Clinical Features, Evaluation, and Diagnosis of Sepsis in Term and Late Preterm Infants - UpToDate

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Clinical features, evaluation, and diagnosis of sepsis in

term and late preterm infants
Author: Morven S Edwards, MD
Section Editors: Sheldon L Kaplan, MD, Joseph A Garcia-Prats, MD
Deputy Editor: Carrie Armsby, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2021. | This topic last updated: Apr 30, 2021.
INTRODUCTION
Sepsis is an important cause of morbidity and mortality among newborn infants. Although the
incidence of sepsis in term and late preterm infants is low, the potential for serious adverse
outcomes is of such great consequence that caregivers should have a low threshold for
evaluation and treatment for possible sepsis in neonates.
The epidemiology, clinical features, diagnosis, and evaluation of sepsis in term and late preterm
infants will be reviewed here. The management and outcome of sepsis in term and late preterm
infants, neonatal sepsis in preterm infants, and evaluation of febrile and ill-appearing neonates
after discharge from the birth hospitalization are discussed separately:
● (See "Management and outcome of sepsis in term and late preterm infants".)
● (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks
gestation".)
● (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks
gestation".)
● (See "Febrile infant (younger than 90 days of age): Outpatient evaluation".)
● (See "Approach to the ill-appearing infant (younger than 90 days of age)".)
TERMINOLOGY
The following terms will be used throughout this discussion on neonatal sepsis:
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● Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger, manifested

by systemic signs of infection and isolation of a bacterial pathogen from the bloodstream. A
consensus definition for neonatal sepsis is lacking [1]. (See 'Diagnosis' below.)
● Term infants are those born at a gestational age of 37 weeks or greater.
● Late preterm infants (also called near-term infants) are those born from 34 through 36
completed weeks of gestation [2]. (See "Late preterm infants".)
● Preterm infants are those born at less than 34 weeks of gestation [2].
Sepsis is classified according to the infant's age at the onset of symptoms.
● Early-onset sepsis is defined as the onset of symptoms before seven days of age, although
some experts limit the definition to infections occurring within the first 72 hours of life [3].
● Late-onset sepsis is generally defined as the onset of symptoms at ≥7 days of age [3].
Similar to early-onset sepsis, there is variability in the definition, ranging from an onset at
>72 hours of life to ≥7 days of age [3,4].
Infants with early-onset sepsis typically present with symptoms during their birth
hospitalization. Term infants with late-onset sepsis generally present to the outpatient setting
or emergency department unless comorbid conditions have prolonged the birth
hospitalization. The approach to evaluation of neonates in the outpatient setting is discussed
separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)" and
"Febrile infant (younger than 90 days of age): Management".)
PATHOGENESIS
The pathogenesis differs based on the timing of onset:
● Early-onset infection – Early-onset infection is usually due to vertical transmission by

ascending contaminated amniotic fluid or during vaginal delivery from bacteria in the
mother's lower genital tract [5]. Maternal chorioamnionitis (or intraamniotic infection) is a
well-recognized risk factor for early-onset neonatal sepsis [6,7]. Maternal group B
streptococcal (GBS) colonization is another important risk factor. (See 'Maternal risk factors'
below and "Group B streptococcal infection in neonates and young infants", section on 'Risk
factors'.)
Use of forceps during delivery and electrodes placed for intrauterine monitoring have been
implicated in the pathogenesis of early-onset sepsis because they penetrate the neonatal
defensive epithelial barriers [8].
● Late-onset infection – Late-onset infections can be acquired by the following mechanisms:
• Vertical transmission, resulting in initial neonatal colonization that evolves into later
infection
• Horizontal transmission from contact with care providers or environmental sources
Disruption of the intact skin or mucosa, which can be due to invasive procedures (eg,
intravascular catheter), increases the risk of late-onset infection. Late-onset sepsis is
uncommonly associated with maternal obstetrical complications.
Metabolic factors, including hypoxia, acidosis, hypothermia, and inherited metabolic disorders
(eg, galactosemia), are likely to contribute to risk for and severity of neonatal sepsis (including
both early- and late-onset). These factors are thought to disrupt the neonate's host defenses (ie,
immunologic response) [8].
EPIDEMIOLOGY
The overall incidence of neonatal sepsis ranges from 1 to 5 cases per 1000 live births [9-11].
Estimated incidence rates vary based on the case definition and population studied. In a
systematic review and meta-analysis of population-based studies from around the world, the
estimated pooled incidence of neonatal sepsis was 22 per 1000 live births, with an associated
mortality rate of 11 to 19 percent [12]. This translates to a global incidence of 3 million cases of
neonatal sepsis per year [12]. Globally, neonatal sepsis and other severe infections were
responsible for an estimated 430,000 neonatal deaths in 2013, accounting for approximately 15
percent of all neonatal deaths [13].
Rates of neonatal sepsis increase with decreasing gestational age:
● Term neonates (≥37 weeks gestational age) – The estimated incidence of sepsis (both early-
and late-onset) in term neonates is 1 to 2 cases per 1000 live births [9,10]. In a prospective
national surveillance study (2006 to 2009), the incidence of early-onset sepsis (defined as
positive blood or cerebrospinal fluid cultures) was 0.98 cases per 1000 live births; the rate
among infants with birth weight >2500 g was 0.57 per 1000 [11].
● Late preterm neonates (34 through 36 weeks gestational age) – The incidence is higher in
late preterm than term infants. In an observational cohort study (1996 to 2007), the
reported incidences of early- and late-onset sepsis (defined as positive blood culture) in late
preterm neonates were 4.4 and 6.3 per 1000, respectively [14].
● Preterm neonates <34 weeks gestational age – The incidence of sepsis in preterm neonates
is discussed separately. (See "Clinical features and diagnosis of bacterial sepsis in preterm
infants <34 weeks gestation", section on 'Incidence'.)
The incidence of early-onset sepsis in the United States has decreased, primarily due to
reduction in group B streptococcal (GBS) infections, owing to the use of intrapartum antibiotic
prophylaxis (IAP) [15-19]. Early-onset GBS infection rates in the United States reported through
the Centers for Disease Control and Prevention's Active Bacterial Core Surveillance Report have
declined from 0.6 per 1000 live births in 2000 to 0.25 per 1000 live births in 2018 [20,21]. Late-
onset GBS infection rates have remained relatively stable in the same interval (0.4 per 1000 live
births in 2000 and 0.28 per 1000 live births in 2018). (See "Group B streptococcal infection in
neonates and young infants", section on 'Epidemiology'.)
ETIOLOGIC AGENTS
Group B Streptococcus (GBS) and Escherichia coli are the most common causes of both early- and
late-onset sepsis, accounting for approximately two-thirds of early-onset infections [16,22-24].
Other bacterial agents associated with neonatal sepsis include ( table 1):
● Listeria monocytogenes, although a well-recognized cause of early-onset sepsis, only

accounts for rare sporadic cases of neonatal sepsis and is more commonly seen during an
outbreak of listeriosis [25,26].
● Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus, is a

potential pathogen in neonatal sepsis [27]. Bacteremic staphylococcal infections in term
infants usually occur in association with skin, bone, or joint sites of involvement.
● Enterococcus, a commonly encountered pathogen among preterm infants, is a rare cause of

sepsis in otherwise healthy term newborn infants.
● Other gram-negative bacteria (including Klebsiella, Enterobacter, and Citrobacter spp) and
Pseudomonas aeruginosa are associated with late-onset infection, especially in infants
admitted to neonatal intensive care units [28].
● Coagulase-negative staphylococci often are a cause of hospital-associated infection in ill

infants (primarily in premature infants and/or infants who have indwelling intravascular
catheters). Coagulase-negative staphylococci may be considered a contaminant in

otherwise healthy term infants who have not undergone invasive procedures.
The patterns of pathogens associated with neonatal sepsis have changed over time, as
reflected by longitudinal databases from single tertiary centers [16,17]. The incidence of early-
onset GBS has declined by 80 percent in the United States with the use of intrapartum antibiotic
prophylaxis (IAP). GBS prevention efforts have not led to an increasing burden of early-onset E.
coli infection [23]. (See "Early-onset neonatal group B streptococcal disease: Prevention".)
Common nonbacterial agents associated with neonatal sepsis include (see 'Differential
diagnosis' below):
● Herpes simplex virus (see "Neonatal herpes simplex virus infection: Clinical features and
diagnosis")
● Enterovirus and parechovirus (see "Enterovirus and parechovirus infections: Clinical

features, laboratory diagnosis, treatment, and prevention", section on 'Neonates' and
"Nosocomial viral infections in the neonatal intensive care unit", section on 'Sepsis-like
illness and meningitis/encephalitis')
● Candida (see "Clinical manifestations and diagnosis of Candida infection in neonates",

section on 'Invasive infection')
MATERNAL RISK FACTORS
Maternal factors that are associated with an increased risk of early-onset sepsis in the neonate,
particularly group B Streptococcus (GBS) infection, include chorioamnionitis (intraamniotic
infection), intrapartum maternal fever, maternal GBS colonization, preterm delivery, and
prolonged rupture of the membranes [5,6,29]. The approach to identifying pregnancies at risk
for neonatal early-onset sepsis and indications for maternal intrapartum antibiotic prophylaxis
(IAP) are discussed separately. (See "Early-onset neonatal group B streptococcal disease:
Prevention", section on 'Identification of pregnancies at increased risk for early-onset neonatal
GBS' and "Early-onset neonatal group B streptococcal disease: Prevention", section on
'Intrapartum antibiotic prophylaxis'.)
Maternal GBS screening and IAP reduces the risk of GBS infection but does not eliminate it. In a
prospective national surveillance study that included 117 term neonates with early-onset GBS
infection, 66 percent were born to mothers who did not receive IAP, because maternal GBS
screening culture was either not performed (29 percent of mothers) or was negative (51 percent
of mothers), and there were no other indications for IAP [11].
CLINICAL MANIFESTATIONS
Clinical manifestations range from subtle symptoms to profound septic shock. Signs and
symptoms of sepsis are nonspecific and include temperature instability (primarily fever),
irritability, lethargy, respiratory symptoms (eg, tachypnea, grunting, hypoxia), poor feeding,
tachycardia, poor perfusion, and hypotension ( table 2) [8].
Because the signs and symptoms of sepsis can be subtle and nonspecific, it is important to
identify neonates with risk factors for sepsis and to have a high index of suspicion for sepsis
when an infant deviates from his or her usual pattern of activity or feeding [8].
Signs and symptoms of neonatal sepsis include:
● Fetal and delivery room distress – The following signs of fetal and neonatal distress
during labor and delivery may be early indicators of neonatal sepsis:
• Intrapartum fetal tachycardia, which may be due to intraamniotic infection (see "Fetal
arrhythmias", section on 'Tachyarrhythmias')
• Meconium-stained amniotic fluid, which is associated with a twofold increased risk of

sepsis [6] (see "Meconium aspiration syndrome: Pathophysiology, clinical
manifestations, and diagnosis", section on 'Meconium composition and passage')
• Apgar score ≤6, which is associated with a 36-fold increased risk of sepsis [30] (see
"Overview of the routine management of the healthy newborn infant", section on
'Apgar score')
● Temperature instability – The temperature of an infected infant can be elevated,

depressed, or normal. Term infants with sepsis are more likely to be febrile than preterm
infants who are more likely to be hypothermic [8]. Temperature elevation in full-term
infants is concerning and, if persistent, is highly indicative of infection [31,32].
● Cardiorespiratory symptoms – Respiratory and cardiocirculatory symptoms are common

in infected neonates. Approximately 85 percent of newborns with early-onset sepsis
present with respiratory distress (eg, tachypnea, grunting, flaring, use of accessory
muscles) [11]. Apnea is less common, occurring in 38 percent of cases, and is more likely in
preterm than term infants. Apnea is a classic presenting symptom in late-onset group B
streptococcal (GBS) sepsis. Early-onset disease can be associated with persistent pulmonary
hypertension of the newborn. (See "Persistent pulmonary hypertension of the newborn".)
Tachycardia is a common finding in neonatal sepsis but is nonspecific. Bradycardia may

also occur. Poor perfusion and hypotension are more sensitive indicators of sepsis, but
these tend to be late findings. In a prospective national surveillance study, 40 percent of
neonates with sepsis required volume expansion and 29 percent required vasopressor
support [11].
● Neurologic symptoms – Neurologic manifestations of sepsis in the neonate include

lethargy, poor tone, poor feeding, irritability, and seizures [8]. Seizures are an uncommon
presentation of neonatal sepsis but are associated with a high likelihood of infection. In a
prospective study in a single neonatal unit, 38 percent of neonates with seizures had sepsis
as the etiology [33]. Seizures are a presenting feature in 20 to 50 percent of infants with
neonatal meningitis [34]. (See "Bacterial meningitis in the neonate: Clinical features and
diagnosis" and "Etiology and prognosis of neonatal seizures".)
● Other findings – Other findings associated with neonatal sepsis and their approximate
frequencies are listed below ( table 2) [8,11]:
• Jaundice – 35 percent
• Hepatomegaly – 33 percent
• Poor feeding – 28 percent
• Vomiting – 25 percent
• Abdominal distension – 17 percent
• Diarrhea – 11 percent
EVALUATION AND INITIAL MANAGEMENT
Neonates with signs and symptoms of sepsis ( table 2) require prompt evaluation and
initiation of antibiotic therapy [5,8]. Because the signs and symptoms of sepsis are subtle and
nonspecific, laboratory testing is performed in any infant with identifiable risk factors and/or
signs and symptoms concerning for sepsis. Our approach is generally consistent with
guidelines published by the American Academy of Pediatrics [5,35].
Early-onset sepsis — The evaluation of a neonate with suspected early-onset sepsis includes all
of the following:
● Review of the pregnancy, labor, and delivery, including risk factors for sepsis and the use
and duration of maternal intrapartum antibiotic prophylaxis (IAP) (see 'Maternal risk
factors' above)
● Comprehensive physical examination (see "Assessment of the newborn infant")
● Laboratory testing (see 'Laboratory tests' below)
The extent of the diagnostic evaluation for sepsis is directed by the infant's symptoms and
maternal risk factors.
Early-onset sepsis calculator — Multivariate predictive models for risk of early-onset sepsis

have been developed and validated in clinical use, including the early-onset sepsis calculator
[29,36-38]. The early-onset sepsis calculator is a web-based tool that can be used to estimate
the risk of early-onset sepsis in individual patients based on risk factors (eg, newborn clinical
condition, highest intrapartum maternal temperature, maternal group B Streptococcus [GBS]
status, administration of maternal IAP, gestational age, duration of rupture of membranes). The
calculator requires the user to input the local incidence of early-onset sepsis. If the local
incidence of early-onset sepsis is unknown, the users should enter "0.5 per 1000." The
calculator provides guidance on the diagnostic evaluation and empiric antibiotic treatment. The
threshold used to trigger evaluation and empiric treatment varies depending on the clinical
circumstances. The early-onset sepsis calculator is not valid for preterm infants (<34 weeks
gestation) and does not apply to late-onset sepsis.
Symptomatic neonates — Infants with signs and symptoms of sepsis ( table 2) should

undergo a full diagnostic evaluation and should receive empiric antibiotic treatment. (See
'Clinical manifestations' above and 'Empiric antibiotic therapy' below.)
A full diagnostic evaluation includes (see 'Laboratory tests' below):
● Blood culture
● Lumbar puncture (if the infant is clinically stable enough to tolerate the procedure and it
will not delay initiation of antibiotic therapy) (see 'Lumbar puncture' below)
● Complete blood count (CBC) with differential and platelet count
● Chest radiograph (if respiratory symptoms are present)
● Cultures from tracheal aspirates if intubated
● C-reactive protein (CRP) and/or procalcitonin (PCT) levels – These tests are not routinely
required but may be helpful in determining length of therapy if followed serially (see 'Other
inflammatory markers' below)
Well-appearing neonates — Well-appearing infants with identified risk factors for neonatal

sepsis, particularly GBS, should be observed for 36 to 48 hours. Based on the nature of the risk
factor(s) and the use and duration of maternal IAP, they may require a limited diagnostic
evaluation (ie, blood culture). Accepted approaches to determining the need for laboratory
evaluation and empiric antibiotics include categorical risk assessment ( algorithm 1), clinical
observation ( algorithm 2), and the early-onset sepsis calculator. The early-onset sepsis
calculator is discussed above (see 'Early-onset sepsis calculator' above). The other two
approaches are discussed in detail separately. (See "Management of neonates at risk for early-
onset group B streptococcal infection", section on 'Approaches to risk assessment'.)
Late-onset sepsis — Infants presenting with signs and symptoms at ≥7 days of age should
undergo prompt evaluation and empiric antibiotic treatment. (See "Management and outcome
of sepsis in term and late preterm infants", section on 'Late-onset sepsis'.)
A full diagnostic evaluation should be performed. In addition to the tests described above for
early-onset sepsis (see 'Symptomatic neonates' above), the following should also be obtained:
● Urine culture
● Cultures from any other potential foci of infection (eg, tracheal aspirates if intubated,
purulent eye drainage, or pustules)
Infants with late-onset sepsis generally present to the outpatient or emergency department
setting unless comorbid conditions have prolonged the birth hospitalization. (See "Approach to
the ill-appearing infant (younger than 90 days of age)" and "Febrile infant (younger than 90
days of age): Management".)
Empiric antibiotic therapy — Indications for empiric antibiotic therapy (after obtaining

cultures) include:
● Ill appearance (see "Approach to the ill-appearing infant (younger than 90 days of age)")
● Concerning symptoms, including temperature instability or respiratory, cardiocirculatory, or

neurologic symptoms (see 'Clinical manifestations' above)
● Cerebrospinal fluid pleocytosis (white blood cell [WBC] count of >20 to 30 cells/microL) (
table 3) (see "Bacterial meningitis in the neonate: Clinical features and diagnosis",
section on 'Interpretation of cerebrospinal fluid')
● Confirmed or suspected maternal chorioamnionitis (intraamniotic infection) (see 'Maternal

risk factors' above)
● High estimated sepsis risk based on a validated risk calculator (see 'Early-onset sepsis
calculator' above)
The empiric antibiotic regimen should include agents active against GBS and other organisms
that most commonly cause neonatal sepsis (eg, E. coli and other gram-negative pathogens) (
table 1). The combination of ampicillin and gentamicin or ampicillin and an expanded-
spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) are
appropriate regimens that provide empiric coverage for these organisms until culture results
are available. Ampicillin and gentamicin is generally the preferred regimen; however, local
antibiotic resistance patterns must be considered. Our suggested empiric regimens in special
circumstances are summarized in the table ( table 4) and discussed in greater detail
separately. (See "Management and outcome of sepsis in term and late preterm infants", section
on 'Initial empiric therapy'.)
LABORATORY TESTS
The goals of the diagnostic evaluation are to identify and treat all infants with bacterial sepsis
and minimize the treatment of patients who are not infected. Laboratory assessment includes
cultures of body fluids that confirm the presence or absence of a bacterial pathogen and other
studies that are used to evaluate the likelihood of infection.
Blood culture — A definitive diagnosis of neonatal sepsis is established by a positive blood

culture. The sensitivity of a single blood culture to detect neonatal bacteremia is approximately
90 percent.
● Blood sampling – The following considerations are important when obtaining a blood
culture:
• Sampling site – Blood cultures can be obtained by venipuncture or arterial puncture or

by sampling from a newly inserted umbilical artery or vascular access catheter. Positive
culture results of blood drawn from indwelling umbilical or central venous catheters
can be difficult to interpret since they can indicate contamination or catheter
colonization rather than a true systemic infection. In such circumstances, obtaining a
peripheral blood culture may help determine if there is a true bloodstream infection
[8].
• Number of cultures – We obtain at least one culture prior to initiating empiric

antibiotic therapy in neonates with a high clinical suspicion for sepsis, although other
institutions may routinely obtain two blood cultures.
• Volume of blood – The optimal volume of blood is based on the weight of the infant. A
minimum blood volume of 1 mL is desirable for optimal detection of bacteremia when
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a single blood culture bottle is used [5]. At the author's institution, the suggested
optimal volume is 2 mL for infants weighing ≤3 kg and 3 mL for those who weigh >3 to
5 kg. Dividing this volume into two aliquots to inoculate an anaerobic as well as the
aerobic culture bottle may optimize recovery of rare strict anaerobic species, and most
neonatal pathogens grow under anaerobic conditions.
● Time to positivity – Automated systems for continuous monitoring of blood cultures are
routinely used in the United States and have shortened the time to identify positive blood
cultures. In most cases of neonatal sepsis, blood cultures become positive within 24 to 36
hours [39].
● Distinguishing infection from contamination – A positive blood culture is diagnostic of

sepsis when a known bacterial pathogen is isolated ( table 1). Isolation of skin flora (eg,
diphtheroids) suggests contamination rather than infection. Contamination is also
suggested when multiple species grow in culture. Coagulase-negative staphylococci may be
pathogenic in patients with indwelling vascular catheters or other invasive devices,
whereas a single blood culture positive for coagulase-negative staphylococci is likely to
represent a contaminant in full-term infants without these risk factors [8].
Lumbar puncture — The clinical presentation of neonatal meningitis is indistinguishable from

that of neonatal sepsis without meningitis. Specific clinical signs of meningitis (eg, bulging
fontanelle, nuchal rigidity) are often lacking in neonates. For this reason, we suggest
performing a lumbar puncture as part of the diagnostic evaluation in symptomatic neonates.
Lumbar puncture should ideally be performed before the initiation of antibiotics for infants in
whom the clinical suspicion for sepsis is high, particularly those with critical illness. However,
lumbar puncture should be deferred if the procedure would compromise the infant's clinical
condition or if the procedure would delay initiation of antibiotics [5].
Lumbar puncture is indicated in neonates with:
● Clinical findings concerning for sepsis ( table 2)

● Positive blood culture
● Worsening clinical status while on antibiotic therapy
Cerebrospinal fluid should be sent for Gram stain, routine culture, cell count with differential,
and protein and glucose concentrations. The interpretation of cerebrospinal fluid needs to
account for variations due to gestational age, chronologic age, and birth weight ( table 3).
The clinical features and diagnosis of neonatal bacterial meningitis are discussed separately.
(See "Bacterial meningitis in the neonate: Clinical features and diagnosis".)
Urine culture — Urine culture obtained by catheter or bladder tap should be included in the
sepsis evaluation for infants one week of age or older. A urine culture need not be routinely
performed in the evaluation of an infant ≤6 days of age, because a positive urine culture in this
setting is a reflection of high-grade bacteremia rather than an isolated urinary tract infection
[5]. (See "Urinary tract infections in neonates".)
Other cultures — In patients with late-onset infection, cultures should be obtained from any
other potential foci of infection (eg, purulent eye drainage or pustules).
Tracheal aspirates can be of value if obtained immediately after intubation. However, they may
reflect lower respiratory tract colonization rather than indicating a causative pathogen in an
infant who has been intubated for several days.
Gram stain or culture of other sites (eg, gastric aspirate, body surface sites [eg, axilla, groin, and
external ear canal]) add little to the evaluation and should not be performed [5].
Complete blood count — A complete blood count (CBC) is used to evaluate the likelihood of
sepsis in a neonate with risk factors or signs of infection. Abnormal findings on a CBC cannot be
used to establish the diagnosis of sepsis.
Early-onset sepsis — For most neonates with suspected early-onset sepsis, we suggest

obtaining a CBC as part of the diagnostic evaluation. In neonates who are undergoing
evaluation because they have identified risk factors for group B Streptococcus (GBS) and who are
otherwise well appearing, it is reasonable to omit the CBC (ie, obtain only a blood culture) [35].
(See "Management of neonates at risk for early-onset group B streptococcal infection", section
on 'Diagnostic evaluation'.)
The CBC does not perform well in predicting risk of infection in neonates and should not be
used as the sole determinant of whether to treat empirically with antibiotics [40-44]. However,
when used in conjunction with other assessments, it may be useful in the evaluation of infants
with suspected early- or late-onset sepsis. The CBC is more useful in identifying neonates who
are unlikely to have sepsis than in identifying infants with sepsis [5,8]. When used in the
evaluation of early-onset sepsis, the predictive value of the CBC improves if obtained after four
to six hours of age [41,45].
Two large multicenter studies have evaluated the diagnostic value of CBCs in early-onset
neonatal sepsis [40,41]. These studies found that low white blood cell (WBC) count
(<5000/microL), absolute neutropenia (absolute neutrophil count [ANC] <1000
neutrophils/microL), relative neutropenia (ANC <5000 neutrophils/microL), and elevated ratio of
immature to total neutrophil counts (I/T ratio) were associated with culture-proven sepsis.
However, none of the tests was sufficiently sensitive to reliably predict neonatal sepsis.
CBCs obtained 6 to 12 hours after delivery are more predictive of sepsis than those obtained
immediately after birth because the WBC and ANC normally increase during the first six hours
of life [40,46].
The following neutrophil indices are used to determine the likelihood of infection:
● I/T ratio – An elevated I/T ratio (≥0.2) has the best sensitivity of the neutrophil indices for
predicting neonatal sepsis and can be helpful as an initial screen when used in combination
with risk factors, clinical assessment, and/or other tests [6,47]. A normal I/T ratio can help
rule out sepsis; however, an elevated value is not highly predictive of sepsis and may be
observed in 25 to 50 percent of uninfected infants [6,47,48].
The I/T ratio is limited by the wide range of normal values, which reduces its positive
predictive value, especially in asymptomatic patients [49]. Inter-reader differences in band
neutrophil identification with manual differential counts is another limitation. In addition,
exhaustion of the bone marrow reserves, which may occur during critical illness, will result
in low band counts and lead to falsely low ratios. (See "Evaluating diagnostic tests", section
on 'How well does the test perform in specific populations?'.)
● ANC – Although both elevated and low neutrophil counts can be associated with neonatal
sepsis, neutropenia has greater specificity since few conditions other than sepsis and
preeclampsia depress the neutrophil count in neonates.
Neutrophil counts vary with gestational age (counts decrease with decreasing gestational
age), type of delivery (counts are lower in infants born by cesarean delivery), site of
sampling (counts are lower in arterial than in venous samples), altitude (counts are higher
at elevated altitudes), and timing after delivery (counts increase during the first six hours of
life) [40].
The lower limit of a normal neutrophil count for infants >36 weeks of gestation is
3500/microL at birth and 7500/microL six to eight hours after delivery ( figure 1) [50]. For
infants born at 28 through 36 weeks of gestation, the lower limits of normal neutrophil
counts at birth and at six to eight hours after birth are 1000/microL and 1500/microL,
respectively ( figure 2).
Late-onset sepsis — CBCs are frequently used to support the diagnosis of late-onset sepsis.
In this setting, CBCs are less variable than in the first days of life. However, WBC indices still
perform poorly in identifying neonates with late-onset sepsis.
In a study of 37,826 neonates (mostly infants continuously hospitalized from birth) who
underwent evaluation for late-onset (defined as 4 to 120 days) sepsis with blood culture and
CBC, abnormal WBC (<1000 or >50,000/microL), high ANC (>17,670/microL), elevated I/T ratio
(≥0.2), and low platelet count (<50,000/microL) were associated with culture positivity [51].
However, sensitivity was inadequate to reliably predict late-onset sepsis.
Screening protocols used to identify serious bacterial infections in febrile infants two to three
months of age are inadequate in neonates as they fail to accurately identify neonates with
serious bacterial infections [52]. (See "Febrile infant (younger than 90 days of age): Outpatient
evaluation", section on 'Traditional criteria'.)
Other inflammatory markers — A number of acute phase reactants have been used to
identify infected newborns. Many of these tests have a high sensitivity; however, they lack
specificity, resulting in a poor predictive value [53]. No single biomarker or panel of screening
tests is sufficiently sensitive to reliably detect neonatal sepsis [54].
● C-reactive protein (CRP) – CRP is increased in inflammatory conditions, including sepsis. A

variety of noninfectious inflammatory conditions can also cause elevated CRP, including
maternal fever, fetal distress, stressful delivery, perinatal asphyxia, meconium aspiration,
and intraventricular hemorrhage [55].
A single measurement of CRP is not a useful aid in the diagnosis of neonatal sepsis,
because it lacks sufficient sensitivity and specificity [56]. However, sequential assessment of
CRP values may help support a diagnosis of sepsis. If the CRP level remains persistently
normal (<1 mg/dL [10 mg/L]), neonatal bacterial sepsis is unlikely [5].
CRP levels can be helpful in guiding the duration of antibiotic therapy in suspected neonatal
bacterial infection. Infants with elevated CRP levels that decrease to <1 mg/dL (10 mg/L) 24
to 48 hours after initiation of antibiotic therapy typically are not infected and generally do
not require further antibiotic treatment if cultures are negative. However, routine use of
serial CRP measurements can be associated with longer length of hospital stay [57].
An elevated CRP level alone does not justify continuation of empiric antibiotics for more
than 36 to 48 hours in well-appearing infants with negative culture results [58]. Additional
evaluation may be warranted to investigate alternative explanations for persistently
elevated CRP values.
● Procalcitonin (PCT) – PCT is the peptide precursor of calcitonin. It is released by

parenchymal cells in response to bacterial toxins, leading to elevated serum levels in
patients with bacterial infections. Several observational studies have suggested that PCT
may be a useful marker to identify neonates who are infected [59-61]. In a 2015 systematic
review of 18 studies, the sensitivity of PCT for detection of neonatal sepsis ranged from 72
to 79 percent and the specificity ranged from 72 to 90 percent [61]. Thus, although PCT is a
promising marker, it does not appear to be reliable as the sole or main diagnostic indicator
for neonatal sepsis.
PCT may have utility in guiding the duration of antibiotic therapy in neonates with
suspected sepsis. In a multicenter randomized trial involving 1710 neonates with suspected
early-onset sepsis, infants assigned to a treatment protocol in which duration of antibiotic
therapy was guided by serial PCT measurements in addition to standard criteria (ie, clinical
examination, blood culture results, WBC, and CRP) had shorter duration of antibiotic
therapy compared with infants managed according to standard criteria without PCT
measurements (55.1 versus 65.0 hours, respectively) [62]. The rate of reinfection was low in
both groups (0.7 percent for the PCT group, and 0.6 percent for the control group).
However, the study protocol's suggested duration of antibiotic therapy was overruled by
the treating clinician in 45 percent of infants in the PCT group and 41 percent of those in
the control group. The findings reinforce the concept that when serial PCT levels are
obtained, they should be used in conjunction with other clinical indicators of sepsis and
should not be the sole basis of decision-making.
● Cytokines, chemokines, and other biomarkers – Both proinflammatory cytokines, such

as interleukin-6 and tumor necrosis factor-alpha, and antiinflammatory cytokines
(interleukin-4 and interleukin-10) are increased in infected infants compared with those
without infections [63-66]. Elevations of serum amyloid A and the cell surface antigen CD64
also have high sensitivity for identifying infants with sepsis [61,67]. However, these
biomarkers are generally not used in clinical practice.
Further research aimed at better understanding the neonatal inflammatory response to sepsis
may result in the identification of sensitive and specific markers of inflammation or the
development of pathogen-specific rapid diagnostic tests for early detection of neonatal sepsis.
With a sensitive and specific marker for systemic bacterial infection, the management of
neonatal sepsis would be significantly altered so that antimicrobial therapy could be safely
withheld in infants for whom sepsis is unlikely.
DIAGNOSIS
Culture-proven sepsis — The isolation of pathogenic bacteria from a blood culture is the gold
standard to confirm the diagnosis of neonatal sepsis. A positive blood culture is diagnostic of
sepsis when a bacterial pathogen is isolated ( table 1). Isolation of skin flora (eg, diphtheroids
and coagulase-negative staphylococci) in culture suggests contamination rather than infection,
although coagulase-negative staphylococci can be pathogenic in patients with indwelling
vascular catheters or other devices [8]. (See 'Blood culture' above and "Management and
outcome of sepsis in term and late preterm infants", section on 'Culture-proven sepsis'.)
Probable sepsis — In some cases, a pathogen may not be isolated in culture, yet the neonate
has a clinical course that is concerning for sepsis (eg, ongoing temperature instability; ongoing
respiratory, cardiocirculatory, or neurologic symptoms not explained by other conditions; or
ongoing laboratory abnormalities suggestive of sepsis [ie, cerebrospinal fluid pleocytosis,
elevated ratio of immature to total neutrophil counts, or elevated C-reactive protein (CRP)]).
A composite of observational assessment and serial laboratory testing is typically used to make
a diagnosis of probable sepsis [68]. The criteria used are usually broad, in an attempt to ensure
that all infected infants are identified, but at the cost of testing and treating a number of
uninfected infants. There is no consensus definition for the diagnosis of probable sepsis in
neonates [1].
Alternative diagnoses ( table 5) should also be entertained when an infant with suspected
sepsis has negative cultures. (See "Management and outcome of sepsis in term and late
preterm infants", section on 'Probable but unproven sepsis' and 'Differential diagnosis' below.)
Infection unlikely — Infants with mild and/or transient symptoms (ie, fever alone or other
symptoms that quickly resolve) who remain well-appearing with normal laboratory values and
negative cultures at 36 to 48 hours are unlikely to have sepsis. Empiric antibiotic therapy should
be discontinued after 36 to 48 hours in these neonates [5,69].
In a retrospective study of 2785 newborns who underwent evaluation for sepsis based on
clinical symptoms (54 percent) or risk factors (46 percent), 22 infants (0.8 percent) were found to
have culture-proven sepsis and 40 (1.4 percent) had probable sepsis (ie, culture-negative clinical
sepsis) [6].
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of neonatal sepsis includes systemic viral, fungal, and parasitic
infections and noninfectious causes of temperature instability and respiratory, cardiocirculatory,
and neurologic symptoms ( table 5). Appropriate microbiologic testing distinguishes neonatal
bacterial sepsis from nonbacterial systemic infections. The clinical history, disease course, chest
radiograph, electrocardiogram (ECG), hyperoxia testing, drug screening, neuroimaging, blood
glucose, serum electrolytes, and newborn screening may assist in distinguishing noninfectious
disorders from neonatal sepsis.
It is often difficult to differentiate neonatal sepsis from other conditions. However, given the
morbidity and mortality of neonatal sepsis, empiric antibiotic therapy should be provided (after
cultures are obtained) to infants with suspected sepsis pending definitive culture-based
diagnosis.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Sepsis in neonates" and
"Society guideline links: Group B streptococcal infection in pregnant women and neonates".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Sepsis in newborn babies (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Epidemiology and microbiology – Sepsis is an important cause of morbidity and mortality

in newborn infants.
• Incidence – Although the incidence of sepsis in term and late preterm infants is low
(approximately 1 to 6 cases per 1000 births), the potential for serious adverse
outcomes, including death, is of such great consequence that caregivers should have a
low threshold for evaluation and treatment for possible sepsis. (See 'Epidemiology'
above.)
• Common pathogens – Group B Streptococcus (GBS) and Escherichia coli are the most
common bacteria causing neonatal sepsis ( table 1). (See 'Etiologic agents' above.)
• Maternal risk factors – Maternal risk factors for neonatal sepsis include
chorioamnionitis (intraamniotic infection), intrapartum fever, preterm delivery,
maternal GBS colonization, and prolonged rupture of membranes. (See "Early-onset
neonatal group B streptococcal disease: Prevention", section on 'Identification of
pregnancies at increased risk for early-onset neonatal GBS'.)
● Clinical manifestations – Clinical manifestations are nonspecific and include fetal distress,
low Apgar score, temperature instability (usually fever), respiratory and cardiocirculatory
symptoms (most commonly, respiratory distress and tachycardia), neurologic symptoms
(irritability, lethargy, poor tone, and seizures), and gastrointestinal abnormalities (poor
feeding, vomiting, and abdominal distension) ( table 2). (See 'Clinical manifestations'
above.)
● Evaluation – Evaluation and initial management of neonates with suspected sepsis should
include a review of the pregnancy, labor, and delivery; complete physical examination;
laboratory evaluation; and prompt initiation of empiric antibiotics (after obtaining cultures).
Our suggested empiric antibiotic regimens are summarized in the table ( table 4) and are
discussed in detail separately. (See 'Evaluation and initial management' above and
"Management and outcome of sepsis in term and late preterm infants", section on 'Initial
empiric therapy'.)
• Early-onset – In neonates <7 days old, the approach to the evaluation depends upon
whether the neonate is symptomatic or well appearing.
Symptomatic neonates should undergo a full diagnostic evaluation including (see

'Symptomatic neonates' above and 'Laboratory tests' above):
- Blood culture
- Complete blood count (CBC) with differential
- Lumbar puncture (if the infant is clinically stable enough to tolerate the procedure
and it will not delay initiation of antibiotic therapy)
- Chest radiograph (if respiratory symptoms are present) and cultures from tracheal
aspirates (if intubated)
- C-reactive protein (CRP) and/or procalcitonin (PCT) levels are not routinely required
but may be helpful in determining length of therapy if followed serially
Empiric antibiotics should be provided to these neonates pending culture results (

table 4). (See 'Symptomatic neonates' above and "Management and outcome of
sepsis in term and late preterm infants", section on 'Early-onset sepsis'.)
For well-appearing newborns who have risk factors for early-onset sepsis, decisions
regarding evaluation and use of empiric antibiotics are based upon the nature of the
risk factor(s) and whether or not the mother received adequate intrapartum antibiotic
prophylaxis (IAP). Accepted approaches include categorical risk assessment (
algorithm 1), clinical observation ( algorithm 2), and the early-onset sepsis
calculator. This is discussed in detail separately. (See "Management of neonates at risk
for early-onset group B streptococcal infection", section on 'Approaches to risk
assessment'.)
• Late-onset – Neonates presenting with signs and symptoms of late-onset sepsis (onset
of symptoms from 7 to 28 days of life) should undergo a full diagnostic evaluation
similar to that described above for early-onset sepsis but also including a urine culture
and cultures from potential foci of infection. Empiric antibiotic treatment should be
initiated in these infants pending culture results ( table 4). (See 'Late-onset sepsis'
above and "Management and outcome of sepsis in term and late preterm infants",
section on 'Late-onset sepsis' and "Febrile infant (younger than 90 days of age):
Management".)
● Diagnosis – Isolation of a pathogen from a blood culture confirms the diagnosis of

neonatal sepsis. (See 'Diagnosis' above.)
The differential diagnosis of neonatal sepsis includes other systemic infections and
noninfectious conditions including respiratory diseases (eg, transient tachypnea of the
newborn and respiratory distress syndrome), cardiac diseases (eg, congenital heart disease
and supraventricular tachycardia), neurologic injury (eg, from anoxia or hemorrhage),
inborn errors of metabolism, and neonatal abstinence syndrome ( table 5). (See
'Differential diagnosis' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 5043 Version 54.0
GRAPHICS
Bacterial pathogens in neonatal sepsis and focal neonatal infections
Common
Some less common pathogens*
pathogens*
Early onset¶
Term and late GBS Enterobacter, Enterococcus, Klebsiella, Listeria, nontypeable

preterm infants
E. coli H. influenzae, other enteric gram-negative bacilli, S. aureus,
(GA ≥34 weeks) viridans streptococci
Preterm infants
E. coli CoNS, Enterobacter, Klebsiella, Listeria, other enteric and
(GA <34 weeks) GBS nonenteric gram-negative bacilli, S. aureus, viridans
streptococci
Late onset¶
Term and late E. coli Enterobacter, Klebsiella, Listeria, N. meningitidis, other enteric
preterm infants
GBS and nonenteric gram-negative bacilli, Salmonella, S.
(GA ≥34 weeks) Additional pneumoniae, viridans streptococci
pathogens Additional pathogens seen in the NICU setting – Citrobacter,
seen in the Enterococcus, Pseudomonas, Serratia
NICU setting –
S. aureus, CoNS
Preterm infants
CoNS Citrobacter, Enterobacter, Enterococcus, Listeria, other enteric
(GA <34 weeks) S. aureus and nonenteric gram-negative bacilli, Pseudomonas,
E. coli Salmonella, Serratia, viridans streptococci
Klebsiella
GBS
Pathogens based on source of infection
Meningitis GBS CoNS, Enterococcus, Listeria, N. meningitides, nontypeable H.

E. coli influenzae, S. aureus, S. pneumoniae, other streptococci
Other gram- (groups A, C, or G and viridans streptococci)
negative
enteric bacilli
Pneumonia GBS C. trachomatis, Citrobacter, Enterobacter, group A

Streptococcus, Klebsiella, Pseudomonas, S. aureus, S.
pneumoniae, Serratia
Urinary tract E. coli Citrobacter, Enterobacter, Enterococcus, Klebsiella, Proteus

infectionΔ
Additional pathogens seen in the NICU setting – CoNS, S.

aureus
Skin and soft S. aureus

tissue infection GBS
Group A
Streptococcus
Vascular S. aureus
catheter- CoNS
associated Enterococcus
infection
Gram-negatives
Intestinal E. coli
source/NEC Klebsiella
Other enteric
gram-negative
bacilli
Clostridium spp
Anaerobes (eg,
Bacteroides)
GA: gestational age; GBS: group B Streptococcus; E. coli: Escherichia coli; H. influenzae: Haemophilus
influenzae; S. aureus: Staphylococcus aureus; CoNS: coagulase-negative staphylococci; NICU: neonatal
intensive care unit; N. meningitidis: Neisseria meningitidis; S. pneumoniae: Streptococcus pneumoniae; C.
trachomatis: Chlamydia trachomatis; NEC: necrotizing enterocolitis.
* This table summarizes bacterial pathogens in neonatal sepsis and in focal neonatal infections.
Common pathogens are listed roughly in order of relative frequency within each category; less common
pathogens are listed alphabetically. The list of pathogens within each category is not exhaustive. This
table does not address nonbacterial causes of neonatal infections (eg, herpes simplex virus, enterovirus,
parechovirus, Candida). Refer to separate UpToDate content for additional information on nonbacterial
pathogens.
¶ The definitions of early and late onset vary in different reports. Within UpToDate content, we generally
define early onset as <7 days after birth for term infants and ≤72 hours after birth for preterm infants;
however, some experts use the ≤72 hours definition regardless of GA. Late onset is generally defined as
≥7 days after birth for term infants and >72 hours after birth for preterm infants. The definitions of early
and late onset as they pertain to GBS disease are somewhat different. Early-onset GBS infection typically
presents within 24 hours of birth but can occur through day 6 after birth. Late-onset GBS typically occurs
at 4 to 5 weeks of age.
Δ Urinary tract infections may not be associated with bacteremia in neonates.
Graphic 61061 Version 9.0
Clinical findings in neonatal sepsis
Finding Frequency*
Hyperthermia +++
Respiratory distress +++
Tachycardia +++
Lethargy ++
Poor feeding ++
Apnea ++
Bradycardia ++
Poor perfusion/hypotension ++
Vomiting ++
Jaundice ++
Hepatomegaly ++
Cyanosis +
Hypothermia +
Irritability +
Seizures +
Abdominal distension +
Diarrhea +
* +++: commonly associated (≥50% of cases); ++: frequently associated (25 to 50%); +: occasionally
associated (<25%).
References:
1. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious Diseases of the Fetus and Newborn Infant, 8th ed,
Remington JS, Klein JO, Wilson CB, et al (Eds), Elsevier Saunders, 2016. p.411.
2. Stoll BJ, Puopolo KM, Hansen NI, et al. Early-Onset Neonatal Sepsis 2015 to 2017, the Rise of Escherichia coli, and the Need
for Novel Prevention Strategies. JAMA Pediatr 2020; 174:e200593.
Approach to evaluating neonates born ≥35 weeks

gestation who are at risk for group B streptococcal
infection: Categorical risk assessment
GBS: group B streptococcus;

IAP: intrapartum antibiotic prophylaxis;

LP: lumbar puncture;
CSF: cerebrospinal fluid.

* Signs of infection in neonates are often nonspecific. Common
findings include abnormal temperature (fever or hypothermia),
respiratory distress, tachycardia, lethargy, poor feeding, apnea,
bradycardia, and/or poor perfusion. For further details, refer to
UpToDates topics on infections in neonates.

¶ If there is a strong clinical suspicion for infection, especially in
neonates who are critically ill, it may be appropriate to perform LP
and CSF culture in addition to the blood culture before starting
empiric antibiotics. However, LP should not be performed if the
procedure would compromise the neonate's condition. Antibiotic
therapy should not be deferred because of procedure delays.

Δ Empiric antibiotic coverage typically consists of ampicillin plus
gentamicin. Refer to separate UpToDate content on treatment of
neonatal GBS and neonatal sepsis for additional details.
◊ For details regarding indications for IAP, refer to UpToDate's topic

on prevention of GBS in pregnancy.

§ Adequate GBS IAP is defined as the administration of penicillin G,
ampicillin, or cefazolin ≥4 hours before delivery.
Reproduced with permission from Pediatrics, Vol. 144, Copyright © 2019 by the AAP.
"Enhanced observation" approach to evaluating

neonates born ≥35 weeks gestation who are at risk
for group B streptococcal infection
GBS: group B Streptococcus; IAP: intrapartum antibiotic prophylaxis;

LP: lumbar puncture; CSF: cerebrospinal fluid.
* Signs of infection in neonates are often nonspecific. Common

findings include abnormal temperature (fever or hypothermia),
respiratory distress, tachycardia, lethargy, poor feeding, apnea,
bradycardia, and/or poor perfusion. For further details, refer to
UpToDate topics on infections in neonates.
¶ If there is a strong clinical suspicion for infection, especially in

neonates who are critically ill, it may be appropriate to perform LP
and CSF culture in addition to the blood culture before starting
empiric antibiotics. However, LP should not be performed if the
procedure would compromise the neonate’s condition. Antibiotic
therapy should not be deferred because of procedure delays.
Δ Empiric antibiotic coverage typically consists of ampicillin plus

gentamicin. Refer to separate UpToDate content on treatment of
neonatal GBS and neonatal sepsis for additional details.
◊ For details regarding indications for IAP, refer to UpToDate's topic

on prevention of GBS in pregnancy.
§ Adequate GBS IAP is defined as the administration of penicillin G,

ampicillin, or cefazolin ≥4 hours before delivery.
Reproduced with permission from Pediatrics, Vol. 144, Copyright © 2019 by the AAP.
Characteristics of cerebrospinal fluid in term and preterm neonates without

bacterial meningitis
Mean
ANC/mm3 or Mean protein Mean glucose
WBC/mm3
Age percent PMNs

(mg/dL)
(mg/dL)
(range or 95th
(range) (range or ±SD) (range or ±SD)
percentile)
Term neonates evaluated in the nursery setting
0 to 24 hours
5 (0 to 90) 3/mm3 (0 to 70) 63 (32 to 240) 51 (32 to 78)
(n = 135)*[1]
0 to 10 days
8.2 (0 to 32) 61.3% 90 (20 to 170) 52 (34 to 119)
(n = 87)¶[2]
Term neonates evaluated in the emergency department settingΔ
0 to 28 days
5.5 (95th 2% (IQR 0 to 5) 69.9 (±25.7) 45.7 (±8.0)
(n = 3467)[3] percentile 16)
Preterm very low birth weight (<1500 g) neonates
0 to 7 days 7 (0 to 30) NR 144 (51 to 270) 50.4 (11 to 138)
(n = 88)[4]
0 to 28 days
5 (0 to 44) 8% (0 to 66) 148 (54 to 370) 67 (33 to 217)
(n = 45)[5]
WBC: white blood cell count; ANC: absolute neutrophil count; PMNs: polymorphonuclear leukocytes; SD:
standard deviation; IQR: interquartile range; NR: not reported; CSF: cerebrospinal fluid.
* CSF obtained from term neonates without any obvious pathology.
¶ CSF obtained from hospitalized neonates at high risk for infection (eg, unexplained jaundice, prolonged
rupture of membranes, maternal fever, etc); infection excluded by sterile cultures (CSF, blood, urine) and
lack of clinical evidence of bacterial or viral infection.
Δ CSF obtained in the emergency department during evaluation for possible infection; infection was
excluded by sterile cultures (CSF, blood, and urine). Infants with positive polymerase chain reaction for
enterovirus were also excluded; however, not all infants underwent enteroviral testing. CSF parameters
were similar in infants who tested negative for enterovirus and those who were not tested.
References:
1. Naidoo BT. The cerebrospinal fluid in the healthy newborn infant. S Afr Med J 1968; 42:933.
2. Sarff LD, Lynn H, Platt MD, et al. Cerebrospinal fluid evaluation in neonates: Comparison of high risk infants with and
without meningitis. J Pediatr 1976; 88:473.
3. Thomson J, Sucharew H, Cruz AT, et al. Cerebrospinal Fluid Reference Values for Young Infants Undergoing Lumbar
Puncture. Pediatrics 2018; 141:e20173405.
4. Mhanna MJ, Alesseh H, Gori A, Aziz HF. Cerebrospinal fluid values in very low birth weight infants with suspected sepsis at
different ages. Pediatr Crit Care Med 2008; 9:294.
5. Rodriguez AF, Kaplan SL, Mason EO. Cerebrospinal fluid values in the very low birth weight infant. J Pediatr 1990; 116:971.
Suggested antimicrobial regimens in the management of neonatal sepsis in

term and late preterm infants
Antibiotic regimen
Empiric therapy
Early onset (<7 days) Ampicillin and gentamicin
Late onset (≥7 days) – Admitted from the Preferred regimen – Ampicillin and gentamicin
community
Alternative – Ampicillin and an expanded-spectrum
cephalosporin (eg, ceftazidime, cefepime, or
cefotaxime [where available])
Late onset (≥7 days) – Hospitalized since birth Gentamicin and vancomycin
Special circumstances:
Suspected meningitis – Early onset Ampicillin and gentamicin*¶
Suspected meningitis – Late onset, admitted Ampicillin, gentamicin, and an expanded-spectrum

from the community cephalosporin (eg, ceftazidime, cefepime, or
cefotaxime [where available])¶
Suspected meningitis – Late onset, Gentamicin, vancomycin, and an expanded-

hospitalized since birth spectrum cephalosporin (eg, ceftazidime, cefepime,
or cefotaxime [where available])¶
Suspected pneumonia Ampicillin and gentamicin
Alternatives:
Ampicillin and expanded-spectrum
cephalosporin, or
Vancomycin and expanded-spectrum
cephalosporin, or
Vancomycin and gentamicin
Suspected infection of soft tissues, skin, Vancomycin or vancomycin and nafcillin

joints, or bones (S. aureus is a likely pathogen)
Suspected intravascular catheter-related Vancomycin and gentamicin

infection
Suspected infection due to organisms found Ampicillin, gentamicin, and clindamycin

in the gastrointestinal tract (eg, anaerobic
Alternatives:
bacteria)
Ampicillin, gentamicin, and metronidazole or
Piperacillin-tazobactam and gentamicin
Pathogen-specific therapy
Group B Streptococcus Penicillin G
E. coli – Ampicillin-sensitive Ampicillin
E. coli – Ampicillin-resistant Expanded-spectrum cephalosporin (eg, ceftazidime,

cefepime, or cefotaxime [where available])
Alternative:
Meropenem
Multidrug-resistant gram-negative bacilli Meropenem

(including ESBL-producing organisms)
L. monocytogenes Ampicillin and gentamicin
MSSA Nafcillin or cefazolin
MRSA Vancomycin
Coagulase-negative staphylococci Vancomycin
S. aureus: Staphylococcus aureus; E. coli: Escherichia coli; ESBL: extended-spectrum beta-lactamase; L.

monocytogenes: Listeria monocytogenes; MSSA: methicillin-susceptible S. aureus; MRSA: methicillin-
resistant S. aureus.
* An expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime)

should be added to the empiric regimen for suspected early-onset meningitis if the cerebrospinal fluid
Gram stain reveals gram-negative bacilli.
¶ If there is concern for meningitis caused by a multidrug-resistant gram-negative organism, a

carbapenem such as meropenem is the preferred agent for empiric therapy.
References:
1. Edwards MS, Baker CJ. Bacterial infections in the neonate. In: Principles and Practice of Pediatric Infectious Diseases, 5th
ed, Long SS, Prober CG, Fischer M (Eds), Elsevier 2018. p.549.
2. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious Diseases of the Fetus and Newborn Infant, 8th ed, Wilson CB,
Nizet V, Maldonado YA, et al (Eds), Elsevier Saunders 2016. p.217.
3. American Academy of Pediatrics. Group B streptococcal infections. In: Red Book: 2018-2021 Report of the Committee on
Infectious Diseases, 31st ed, Kimberlin DW (Ed), American Academy of Pediatrics 2018. p.762.
4. American Academy of Pediatrics. Serious bacterial infections caused by Enterobacteriaceae (with emphasis on septicemia
and meningitis in neonates). In: Red Book: 2018-2021 Report of the Committee on Infectious Diseases, 31st ed, Kimberlin
DW (Ed), American Academy of Pediatrics 2018. p.328.
Range of neutrophil count for newborn infants born with a

gestational age >36 weeks during the first 72 hours of life
Neutrophils per microL of blood during the first 72 hours after the birth of
term and near-term (>36 weeks of gestation) neonates. A total of 12,149
values were obtained for the analysis. The 5th percentile, the mean, and the
95th percentile values are shown.
Reprinted by permission from Macmillan Publishers Ltd: Schmutz N, Henry E, Jopling J,

Christensen RD. Expected ranges for blood neutrophil concentrations of neonates: the Manroe
and Mouzinho charts revisited. J Perinatol 2008; 28:275. http://www.nature.com/jp/index.html.
Copyright © 2008.
Normal range of neutrophil count for newborn infants with a

gestational age between 28 and 36 weeks during the first 72 hours
of life
Neutrophils per microL of blood during the first 72 hours after the birth of 28- to 36-week
gestation preterm neonates. A total of 8896 values were obtained for the analysis. The
5th percentile, the mean, and the 95th percentile values are shown.
Reprinted by permission from: Macmillan Publishers Ltd: Schmutz N, Henry E, Jopling J, Christensen RD.
Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. J
Perinatol 2008; 28:275. http://www.nature.com/jp/index.html. Copyright © 2008.
Differential diagnosis of neonatal sepsis
Diagnosis Distinguishing features Diagnostic tests
Other systemic neonatal infections
Viral infections:
Herpes simplex virus Mucocutaneous vesicles, CSF Viral culture; HSV PCR
pleocytosis, elevated CSF protein,
thrombocytopenia, hepatitis
Enteroviruses Fulminant systemic disease, Viral culture; EV PCR

myocarditis, hepatitis,
encephalitis
Parechovirus Encephalitis/meningitis, rash on HPeV PCR (available through

palms and soles CDC)
Cytomegalovirus Thrombocytopenia, Viral culture; CMV PCR

periventricular intracranial
calcifications, microcephaly,
sensorineural hearing loss,
chorioretinitis
Influenza viruses Respiratory symptoms, Viral culture; influenza-specific

rhinorrhea, gastrointestinal antigen detection or
symptoms immunofluorescence assay
Respiratory syncytial virus Respiratory symptoms, Viral culture; RSV-specific antigen

rhinorrhea, cough, apnea, detection or
pneumonia immunofluorescence assay
Spirochetal infections – Skeletal abnormalities RPR or VDRL

Syphilis (osteochondritis and periostitis),
pseudoparalysis, persistent
rhinitis, maculopapular rash
(particularly on palms and soles
or in diaper area)
Parasitic infections:
Congenital malaria Anemia, splenomegaly, jaundice Detection of parasitemia on

blood smear
Toxoplasmosis Intracranial calcifications Toxoplasma gondii serology

(diffuse), hydrocephalus,
chorioretinitis, mononuclear CSF
pleocytosis, elevated CSF protein
Fungal infection – Candidiasis Persistent hyperglycemia, Isolation of Candida in blood,

thrombocytopenia, multiorgan urine, or CSF culture
failure
Noninfectious causes of temperature instability in neonates
Altered environmental Transient; no other systemic symptoms; resolves with simple

temperature nonpharmacologic measures
Dehydration Clinical history of poor feeding or fluid losses (eg, vomiting and/or
diarrhea)
Neonatal abstinence History of maternal drug use; Positive drug screening tests
syndrome sweating, sneezing, nasal
stuffiness, and yawning
CNS insult (eg, anoxia or History of perinatal asphyxia; Abnormal neuroimaging studies
hemorrhage) focal neurologic findings or
seizures
Hypothyroidism Hypotonia, lethargy, Abnormal T4 or TSH level on

hypothermia, large fontanels newborn screen
Congenital adrenal Ambiguous genitalia (females), Abnormal 17a-

hyperplasia adrenal insufficiency and salt- hydroxyprogesterone level on
wasting (hyponatremia, newborn screen
hyperkalemia, dehydration)
Noninfectious causes of respiratory and cardiocirculatory symptoms in neonates
Transient tachypnea of the Onset of symptoms within two CXR findings include increased
newborn hours after delivery; symptoms lung volumes, mild cardiomegaly,
usually resolve within 24 hours prominent vascular markings,
fluid in the interlobar fissures,
and pleural effusions
Respiratory distress syndrome Most common in preterm infants; CXR findings include low lung
rare in term infants; onset of volume and diffuse
symptoms within first few hours reticulogranular ground glass
after delivery, progressively appearance with air
worsens over first 48 hours of life bronchograms
Meconium aspiration History of meconium-stained Initial CXR may show streaky,

amniotic fluid; respiratory linear densities; as the disease
distress occurs immediately after progresses, the lungs may
birth appear hyperinflated with diffuse
patchy densities
Pneumothorax Asymmetric chest rise, decreased CXR will usually detect

breath sounds on affected side; symptomatic pneumothoraces
hypotension (in cases of tension
pneumothorax)
Congenital anomalies Often occur with other congenital CDH is often diagnosed by
(including tracheal- anomalies including VACTERL and routine antenatal ultrasound
esophageal fistula, choanal CHARGE associations; choanal screening; postnatal CXR shows
atresia, and diaphragmatic atresia is characterized by noisy herniation of abdominal contents
hernia) labored breathing while feeding into hemithorax; TEF is
diagnosed with upper
gastrointestinal series and/or
bronchoscopy
Cardiac arrhythmias (eg, Abrupt onset and termination of Abnormal ECG

supraventricular tachycardia) rapid heart rate
Congenital heart disease Infants with ductal-dependent Abnormal hyperoxia test;

lesions may initially lack abnormal echocardiography
symptoms then develop cyanosis
and rapid clinical deterioration as
the PDA closes in the first few
days of life
Noninfectious causes of neurologic symptoms in neonates
Hypoglycemia Common in infants who are large Abnormal blood glucose level
for gestational age and/or infants
of diabetic mothers
Hypercalcemia Increased neuromuscular Abnormal serum calcium level

irritability and seizures;
associated with prematurity,
maternal diabetes, and perinatal
asphyxia
Hypermagnesemia Generalized hypotonia, Abnormal serum magnesium

respiratory depression and level
apnea; typically results from
maternal treatment with
magnesium sulfate
CNS insult (eg, anoxia or History of perinatal asphyxia; Abnormal neuroimaging studies
hemorrhage) focal neurologic findings or
seizures
Congenital CNS Abnormal head circumference Abnormal neuroimaging studies

malformations (eg,
hydrocephalus)
Inborn errors of metabolism Otherwise unexplained acid-base Positive newborn screen for
disorders, hyperammonemia, inborn errors of metabolism

hypoglycemia, hematologic
abnormalities, liver dysfunction,
and renal disease
Pyridoxine deficiency Refractory seizures Abnormal plasma pyridoxal-5-

phophate level
CSF: cerebral spinal fluid; HSV: herpes simplex virus; PCR: polymerase chain reaction; EV: enterovirus;
HPeV: human parechovirus; CMV: cytomegalovirus; RSV: respiratory syncytial virus; RPR: rapid plasma
reagin; VDRL: venereal disease research laboratory; CNS: central nervous system; T4: thyroxine; TSH:
thyrotropin; CXR: chest radiograph; CDH: congenital diaphragmatic hernia; VACTERL: malformations of
the vertebrae, anus, cardiac structures, trachea, esophagus, renal system, and limbs; CHARGE: coloboma
of the iris or choroid, heart defect, atresia of the choanae, retarded growth and development,
genitourinary abnormalities, and ear defects; TEF: tracheoesophageal fistula; ECG: electrocardiogram;
PDA: patent ductus arteriosus.
Adapted from: Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious diseases of the fetus and newborn infant, 7th ed,
Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010.
Contributor Disclosures
Morven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer [Group B Streptococcus]. Other
Financial Interest: Texas State University personal services agreement [Chagas disease]. Sheldon L
Kaplan, MD Grant/Research/Clinical Trial Support: Pfizer [Streptococcus pneumoniae]; Merck
[Staphylococcus aureus]; MeMed Diagnostics [Bacterial and viral infections]; Allergan [Staphylococcus
aureus]. Consultant/Advisory Boards: MeMed Advisory Board [Diagnostics bacterial and viral infections].
Other Financial Interest: Pfizer [PCV13, linezolid]; Elsevier [Pediatric infectious diseases]. Joseph A Garcia-
Prats, MD Nothing to disclose Carrie Armsby, MD, MPH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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21/10/21 12:49 Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants - UpToDate

Official reprint from UpToDate®

Clinical features, evaluation, and diagnosis of sepsis in

● Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger, manifested

● Term infants are those born at a gestational age of 37 weeks or greater.

Sepsis is classified according to the infant's age at the onset of symptoms.

The pathogenesis differs based on the timing of onset:

● Early-onset infection – Early-onset infection is usually due to vertical transmission by

● Late-onset infection – Late-onset infections can be acquired by the following mechanisms:

Rates of neonatal sepsis increase with decreasing gestational age:

● Listeria monocytogenes, although a well-recognized cause of early-onset sepsis, only

● Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus, is a

● Enterococcus, a commonly encountered pathogen among preterm infants, is a rare cause of

● Coagulase-negative staphylococci often are a cause of hospital-associated infection in ill

catheters). Coagulase-negative staphylococci may be considered a contaminant in

● Enterovirus and parechovirus (see "Enterovirus and parechovirus infections: Clinical

● Candida (see "Clinical manifestations and diagnosis of Candida infection in neonates",

MATERNAL RISK FACTORS

Signs and symptoms of neonatal sepsis include:

• Meconium-stained amniotic fluid, which is associated with a twofold increased risk of

● Temperature instability – The temperature of an infected infant can be elevated,

● Cardiorespiratory symptoms – Respiratory and cardiocirculatory symptoms are common

Tachycardia is a common finding in neonatal sepsis but is nonspecific. Bradycardia may

● Neurologic symptoms – Neurologic manifestations of sepsis in the neonate include

EVALUATION AND INITIAL MANAGEMENT

Early-onset sepsis calculator — Multivariate predictive models for risk of early-onset sepsis

Symptomatic neonates — Infants with signs and symptoms of sepsis ( table 2) should

A full diagnostic evaluation includes (see 'Laboratory tests' below):

Well-appearing neonates — Well-appearing infants with identified risk factors for neonatal

Empiric antibiotic therapy — Indications for empiric antibiotic therapy (after obtaining

● Concerning symptoms, including temperature instability or respiratory, cardiocirculatory, or

● Confirmed or suspected maternal chorioamnionitis (intraamniotic infection) (see 'Maternal

Blood culture — A definitive diagnosis of neonatal sepsis is established by a positive blood

• Sampling site – Blood cultures can be obtained by venipuncture or arterial puncture or

• Number of cultures – We obtain at least one culture prior to initiating empiric

● Distinguishing infection from contamination – A positive blood culture is diagnostic of

Lumbar puncture — The clinical presentation of neonatal meningitis is indistinguishable from

Lumbar puncture is indicated in neonates with:

● Clinical findings concerning for sepsis ( table 2)

Early-onset sepsis — For most neonates with suspected early-onset sepsis, we suggest

perform poorly in identifying neonates with late-onset sepsis.

● C-reactive protein (CRP) – CRP is increased in inflammatory conditions, including sepsis. A

● Procalcitonin (PCT) – PCT is the peptide precursor of calcitonin. It is released by

● Cytokines, chemokines, and other biomarkers – Both proinflammatory cytokines, such

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Epidemiology and microbiology – Sepsis is an important cause of morbidity and mortality

Symptomatic neonates should undergo a full diagnostic evaluation including (see

Empiric antibiotics should be provided to these neonates pending culture results (

● Diagnosis – Isolation of a pathogen from a blood culture confirms the diagnosis of

Use of UpToDate is subject to the Subscription and License Agreement.

Bacterial pathogens in neonatal sepsis and focal neonatal infections

Term and late GBS Enterobacter, Enterococcus, Klebsiella, Listeria, nontypeable

Pathogens based on source of infection

Meningitis GBS CoNS, Enterococcus, Listeria, N. meningitides, nontypeable H.

Pneumonia GBS C. trachomatis, Citrobacter, Enterobacter, group A

Urinary tract E. coli Citrobacter, Enterobacter, Enterococcus, Klebsiella, Proteus

Additional pathogens seen in the NICU setting – CoNS, S.

Skin and soft S. aureus

Δ Urinary tract infections may not be associated with bacteremia in neonates.

Graphic 61061 Version 9.0

Clinical findings in neonatal sepsis