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

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Clinical features, evaluation, and diagnosis of sepsis in

term and late preterm neonates
Author: Joseph B Cantey, MD, MPH
Section Editors: Joseph A Garcia-Prats, MD, Morven S Edwards, MD
Deputy Editor: Laurie Wilkie, MD, MS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Jan 10, 2023.
INTRODUCTION
Sepsis is an important cause of morbidity and mortality among newborn infants. Although
the incidence of sepsis in term and late preterm neonates 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 neonates will be reviewed here. The management and outcome of sepsis in term
and late preterm neonates are discussed separately. (See "Management and outcome of
sepsis in term and late preterm neonates".)
Other related topics include:
● Sepsis in preterm neonates (see "Clinical features and diagnosis of bacterial sepsis in
preterm infants <34 weeks gestation" and "Treatment and prevention of bacterial
sepsis in preterm infants <34 weeks gestation")
● Group B streptococcal (GBS) infection in neonates and infants, including management
of well-appearing newborns at risk for GBS (see "Group B streptococcal infection in
neonates and young infants" and "Management of neonates at risk for early-onset
group B streptococcal infection")
● Outpatient evaluation and management of febrile neonates (see "The febrile neonate
(28 days of age or younger): Outpatient evaluation and initial management")
● Evaluation and management of ill-appearing infants (see "Approach to the ill-appearing
infant (younger than 90 days of age)")
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TERMINOLOGY
The following terms will be used throughout this discussion on neonatal sepsis:
● Term neonates are those born at a gestational age of 37 weeks or greater.
● Late preterm neonates (also called near-term neonates) are those born from 34
through 36 completed weeks of gestation [1]. (See "Late preterm infants".)
● 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 [2]. (See
'Diagnosis' below.)
Sepsis is classified according to the neonate's age at the onset of symptoms.
• Early-onset sepsis (EOS) is defined as the onset of symptoms before 72 hours of

age [3-5], although some experts extend the definition to infections occurring within
the first seven days after birth.
• Late-onset sepsis (LOS) is generally defined as the onset of symptoms at ≥72 hours
of age [3]. Similar to EOS, there is variability in the definition, ranging from an onset
at >72 hours of life to ≥7 days of age.
Newborn infants with EOS typically present with symptoms during their birth
hospitalization. Term neonates with LOS generally present to the outpatient setting or
emergency department unless comorbid conditions have prolonged the birth
hospitalization. The approach to evaluating febrile neonates in the outpatient setting is
discussed separately. (See "The febrile neonate (28 days of age or younger): Outpatient
evaluation and initial management", section on 'Neonates 8 to 21 days old'.)
PATHOGENESIS
The pathogenesis differs based on the timing of onset:
● Early-onset sepsis (EOS) – EOS is usually due to vertical transmission by ascending

contaminated amniotic fluid or during vaginal delivery from bacteria in the mother's
lower genital tract [4]. Maternal chorioamnionitis (or intra-amniotic infection) is a well-
recognized risk factor for EOS [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 EOS because they penetrate the neonatal
defensive epithelial barriers [8].
● Late-onset sepsis (LOS) – LOS 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 LOS. LOS 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 EOS and LOS). 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
three 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 EOS (defined as
positive blood or cerebrospinal fluid cultures) was 0.98 cases per 1000 live births; the
rate among neonates 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 neonates. In an observational cohort study (1996 to 2007),
the reported incidences of EOS and LOS (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 EOS 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'.)
GBS prevention efforts have not increased the burden of early-onset Escherichia coli infection
[22].
ETIOLOGIC AGENTS
Group B Streptococcus (GBS) and E. coli are the most common causes of both EOS and LOS,
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 EOS, 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 neonates usually occur in association with skin, bone, or joint sites of
involvement.
● Enterococcus, a commonly encountered pathogen among preterm neonates, 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 LOS, especially in neonates admitted
to neonatal intensive care units [28].
● Coagulase-negative staphylococci often are a cause of hospital-associated infection in

ill neonates (primarily in premature neonates and/or neonates who have indwelling
intravascular catheters). Coagulase-negative staphylococci may be considered a
contaminant in otherwise healthy term neonates who have not undergone invasive
procedures.
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')
● 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 EOS in the neonate,
particularly group B Streptococcus (GBS) infection, include intra-amniotic infection (clinical
chorioamnionitis), intrapartum maternal fever, maternal GBS colonization, preterm birth,
and prolonged rupture of the membranes (PROM) [4,6,29]. Though the duration of ruptured
membranes is commonly considered when assessing the neonate's risk of infection, it is
unclear whether PROM is an independent risk factor for sepsis in the absence of intra-
amniotic infection [30]. The approach to identifying pregnancies at risk for neonatal EOS and
indications for maternal intrapartum antibiotic prophylaxis (IAP) are discussed separately.
(See "Prevention of early-onset group B streptococcal disease in neonates", section on
'Identification of pregnancies at increased risk for early-onset neonatal GBS' and "Prevention
of early-onset group B streptococcal disease in neonates", section on 'Intrapartum antibiotic
prophylaxis'.)
Maternal GBS screening and IAP reduce the risk of GBS infection but do 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) [11].
CLINICAL MANIFESTATIONS
Clinical manifestations range from subtle symptoms to profound septic shock. Signs and
symptoms of sepsis are nonspecific and include temperature instability (hypothermia or
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 a newborn deviates from their 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 intra-amniotic 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')
• Low 5- or 10-minute Apgar score, particularly if concerning findings persist (see

"Overview of the routine management of the healthy newborn infant", section on
'Apgar score')
● Temperature instability – The temperature of an infected neonate can be elevated,

depressed, or normal. Term neonates with sepsis are more likely to mount a febrile
response to infection; whereas preterm neonates are more likely to be hypothermic [8].
In term newborns, persistent fever is highly indicative of infection [31,32].
● Cardiorespiratory symptoms – Respiratory and cardiocirculatory symptoms are

common in infected neonates. Approximately 85 percent of newborns with EOS present
with respiratory distress (eg, tachypnea, grunting, flaring, use of accessory muscles)
[11]. EOS can be associated with persistent pulmonary hypertension of the newborn.
(See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and
diagnosis".)
Apnea is less common, occurring in 30 to 40 percent of cases, and is more likely in

preterm than term neonates. Apnea is a classic presenting symptom in late-onset
group B streptococcal (GBS) sepsis.
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 neonates 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 [4,8]. Because the signs and symptoms of sepsis are subtle
and nonspecific, the threshold for performing laboratory testing is low. Our approach is
generally consistent with guidelines published by the American Academy of Pediatrics [4,35].
Early-onset presentation — The evaluation of a neonate with suspected EOS (onset within

first 72 hours after birth) 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 – The extent of the evaluation is directed by the neonate's signs and
symptoms (if present) and maternal risk factors, as discussed in the following sections.
Early-onset sepsis calculator — A multivariate predictive model for determining the risk of
EOS, the EOS calculator, has been developed and validated in various clinical settings [29,36-
38]. The EOS calculator is a web-based tool that can be used to estimate the risk of EOS 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 EOS. If the local incidence of EOS is unknown, the
users should enter "0.5 per 1000." The calculator provides guidance on whether diagnostic
evaluation and empiric antibiotic treatment are warranted. The threshold used to trigger
evaluation and empiric treatment varies, depending on the clinical circumstances. The EOS
calculator is not valid for preterm neonates (<34 weeks gestation) and does not apply to
LOS.
Symptomatic neonates — Neonates with signs and symptoms of EOS ( table 2) should

undergo a full diagnostic evaluation and should receive empiric antibiotic treatment. (See
"Management and outcome of sepsis in term and late preterm neonates", section on 'Early-
onset sepsis'.)
The evaluation includes:
● Blood culture. (See 'Blood culture' below.)
● Lumbar puncture (LP) – Practice has shifted regarding performing LP in neonates

undergoing evaluation for clinically suspected EOS [4]. In our practice, we perform LP if
the newborn is ill-appearing (provided they can tolerate the procedure) or if there are
other concerning signs (irritability, bulging fontanelle, seizures). In addition, if the
blood culture is positive, then LP should be performed [4]. Other experts advise
performing LP in all neonates undergoing evaluation for clinically suspected EOS. (See
'Lumbar puncture' below.)
LP is not necessary in well-appearing newborns undergoing evaluation for EOS based

upon identified risk factors, as discussed below. (See 'Well-appearing neonates' below.)
● Chest radiograph if there are respiratory findings.
● Cultures from tracheal aspirates if the neonate is intubated. (See 'Other cultures'
below.)
Well-appearing neonates — Well-appearing newborns with identified risk factors for EOS,

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 EOS calculator. The EOS 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 presentation — Neonates presenting with signs and symptoms at ≥72 hours of

age should undergo prompt evaluation and empiric antibiotic treatment. (See "Management
and outcome of sepsis in term and late preterm neonates", section on 'Late-onset sepsis'.)
The diagnostic evaluation includes all of the following:
● Blood culture (see 'Blood culture' below)

● LP (if the neonate is clinically stable enough to tolerate the procedure and it will not
delay initiation of antibiotic therapy) (see 'Lumbar puncture' below)
● Chest radiograph (if respiratory symptoms are present)
● Urine culture (see 'Urine culture' below)
● Cultures from any other potential foci of infection (eg, tracheal aspirates if intubated,
purulent eye drainage, or pustules) (see 'Other cultures' below)
In addition, some clinicians obtain a complete blood count (CBC) with differential and/or
other inflammatory markers (eg, C-reactive protein [CRP], and/or procalcitonin [PCT]). In our
practice, we do not routinely perform these tests because they add little information and do
not impact clinical decisions. These tests are described in greater detail below. (See
'Complete blood count' below and 'Other inflammatory markers' below.)
Neonates with LOS generally present to the outpatient or emergency department setting
unless comorbid conditions have prolonged the birth hospitalization. Additional details
regarding the evaluation of febrile or ill-appearing neonates are provided separately. (See
"Approach to the ill-appearing infant (younger than 90 days of age)" and "The febrile
neonate (28 days of age or younger): Outpatient evaluation and initial management",
section on 'Neonates 8 to 21 days old'.)
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)
● High estimated risk of EOS based on a validated risk calculator (see 'Early-onset
sepsis calculator' 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')
● Positive blood, urine, or CSF culture

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). Our suggested empiric regimens are summarized in the table
( table 4) and discussed in greater detail separately. (See "Management and outcome of
sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)
LABORATORY TESTS
The goals of the diagnostic evaluation are to identify and treat all neonates 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 (with ≥1 mL of blood) to detect neonatal
bacteremia approaches 90 percent [39].
● 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
neonate. A minimum blood volume of 1 mL is desirable for optimal detection of
bacteremia when a single blood culture bottle is used [4]. At the author's institution,
the suggested optimal volume is 2 mL for neonates 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
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blood cultures. In most cases of neonatal sepsis, blood cultures become positive within
24 to 36 hours [40].
● 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 neonates without these
risk factors [8].
Lumbar puncture — Specific clinical signs of meningitis (eg, bulging fontanelle, nuchal

rigidity) may be lacking in neonates. For this reason, we suggest performing LP in all
neonates with suspected LOS, provided the neonate is stable enough to tolerate the
procedure and it will not delay initiation of antibiotics. We also suggest performing LP in the
evaluation of suspected EOS if the newborn is ill appearing or has other concerning findings
(irritability, bulging fontanelle, seizures). Other experts advise performing LP in all neonates
undergoing evaluation for clinically suspected EOS. LP is not necessary in well-appearing
newborns undergoing evaluation for EOS based upon identified risk factors, as discussed
above (see 'Well-appearing neonates' above). However, LP should be performed if the blood
culture is positive [4].
If LP is performed, 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
evaluation for LOS (ie, onset at ≥72 hours after birth). A urine culture need not be routinely
performed in the evaluation of suspected EOS (onset within the first 72 hours after birth),
because a positive urine culture in this setting is a reflection of high-grade bacteremia rather
than an isolated urinary tract infection [4]. (See "Urinary tract infections in neonates".)
Other cultures — In neonates 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 first intubation. However,
the trachea and proximal bronchi are not sterile, so a positive tracheal culture may represent
colonization rather than infection, particularly in a neonate 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 [4].
Complete blood count — A complete blood count (CBC) was commonly used in the past to
evaluate the likelihood of sepsis in a neonate with risk factors or signs of infection. However,
the CBC has poor sensitivity and specificity and cannot establish or exclude the diagnosis of
neonatal sepsis. At the author's institution, CBCs are no longer routinely performed in the
evaluation of suspected early- or late-onset neonatal sepsis because they add little
information and do not impact clinical decisions. Other centers may continue to routinely
perform CBCs in this setting.
● Early-onset sepsis – For most neonates with suspected EOS, we suggest not obtaining
a CBC as part of the diagnostic evaluation. The CBC does not perform well in predicting
risk of EOS in neonates. If a CBC is obtained, it should not be used as the sole
determinant of whether to treat empirically with antibiotics [41-45]. The CBC can be
used in combination with risk factors, clinical assessment, and/or other tests. However,
it adds little to these other assessments. CBCs obtained 6 to 12 hours after delivery are
more predictive of sepsis than those obtained immediately after birth because the
white blood cell count (WBC) and absolute neutrophil count (ANC) normally increase
during the first six hours after birth [41,42,46,47].
Large multicenter studies have evaluated the diagnostic value of CBCs in neonatal EOS
[6,41,42,48-50]. These studies demonstrated correlations between various WBC
parameters (including WBC count, ANC, and ratio of immature to total neutrophils [I/T
ratio]) and culture-proven sepsis; however, none were sufficiently sensitive or specific
to reliably predict neonatal sepsis.
● Late-onset sepsis – CBCs are less variable at >72 hours after birth than they are in the
first few days of life. However, WBC indices still perform poorly in identifying neonates
with LOS [51].
Other inflammatory markers — A number of acute phase reactants have been used to
identify infected newborns. Many of these tests have acceptable sensitivity; however, they all
lack specificity, resulting in poor positive predictive value [52]. No single biomarker or panel
of screening tests is sufficiently sensitive to reliably detect neonatal sepsis [53].
● 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 [54].
A single measurement of CRP is not a useful aid in the diagnosis of neonatal sepsis,
because it lacks sufficient sensitivity and specificity [55]. However, sequential
assessment of CRP values may help to exclude the diagnosis of sepsis. If the CRP level
remains persistently normal (<1 mg/dL [10 mg/L]), bacterial sepsis is unlikely [4].
CRP levels may be helpful in guiding the duration of antibiotic therapy in suspected
neonatal bacterial infection. Neonates 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, we do not routinely use serial CRP measurements for this purpose
since this practice appears to be associated with longer length of hospital stay [56].
An elevated CRP level alone does not justify continuation of empiric antibiotics for more
than 36 to 48 hours in well-appearing neonates with negative culture results [57].
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
elevated PCT levels are associated with infection in neonates [58-60]. In a systematic
review of 18 studies, the sensitivity of PCT for detecting neonatal sepsis ranged from 72
to 79 percent, and the specificity ranged from 72 to 90 percent [60]. Thus, although PCT
is a promising marker, it does not appear to be reliable as the sole or main diagnostic
indicator for neonatal sepsis.
data randomized clinical trial suggested that adding serial PCT measurements to other
standard assessments (ie, clinical examination and culture results) may shorten
duration of antibiotic therapy [61]. However, in this trial, the treating clinicians
overruled the study protocol's suggested duration of antibiotic therapy in >40 percent
of the enrolled neonates, which limits the certainty of the study's findings. Additional
data are needed before monitoring PCT levels can be adopted into routine neonatal
clinical practice. If 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 neonates compared with
those without infections [62-65]. Elevations of serum amyloid A and the cell surface
antigen CD64 also have high sensitivity for identifying neonates with sepsis [60,66].
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 neonates for whom sepsis is unlikely.
DIAGNOSIS
The diagnosis of sepsis is based upon isolating a pathogenic organism in culture. Few
neonates who undergo sepsis evaluation are ultimately diagnosed with sepsis.
This was demonstrated in a retrospective study of 2785 newborns who underwent

evaluation for sepsis based on clinical symptoms (54 percent) or risk factors (46 percent) [6].
Culture-proven sepsis was identified in 22 neonates (0.8 percent) and culture-negative
clinical sepsis ("probable sepsis") was diagnosed in 40 neonates (1.4 percent).
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 pathogenic organism 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
neonates", 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 laboratory abnormalities suggestive of sepsis [cerebrospinal fluid
pleocytosis, persistently elevated C-reactive protein]).
A composite of observational assessment and serial laboratory testing is typically used to

make a diagnosis of probable sepsis [67]. The criteria used are usually broad in an attempt
to ensure that all infected neonates are identified, but at the cost of testing and treating a
number of uninfected neonates. There is no consensus definition for the diagnosis of
probable sepsis in neonates [2].
Alternative diagnoses ( table 5) should also be entertained when a neonate with suspected
sepsis has negative cultures. (See "Management and outcome of sepsis in term and late
preterm neonates", section on 'Probable but unproven sepsis' and 'Differential diagnosis'
below.)
Infection unlikely — Neonates with mild and/or transient symptoms (ie, fever alone or
other symptoms that quickly resolve) who remain well-appearing with 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 [4,68].
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). The clinical history, disease course,
and laboratory findings may help to distinguish neonatal sepsis from other infectious and
noninfectious disorders. Ultimately, appropriate microbiologic testing is required to confirm
the diagnosis.
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 obtaining cultures) 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 – The incidence of sepsis in term and late preterm infants is

approximately 1 to 6 cases per 1000 births. (See 'Epidemiology' above.)
• Common pathogens – Group B Streptococcus (GBS) and Escherichia coli are the most
common bacteria causing neonatal sepsis. Other pathogens are summarized in the
table ( table 1). (See 'Etiologic agents' above.)
• Maternal risk factors – Maternal risk factors for neonatal sepsis include intra-
amniotic infection, intrapartum fever, preterm delivery, maternal GBS colonization,
and prolonged rupture of membranes. (See "Prevention of early-onset group B
streptococcal disease in neonates", section on 'Identification of pregnancies at
increased risk for early-onset neonatal GBS'.)
● Clinical manifestations – Clinical manifestations are nonspecific and include

( table 2) (see 'Clinical manifestations' above):
• Fetal distress
• Temperature instability (fever or hypothermia)
• Respiratory and cardiocirculatory symptoms (most commonly respiratory distress
and tachycardia)
• Neurologic symptoms (irritability, lethargy, poor tone, and seizures)
• Gastrointestinal abnormalities (poor feeding, vomiting, and abdominal distension)
● Evaluation of suspected early-onset sepsis (EOS) – The evaluation of a neonate with

suspected sepsis within first 72 hours after birth includes review of the pregnancy,
labor, and delivery; physical examination; and laboratory evaluation directed by the
neonate's signs and symptoms (if present) and maternal risk factors (see 'Early-onset
presentation' above):
• Symptomatic newborns – Neonates with signs and symptoms of EOS ( table 2)

should undergo a full diagnostic evaluation and should receive empiric antibiotic
treatment as summarized in the table ( table 4) and discussed separately. (See
"Management and outcome of sepsis in term and late preterm neonates", section
on 'Early-onset sepsis'.)
The evaluation includes:
- Blood culture (see 'Blood culture' above)

- Lumbar puncture (LP) if the newborn is ill-appearing or if there are other
concerning signs (irritability, bulging fontanelle, seizures) (see 'Lumbar
puncture' above)
- Chest radiograph if there are respiratory findings
• Well-appearing newborns – The approach to evaluating well-appearing newborns

who have risk factors for EOS is discussed separately. (See "Management of
neonates at risk for early-onset group B streptococcal infection".)
● Evaluation of suspected late-onset sepsis (LOS) – Neonates presenting with clinical

signs of sepsis at ≥72 hours after birth should undergo a full diagnostic evaluation and
should receive empiric antibiotic treatment as summarized in the table ( table 4) and
discussed separately. (See "Management and outcome of sepsis in term and late
preterm neonates", section on 'Early-onset sepsis'.)
The evaluation includes (see 'Late-onset presentation' above):
• Blood culture (see 'Blood culture' above)

• LP (provided the neonate is stable enough to tolerate the procedure and it will not
delay antibiotic therapy) (see 'Lumbar puncture' above)
• Chest radiograph (if respiratory symptoms are present)
• Urine culture (see 'Urine culture' above)
• Cultures from any other potential foci of infection (eg, tracheal aspirates if
intubated, purulent eye drainage, or pustules) (see 'Other cultures' above)
We do not typically obtain complete blood counts (CBCs) or other inflammatory

markers (eg, C-reactive protein, procalcitonin) as part of the evaluation for neonatal
sepsis (EOS or LOS) since these tests are not sufficiently sensitive or specific to confirm
or exclude the diagnosis. Other centers may routinely perform these tests. (See
'Complete blood count' above and 'Other inflammatory markers' above.)
● Diagnosis – Isolation of a pathogen from a blood culture confirms the diagnosis of

neonatal sepsis. (See 'Diagnosis' above.)
● Differential diagnosis – 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 Terms of Use.
Topic 5043 Version 58.0
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,

preterm E. coli nontypeable H. influenzae, other enteric gram-negative
infants bacilli, S. aureus, viridans streptococci
(GA ≥34
weeks)
Preterm E. coli CoNS, Enterobacter, Klebsiella, Listeria, other enteric

infants GBS and nonenteric gram-negative bacilli, S. aureus,
(GA <34 viridans streptococci
weeks)
Late onset ¶
Term and late E. coli Enterobacter, Klebsiella, Listeria, N. meningitidis, other

preterm GBS enteric and nonenteric gram-negative bacilli,
infants Salmonella, S. pneumoniae, viridans streptococci
Additional
(GA ≥34 Additional pathogens seen in the NICU setting –
pathogens
weeks) Citrobacter, Enterococcus, Pseudomonas, Serratia
seen in the
NICU setting
– S. aureus,
CoNS
Preterm CoNS Citrobacter, Enterobacter, Enterococcus, Listeria, other

infants S. aureus enteric and nonenteric gram-negative bacilli,
(GA <34 Pseudomonas, Salmonella, Serratia, viridans
E. coli
weeks) streptococci
Klebsiella
GBS
Pathogens based on source of infection
Meningitis GBS CoNS, Enterococcus, Listeria, N. meningitides,

E. coli nontypeable H. influenzae, S. aureus, S. pneumoniae,
Other gram- other streptococci (groups A, C, or G and viridans
negative streptococci)
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,

infection Δ Proteus
Additional pathogens seen in the NICU setting – CoNS,
S. aureus
Skin and soft S. aureus

tissue GBS
infection
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 <72 hours after birth and late onset as ≥72 hours. However, some
experts use <7 days versus ≥7 days, respectively, for these definitions. 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 12.0
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, 8 th 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
UpToDate's 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, Page e20191881, 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, Page e20191881, Copyright ©
2019 by the AAP.
Characteristics of cerebrospinal fluid in term and preterm neonates

without bacterial meningitis
Mean Mean protein Mean glucose

ANC/mm 3 or
WBC/mm 3 (mg/dL) (mg/dL)
Age percent PMNs
(range or 95 th (range or (range or
(range)
percentile) ±SD) ±SD)
Term neonates evaluated in the nursery setting
0 to 24 hours 5 (0 to 90) 3/mm 3 (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 setting Δ
0 to 28 days 5.5 (95 th 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 5 (0 to 44) 8% (0 to 66) 148 (54 to 370) 67 (33 to 217)

days
(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 (<72 hours) Ampicillin and an aminoglycoside (typically

gentamicin)*
Late onset (≥72 hours) – Admitted from the Preferred regimen – Ampicillin and an
community aminoglycoside (typically gentamicin)*
Alternative – Ampicillin and an expanded-

spectrum cephalosporin (eg, ceftazidime,
cefepime, or cefotaxime [where available])
Late onset (≥72 hours) – Hospitalized since Vancomycin or nafcillin/oxacillin ¶ , and

birth
An aminoglycoside (typically gentamicin)*
Special circumstances:
Suspected meningitis (eg, CSF Same as above except substitute an expanded-

pleocytosis) spectrum cephalosporin (eg, ceftazidime,
cefepime, or cefotaxime [where available]) for
the aminoglycoside Δ
Suspected pneumonia Ampicillin and an aminoglycoside (typically

gentamicin)*
Alternatives:
Ampicillin and expanded-spectrum
cephalosporin, or
Vancomycin and expanded-spectrum
cephalosporin, or
Vancomycin and an aminoglycoside
(typically gentamicin)*
Suspected infection of skin, umbilicus, Vancomycin and an aminoglycoside (typically

soft tissues, joints, or bones (S. aureus is a gentamicin)*, or
likely pathogen)
Vancomycin, nafcillin, and an aminoglycoside
(typically gentamicin)*, or
Vancomycin and an expanded-spectrum

cephalosporin (eg, ceftazidime, cefepime, or
cefotaxime [where available])
Suspected intravascular catheter-related Vancomycin and an aminoglycoside (typically

infection gentamicin)*
Suspected infection due to organisms Ampicillin, an aminoglycoside (typically

found in the gastrointestinal tract (eg, gentamicin)*, and clindamycin
anaerobic bacteria)
Alternatives:
Ampicillin, an aminoglycoside (typically

gentamicin)*, and metronidazole or
Piperacillin-tazobactam and an
aminoglycoside (typically 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 Oxacillin/nafcillin or cefazolin
MRSA Vancomycin
Coagulase-negative staphylococci Vancomycin
This table summarizes our suggested antibiotic regimens for empiric and pathogen-specific
therapy for neonatal sepsis. The initial choice of empiric therapy depends on the neonate's age,
likely pathogens, and presence of an apparent source of infection (eg, skin, joint, or bone
involvement). Local antibiotic susceptibility patterns should also be considered.
CSF: cerebrospinal fluid; E. coli: Escherichia coli; ESBL: extended-spectrum beta-lactamase; L.

monocytogenes: Listeria monocytogenes; MSSA: methicillin-susceptible Staphylococcus aureus;
MRSA: methicillin-resistant Staphylococcus aureus.
* In centers with a high prevalence of gentamicin resistance among gram-negative isolates, an

alternative aminoglycoside (eg, amikacin) may be preferred. Refer to UpToDate's topics on
neonatal sepsis for additional details.
¶ Nafcillin or oxacillin can be used in the empiric regimen in lieu of vancomycin if the neonate is
not critically ill and has a recent negative MRSA screening test.
Δ 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.
Differential diagnosis of neonatal sepsis
Diagnosis Distinguishing features Diagnostic tests
Other systemic neonatal infections
Viral infections:
HSV Mucocutaneous vesicles, CSF HSV PCR; viral culture

pleocytosis, elevated CSF
protein, thrombocytopenia,
hepatitis
Enteroviruses Fulminant systemic disease, EV PCR

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

on palms and soles CDC)
CMV Thrombocytopenia, CMV PCR; viral culture

periventricular intracranial
calcifications, microcephaly,
sensorineural hearing loss,
chorioretinitis
Influenza Respiratory symptoms, Influenza PCR, rapid molecular

rhinorrhea, gastrointestinal assay, or antigen detection
symptoms test
RSV Respiratory symptoms, RSV PCR or antigen detection

rhinorrhea, cough, apnea, test
pneumonia
SARS-CoV-2 Respiratory symptoms, cough, SARS-CoV-2 PCR or antigen

tachypnea, gastrointestinal detection test
symptoms
Spirochetal infections:
Syphilis Skeletal abnormalities RPR or VDRL

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

jaundice 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

hemorrhage) focal neurologic findings or studies
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; lung volumes, mild
symptoms usually resolve cardiomegaly, prominent
within 24 hours vascular markings, fluid in the
interlobar fissures, and pleural
effusions
Respiratory distress Most common in preterm CXR findings include low lung
syndrome infants; rare in term infants; volume and diffuse
onset of symptoms within first reticulogranular ground glass
few hours after delivery, appearance with air
progressively worsens over bronchograms
first 48 hours of life
Meconium aspiration History of meconium-stained Initial CXR may show streaky,

amniotic fluid; respiratory linear densities; as the disease
distress occurs immediately progresses, the lungs may
after birth
appear hyperinflated with

diffuse patchy densities
Pneumothorax Asymmetric chest rise, CXR will usually detect

decreased breath sounds on symptomatic pneumothoraces
affected side; hypotension (in
cases of tension
pneumothorax)
Congenital anomalies Often occur with other CDH is often diagnosed by

(including tracheal- congenital anomalies routine antenatal ultrasound
esophageal fistula, choanal including VACTERL and screening; postnatal CXR
atresia, and diaphragmatic CHARGE associations; choanal shows herniation of
hernia) atresia is characterized by abdominal contents into
noisy labored breathing while hemithorax; TEF is diagnosed
feeding with upper gastrointestinal
series and/or bronchoscopy
Cardiac arrhythmias (eg, Abrupt onset and termination Abnormal ECG

supraventricular of rapid heart rate
tachycardia)
Congenital heart disease Infants with ductal-dependent Abnormal pulse oximetry

lesions may initially lack screen; abnormal
symptoms then develop echocardiography
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 Abnormal blood glucose level

large 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

hemorrhage) focal neurologic findings or studies
seizures
Congenital CNS Abnormal head circumference Abnormal neuroimaging

malformations (eg, studies
hydrocephalus)
Inborn errors of Otherwise unexplained acid- Positive newborn screen for

metabolism base disorders, inborn errors of metabolism
hyperammonemia,
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;
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; RPR: rapid plasma reagin; VDRL:
venereal disease research laboratory; CNS: central nervous system; T4: thyroxine; TSH:
thyrotropin; CXR: chest radiograph; 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; CDH: congenital diaphragmatic hernia; 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,
7 th ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010.

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7/3/23, 19:28 Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates - UpToDate

Official reprint from UpToDate®

Clinical features, evaluation, and diagnosis of sepsis in

Other related topics include:

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

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

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

• Early-onset sepsis (EOS) is defined as the onset of symptoms before 72 hours of

The pathogenesis differs based on the timing of onset:

● Early-onset sepsis (EOS) – EOS is usually due to vertical transmission by ascending

● Late-onset sepsis (LOS) – LOS can be acquired by the following mechanisms:

Metabolic factors including hypoxia, acidosis, hypothermia, and inherited metabolic

Rates of neonatal sepsis increase with decreasing gestational age:

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

● Enterococcus, a commonly encountered pathogen among preterm neonates, is a rare

● Other gram-negative bacteria (including Klebsiella, Enterobacter, and Citrobacter spp)

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

• Intrapartum fetal tachycardia, which may be due to intra-amniotic infection (see

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

• Low 5- or 10-minute Apgar score, particularly if concerning findings persist (see

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

● Cardiorespiratory symptoms – Respiratory and cardiocirculatory symptoms are

Apnea is less common, occurring in 30 to 40 percent of cases, and is more likely in

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 presentation — The evaluation of a neonate with suspected EOS (onset within

Symptomatic neonates — Neonates with signs and symptoms of EOS ( table 2) should

The evaluation includes:

● Blood culture. (See 'Blood culture' below.)

● Lumbar puncture (LP) – Practice has shifted regarding performing LP in neonates

LP is not necessary in well-appearing newborns undergoing evaluation for EOS based

● Chest radiograph if there are respiratory findings.

Well-appearing neonates — Well-appearing newborns with identified risk factors for EOS,

Late-onset presentation — Neonates presenting with signs and symptoms at ≥72 hours of

The diagnostic evaluation includes all of the following:

● Blood culture (see 'Blood culture' below)

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

● Concerning symptoms, including temperature instability or respiratory,

● Positive blood, urine, or CSF culture

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

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

● Time to positivity – Automated systems for continuous monitoring of blood cultures

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

Lumbar puncture — Specific clinical signs of meningitis (eg, bulging fontanelle, nuchal

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

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

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

Further research aimed at better understanding the neonatal inflammatory response to

This was demonstrated in a retrospective study of 2785 newborns who underwent

Culture-proven sepsis — The isolation of pathogenic bacteria from a blood culture is the

A composite of observational assessment and serial laboratory testing is typically used to

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS