgG) and immunoglobulin E (IgE) may be
synthesized in utero, Most of the IgG is acquired from the mother during
late gestation.
The neonates may receive immunoglobulin A (IgA) from breastfeeding but
does not secrete IgA until 2-5 weeks after birth.
Complement protein production can be detected as early as 6 weeks'
gestation; however, the concentration of the various components of the
complement system widely varies among individual neonates.
Although some infants have had complement levels comparable with those in
adults, deficiencies appear to be greater in the alternative pathway than in
the classic pathway.
The terminal cytotoxic components of the complement cascade that leads to
killing of organisms, especially gram-negative bacteria, are deficient.
This deficiency is more marked in preterm infants, Mature complement
activity is not reached until infants are aged 6-10 months.

Neonatal sera have reduced opsonic efficiency against GBS, E coli, and S
pneumoniae because of decreased levels of fibronectin, a serum protein
that assists with neutrophil adherence and has opsonic properties.
Barrier function:
The physical and chemical barriers to infection in the human body are
present in the newborn but are functionally deficient.
Skin and mucus membranes are broken down easily in the premature
infant.
Neonates who are ill and/or premature are additionally at risk because of
the invasive procedures that breach their physical barriers to infection.
Because of the interdependence of the immune response, these
individual deficiencies of the various components of immune activity
in the neonate conspire to create a hazardous situation for the neonate
exposed to infectious threats.

PATHOGENESIS
Early-onset neonatal sepsis occurs in utero from either a
transplacental or, more commonly, ascending bacteria
entering the uterus from the vaginal environment
following membrane rupture.
Additionally, the newborn child might become infected when
exposed to potentially pathogenic bacteria, viruses, or
fungi during passage through the birth canal.
The human birth canal is colonised with aerobic and
anaerobic bacterial organisms that can be vertically
transmitted from an ascending infection of the amniotic
fluid or natal infection of the neonates during labour or
delivery.

A. Pathogenesis of Intrauterine Infection;
Intrauterine infection is a result of clinical or subclinical
maternal infection with a variety of agents
(cytomegalovirus [CMV], Treponema pallidum, Toxoplasma
gondii, rubella virus, varicella virus, parvovirus B19) and
hematogenous transplacental transmission to the fetus.
Transplacental infection may occur at any time during
gestation, and signs and symptoms may be present at birth
or may be delayed for months or years.

Infection may result in early spontaneous abortion, congenital
malformation, intrauterine growth restriction, premature birth,
stillbirth, acute or delayed disease in the neonatal period, or
asymptomatic persistent infection with sequelae later in life.
In some cases, no apparent effects are seen in the newborn infant.
The timing of infection during gestation affects the outcome:-
.First-trimester infection; may alter embryogenesis, with resulting
congenital malformations eg; (congenital rubella).
.Third-trimester infection; often results in active infection at the time
of delivery eg; (toxoplasmosis, syphilis) .
Infections that occur late in gestation may lead to a delay in clinical
manifestations until some time after birth eg; (syphilis).

B. Pathogenesis of Ascending Bacterial Infection:
In most cases, the fetus or neonate is not exposed to potentially pathogenic
bacteria until the membranes rupture and the infant passes through the birth
canal and/or enters the extrauterine environment.
Chorioamnionitis;
1. Microbial invasion of amniotic fluid most often associated with PROM
>18-24 hours
2. Clinical syndrome of intrauterine infection including:
a. Maternal fever >100.4°F PLUS at least 2 of the following criteria:
b. Uterine tenderness
c. Foul-smelling vaginal discharge/amniotic fluid
d. Maternal leukocytosis
e. Maternal and/or fetal tachycardia
3. Diagnosed by amniotic fluid analysis or placenta pathologic
examination,

CausativeAgents;
ORGANISMS (all babies);
 Group B strep (most common G+) 41%
 Other strep 23%
 Coliforms (E. coli most common G-) 17%
 Staph aureus 4%
 Listeria 2%
 Nosocomial infections
 Candida
 Note: 73% G+ and 27% G

ORGANISMS (VLBW);
 Group B strep (most common G+) 12%
 Other strep 9%
 Coliforms (E. coli most common G-) 41%
 CONS 15%
 Listeria 2%
 Nosocomial infections
 Candida 2%
 Note: 45% G+ and 53% G

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

B.Ascending/Birth Canal;
 Organisms - GI/GU flora, Cervical/Blood
E. Coli . Herpes
GBS .Candida
Chlamydia . HIV
Ureaplasma . Mycoplasma
Listeria . Hepatitis
Enterococcus .Anaerobes
Syphilis

Riskfactors:
Risk factors implicated in neonatal sepsis reflect the level stress and
illness experienced by the fetus at delivery, as well as the hazardous
uterine environment surrounding the fetus before delivery.
The most common risk factors associated with early-onset neonatal sepsis
are as follows:
a. Maternal risk factors;
 Maternal GBS colonization (especially if untreated during labor).
 Premature rupture of membranes (PROM).
 Preterm rupture of membranes.
 Prolonged rupture of membranes.
 Prematurity.
 Maternal urinary tract infection.
 Chorioamnionitis

 Maternal fever greater than 38°C
 Maternal urinary tract infection (UTI)
 Poor prenatal care
 Poor maternal nutrition
 Low socioeconomic status
 African American mother
 History of recurrent abortion
 Maternal substance abuse

b. Fetal risk factors;
 Low Apgar score (< 6 at 1 or 5 minutes)
 Premature neonate less than 37 weeks of gestation, Low birth weight and
Small for Gestational Age(SGA)
 Male sex
 Stable intranatal fetal tachycardia
 Asphyxia/Resuscitation
 Hypothermia
 Invasive procedures
 Artificial feeding
 Non-insurance fetus
 Low birth weight

 Difficult delivery
 Birth asphyxia
 Meconium staining
 Congenital anomalies
 Lack of “Skin-to-skin” contact with mother.
 Long-term Hospitalization; Irrational antibiotic therapy.
 Poor sanitary habits of medical personnel.
 It is essential to know the evidence-based risk factors of neonatal
infection as modern strategies of prophylaxis are precisely based on
this data.

COMMONSITESOFINFECTION:
 Trivial but may be serious :
 Eyes – opthalmia neonatorum
 Skin
 Umbilicus
 Oral thrush
 Severe systematic :
 Respiratory tract
 Septicaemia
 Meningitis
 Intra – abdominal infections

ClinicalPresentation:
History;
An awareness of the many risk factors associated with neonatal
sepsis prepares the clinician for early identification and effective
treatment, thereby reducing mortality and morbidity.
Among these risk factors are the following:
 Maternal group B Streptococcus (GBS) status.
 Premature rupture of membranes (PROM).
 Prematurity.
 Chorioamnionitis.

Risk factors implicated in neonatal sepsis reflect the stress and illness of
the fetus at delivery, as well as the hazardous uterine environment
surrounding the fetus before delivery.
An awareness of the many risk factors associated with neonatal sepsis
prepares the clinician for early identification and effective treatment,
thereby reducing mortality and morbidity.
Physical Examination:
The clinical signs of neonatal sepsis are nonspecific and are associated
with characteristics of the causative organism and the body's response
to the invasion.
These nonspecific clinical signs of early sepsis syndrome are also
associated with other neonatal diseases, such as respiratory distress
syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a
traumatic delivery.

Given the nonspecific nature of these signs, providing treatment for
suspected neonatal sepsis while excluding other disease processes is
prudent.
A systematic physical assessment of the infant is best performed in series
and should include observation, auscultation, and palpation in that
order to obtain the most information from the examination.
Changes in findings from one examination to the next provides important
information about the presence and evolution of sepsis.
Signs and Symptoms :
The clinical signs and symptoms of sepsis and SIRS in the neonate are
very different from the older children's.
initial diagnosis of sepsis is, by necessity, a clinical one because it is
imperative to begin treatment befor the results of culture are available

Clinical S/Sx of sepsis are nonspecific, and the differential diagnosis is
broad.
Non-specific/Common:
Temperature irregularity; Hypo- or hyperthermia (greater heat output
required by the incubator or radiant warmer to maintain a neutral thermal
environment or frequent adjustments of the infant servo control probe).
Change in behavior; Lethargy, irritability (23%), or change in tone.
Skin; Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae,
rashes, sclerema, or jaundice.

A. Clinical Manifestations of Transplacental Intrauterine
Infections;
Infection with agents that cross the placenta (CMV, T. pallidum, T. gondii,
rubella, parvovirus B19) may be asymptomatic at birth or may cause a
spectrum of disease ranging from relatively mild symptoms to
multisystem involvement with severe and life-threatening complications.
For some agents, disease is characterized by chronicity, recurrence, or
both, and the agent may cause ongoing injury.
Clinical signs and symptoms do not help make a specific etiologic
diagnosis but, rather, raise suspicion of an intrauterine infection and
help distinguish these infections from acute bacterial infections that
occur during labor and delivery.

The following signs and symptoms are common to many of these agents;
.intrauterine growth restriction.
.microcephaly or hydrocephalus.
.intracranial calcifications.
.chorioretinitis.
.cataracts.
.myocarditis.
.pneumonia.
.hepatosplenomegaly.
.direct hyperbilirubinemia.
.anemia.
.thrombocytopenia.
.hydrops fetalis.
.skin manifestations.

Many of these agents cause late sequelae, even if the infant is
asymptomatic at birth.
These adverse outcomes include;
.sensorineural hearing loss.
.visual disturbances (including blindness).
.Seizures.
.neurodevelopmental abnormalities.
INITIAL SIGNS AND SYMPTOMS OF INFECTION IN
NEWBORN ;
Neurologic signs:
Acute and chronic histologic features are associated with specific
organisms.

Meningitis due to early-onset neonatal sepsis usually occurs within 24-48
hours and is dominated by non-neurologic signs.
Neurologic signs may include stupor and irritability.
Overt signs of meningitis occur in only 30% of cases.
Even culture-proven meningitis may not demonstrate white blood cell (WBC)
changes in the cerebrospinal fluid (CSF).
Neurologic signs include the following;
.Impairment of consciousness (i.e., stupor with or without irritability)
.Coma
.Seizures
.Bulging anterior fontanelle
.Extensor rigidity
.Focal cerebral signs
.Cranial nerve signs
.Nuchal rigidity

Respiratory presentation:
A. Congenital pneumonia and intrauterine infection;
Inflammatory lesions are observed post mortem in the lungs of infants
with congenital and intrauterine pneumonia.
They may result not from the action of the microorganisms themselves
but, rather, from aspiration of amniotic fluid containing maternal
leukocytes and cellular debris.
Tachypnea, irregular respirations, moderate retraction, apnea, cyanosis,
and grunting may be observed.
Neonates with intrauterine pneumonia may also be critically ill at birth
and require high levels of ventilatory support.
The chest radiograph may depict bilateral consolidation or pleural
effusions

B. Congenital pneumonia and intrapartum infection;
Neonates who are infected during the birth process may acquire
pneumonia through aspiration of microorganisms during delivery.
Klebsiella species and S aureus are especially likely to generate severe lung
damage, producing microabscesses and empyema
Early-onset GBS pneumonia has a particularly fulminant course, with
significant mortality in the first 48 hours of life.
Intrapartum aspiration may lead to infection with pulmonary changes,
infiltration, and destruction of bronchopulmonary tissue.
This damage is partly due to the granulocytes’ release of prostaglandins
and leukotrienes.

Fibrinous exudation into the alveoli leads to inhibition of pulmonary
surfactant function and respiratory failure, with a presentation similar
to that of RDS.
Vascular congestion, hemorrhage, and necrosis may occur.
Infectious pneumonia is also characterized by pneumatoceles within the
pulmonary tissue.
Coughing, grunting, costal and sternal retractions, nasal flaring,
tachypnea or irregular respiration, rales, decreased breath sounds, and
cyanosis may be observed.
Radiographic evaluation may demonstrate segmental or lobar atelectasis
or a diffuse reticulogranular pattern, much like what is observed in
RDS.
Pleural effusions may be observed in advanced disease.

C. Postnatal pneumonia;
Postnatally acquired pneumonia may occur at any age, because these
infectious agents exist in the environment, the likely cause depends heavily
on the infant’s recent environment.
If the infant has remained hospitalized in a neonatal intensive care unit
especially with endotracheal intubation and mechanical ventilation, the
organisms may include Staphylococcus or Pseudomonas species.
Cardiac presentations:
In overwhelming sepsis, an initial early phase characterized by pulmonary
hypertension, decreased cardiac output, and hypoxemia may occur.

This phase is followed by further progressive decreases in cardiac output with
bradycardia and systemic hypotension.
The infant manifests overt shock with pallor, poor capillary perfusion, and
edema.
These late signs of shock are indicative of severe compromise and are strongly
associated with mortality.
Gastrointestinal presentations:
The symptoms present in this system are feed intolerance, vomiting, diarrhea,
abdominal distension paralytic ileus, and necrotising enterocolitis.
Hepatic presentations:
The common hepatic signs are hepatomegaly and direct hyperbilirubinemia.
Infants with the onset of jaundice after 8 days of age, or with direct
hyperbilirubinemia, were more likely to have urinary tract infection.

Renal presentations:
Renal failure occurred in 26% neonates with sepsis.
Although ARF in neonates has been reported to be predominantly oliguric, it
was observed that ARF secondary to neonatal sepsis was predominantly
non oliguric.
Low birth weight was an important risk factor for the development of ARF.
Culture positivity, associated meningitis, DIC, shock and need for assisted
ventilation were poor prognostic indicators and were significantly
associated with mortality.
So, greater awareness of this entity among practitioners and better
management of this condition.

Hematological manifestations:
Hematological signs are bleeding, petechiae, and purpura.
Metabolic presentations:
Hypoglycemia, hyperglycemia, metabolic acidosis, and jaundice are all
metabolic signs that commonly accompany neonatal sepsis.
The infant has an increased glucose requirement as a result of the septic
state.
The infant may also be malnourished as a consequence of diminished
energy intake.
Hypoglycemia accompanied by hypotension may be secondary to an
inadequate response from the adrenal gland and may be associated
with a low cortisol level.

Metabolic acidosis is due to switching to anaerobic metabolism with the
production of lactic acid.
Jaundice occurs in response to decreased hepatic glucuronidation caused
by both hepatic dysfunction and increased erythrocyt destruction.
Skin manifestations:
Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae, rashes,
sclerema, or jaundice
When infants are hypothermic or are not kept in a neutral thermal
environment, efforts to regulate body temperature can cause metabolic
acidosis.

Predictive Value of Skin Color for Illness
Severity in the High-Risk Newborn:
A relationship between skin color and illness severity in the newborn is commonly
acknowledged but until now has not been validated.
Up to date, medical applications of colorimetry are limited to the assessment of
skin microcirculation and pigmentary changes.
With the sole exception of transcutaneous bilirubinometry little information is
currently available regarding quantitative color data in the newborn.
skin color remains a rather undervalued measurement for diagnostic, prognostic,
and therapeutic purposes for the newborn infant with infection.

DifferentialDiagnoses:
Because signs and symptoms of neonatal sepsis are nonspecific, non
infectious etiologies need to be considered.
If the infant is presenting with respiratory symptoms, respiratory distress
syndrome, transient Tachypnea of the newborn, meconium aspiration,
and aspiration pneumonia are considered.
If the infant is showing CNS symptoms, then intracranial hemorrhage,
drug withdrawal, and inborn errors of metabolism are considered.
Patients with feeding intolerance and bloody stool may have necrotizing
enterocolitis, gastrointestinal perforation, or intestinal obstruction.

Some nonbacterial infections like disseminated herpes simplex virus can
be indisnguishable from bacteria; sepsis and should be considered in
the differential diagnoses especially if the infant has fever.
We can summarize the DD. as the following:
Neurologic:
 Intracranial hemorrhage: spontaneous, child abuse .
 Hypoxic-ischemic encephalopathy.
 Neonatal seizures .
 Infant botulism.
Respiratory:
 Respiratory distress syndrome.

 Aspiration pneumonia: Amniotic fluid, meconium, or gastric contents.
 Lung hypoplasia.
 Tracheoesophageal fistula.
 Transient tachypnea of the newborn.
Cardiac :
 Congenital: Hypoplastic left heart syndrome, other structural disease,
PPHN
 Acquired: Myocarditis, hypovolemic or cardiogenic shock, PPHN.
Gastrointestinal:
 Necrotizing enterocolitis
 Spontaneous GI perforation
 Structural abnormalities

Hematologic:
 Neonatal purpura fulminans.
 Immune-mediated thrombocytopenia.
 Immune-mediated neutropenia.
 Severe anemia.
 Malignancies (congenital leukemia).
 Hereditary clotting disorders.
Metabolic:
 Hypoglycemia
 Adrenal disorders: Adrenal hemorrhage, adrenal insufficiency, congenital
adrenal hyperplasia.
 Inborn errors of metabolism: Organicacidurias, lactic acidoses, urea cycle
disorders, galactosemia.

Diagnosis:
Despite long time of studies, there is still no consensus regarding the best
screening test or panel of tests for rapid detection of neonatal sepsis
Recently, new acute phase proteins, cytokines, cell surface antigens, and
bacterial genome are used to improve the neonatal sepsis diagnosis but
data are still under evaluation and most of these tests are either not
clinically available or they are expensive.
Not one specific test can definitively rule out or confirm sepsis with 100%
certainty.

Therefore, it can take a combination of laboratory tests, imaging, and
clinical manifestations to diagnose neonatal sepsis.
A. CLINICALLY:
1.HISTORY (SPECIFIC RISK FACTORS):
 Maternal infection during gestation or at parturition (type and
duration of antimicrobial therapy).
 Urinary tract infection.
 Chorioamnionitis.
 Maternal colonization with GBS, Neisseria gonorrhoeae, herpes
simplex.
 Gestational age/birthweight

 Multiple birth.
 Duration of membrane rupture.
 Complicated delivery.
 Fetal tachycardia (distress)
 Age at onset (in utero, birth, early postnatal, ).
 Location at onset (hospital, community).
 Medical intervention.
 Vascular access.
 Endotracheal intubation.
 Parenteral nutrition.

2.EVIDENCE OF OTHER DISEASES:
 Congenital malformations (heart disease, neural tube defect).
 Respiratory tract disease (RDS, aspiration).
 Metabolic disease, e.g., galactosemia.
3. EVIDENCE OF FOCAL OR SYSTEMIC DISEASE:
 General appearance, neurologic status.
 Abnormal vital signs.
 Organ system disease.
 Feeding, stools, urine output, extremity movement.

B. LABORATORYSTUDIES:
No single test alone was sufficiently reliable to use as predictor of
neonatal septicemia.
1. Evidence of Infection;
 Culture from a normally sterile site (blood, CSF, other).
 Demonstration of a microorganism in tissue or fluid.
 Antigen detection (urine, CSF).
 Maternal or neonatal serology (syphilis, toxoplasmosis).
 Autopsy.
2. Evidence of Inflammation;
 Leukocytosis, increased immature/total neutrophil count ratio.
 Acute-phase reactants: CRP, ESR, and PCT.

 Cytokines:interleukin 6.
 Pleocytosis in CSF or synovial or pleural fluid.
 Disseminated intravascular coagulation: fibrin split products.
3. Evidence of Multiorgan System Disease;
 Metabolic acidosis: pH, PCO2.
 Pulmonary function: PO2, PCO2.
 Renal function: BUN, creatinine.
 Hepatic injury/function: bilirubin, ALT, AST ammonia, PT,
PTT.
 Bone marrow function: neutropenia, anemia,
thrombocytopenia.

1. Cultures:
 Blood Culture;
The isolation of an organism confers many advantages, including the optimal
choice and duration of antibiotic treatment.
Blood cultures are still the “gold standard” in the diagnosis of neonatal sepsis.
However, obtaining cultures from neonates can be difficult as sample volume
are small and a substantial number of cultures turn out to contaminated
or negative.
The minimum volume required for a reliable culture result has been
estimated as 1.0 ml as some recent studies have shown that up to one-
quarter of all neonates with sepsis have bacteremia involving low colony
counts (≤4 CFU/ml), and two-thirds of those <2 months old have colony
counts of( <10 CFU/ml).

The blood is most frequently drawn from a peripheral vein, but samples
obtained from an umbilical artery catheter (UAC) shortly after insertion
are also acceptable.
Blood drawn from the umbilical vein has a much greater risk of being
contaminated unless obtained during delivery from a carefully cleaned
segment of a doubly clamped cord.
Two blood cultures from different sites are no more accurate than one blood
culture of at least 1 mL volume for detecting neonatal infection.
At least 96% of positive blood cultures considered clinically significant grow
within 48 hours and 97–99% within 72 hours; organisms which took >72
hours to grow are almost always contaminants.
The higher the level of bacteremia, the quicker the blood cultures grow, so
Gram-negative bacilli grow quicker in blood cultures than Gram-positive
organisms.

Thus the time to positivity of blood cultures is a clinically useful surrogate
measure of the level of bacteremia and hence the likelihood of true
infection.
Furthermore, obtaining adequate samples from premature infants can be
challenging in view of the concerns about blood volume depletion in these
infants.
DISADVANTIGE;
False negative results; may arise from:
-insufficient or missing living bacteria in the sample resulting from low
specimen volume, only transient bacteremia.
-administration of antibiotics prior to sampling including administration
of intrapartum antibiotics to the mother.
False positive results may arise from: sample contamination.
The microbiological results are not available until 24 to 48 hours after
sampling and thus have no influence on the initial choice on whether to
initiate or withhold antibiotic therapy.

Urine Culture:
Neonatal UTI is primarily a late-onset infection.
In early-onset sepsis positive urine cultures are rare and usually reflect
concomitant bacteremia with presumed embolic renal spread, rather than
primary UTI.
Urine culture is not routinely recommended in suspected early-onset sepsis.
Gastric aspirates:
Gastric aspirate microscopy for pus cells and/or bacteria has a low sensitivity
(71–89%) and specificity (49–87%) for rapid diagnosis of early sepsis.
An infant with early-onset respiratory distress whose gastric aspirate is
negative for pus cells and bacteria on microscopy is at low risk for early-
onset infection, which is potentially useful for deciding not to treat with
empiric antibiotics.

Tracheal Aspirates:
Cultures and Gram stains of tracheal aspirate specimens may be of value if
obtained immediately after endotracheal tube placement.
Once an infant has been intubated for several days, tracheal aspirates are of
no value in the evaluation of sepsis.
Bacteria seen on tracheal secretion Gram stain in neonates <12 hours old had
74% sensitivity and 47% predictive accuracy for bacteraemia in some
studies, the specificity was 98%.
This suggests limited usefulness in guiding management of possible early
sepsis.
However, routine respiratory tract cultures may identify particularly virulent
colonizing organisms, for example, Pseudomonas, and particularly multi-
resistant organisms for infection control purposes and to guide antibiotic
use if the infant develops suspected sepsis

Lumbar Puncture and CSF:
The indications for lumbar puncture in the newborn are not as clear cut as
previously believed.
While lumbar puncture (LP) is an important means of obtaining
cerebrospinal fluid (CSF) to rule out the presence of meningitis in infants
with suspected sepsis, its routine use in neonates is controversial.
The risk of concomitant meningitis in high-risk neonates who appear healthy
or those whose clinical signs appear to be due to noninfectious conditions
such as RDS is very low.
For early onset sepsis; LP is indicated only if;
a-blood culture is positive.
b-clinically deteriorated, even with treatment.
c-Symptomatic infants , because the incidence of meningitis is 1–2% and
about a third of infants with meningitis have negative blood
cultures.
d- VLBW infants, as meningitis is likely to happen without sepsis.

Conditions that may lead to a delay or cancellation of lumbar puncture
include;
a. Severely ill infants with either cardiovascular or respiratory distress.
b. Tense or bulging anterior fontanelle (for which a CT scan or MRI may
be indicated to rule out significantly raised intracranial pressure prior
to LP).
c. The presence of severe thrombocytopenia.
d. Infection around the lumbo-sacral region.
CSF interpretation:
The CSF profile, like any other laboratory determination, should be
evaluated within the clinical context of the individual case.

Reference Range:
 Characteristics of normal spinal fluid are ;
 Total volume: 150mL
 Color: Colorless, clear, like water
 Opening pressure - 90-180 mm H 2O.
 Osmolarity at 37°C: 281 mOsm/L
 Specific gravity: 1.006 to 1.008
 Acid-base balance:
-pH: 7.28-7.32.
- Pco2: 47.9 mm Hg.
-HCO3-: 22.9 mEq/L.

 Sodium: 135-150 mmol/L.
 Potassium: 2.7-3.9 mmol/L.
 Chloride: 116-127 mmol/L.
 Calcium: 2.0-2.5 mEq/L (4.0 to 5.0 mg/dL).
 Magnesium: 2.0-2.5 mEq/L (2.4 to 3.1 mg/dL).
 Lactic acid: 1.1-2.8 mmol/L.
 Glucose: 45-80 mg/dL.
 Glutamine - 8-18 mg/dL.
 Lactate dehydrogenase (LDH) - <2.0-7.2 U/mL.
 Proteins ( 20-40 mg/dL.): at different levels of spinal tap:
 Lumbar: 20-40 mg/dL.
 Ventricular: 10-15 mg/dL.

 Erythrocyte count:
-Newborn: 0-675/mm3
 Leukocyte count:
-preterm and term babies ; <20 cells/mm3.
Interpretation:
The range of normal values for CSF parameters is different for neonates than for older
infants and children, and also varies according to gestational age, chronologic age, and
birth weight.
 Cell count;
In the neonate, a CSF WBC cell count of >20 to 30 cells/mm3 is consistent with meningeal
inflammation, and bacterial meningitis should be a consideration.
The CSF WBC is typically greater in neonates with gram-negative meningitis than with
meningitis caused by gram-positive organisms.

 Protein :
In the neonate, a CSF protein of >150 mg/dL in preterm and >100 mg/dL
in term infants is consistent with bacterial meningitis, but CSF protein
values are highly variable in neonates both with and without
meningitis.
Causes of elevated CSF protein that should be considered in the neonate
without CSF pleocytosis include;
- parameningeal infections (eg, brain abscess).
- congenital infections.
- intracranial hemorrhage.
 Glucose:
-preterm infant; <20 mg/dl (1.1 mmol/L).
- term infant ; <30 mg/dL (1.7 mmol/L).

This values are consistent with bacterial meningitis in the neonate, but
CSF glucose values are highly variable in infants both with and without
meningitis.
The ratio of CSF to serum glucose is not useful in acutely ill neonates
(their serum glucose may be increased secondary to stress or
administration of intravenous glucose before the time of evaluation).
 Gram stain:
The presence of an organism on CSF Gram stain can suggest the diagnosis
of bacterial meningitis and has the advantage of providing a
presumptive etiologic diagnosis before culture results are available.
However, the absence of organisms on Gram stain does not exclude the
diagnosis.

Approximately 20% of neonates with culture-confirmed bacterial
meningitis have negative Gram-stained smears, especially those whose
illness is caused by Listeria monocytogenes.
Neonates with culture-proven meningitis can have negative Gram-stained
smears if the concentration of organisms in the CSF is low.
Traumatic LP:
Some guidelines suggest that in traumatic taps you can allow ;
- One white blood cell for every 500 to 700 red blood cells.
-0.01g/L protein for every 1000 red cells.
However rules based on a predicted white cell count in the CSF are not
reliable.
If there are more white cells than the normal range for age, the safest
option is to treat.

PCR:
real-time PCR-based technique requested for CSF from patients with clinical
and/or CSF features of viral meningitis.
2. Haematologic tests:
A. Complete Blood Count with differential:
Evaluation of complete blood count (CBC) and differential was the first test
used to diagnose neonatal sepsis, hematological indices still being the
most extensively used in practice, currently in association with new
markers for infection.

White cell counts;
 No established norms.
 5,000 to 30,000 mm3 as a general guide
- Preterm: 6,000 – 19,000 mm3.
- Term: 10,000 – 26,000 mm3.
 Total white blood cells counts have a poor positive predictive value (PPV) for
sepsis.
 Very low WBC counts may be more concerning than high WBC counts.
 Normal WBC counts may be initially observed in as many as 50% of
cases of culture-proven sepsis.
 Infants who are not infected may also demonstrate abnormal WBC
counts related to the stress of delivery or to any of several other
factors.

Differential (Granulocytes, Monocytes,
Lymphocytes):
Normal neutrophil values are age dependent, with a peak during the first 12 to
14 h of age (range, 7,800 cells/mm3 to 14,500 cells/mm3).
During 72 h to 240 h, the values range from 2,700 cells/mm3 to 13,000
cells/mm3 in full-term infants.
Neutropenia has greater specificity for neonatal sepsis, but the definition of
neutropenia is dependent on gestational age, delivery method, and
altitude.
Neutropenia is considered a better and more specific marker for EOS
compared to neutrophilia because less factors - other than infection cause a
decrease in neutrophil count.

Absolute immature neutrophil counts peak at 12 h of age, from a maximum
value of 1,100 cells/mm3 to 1,500 cells/mm3 at 12 h.
In contrast, a maximum normal ratio of immature to total white blood cells
(I:T ratio) of 0.16 occurs at birth and reaches a nadir of 0.12 with increasing
postnatal age.
A single value of the I:T ratio (>0.3) has a very high negative predictive value
(NPV) (99%) but a very poor positive predictive value (25%) for neonatal
sepsis .
A combination of 2 serial normal I:T ratios and a negative blood culture at 24 h
in a neonate shortly after birth was accurate in ruling out neonatal sepsis.
Typically, neonates with viral infections, including HSV, enteroviruses, have
normal WBC counts or very mild leukopenia

Interpretation of the Immature/Total (I/T) Neutrophil Ratio: :
. < 0.2 is normal.
. > 0.2 – 0.4 may be suggestive of infection.
. > 0.8 carries a higher risk of death.
Platelet counts:
Despite the frequency of low platelet counts in infected infants, they are nonspecific, insensitive,
and late indicator of sepsis.
Moreover, platelet counts are not useful to follow clinical response to antimicrobial agents,
because they often remain depressed for days to weeks after a sepsis episode.
Hematological scoring system as an early diagnostic tool for
neonatal sepsis:
Hematological scoring system is sensitive, simple, quick, cost effective and readily
available tool for early diagnosis of neonatal sepsis.
It may aid the clinicians in early diagnosis of neonatal sepsis and unnecessary
exposure of infants to antibiotics can be avoided

B. Biochemical and immunologic tests:
Acute phase reactants:
Erythrocyte Sedimentation Rate;
The ESR measures the distance that a vertical column of anticoagulated blood
has fallen in one hour.
Although there have been abundant publications on the clinical use of ESR in
the last several decades, its value and specificity in diagnosis of infections
remains unclear.
Any condition that affects red blood cells or fibrinogen levels alters the value
of the ESR.
Non-inflammatory conditions such as age, anemia, pregnancy, drugs, and
obesity can cause elevation in ESR.

Causes for decreased ESR level include polycythemia, disorders of erythrocytes such
as sickle cell disease or hereditary spherocytosis, low fibrinogen levels, and
severe liver disease.
The ESR rises within 24–48 hours of the onset of inflammation and falls back slowly
with resolution of inflammation.
C-Reactive Protein;
CRP was first described in 1930 by Tillet and Francis at Rocke-feller University.
They observed a precipitation reaction between serum from patients suffering
acute pneumococcal pneumonia and the extracted polysaccharide fraction C
from the pneumococcal cell wall.
This reaction could not be observed when using serum of either healthy controls or
the same pneumonia patients after they had recovered.

In view of the fact that the polysaccharide fraction was a protein, the C-reactive
component in the serum was named C-reactive protein.
By the 1950s, CRP had been detected in more than 70 disorders including acute
bacterial, viral, and other infections, as well as noninfectious diseases such as
acute myocardial infarction, rheumatic disorders, and malignancies.
All of these disorders of disparate etiology had in common the theme of
inflammation and/or tissue injury.
The principal ligand to CRP is phosphocholine, which is found in lipopolysaccharide,
bacterial cell walls, as well as in most biological membranes.
After binding, CRP is recognized by the complement system; CRP activates it, and
promotes phagocytosis of the ligand by neutrophil granulocytes, macrophages,
and other cells.

CRP further activates monocytes and macrophages, and stimulates the production
of proinflammatory cytokines.
CRP is part of the acute-phase response, a physiological and metabolic reaction to
an acute tissue injury of different etiologies (trauma, surgery, infection, acute
inflammation, etc.) which aims to neutralize the inflammatory agent and to
promote the healing of the injured tissue.
After a trauma or the invasion of microorganisms, an acute inflammatory reaction is
initiated by activation of local resident cells which promote the recruitment and
activation of further inflammatory cells, including fibroblasts, leukocytes, and
endothelial cells.
Once activated, they release proinflammatory cytokines including IL-1, TNF- , and
IL-6. These cytokines induce the production of proteins of the acute-phase
response in the liver.
These include but are not limited to components of the complement system,
coagulation factors, protease inhibitors, metal-binding proteins, and CRP.

During the acute-phase-response, CRP’s hepatic synthesis rate increases within
hours and can reach 1,000- fold levels.
Levels remain high as long as the inflammation or tissue damage persists and then
decrease rapidly.
CRP in Neonatal Sepsis:
Any elevation of serum CRP in the neonate always represents endogenous
synthesis, since it passes the placenta in exceedingly low quantities.
De novo hepatic synthesis starts very rapidly after a single stimulus with serum
concentrations rising above 5 mg/l by about 6-8 h and peaking at around 48 h.
For the diagnosis of early-onset sepsis in clinical practice, the sensitivity is more
important compared to the specificity, as the consequences of unnecessarily
treating an uninfected infant bear fewer complications than not treating an
infected child.

The sensitivity of CRP is known to be the lowest during the early stages of
infection.
For a single CRP determination at the time of initial evaluation as well as for
determinations from cord blood, the CRP diagnostic accuracy varies widely
within an unacceptable range of sensitivity.
This may be related to the arbitrary choice of optimal cutoff points as well as the
insensitive analytic methods with various limits of quantification used in the
past to detect the CRP pattern in the earliest course of infection, in particular in
the very early neonatal period.
A raised CRP is not necessarily diagnostic for sepsis, as elevations may also occur
due to the physiologic rise after birth or non-infection-associated conditions.
Therefore, concerns were raised about the reliability of CRP during the early
stage of the disease being neither able to diagnose nor to rule out an infection
with certainty.

A repeat CRP 24– 48 h after the initiation of antibiotic therapy has been
reported to carry a 99% negative predictive value in accurately identifying, in
the early neonatal period, infants not infected.
Serial CRP measurements at 24 and 48h can be helpful in monitoring the
response to treatment in infected neonates, to determine the duration of
antibiotic therapy, and to recognize possible complications.
A CRP level that returned again to the normal range may indicate that the
duration of antibiotic treatment has been sufficient, allowing
discontinuation of antibiotics, provided the clinical condition of the child
improved and culture results were negative.

Thus, CRP has been proposed as a key decision parameter for guiding the
duration of antibiotic therapy.
However, CRP was not the single criterion, other criteria included in the
decision of whether or not to discontinue antibiotics were clinical status,
culture results, and results of other laboratory tests.
C-reactive protein (CRP) is the most extensively studied acute-phase reactant
so far, and despite the ongoing rise (and fall) of new infection markers, its
wide availability and its simple, fast, and cost-effective determination make
it one of the preferred indices in many neonatal intensive care units (NICUs).
As part of the acute-phase reaction to infection, it plays a central role in the
humoral response to bacterial invasion.

The delayed synthesis during the inflammatory response accounts for its low
sensitivity during the early phases of the disease.
Diagnostic accuracy clearly improves by the performance of serial
determinations and by the combination with earlier markers such as
interleukins or procalcitonin.
Conclusion for role of CRP in EONS;
The delayed induction of the hepatic synthesis of CRP during the inflammatory
response to infection lowers its sensitivity during the early phases of sepsis.
The performance of serial determinations 24–48 h after the onset of symptoms is
recommended, as it clearly improves diagnostic accuracy.

CRP is particularly useful for monitoring the response to treatment.
A repeated determination of CRP 24–48 h after the initiation of antibiotic
therapy has been reported to carry a 99% negative predictive value in
accurately identifying uninfected neonates, though nothing replaces a
clinical impression and the gold standard (i.e. culture results).
CRP values undergo a physiological 3-day rise after birth.
This physiologic dynamics as well as certain maternal and perinatal factors
may affect interpretation of what constitutes ‘normal’ CRP values in healthy
neonates.
Furthermore, some reports suggest noninfectious confounders such as
meconium aspiration syndrome and perinatal maternal risk conditions may
significantly elevate CRP values in symptomatic or at-risk neonates and thus
confound interpretation of CRP values in the diagnosis of sepsis.

Currently, the most used cutoff value is 10 mg/l irrespective of the gestational
and postnatal age of the neonate.
CRP has the best diagnostic accuracy when combined with another infection
marker that compensates for its diagnostic weakness and provides reliable
sensitivity during the early phases of sepsis.
conclusion :
 normal serum CRP cannot be used as the sole test to rule out early onset
neonatal infection because the test sensitivity is too low.
 Accuracy is low during the early phase of infection.
 A normal initial CRP is not sufficient to justify withholding antibiotics.
 Serial determinations 24 to 48 hours after the onset of symptoms improves
diagnostic accuracy.
 C - reactive protein should NOT be checked as a routine part of a sepsis screen,
especially if a decision has already been made to start the antibiotics based on
the clinical picture.

Procalcitonin:
Procalcitonin (PCT) is a propeptide of calcitonin, produced by macrophages and
hepatocytes. Serum PCT levels increase rapidly in 2-4h and peaks at 6-12h in
response to bacterial infection.
PCT levels are elevated in early and late onset neonatal sepsis and necrotizing
enterocolitis.
The advantages of PCT over CRP in sepsis include:
-Rapid rise in response to infection (useful in EOS).
-Levels decline with control of infection (half life is 24h).
-Not typically affected by viral infections (specific for bacterial sepsis).
-It correlates with severity of infection.

PCT also has its own limitations. PCT is increased in newborns requiring
neonatal resuscitation, maternal GBS colonization and prolonged rupture
of membranes ≥18 h.
PCT in healthy neonates increases gradually from birth to its peak at 24h and
decrease by 48h .
Therefore, to improve its diagnostic accuracy, specific cutoff values needs to
be established with respect to different gestational age and postnatal age.
Overall, in EOS, PCT might be a better biomarker than CRP

PCT Value
(ng/mL)
Interpretation Recommendation
0.1 – 0.5 Low likelihood for sepsis Antibiotic discouraged
>0.5 Increased likelihood for
sepsis
Antibiotic encouraged
>2.0 High risk of sepsis/
septic shock
Antibiotic strongly
encouraged

Cytokine Profile:
Cytokines play a vital role in sepsis, They are produced by neutrophils and
various other immune cells in response to sepsis.
It is well established that levels of cytokines such as tumor necrosis factor
(TNF)-α, interleukin (IL)-1β, IL-6 and IL-8 are elevated in the serum in sepsis.
IL-6 is an inducer of CRP and has been extensively studied among all the
cytokines in sepsis.
IL-6 is a very early marker with a very high sensitivity,
The limitation;
- it has short half-life and hence less useful if not obtained within the first
few hours of life.
-may not be practical or cost-effective because enzyme immunoassay is
expensive and time consuming.

Evaluation of a composite set of markers involving acute phase reactants,
leukocytes and cytokines/chemokines may increase sensitivity and
specificity in the diagnosis of sepsis, for eg; CRP and IL-6 , CRP and
leukocyte indices.
The lack of widespread hospital laboratory availability of the tests and the
need for serial measurements may be limiting issues for their routine use.
Cell surface markers (Neutrophil CD64 and Neutrophil/
Monocyte CD11b):
Various cell surface antigen markers are activated by infection and their detection
is made possible by advances in flow cytometry technologies.
Neutrophil CD64 and neutrophil/monocyte CD11b are such cell surface antigenic
markers that are activated by bacteria and therefore could be a potential tool in
the diagnosis of neonatal sepsis.

Advantages in using CD64:
a) Studies require minimal blood (50 µL of whole blood).
b) results are obtained in (few hours within 4 hours).
c) the persistent expression of CD64 for at least 24 hours gives the marker
a wide diagnostic window (in contrast to IL-6).
d) reliability is proven in neonatal sepsis.
Disadvantage in using CD64 :
-High cost.
-availability of resources are likely the barriers for its use in clinical
practice.

Molecular Techniques for Early Detection of Neonatal Sepsis:
Molecular techniques for diagnosis of infection may be useful in infants whose
mothers have received intrapartum antibiotics, may provide rapid results
and have better sensitivity compared to blood cultures.
Amplification methods such as polymerase chain reaction (PCR) for the
bacterial rRNA gene or hybridization methods such as microarrays have
been evaluated in clinical studies in neonates.
Genomics and Proteomics for Early Detection of Neonatal
Sepsis:
In the quest to discover novel biomarkers with high sensitivity and
specificity in sepsis, the fields of proteomics and genomics are
helping us understand the fundamental mechanisms of sepsis.
In sepsis, genomics is used to identify genes that are preferentially up
regulated in infection using sophisticated DNA sequencing methods
and bioinformatics.

Host genetic background is an important factor influencing the host
response to infection.
Genomics potentially could uncover this host genetic variability that
likely results in the variable clinical presentation and outcome of
neonates infected with similar pathogens.
Proteomics is used to analyze the structure, function and interaction of
specific proteins that are elevated in blood or other samples as a result
of infection using mass spectrometric methods.
Proteomic methods have identified several proteins, that are increased in
neonatal sepsis.
Proteomic analyses of amniotic fluids have also provided useful
information regarding the fetal response to intra-amniotic
inflammation.

Combinations of tests as asepsis screen:
No single test alone was sufficiently reliable to use as predictor of
neonatal septicemia.
The combination of sepsis makers yielded diagnostic results than single
tests and proved to be an valuable aid for early diagnosis of neonatal
sepsis.
C. Radiological studies:
1.Chest radiograph:
It should be obtained in cases with respiratory symptoms, although it is
often impossible to distinguish congenital Pneumonia from RDS
causes.

2. Brain CT, MRI, and Ultrasonography:
A.CT scanning or MRI;
may be needed late in the course of complex neonatal meningitis to
document obstructive hydrocephalus, the site where the obstruction is
occurring, and the occurrence of major infarctions or abscesses.
Signs of chronic disease (eg, ventricular dilation, multicystic
encephalomalacia, and atrophy) may also be demonstrated on CT scanning
or MRI.
B. Head Ultrasonography;
neonates with meningitis may reveal evidence of ventriculitis, abnormal
parenchymal echogenicities, extracellular fluid, and chronic changes.
Serially, head Ultrasonography can reveal the progression of
complications.

Treatmentguidelines
A. General measures:
For the majority of cases, a decision about whether an infant requires a sepsis
workup and antibiotics is usually straightforward.
These infants either are clinically sick or have a positive history of an
increased risk for sepsis with clinical signs, thereby making the antibiotic
decision easy.
However, if an infant does not have a clear-cut history and clinical
presentation, the decision is more difficult.
One single test is often not helpful and it is necessary to repeat the test.
Once the decision is made to treat the infant, treatment usually involves at
least 36–48 hours of antibiotics after obtaining cultures.
The following guidelines can be used to help make the decision to treat:

A. CDC recommendations should be followed if
possible:
The CDC now recommends universal prenatal screening for vaginal and rectal GBS
of all pregnant women at 35–37 weeks’ gestation.
The following are CDC recommendations for the management of all newborns;
If antibiotics are given, use broad spectrum for the most common causes of
sepsis (IV ampicillin for GBS and coverage for other organisms [E. coli and other
gram-negative organisms]).
When deciding antibiotics, check local antibiotic resistance patterns.
If there are any signs of sepsis during the observation period, the infant should
receive a full diagnostic evaluation.
GBS prophylaxis is indicated if there are one or more of the following:
a. Positive GBS vaginal rectal screening in late gestation (optimal at 35–37 weeks’
gestation).

b.GBS status unknown at onset of labor (culture not done, culture incomplete, or
unknown results) with one or more intrapartum risk factors, including delivery <37
weeks’ gestation, ROM ≥18 hours or intrapartum T ≥100.4°F (38.0°C), intrapartum
nucleic acid amplification test (NAAT) positive for GBS.
c.GBS bacteriuria during any trimester during the current pregnancy (intrapartum
antibiotic prophylaxis [IAP] not indicated if culture and sensitivity [C/S] done
before onset of labor with intact membranes).
d.History of a previous infant with invasive GBS disease.
B. CDC treatment plan for secondary prevention of early-onset GBS
among all newborns (term and preterm):
a. Any signs of sepsis;
- Full diagnostic workup (CBC with differential and platelets, blood culture, chest x-
ray [CXR] with abnormal respiratory signs, LP if stable enough to tolerate, and
sepsis is strongly suspected).
-Give empiric antibiotics.

b. Well infant, mother with suspected chorioamnionitis;
- Consultation with OB department is important to discuss level of
clinical assessment of chorioamnionitis.
- Perform a limited evaluation: Do a blood culture at birth, CBC with
differential, platelet count at birth and/or at 6–12 hours of life.
- Start empiric antibiotics.
c. Well infant, mother without chorioamnionitis, and GBS prophylaxis
not indicated for the mother;
- Routine clinical care.
- If signs of sepsis develop, do a full diagnostic evaluation.
- Start antibiotics.

d. Well infant, mother had indication for GBS prophylaxis but did not receive
adequate prophylaxis.
i. Infant ≥37 weeks and ROM <18 hours.
Observe infant for 48 hours or more;
- no testing.
- Some recommend CBC and differential at 6–12 hours.
- If signs of sepsis develop, do a full diagnostic evaluation and start
antibiotics.
ii. Infant <37 weeks or ROM ≥18 hours.
Limited evaluation (blood culture at birth, CBC with differential at birth
and/or at 6–12 hours of life) with
-observation for 48 hours or more.
-Some experts recommend a CBC and differential at 6–12 hours.
-If signs of sepsis develop;
. do a full diagnostic evaluation
. start antibiotics.

e. Well infant, GBS prophylaxis indicated for mother and she received
adequate intrapartum GBS prophylaxis (≥4 hours of IV penicillin,
ampicillin, or cefazolin before delivery).;
Observe for 48 hours or more;
-no testing necessary.
-If signs of sepsis develop, do a full diagnostic evaluation and start
antibiotics.
-Infant may go home after 24 hours if ≥37 weeks’ gestation and
discharge criteria have been met.
-Well-appearing infants at gestational age (GA) of 35–36 weeks do
not routinely require diagnostic evaluations.

C. The AAP guidelines recognize the clinical
challenges in this area:
The concern of overtreatment is validated by recent data showing that
prolonged antibiotic treatment >5 days in preterm infants had a higher
incidence of NEC, late-onset sepsis, and mortality.
They have come up with management plans for neonates with suspected or
proven early-onset bacterial sepsis.
When reviewing these specific guidelines, remember these key points;
.If the mother was diagnosed with chorioamnionitis, it is important
to talk to the obstetricians and confirm the diagnosis since it has
major treatment implications for the infant.
.Inadequate IAP means the mother received another antibiotic (not
penicillin, ampicillin, or cefazolin) or received the correct antibiotic
but the duration was <4 hours.

a. Any critically ill infant; Requires a complete sepsis evaluation and
antibiotics (even if there are no risk factors).
b. Any mature infant without risk factors for infection, with mild findings
(tachypnea with or without O2 requirement).
- Observe for ~6 hours after birth.
- With improvement (tachypnea is resolving, O2 requirement is
decreasing).
antibiotics are probably not indicated but continued observation.
- With worsening clinical state, obtain cultures and start antibiotics
empirically.
c. Healthy-appearing, asymptomatic infant <37 weeks with one risk factor
for sepsis; For example, intrapartum antimicrobial prophylaxis indicated but
inadequate or PROM ≥18 hours or chorioamnionitis;
i. Do blood culture at birth, WBC and differential and optional CRP at age
6–12 hours.

ii. Start broad-spectrum antibiotics; Now what? Re-evaluate
(a) Blood culture positive;
- Continue antibiotics.
- Lumbar puncture is indicated in any infant with a positive blood culture
or if sepsis is highly suspected (based on clinical signs, response to
treatment, or lab results).
(b) Blood culture negative, infant well, lab values abnormal;
- Continue antibiotics in the infant for a total of 72 hours if mother
received antibiotics during labor and delivery.
- If at 72 hours the physical examination is normal, the antibiotics can be
discontinued.
(c) Blood cultures negative, infant well, lab values normal;
Discontinue antibiotics after 48 hours.

d. Healthy-appearing, asymptomatic infant ≥37 weeks withrisk factor
of
chorioamnionitis.
i. Blood culture at birth, WBC and differential and optional CRP at age 6–12 hours.
ii. Start broad-spectrum antibiotics. Now what? Re-evaluate
(a) Blood culture positive.
-Continue antibiotics.
-Lumbar puncture is indicated in any infant with a positive blood culture or if
sepsis is highly suspected (based on clinical signs, response to treatment, or
lab results).
(b) Blood culture negative, infant well, lab values abnormal;
-Continue antibiotics for a total of 48–72 hours in the infant if mother received
antibiotics during labor and delivery.
-Discontinue antibiotics at 48–72 hours if the physical examination remain normal.
(c) Blood culture negative, infant well, lab values normal;
Discontinue antibiotics and discharge by 48 hours.

e. Healthy-appearing, asymptomatic infant ≥37 weeks with risk factors for sepsis
but not chorioamnionitis: PROM ≥18 hours or intrapartum antimicrobial
prophylaxis indicated but inadequate.
i. Observation without doing any lab tests; Acceptable if observation is every
2–4 hours for a minimum of 24 hours. OR
ii. do lab tests; Do WBC and differential and optional CRP at age 6–12 hours.
iii. No antibiotics necessary, observation. Now what? Re-evaluate.
(a) Lab values abnormal; Do blood culture. If the blood culture is negative and
the infant is well then discharge by 48 hours.
(b) Lab values normal. Infant well, discharge by 48 hours. Discharge at 24
hours is acceptable only if other discharge criteria are met, access to
medical care is readily available, and there is an able person who can fully
comply with instructions for home observation.

B. Antibiotic therapy:
1. If the decision is to treat:
a. Obtain cultures of the blood and spinal fluid if indicated. Lumbar
puncture is indicated if there is a positive blood culture or sepsis is highly
suspected based on clinical signs or lab values, or if infants do not respond to
treatment. Any other cultures that seem appropriate should be sent to the
laboratory (eg, if there is eye discharge, send a Gram stain and culture).
Tracheal aspirate Gram stain and culture if pneumonia is suspected and there
is an increase in tracheal secretions.
b. Ampicillin and gentamicin are the antibiotics most commonly used for
empirical initial therapy in a newborn with sepsis.

Once a pathogen is identified, use narrow therapy if possible unless synergism is
necessary. If GBS is documented, penicillin G or ampicillin is given, but an
aminoglycoside is often added for synergism.
Recent reviews have documented that in infants (≥32 weeks’ gestation), once-a-day
gentamicin is superior to multiple doses a day because it achieves higher peak
levels and avoids toxic trough levels.
Third-generation cephalosporins are an alternative to gentamicin, but recent studies
have shown resistance and increased candidiasis with use.
Cefotaxime should only be used in infants with gram-negative meningitis.
Cefotaxime and an aminoglycoside should be used in infants with gram-negative
meningitis until susceptibility testing is back.

c. If the cultures are positive, treat accordingly;
.Bacteremia without source: treat for 10 days.
.Uncomplicated GBS meningitis: treat for 14 days.
. Gram-negative meningitis: treat for 21 days or 14 days after obtaining
a negative culture.
2. Discontinuing antibiotics:
a. See AAP management guidelines above for neonates with suspected or
proven early-onset bacterial sepsis.
b. Other recommendations;
i. If the cultures are negative, the patient is doing well, and the risk of
sepsis low; Antibiotics may be stopped after 48 hours (for asymptomatic
term infants, negative cultures after 36 hours may be sufficient).

A normal I:T ratio and serial negative CRP might help determine whether
antibiotics can be stopped because of their high negative predictive value.
Use of procalcitonin concentrations may also be helpful in deciding when to
stop antibiotics.
ii. If the cultures are negative but the infant had signs of sepsis (clinical
sepsis); Some clinicians treat the infant for 7–10 days.

C. Adjuvant therapy:
In addition to the administration of antibiotics, great attention to supportive care is
needed.
Antibiotics should be considered as only part of the management of a septic
neonate.
Of importance are: thermal care, incubator nursing, phototherapy if warranted,
monitoring of oxygen saturation, heart rate and blood pressure.
Respiratory support is needed for hypoxia, hypercapnea, respiratory distress and
apnea.
Cardiovascular inotropic support is often needed.
Correction of fluid, electrolyte, glucose and haematological derangements (including
blood, platelets and clotting factors).
Only the very unstable infant usually needs enteral feedings withhold, consider
parenteral alimentation if oral feeding is not possible.

Conclusions(summary)
Neonatal sepsis is a major cause of morbidity and mortality.
Peri-natal history is crucial in diagnosing, prevention, and treatment of Early Onset
Neonatal sepsis (EONS).
Diagnostic tests for early-onset sepsis (other than blood or CSF cultures) are useful
for identifying infants with a low probability of sepsis but not at identifying
infants likely to be infected.
Cultures of superficial body sites, gastric aspirates, and urine are of no value in the
diagnosis of early-onset sepsis.
Lumbar puncture is not needed in all infants with suspected sepsis (especially those
who appear healthy) but should be performed for infants with signs of sepsis
who can safely undergo the procedure, for infants with a positive blood culture,
for infants likely to be bacteremic (on the basis of laboratory data), and infants
who do not respond to antimicrobial therapy in the expected manner.

The optimal treatment of infants with suspected early-onset sepsis is
broad-spectrum antimicrobial agents (ampicillin and an
aminoglycoside).
Once the pathogen is identified, antimicrobial therapy should be
narrowed (unless synergism is needed).
Antimicrobial therapy should be discontinued at 48 hours in clinical
situations in which the probability of sepsis is low, based on clinical
data, and laboratory supportive.

Early neonatal sepsis

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