Continuing Education Activity

Neonatal sepsis refers to an infection involving bloodstream in newborn infants less than 28
days old. It continues to remain a leading cause of morbidity and mortality among infants,
especially in middle and lower-income countries. It is divided into early-onset sepsis (EOS)
or late-onset sepsis (LOS) based on the age of presentation after birth with different experts
using 72 hours or 7 days as the cutoff. This activity describes the treatment and evaluation of
neonatal sepsis and explains the role of the interprofessional team in managing patients with
this condition.
Objectives:
 Describe the etiology of early and late onset neonatal sepsis.
 Describe various clinical and laboratory findings associated with neonatal sepsis
 Review the various treatment and management options available for neonatal sepsis.
 Explain the importance of improving care coordination amongst interprofessional
team members to improve outcomes for neonates affected by sepsis.
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Introduction
Neonatal sepsis refers to an infection involving the bloodstream in newborn infants less than
28 days old. It remains a leading cause of morbidity and mortality among neonates, especially
in middle and lower-income countries [1]. Neonatal sepsis is divided into two groups based
on the time of presentation after birth: early-onset sepsis (EOS) and late-onset sepsis (LOS).
EOS refers to sepsis in neonates at or before 72 hours of life ( some experts use seven days),
and LOS is defined as sepsis occurring at or after 72 hours of life [2].
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Etiology
Early-onset sepsis(EOS) is generally caused by the transmission of pathogens from the
female genitourinary system to the newborn or the fetus. These pathogens can ascend the
vagina, the cervix, and the uterus, and can also infect the amniotic fluid. Neonates can also
become infected in utero or during delivery as they pass through the vaginal canal. Typical
bacterial pathogens for EOS include Group B streptococcus (GBS), Escherichia coli,
coagulase-negative Staphylococcus, Haemophilus influenza, and Listeria monocytogenes.
Maternal factors that increase the risk of neonatal sepsis include chorioamnionitis, GBS
colonization, delivery before 37 weeks, and prolonged rupture of membranes greater than 18
hours [3].
Late-onset sepsis (LOS) usually occurs via the transmission of pathogens from the
surrounding environment after delivery, such as contact from healthcare workers or
caregivers. A percentage ofLOS may also be caused by a late manifestation of vertically
transmitted infection. Infants requiring intravascular catheter insertion, or other invasive
procedures that disrupt the mucosa, are at increased risk for developing LOS.
Preterm neonates are at higher risk for sepsis/infection than term neonates. The increased
susceptibility for infections seen in preterm neonates is mainly due to :
 Deficient immune system, mainly due to decreased IgG antibodies and incompetent
opsonization and complement activation
 Comprised innate immune system, caused primarily by the immature epithelial barrier
 The increased need for invasive devices ( vascular access, endotracheal tube, feeding
tubes and uriarny tract catheters) due to associated severe illnesses
Coagulase-negative staphylococcal species, especially Staphylococcus epidermis, is the
leading cause, responsible for greater than 50% of LOS cases in industrialized countries.
However, many other bacterial and viral pathogens can be associated with LOS [3].
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Epidemiology
The epidemiology of neonatal sepsis has been changing with time [4]. The incidence of EOS
has decreased since the 1990s due to the introduction of universal screening of group B
streptococcus (GBS) in pregnant women and intrapartum antibiotic prophylaxis (IAP) [5].
However, rates of LOS have remained relatively the same. Escherichia coli now accounts for
more cases of EOS [6]. In the United States, the incidence of EOS with positive blood
cultures is estimated to be 0.77 to 1 per 1,000 live births [7][8]. Due to the nonspecific
neonatal presentation for sepsis and the high risk of mortality and morbidity without
treatment, many asymptomatic neonates undergo a sepsis workup if risk factors are present
and/or clinically indicated. Although approximately 7% to 13% of all neonates are worked up
for sepsis, only 3% to 8% have positive cultures [3]. Maternal administration of antibiotics
and the low blood volume obtained for blood culture could explain the low rate of positive
blood cultures. The incidence of sepsis is significantly higher in premature infants, as well as
those with very low birth weight (<1000 grams). African American infants have an increased
risk of GBS and LOS, likely secondary to the higher rate of GBS carrier rates in African
American females. Males have a higher risk of sepsis and meningitis, especially with gram-
negative enteric bacilli [3].
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Pathophysiology
The immature immune system is the major contributing factor for increased neonatal
susceptibility to sepsis. The immature function of polymorphonuclear neutrophils,
macrophages, and T lymphocytes makes these cells incapable of carrying out a complete
inflammatory response in neonates. Furthermore, neonates have a limited number of
immunoglobulins at birth and cannot generate a quantitative and/or qualitative adequate
mounting response against infectious agents. The insufficient time that premature has in the
uterus decrease the transfer of immune globulins to the fetus. This deficiency in
immunoglobulins makes premature infants at much higher risk for sepsis when compared to
term infants [9].
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History and Physical

Signs and symptoms of neonatal sepsis can range from nonspecific or vague symptoms to
hemodynamic collapse. Early symptoms may include irritability, lethargy, or poor feeding.
Others may quickly develop respiratory distress, fever, hypothermia or hypotension with poor
perfusion and shock. Sometimes the diagnosis may only be suspected on the basis of
laboratory findings, which may reveal hyperglycemia or hypoglycemia, acidosis, or
hyperbilirubinemia. A high index of suspicion is, therefore, necessary for timely diagnosis.
Therefore, physicians must be aware of any factors that may increase an infant’s risk of
developing sepsis. Prematurity and very low birth weights are also important risk factors to
consider. Maternal factors that put neonates at risk of early-onset sepsis include GBS status,
the presence of chorioamnionitis, infant prematurity, or prolonged rupture of
membranes [3]. For late-onset infection, consider whether the patient has indwelling foreign
bodies such as a central venous catheter or endotracheal tube, is dependent on parenteral
nutrition, or receives proton-pump inhibitor or histamine-2 blocking therapy.
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Evaluation
Neonates with bacteremia can be asymptomatic and have a normal physical examination.
Thus laboratory testing plays an important role in diagnosis. In a neonate with suspected
sepsis, blood culture should be immediately drawn. It is recommended to draw at least 1 ml
of blood as low-level bacteremia may not be detected with smaller aliquotes [10]. Cultures
should also be drawn from the catheter site if one is in place. Urine cultures are usually not
recommended for evaluation of EOS but should be considered for evaluation of LOS [11].
Lumbar puncture with cerebrospinal fluid (CSF) analysis and culture should be evaluated in
any infant with positive blood culture or if the neonate has a clinical presentation that
suggests central nervous system involvement. Lumbar puncture should be repeated within 48
hours of therapy to confirm sterility of the CSF. New technology using polymerase chain
reaction (PCR) is currently being studied as a diagnostic tool to identify sepsis and the
causative organism faster than blood cultures [12]
CSF analysis may reveal:
 Elevated protein level
 Elevated WBC
 Positive cultures
 Decreased glucose concentration
 Positive PCR
Complete blood count (CBC) with differential and C-reactive protein (CRP) are also
important lab tests to obtain and are often collected on a serial basis. These indices are poor at
identifying neonatal sepsis but are better used for ruling it out [10]. Neutropenia has better
specificity than neutrophilia as a marker of neonatal sepsis [13]. Elevated immature to total
neutrophil (I/T)ratio of more than 0.27 has a very high negative predictive accuracy (99%)
but an inadequate positive predictive value (25%) as it may be elevated in up to 50% of
uninfected infants [14][15]. These counts may be falsely elevated, especially after birth. It is
better to perform CBC 6 to 12 hours to avoid the normal physiological CBC parameters'
changes seen immediately after delivery[16].
CRP levels start rising within 6 to 8 hours during an infectious episode in neonates and peak
at about 24 hours [17]. Persistently normal CRP levels provide strong evidence against
bacterial sepsis. This good correlation can be used to support the clinical judgment of
stopping antibiotics in an otherwise well-appearing neonate. Other inflammatory markers,
including procalcitonin, haptoglobin, and cytokines, can also be obtained to support the
diagnosis or evaluate treatment efficacy. Radiography of the chest may be performed to look
for any pulmonary findings in a neonate with respiratory symptoms or signs.
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Treatment / Management
Empiric treatment with antibiotics should be started as soon as sepsis is clinically suspected,
even without confirmatory lab data. In general, antimicrobial resistance patterns of common
bacteria in the neonatal intensive care unit should guide antibiotics' initial choice. Typical
treatment regimens include intravenous (IV) ampicillin and aminoglycosides to cover for the
most common pathogens in EOS (GBS, E. coli, and L. monocytogenes) [10]. With LOS,
nosocomial coverage should be provided for the hospital-acquired pathogens such as
coagulase-negative Staphylococcus, S. aureus, and Pseudomonas species. It is recommended
to start these patients on a combination of vancomycin and an aminoglycoside [18].
Aminoglycosides have poor CNS penetration; for that reason, a third-generation
cephalosporin should be considered if CNS infection is suspected [19]. However, ceftriaxone
should be avoided, as it can lead to hyperbilirubinemia and the serious precipitation of
calcium-ceftriaxone crystals. Increasing antibiotic resistance is a concern for neonatal sepsis.
Antibiotics stewardship teams play an essential role in preventing the unjustified prolonged
use of antibiotics [20].
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Differential Diagnosis
Given the nonspecific signs of neonatal sepsis, several differentials must be considered,
including but not limited to:
 Infection due to other agents ( virus, fungal or parasite)
 Congenital heart disease
 Neonatal encephalopathy
 Metabolic disease
 Prematurity and associated complications ( respiratory distress syndrome,
intraventricular hemorrhage, apnea of prematurity, and others)
 Hypo or hyperthyroidism
 Transient tachypnea of the newborn
 Meconium aspiration
 Hypoglycemia
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Treatment Planning
The treatment regimen for neonatal sepsis varies based on various risk factors and conditions.
The typical antibiotics used are discussed above. The duration of therapy can vary based on
the isolated organisms, type of the infection, the presence of any neonatal complications.
Neonates with positive blood cultures typically respond to treatment within 24 to 48 hours,
and repeat cultures and studies are usually negative by 72 hours [3]. Persistent positive blood
cultures should alert the clinicians to a seeding focus that should be managed ( central venous
access, cardiac vegetations, abscess or osteomyelitis). Many providers would continue
intervenous therapy for 7 to 14 days based on the organism, or longer if meningitis was
suspected [18]. Increasing the duration of antibiotics may be necessary for some situations.
Increasing the incidence of antibiotic resistance necrotizing enterocolitis or death are two
crucial principles that should motivate the clinicians to tailor the antimicrobial therapy if
clinically indicated[21].
The treatment for suspect EOS with negative cultures is also variable. Cultures can be
negative for various reasons, including maternal antibiotic use, initiation of antibiotics prior
to obtaining cultures, or false-negative tests. Determining adequate antibiotic therapy without
any positive cultures can make the determining duration of therapy difficult. Most neonates
with highly suspected clinical sepsis with negative culture will receive 7-10 days of
antimicrobial therapy [3].
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Prognosis
Mortality rates are inversely proportional to gestational age, such that preterm or younger
neonates have higher mortality rates than do term neonates [22]. E. coli has also been found
to be associated with a higher mortality rate when compared with GBS. As noted above, the
introduction of GBS intrapartum antibiotic prophylaxis has decreased mortality rates caused
by GBS. The treatment of clinically suspected neonates with negative cultures has also
significantly decreased mortality rates.Preterm infants with sepsis may develop impaired
neurodevelopment. Also, others may have vision impairment. Those infants pretreated with
aminoglycosides may also develop ototoxicity and nephrotoxicity.
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Complications
Neonatal sepsis remains a significant contributor to morbidity and mortality in neonates.
Prematurity and delayed treatment are commonly associated with adverse outcomes. VLBW
infants have been found to have a higher risk of chronic lung disease, and extremely low birth
weight (ELBW) infants are at a greater risk of neurodevelopmental risks, such as hearing and
visual deficits, cerebral palsy, and impaired psychomotor and mental development [23]. On
the other hand, the unnecessary overuse of antibiotics can increase the chances of severe
candidiasis and multi-drug resistant organisms.
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Consultations
Pediatricians or neonatologists can adequately manage neonatal sepsis. However, the
following subspecialties and ancillary services can provide essential support in complicated
cases:
  Pediatric surgery: to manage associated surgical complications ( gastrointestinal
perforation, abscess, necrotizing fasciitis, omphalitis, and others)
 Pediatric infectious disease specialist if the infant is not responding to antibiotics, or if
there is concern regarding adequate antimicrobial coverage
 Pediatric pharmacists can provide meaningful input and recommendations about
monitoring trough levels to avoid toxic antibiotic levels
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Deterrence and Patient Education

Educating the neonate's family about the disease process and keeping them updated
throughout the treatment process is an integral part of management. Neonatal sepsis is often
an unexpected and scary situation for parents and caregivers. Doctors should be mindful of
this and ensure that parents be informed of all of the tests that must be performed, the
importance of each test, and the results. Any changes in antibiotics or the treatment plan must
be communicated to the parents.Upon hospital discharge, caregivers of all infants, including
healthy newborns, should be educated to watch for signs of illness or sepsis. These may
include fever, jaundice, increased lethargy, a decline in feeding habits, difficulty or increased
breathing, and cyanosis of the fingertips and toes. Caregivers should be informed to call their
doctors if their neonate experiences any of these symptoms, as they could indicate LOS.
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Enhancing Healthcare Team Outcomes

Neonatal sepsis is a significant cause of morbidity and mortality in neonates. Attempts to
prevent sepsis's development or progression have been a driving factor for many quality
improvement projects in newborn nurseries and NICUs.Managing such infants is complex
and requires multidisciplinary care approach ( Clinicians, nurses, pharmacies, lactation
consultant, and social worker) supported by medical decisions made during family-based care
rounds. Obstetric physicians are important in ensuring that GBS screening and all other
prenatal screening for infections are performed and adequately treated before and during
delivery. Nursery nurses are also important in preventing and managing neonatal sepsis as
they can pick up and detect early signs of sepsis. In-hospital pediatricians are essential in
managing the evolving treatment of neonatal sepsis and making adjustments as necessary.
They are also important in reaching out to the proper consultants, such as pediatric surgeons
and pharmacists. Despite optimal treatment, neonatal sepsis continues to have high mortality
rates and poor outcomes. While the mortality rates have started to decline, the recovery for
most infants is prolonged, and there is a risk for neurodevelopmental disabilities.
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Review Questions
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