146: SEPSIS 1175

146 Sepsis
Neonatal sepsis is a clinical syndrome of systemic illness accompanied by bacteremia occurring
in the first month of life. It can be classified into 2 relatively distinct syndromes based on the age
of presentation: early-onset and late-onset sepsis. These 2 entities will be discussed separately.

NEONATAL EARLY ONSET SEPSIS

I. Definition. Early-onset sepsis (EOS) is defined by the Centers for Disease Control and
Prevention (CDC) as blood and/or cerebrospinal fluid (CSF) culture–proven infection
occurring in the newborn at <7 days of age. For the continuously hospitalized very
low birthweight (VLBW; <1500 g) infant, EOS is defined as culture-proven infection
occurring at <72 hours of age.
II. Incidence. The overall incidence of EOS in the United States is estimated at 0.77 to
0.98 per 1000 live births. Incidence is strongly influenced by gestational age (GA) at
birth. Among infants born at ≥37 weeks’ gestation, the incidence is around 0.53 per
1000 live births, whereas in the preterm population, the incidence is 3.7 per 1000 live
births (7 times higher), and among VLBW infants, it is approximately 11 per 1000 live
births (20 times higher).
III. Pathophysiology 
A. Infants usually present with a multisystem, sometimes fulminant, illness with
prominent respiratory symptoms. Typically, the infant has acquired the organ-
ism during the antepartum or intrapartum period from the maternal genital tract.
Several infectious agents, notably treponemes, viruses (eg, herpes simplex virus,
enteroviruses, and parechoviruses), Listeria, and probably Candida, can be acquired
transplacentally via hematogenous routes. Acquisition of other organisms is asso-
ciated with the birth process. With rupture of membranes, vaginal flora or other
bacterial pathogens may ascend to reach the amniotic fluid and the fetus. Cho-
rioamnionitis develops, leading to fetal colonization and infection. Aspiration of
infected amniotic fluid by the fetus or neonate may play a role in the resultant
respiratory symptoms. Finally, the infant may be exposed to vaginal flora as it passes
through the birth canal. The primary sites of colonization tend to be the skin, naso-
pharynx, oropharynx, conjunctiva, and umbilical cord. Trauma to these mucosal
surfaces may lead to infection. The disease may present suddenly with a fulminant
course that can progress rapidly to septic shock and death.
B. Microbiology. The principal pathogens involved in EOS have tended to change
with time. Before 1965, Staphylococcus aureus and Escherichia coli used to be the
most commonly isolated organisms. In the late 1960s and early 1970s, group B
Streptococcus (GBS) emerged as the most common microorganism. Currently,
most centers continue to report GBS as the most common microorganism, even
though the incidence has decreased considerably after the widespread adoption of
universal antenatal screening for GBS colonization at 35 to 37 weeks’ gestation and
intrapartum antibiotic prophylaxis (IAP) with penicillin or ampicillin for colonized
women. The incidence of EOS secondary to GBS decreased from 1.7 per 1000
live births in 1993 to 0.22 per 1000 in 2016 (>85% reduction). The second most
common bacteria are gram-negative enteric organisms, especially E coli. An increase
in the incidence of E coli has been noted in EOS in VLBW infants to the extent that
E coli is currently the predominant microorganism in this group of patients. GBS
and E coli account for two-thirds of all cases of EOS. Other pathogens causing
EOS include Listeria monocytogenes, S aureus, enterococci, other gram-negative
bacteria (Klebsiella, Citrobacter, Serratia, and Enterobacter), anaerobes (especially
Bacteroides fraglis), Haemophilus influenzae, and Streptococcus pneumoniae.
1176 INFECTIOUS DISEASES

IV. Risk factors for neonatal early-onset sepsis 

A. Prematurity and low birthweight. Prematurity (especially if <35 weeks’ gestation)
is the single most significant factor correlated with sepsis. The risk increases in
proportion to the decrease in birthweight and GA.
B. Rupture of membranes ≥18 hours. The risk for proven sepsis increases 10-fold.
C. Maternal peripartum infection. Infections such as chorioamnionitis manifesting
as maternal fever, urinary tract infection (UTI) especially GBS bacteriuria,
rectovaginal colonization with GBS, and perineal colonization with E coli are
well-recognized risk factors for EOS. Chorioamnionitis is an imprecise and
heterogeneous disorder; the National Institute of Child Health and Human
Development (NICHD) convened a group of experts in 2015 to a workshop that
issued evidence-based recommendations with regard to this issue. The group
proposed to replace the term chorioamnionitis with a more general descriptive
term: “intrauterine inflammation or infection or both,” abbreviated as “triple I.”
However, this terminology has not been widely accepted yet. The American College
of Obstetricians and Gynecologists (ACOG) endorsed the recommendations of
the NICHD workshop but chose to use the term “intraamniotic infection” instead.
D. Previous delivery of a neonate with group B streptococcal disease. 
E. Fetal and intrapartum distress. Infants who had intrapartum fetal tachycardia,
meconium-stained amniotic fluid, were born by traumatic delivery, or were severely
depressed at birth and required intubation and resuscitation are either infected in
utero or at significant risk for EOS.
F. Multiple gestation. 
G. Metabolic factors. Hypoxia, acidosis, inherited metabolic disorders (eg, galacto-
semia predisposing to E coli sepsis), and immune defects (eg, asplenia) are factors
that predispose to, as well as increase the severity of, sepsis.
H. Other factors. Males are affected 4 times more often than females, and the possibil-
ity of a sex-linked genetic basis for host susceptibility is postulated. Black African
descent is an independent risk factor for EOS with GBS. Reasons for the dispropor-
tionately high disease burden among black populations cannot be fully explained
by prematurity or socioeconomic status. However, Black African descent is known
to be associated with higher rates of GBS colonization.
V. Clinical presentation of neonatal early-onset sepsis. Because the initial diagnosis of
sepsis is, by necessity, a clinical one, it is crucial to begin treatment before the results
of cultures are available. Clinical signs and symptoms of sepsis are nonspecific, and the
differential diagnosis is broad. Some signs are subtle or insidious, and therefore, a high
index of suspicion is required to identify and evaluate infected neonates. Clinical signs
and symptoms most often mentioned include the following:
A. Temperature irregularity. Hypothermia is more common than fever as a presenting
sign for bacterial sepsis in premature infants. Hyperthermia is more common in full-
term infants beyond the first 24 hours of life and if viral agents (eg, herpes) are involved.
B. Change in behavior. Lethargy, irritability, seizures, or change in tone.
C. Skin.  Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae, rashes,
sclerema, and jaundice singularly or in combinations are known signs of sepsis.
D. Cardiopulmonary. Tachypnea, respiratory distress (grunting, flaring, and retrac-
tions), apnea within the first 24 hours of birth, tachycardia, and hypotension singu-
larly or in combinations should suggest sepsis. Hypotension tends to be a late sign.
E. Metabolic. Metabolic findings include hyperkalemia, hyponatremia, hyperglyce-
mia, or metabolic acidosis. There is no evidence that hypoglycemia occurring in
isolation is a risk factor or manifestation of EOS.
VI. Diagnosis 
A. Differential diagnosis.  Because signs and symptoms of neonatal sepsis are
nonspecific, noninfectious etiologies need to be considered. If the infant is presenting
with respiratory symptoms, respiratory distress syndrome, transient tachypnea of the
newborn, meconium aspiration, and aspiration pneumonia are considered. If the
146: SEPSIS 1177

infant is showing central nervous system (CNS) symptoms, then meningitis, intracranial
hemorrhage, drug withdrawal, and inborn errors of metabolism are considered.
B. Laboratory studies 
1. Cultures.  Blood and other normally sterile body fluids (eg, tracheal aspi-
rate and CSF) should be obtained for culture. Body surface cultures are not
recommended.
a. Blood cultures. Modern, computer-assisted automated blood culture systems use
optimized enriched culture media with antimicrobial neutralization properties;
they provide continuous-read detection and are able to identify up to 94% to
96% of all microorganisms by 36 hours of incubation. Results may vary because
of a number of factors, including maternal antibiotics administered before birth,
organisms that are difficult to grow and isolate (ie, anaerobes), and sampling
error with small sample volumes (the minimum volume for blood culture is
1 mL). The concerns about low-level bacteremia and the effect of intrapartum
antibiotic administration are not substantiated as these systems have been
shown to reliably detect bacteremia at a level of 1 to 10 colony-forming units
per mL if a minimum blood volume of 1 mL is inoculated. Additionally, several
studies have reported no effect of intrapartum antibiotic therapy on time to
positivity since the culture media contains antimicrobial neutralization elements
that efficiently neutralize β-lactam antibiotic agents as well as gentamicin. One
aerobic blood culture is typically obtained in cases of EOS, however, the use of 2
separate culture bottles (1 aerobic and 1 anaerobic) may provide the opportunity
to determine if commensal species are true infections by comparing growth in
the 2 cultures. In some clinical situations where the infant is critically ill, it may
be appropriate to treat for “presumed” sepsis despite negative cultures.
b. Lumbar puncture. Some controversy currently exists regarding whether a
lumbar puncture (LP) is needed in asymptomatic newborns being worked up
for presumptive EOS. Many institutions perform LPs only on infants who are
clinically ill, infants who have CNS symptoms such as apnea or seizures, or
in cases of documented positive blood cultures or if the decision is made to
extend antibiotics beyond 48 hours for presumptive clinical sepsis.
c. Urine cultures. In neonates <24 hours of age, a sterile urine specimen is not
recommended given that the occurrence of UTIs is exceedingly rare in this
age group.
d. Tracheal cultures may be obtained shortly after intubation (within 3 hours)
in ill neonates with a clinical picture suggestive of early-onset pneumonia or
if the mother developed intraamniotic infection with overwhelming EOS of
the newborn. Tracheal aspirates done after several hours or days of intubation
are of limited value.
2. Gram stain. Gram staining is especially helpful for the study of CSF. Gram-
stained smears and cultures of amniotic fluid are helpful in diagnosing intraam-
niotic infection. A Gram stain of tracheal aspirate can show the infecting
microorganism in EOS/pneumonia.
3. Molecular testing. Molecular methods for detection of neonatal sepsis in blood
include polymerase chain reaction (PCR) and DNA microarray–based meth-
ods. Most of these tests hold the promise of rapid detection directly from blood
without prior culture combined with high sensitivity and specificity in relation
to cultures and with using small volume of blood. A recent Cochrane review
that evaluated 35 studies found a summary estimate of sensitivity of 0.90 and
specificity of 0.93 and concluded that molecular assays have the advantage of
producing rapid results and may perform well as add-on tests.
4. Other laboratory tests 
a. Complete blood count with differential. These values alone are very non-
specific. There are reference values for total white blood cell (WBC) count
and absolute neutrophil counts as a function of postnatal age in hours
1178 INFECTIOUS DISEASES

(they peak during the first 12–14 hours of age; see Chapter 78, particularly
Tables 78–1 and 78–2). Neutropenia may be a significant finding with an
ominous prognosis when associated with EOS. The presence of immature
forms is more specific but still rather insensitive. Ratio of immature to total
polymorphonuclear cells (I/T) >0.2 has good predictive value, if present. The
diagnostic yield of WBC count improves when testing is done after 6 hours
of age. A variety of conditions other than sepsis can alter neutrophil counts
and ratios, including maternal hypertension and fever, neonatal asphyxia,
maternal intrapartum oxytocin, hypoglycemia, stressful labor, meconium
aspiration syndrome, pneumothorax, and even prolonged crying. Serial WBC
counts obtained several hours apart may be helpful in establishing a trend.
Decreased platelet count can be associated with EOS; however, this is usually
a late sign and very nonspecific.
b. Acute-phase reactants (APRs). APRs are complex multifunctional group
comprising complement components, coagulation proteins, protease inhibi-
tors, C-reactive protein (CRP), and others that rise in concentration in the
serum in response to inflammation. The inflammation may be secondary
to infection, trauma, or other processes of cellular destruction. An elevated
APR does not distinguish between infectious and noninfectious causes of
inflammation. Except for CRP and procalcitonin (PCT), most APRs are not
commercially available for routine testing.
i. C-reactive protein is an APR that increases the most in the presence of
inflammation caused by infection or tissue injury. The highest concentra-
tions of CRP are reported in patients with bacterial infections, whereas
moderate elevations typify chronic inflammatory conditions. Synthesis of
CPR by hepatocytes is modulated by cytokines. Interleukin (IL)-1β, IL-6,
IL-8, and tumor necrosis factor (TNF) are the most important regulators
of CRP synthesis. CRP secretion starts within 4 to 6 hours after the inflam-
matory stimulus and peaks at approximately 36 to 48 hours. The biologic
half-life of CRP is 19 hours, with a 50% reduction daily after the acute-
phase stimulus resolves. A single normal value (<1 mg/dL) cannot rule out
infection because the sampling may have preceded the rise in CRP; if a
single value is obtained, it needs to be done after 18 hours of age. If CRP is
obtained, serial determinations are better than a single value. Two normal
CRP determinations (8–24 hours after birth and 24 hours later) have been
shown to have a negative predictive value of 99.7% for proven neonatal
sepsis. CRP elevations in noninfected neonates have been seen with fetal
hypoxia, respiratory distress syndrome (RDS), and meconium aspiration;
after trauma/surgery; and after immunizations. Serial abnormal CRP val-
ues alone should not be used to decide whether to administer antibiotics
in the absence of a culture-confirmed infection. A false-positive rate of
8% has been found in healthy neonates. Nonetheless, CRP is a valuable
adjunct in the diagnosis of sepsis (ruling it out when serial CRPs are low),
monitoring the response to treatment, and guiding duration of treatment.
ii. Procalcitonin is a propeptide of calcitonin that is released by paren-
chymal cells in response to bacterial toxins. A recent systematic review
showed a sensitivity of 0.85 and specificity of 0.54 for detection of neo-
natal sepsis (EOS and late-onset sepsis [LOS]) at the PCT cutoff of 2.0
to 2.5 ng/mL. A recent multicenter randomized controlled trial showed
that PCT seems to have some utility in guiding the duration of antibiotic
therapy in neonates with suspected EOS. A physiologic increase in the
PCT concentration occurs within the first 24 hours of birth.
iii. Cytokines interleukin-6, interleukin-8, and tumor necrosis factor are
produced primarily by activated monocytes and macrophages and are
major mediators of the systemic response to infection. Studies have shown
that combining cytokines with CRP may be better than using CRP alone.
146: SEPSIS 1179

iv. Neutrophil surface antigens CD11, CD14, and CD64 are promising

markers of early infection that correlate well with CRP but peak earlier.
Presepsin (soluble CD14 subtype) has attracted recent attention because
of its utility as a sepsis marker in adults. Preliminary studies in neonates
have shown that most variables commonly affecting CRP and PCT values
do not affect presepsin levels, which suggests that presepsin could become
an effective sepsis marker in neonates.
C. Imaging studies. Chest radiograph should be obtained in cases with respiratory
symptoms, although it is often impossible to distinguish GBS or Listeria pneumonia
from uncomplicated RDS. One distinguishing feature is the presence of pleural
effusion, which occurs in 67% of cases of pneumonia.
D. Other studies. Examination of the placenta and fetal membranes may disclose evi-
dence of chorioamnionitis and thus an increased potential for neonatal infection.
VII. Management. Isolation precautions for all infectious diseases, including maternal and
neonatal precautions, breast feeding, and visiting issues, can be found in Appendix F.
Chapter 78 (on call problem “Post-delivery Antibiotics”) discusses which infants
should be considered for antibiotics.
A. Prevention: group B Streptococcus prophylaxis. Because of the widespread use of
IAP, EOS secondary to GBS has been reduced by >85%. Fortunately, GBS preven-
tion efforts have not led to an increasing burden of early-onset E coli infections.
Approximately 20% to 30% of pregnant women are colonized with GBS in the
vaginal or rectal area. Consensus guidelines regarding management of GBS were
published by the CDC in 1996 and were later revised in 2002 and in 2010. In 2017,
representatives from the CDC, AAP, ACOG, and other stakeholder organizations
agreed to review and revise the 2010 GBS guidelines. It was decided that the AAP
would revise neonatal care recommendations and ACOG would revise obstetric
care guidelines. These separate but congruent clinical reports were published in
July 2019 and replaced the CDC 2010 GBS perinatal guidelines. They recommend
that all pregnant women should be screened at 36 0/7 to 37 6/7 weeks’ gestation
for vaginal and rectal GBS colonization. At the time of labor or rupture of mem-
branes, IAP should be given to all pregnant women identified as GBS carriers.
Women with GBS isolated from the urine (GBS bacteriuria, any colony count)
during their current pregnancy should receive IAP because such women usually
are heavily colonized with GBS and are at increased risk of delivering an infant with
EOS. Women who have previously given birth to an infant with invasive GBS
disease should receive IAP as well. Additionally, women who were GBS colonized
during a previous pregnancy have a 50% likelihood of GBS carriage in the cur-
rent pregnancy, therefore, ACOG guidelines recommend that if a woman with
unknown GBS status presents in labor and is known to have had GBS colonization
in a previous pregnancy, IAP should be considered for such woman. Penicillin
is the drug of choice, but ampicillin is an acceptable alternative. First generation
cephalosporins (ie, cefazolin) are recommended for women whose reported peni-
cillin allergy indicates a low risk of anaphylaxis or is of uncertain severity. Penicillin
allergy skin testing, if available, is safe during pregnancy and can be recommended
to “penicillin-allergic” women to ascertain their true risk of anaphylaxis. Clindamy-
cin is the recommended alternative to penicillin only if the GBS isolate is known to
be susceptible to clindamycin. Vancomycin is used when there is a high-risk penicil-
lin allergy and when GBS isolate is not susceptible to clindamycin. The risk-based
approach is not acceptable except for circumstances in which screening results are
not available before labor and delivery. In these circumstances, IAP should be given
to women <37 weeks’ gestation, those with rupture of membranes ≥18 hours, and
women who have a fever ≥38°C (100.4°F). Women with GBS colonization in one
pregnancy have an estimated 50% risk of colonization in a subsequent pregnancy,
therefore GBS IAP may be considered for such women. The guidelines recognize the
availability of commercial nucleic acid amplification tests (NAAT) such as PCR
for rapid detection of GBS. If available, NAAT intrapartum rectovaginal testing can
1180 INFECTIOUS DISEASES

be performed on women with unknown GBS status and no intrapartum GBS risk
factors. IAP should be given if the NAAT testing returns positive or an intrapartum
risk factor develops regardless of NAAT results. In addition, the guidelines specifi-
cally addressed threatened preterm labor (PTL) and preterm prelabor rupture of
membranes (pPROM) with detailed algorithms. Briefly, women with threatened
PTL or pPROM should be screened for GBS colonization on admission unless a GBS
culture was obtained within the preceding 5 weeks. In both of these situations, women
should receive GBS prophylaxis (typically for 48 hours) unless the screening results
are negative. The recommendations also provide clarification on optimal GBS cultur-
ing methods. On the neonatal side, the GBS guidelines (published by AAP) review the
epidemiology of neonatal GBS disease and provide specific algorithms for neonatal
management based on risk assessment and gestational age (see next sections).
B. Neonatal risk assessment for infants born at ≥35 weeks’ gestation. The AAP
report acknowledges and endorses 3 commonly used approaches to risk assessment
among infants born at ≥35 weeks’ gestation as follows:
1. Categorical risk assessment. This approach uses risk factor (mainly maternal
intrapartum fever–oral temperature >38°C) to identify infants at increased
risk for EOS due to GBS (Figure 146–1A). Different versions of this approach

A B C
Categorical Risk Assessment Neonatal Early-Onset Enhanced Observation
Sepsis Calculator

Yes Blood culturesa Yes Blood culturesa

https://neonatalsepsiscalculator.kaiserpermanente.org

Signs of Predictor Scenario Signs of

clinical illness Empiric clinical illness Empiric
Incidence of
antibiotics Early–Onset antibiotics
Yes
Sepsis ? No
Gestational weeks
age ?
Maternal Serial physical
Maternal days Yes examination
Yes Blood culturesa intrapartum
intrapartum and vital sign
Empiric
Highest Fahrenheit temperature
temperature maternal
for 36–48 hours
antibiotics antepartum ≥38°C (100.4°F)
≥38°C (100.4°F) temperature
? or inadequate Blood culturesa
indicated GBS and empiric
Yes ROM
(Hours) ? IAP? antibiotics if
Maternal No infant develops
GBS IAP No GBS status
Negative
Routine ? signs of clinical
indicated for Positive
Routine illness
newborn care
mother? Unknown
newborn care
Yes Type of
Broad spectrum
Clinical intrapartum
antibiotics
antibiotics > 4 hrs prior to
birth
No observation ?
Adequate GBS
for 36–48 Broad spectrum
IAPb given? antibiotics 2-3.9 hrs prior
hours to birth

Yes after birth GBS specific antibiotics >

2 hrs prior to birth

No antibiotics or any
Routine antibiotics < 2 hrs prior
to birth
newborn care

FIGURE 146–1. Options for EOS risk assessment among infants born ≥35 weeks’ gestation.
(A) Categorical risk assessment. (B) Neonatal Early-Onset Sepsis Calculator. (The screenshot
of the Neonatal Early-Onset Sepsis Calculator [https://neonatalsepsiscalculator.kaiserpermanente
.org/] was used with permission from Kaiser-Permanente Division of Research.) (C) Enhanced
observation. aConsider lumbar puncture and CSF culture before initiation of empiric
antibiotics for infants who are at the highest risk of infection, especially those with critical
illness. Lumbar puncture should not be performed if the infant’s clinical condition would be
compromised, and antibiotics should be administered promptly and not deferred because
of procedure delays. bAdequate GBS IAP is defined as the administration of penicillin G,
ampicillin, or cefazolin ≥4 hours before delivery. (Reproduced with permission from Puopolo KM,
Lynfield R, Cummings JJ, et al: Management of Infants at Risk for Group B Streptococcal Disease,
Pediatrics. 2019 Aug;144(2). pii: e20191881.)
146: SEPSIS 1181

have been published previously including the algorithm published by CDC in

2010. For the purpose of categorical risk assessment, maternal intrapartum
temperature >38°C is used as a surrogate for intraamniotic infection (called
chorioamnionitis in the 2010 CDC algorithm). The administration of penicillin
G, ampicillin, or cefazolin >4 hours before delivery is considered adequate GBS
IAP; other antibiotics or other durations of treatment <4 hours are considered
inadequate for this approach. It has been recognized that the risk of EOS is highly
variable when maternal fever (any degree) is used alone as the principal cat-
egorical risk. Other important factors that modify the risk substantially include
gestational age, duration of ROM, and timing and content of administered intra-
partum antibiotics. Adopting this approach may result in many relatively low
risk infants receiving empirical antibiotic treatment unnecessarily, especially if
their only risk is exposure to low-grade maternal fever.
2. Multivariate risk assessment (the Neonatal Early-Onset Sepsis Calculator): 
Multivariate risk assessment integrates the individual infant’s combination of
objective quantifiable risk factors and his/her clinical examination to estimate
the individual infant’s risk of EOS (including EOS secondary to GBS). Predictive
models based on gestational age at birth (weeks and days), highest maternal
intrapartum temperature (centigrade or Fahrenheit), maternal GBS colonization
status (positive, negative, uncertain), duration of ROM (hours), and type and
duration of intrapartum antibiotic therapies (1 of 4 categories) have been
developed and validated. The models are available as web-based Neonatal
Early-Onset Sepsis Calculator (Figure 146–1B) (neonatalsepsiscalculator
.kaiserpermanente.org). The calculator begins with the previous probability of
EOS (typically of 0.5/1000 in the United States, unless local incidence of EOS
is known to differ). When using the calculator, only penicillin, ampicillin, or
cefazolin should be considered as “GBS-specific antibiotics.” The administration
of clindamycin or vancomycin alone for intrapartum GBS prophylaxis for any
duration is currently recommended to be entered as “no antibiotics.” Entering
the data listed above in the calculator produces risk estimate of EOS per 1000
births and recommends further action based on infant’s examination ranging
from enhanced clinical observation to blood culture and empirical antibiotic
therapy. Using the original dataset, if the hypothetical risk of sepsis ranged from
0.65 to 1.54 per 1000 live births (based solely on objective risk factors), 823 well-
appearing neonates born to women with maternal fever/possible intraamniotic
infection would need treatment to capture the one truly infected neonate (the
number needed to treat). Such newborns account for 11% of all live births. For
example, if a well-appearing newborn infant is born at 39 2/7 weeks’ gestation
to a GBS positive mother with maximum intrapartum temperature of 38.5°C
(called by obstetricians as chorioamnionitis), with ROM for 18 hours and IAP
with Penicillin G, one dose 3 hours prior to delivery, this infant’s sepsis risk score
is calculated at 1.13. The management of the infant in this scenario would be
different if categorical risk assessment is used (blood culture followed by empirical
antibiotics) compared to Neonatal Sepsis Calculator (no culture, no antibiotics;
vitals every 4 hours for 24 hours). Several retrospective and prospective studies
have demonstrated the utility of the sepsis calculator in substantially reducing
laboratory testing and exposure to antimicrobial agents (compared to categorical
risk strategy) in populations of well-appearing neonates with gestational age
≥35 weeks without missing EOS, provided that these neonates receive continued
observation for 48 hours after birth. Centers that opt for this approach will need
to develop a structured method for close clinical observation of infants at specific
levels of estimated risk.
3. Risk assessment based on clinical condition (enhanced observation): This
approach relies on clinical signs of illness to identify infants with EOS
(including that secondary to GBS) regardless of neonatal or maternal
1182 INFECTIOUS DISEASES

risk factors (Figure 146–1C). Infants who appear ill at birth and those
who develop signs of illness over the first 48 hours after birth are treated
empirically with antibiotic agents (after blood culture is obtained). Among
term infants, “good clinical condition” at birth is associated with a reduction
in risk for EOS of approximately 60% to 70%. Researchers at 1 center in Italy
reported a cohort of 7628 term infants who were managed with a categorical
approach to risk identification and compared the outcomes with a cohort of
7611 infants who were managed with serial physical examinations every 4 to
6 hours through 48 hours of age. Significant decreases in the use of laboratory
tests, blood cultures, and empirical antibiotic agents were observed in the
second cohort. Two infants who developed EOS in the second cohort were
identified as they developed signs of illness. This approach is embraced by
the NICHD workshop on chorioamnionitis. Centers that adopt this approach
need to establish processes to ensure serial, structured, documented physical
assessments and develop clear criteria for additional evaluation and empirical
antibiotic administration. Physicians and families must understand that the
identification of initially well-appearing infants who develop clinical illness is
not a failure of care, but rather an anticipated outcome of this approach to EOS
(including EOS due to GBS). Additionally, it may be reasonable to consider
supplementing the structured clinical examination with a limited evaluation
(eg, CBC, CRP) at 6 hours of age.
The AAP guidelines stop short of recommending one approach over
the other. Instead, they recommend that birth centers consider the devel-
opment of locally tailored, documented guidelines for EOS risk assessment
and clinical management. They also recommend ongoing surveillance once
guidelines are implemented.
C. Neonatal risk assessment for infants born at ≤ 34 6/7 weeks’ gestation. The AAP
report on GBS addresses infants born at ≤34 6/7 weeks’ gestation at risk for GBS
in a similar fashion to infants at risk from all other causes of EOS. It indicates that
those infants can be categorized by level of risk for EOS by the circumstances of
their preterm birth as follows (Figure 146–2):
1. Preterm infants at highest risk for EOS.  Infants born preterm because of
maternal cervical incompetence, preterm labor, pPROM, clinical concern for
intraamniotic infection, and/or acute onset of unexplained nonreassuring fetal
status are at the highest risk for EOS. Such neonates should undergo EOS evalu-
ation with a blood culture and empiric antibiotic treatment.
2. Preterm infants at lowest risk for EOS. Preterm infants at lowest risk for EOS
(including EOS due to GBS) are those born under circumstances that include all
of these criteria: (1) maternal and/or fetal indications for preterm birth (such as
maternal preeclampsia or other noninfectious medical illness, placental insuffi-
ciency, or fetal growth restriction), (2) birth by cesarean delivery, and (3) absence
of labor, attempts to induce labor, or any ROM before delivery. Acceptable initial
approaches to these infants include (1) no laboratory evaluation and no empiri-
cal antibiotic therapy or (2) blood culture and clinical monitoring. For infants
who do not improve after initial stabilization and/or those who have severe
systemic instability, the administration of empirical antibiotics may be reason-
able but is not mandatory.
3. Preterm infants delivered for maternal and/or fetal indications but who are
ultimately born by vaginal or cesarean delivery after efforts to induce labor
and/or with ROM before delivery. Those infants are subject to factors associ-
ated with the pathogenesis of EOS due to GBS or other bacteria. If the mother
has an indication for GBS prophylaxis and appropriate treatment (penicillin,
ampicillin, or cefazolin >4 hours before delivery) is not given or if any other
concern for infection arises during the process of delivery, the infant should
be managed as recommended above for preterm infants at higher risk for EOS
146: SEPSIS 1183

Infant born in association Infant born by induction of Infant born by cesarean

with any of: preterm labor; No labor with or without cervical No section for maternal/fetal
prelabor ROM; or any concern ripening (resulting in either indications with ROM at
for intraamniotic infectiona vaginal or cesarean delivery) time of delivery

Yes Yes Yes

Blood culturesb Any of the following are present: Approaches included:

Empiric antibiotics
No
c no empiric antibiotic therapy

infection monitoring

cardiovascular instability
Yes

Blood culturesb
Empiric antibiotics

FIGURE 146–2. EOS risk assessment among infants born ≤34 weeks’ gestation. aIntraamniotic
infection should be considered when a pregnant woman presents with unexplained decreased
fetal movement and/or there is sudden and unexplained poor fetal testing. bLumbar
puncture and CSF culture should be performed before initiation of empiric antibiotics for
infants who are at the highest risk of infection unless the procedure would compromise the
infant’s clinical condition. Antibiotics should be administered promptly and not deferred
because of procedural delays. cAdequate GBS IAP is defined as the administration of
penicillin G, ampicillin, or cefazolin ≥4 hours before delivery. dFor infants who do not
improve after initial stabilization and/or those who have severe systemic instability, the
administration of empiric antibiotics may be reasonable but is not mandatory. (Reproduced
with permission from Puopolo KM, Lynfield R, Cummings JJ, et al: Management of Infants at
Risk for Group B Streptococcal Disease, Pediatrics. 2019 Aug;144(2). pii: e20191881.)

(Section VII.C.1). Otherwise, an acceptable approach to these infants is close

observation for those infants who are well appearing at birth and to obtain a
blood culture and initiate antibiotic therapy for infants with respiratory and/or
cardiovascular instability after birth.
D. Empiric antibiotic therapy. Treatment for EOS is often begun before a definite
causative agent is identified. It usually consists of ampicillin and gentamicin.
(Dosages are presented in Chapter 155.) This empirical regimen covers the most
commonly encountered microorganisms, namely GBS and E coli, and has proved
to be efficacious over the years. Third-generation cephalosporins should be avoided
as an empirical therapy for EOS because they are associated with increased risk for
antibiotic resistance and invasive fungal infections. Third-generation cephalosporins
may be considered for infants suspected to have meningitis or who have renal
impairment. According to recent CDC surveillance studies, approximately 1.7% of
all E coli EOS cases were resistant to both ampicillin and gentamicin; therefore, the
empirical addition of broader spectrum antibiotics should be considered in critically
ill newborns who deteriorate despite being on ampicillin and gentamicin, or in
preterm infants exposed to prolonged antepartum maternal antibiotic treatment.
When blood cultures are sterile, antibiotic therapy should be discontinued by 36
to 48 hours of incubation, unless there is clear evidence of site-specific infection or
unexplained persistent cardiorespiratory instability. Laboratory test abnormalities
alone rarely justify prolonged empirical antibiotic administration, particularly
among preterm infants at a lower risk for EOS.
E. Continuing therapy is based on culture and sensitivity results, clinical course, and
occasionally other serial laboratory studies (eg, CRP and PCT). Monitoring for
1184 INFECTIOUS DISEASES

antibiotic toxicity is important, as is monitoring levels of aminoglycosides. When

GBS is documented as the causative agent, penicillin G is the drug of choice; however,
an aminoglycoside is often added for a few days because of documented synergism
in vitro.
F. Complications and supportive therapy 
1. Respiratory. Ensure adequate oxygenation with blood gas monitoring, and initi-
ate oxygen therapy or ventilator support if needed.
2. Cardiovascular.  Support blood pressure and perfusion to prevent shock. Use
volume expanders such as normal saline, and monitor the intake and output of
fluids. Inotropes such as dopamine or dobutamine may be needed (see Chapter 70).
3. Hematologic 
a. Disseminated intravascular coagulation. With disseminated intravascular
coagulation (DIC), one may observe generalized bleeding at puncture sites,
the gastrointestinal tract, or CNS. In the skin, large-vessel thrombosis may
cause gangrene. Laboratory parameters consistent with DIC include thrombo-
cytopenia, increased prothrombin time, and increased partial thromboplastin
time. There is an increase in fibrin split products or d-dimers. Treatment
options include fresh-frozen plasma, 10 mL/kg; vitamin K (see Chapter 155);
platelet infusion; and possible exchange transfusion (see Chapter 34).
b. Neutropenia. Multiple factors contribute to the increased susceptibility of
neonates to infection, including developmental quantitative and qualitative
neutrophil defects. Colony-stimulating factors comprise a group of cyto-
kines that are central to the hematopoiesis of blood cells, as well as to the
maintenance of homeostasis and overall immune competence. Granulocyte
colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-
stimulating factor (GM-CSF) have been used in neonates with established
sepsis associated with neutropenia, in neutropenic infants without sepsis,
and prophylactically in neonates at risk for sepsis. Limited data suggest that
colony-stimulating factor administration may reduce mortality when sys-
temic infection is accompanied by severe neutropenia. Intravenous immuno-
globulin does not appear useful either as a prophylactic agent or as an adjunct
to antibiotic therapy in serious neonatal infection.
4. Central nervous system. Implement seizure control measures using pheno-
barbital, and monitor for the syndrome of inappropriate antidiuretic hormone
(decreased urine output, hyponatremia, decreased serum osmolarity, and
increased urine specific gravity and osmolarity).
5. Metabolic. Monitor for and treat hypoglycemia or hyperglycemia. Metabolic acidosis
may accompany sepsis and is treated with bicarbonate and fluid replacement.
G. Future developments. Intensive research continues in the development of vaccines
(especially for GBS). Research is also ongoing into blocking some of the body’s own
inflammatory mediators that result in significant tissue injury, including endotoxin
inhibitors, cytokine inhibitors, nitric oxide synthetase inhibitors, and neutrophil
adhesion inhibitors.
VIII. Prognosis. With early diagnosis and treatment, most infants will recover and not have
long-term complications. However, the mortality rate is still significant for EOS, especially
in VLBW infants. For term and late preterm infants, the reported mortality is approxi-
mately 3%, whereas EOS mortality for VLBW infants is approximately 16%. Neonatal
EOS is a risk factor for long-term neurodevelopmental impairment in premature infants.

NEONATAL LATE-ONSET SEPSIS

I. Definition. Neonatal LOS is defined by the CDC as blood and/or CSF culture–proven
infection occurring in the newborn after 7 days of age caused by a postnatal acquisition
(nosocomial or community sources). For the continuously hospitalized VLBW infant,
LOS is defined as culture-proven infection occurring at >72 hours of age.
146: SEPSIS 1185

II. Incidence of neonatal late-onset sepsis. The overall incidence of primary sepsis (EOS
and LOS) is 1 to 2 per 1000 live births. The incidence of LOS in term infants is hard
to know; however, a study that looked at late preterm infants hospitalized in the first
3 months of life identified LOS in 6.3 per 1000 admissions. According to the CDC,
late-onset GBS infection rates have remained relatively stable over the past 20 years
and are not impacted by intrapartum antibiotics prophylaxis (0.32 per 1000 live births
in 2015). Incidence of LOS is much higher for VLBW infants; according to data from
the NICHD Neonatal Research Network (NICHD-NRN), the incidence is 32% and
appears to be decreasing in recent years (37% in 2005, 27% in 2012).
III. Pathophysiology of neonatal late-onset sepsis.  LOS is usually more insidious
(compared to EOS), but it can be fulminant at times. It is usually not associated with
early obstetric complications. In addition to bacteremia, these infants may have an
identifiable focus, most often meningitis in addition to sepsis. Bacteria responsible
for LOS and meningitis include those acquired after birth from the maternal genital
tract (vertical transmission) as well as organisms acquired after birth from human
contact or from contaminated equipment/environment (nosocomial). Therefore,
horizontal transmission appears to play a significant role in LOS. The reasons for
the delay in development of clinical illness, the predilection for CNS disease, and
the less severe systemic and cardiorespiratory symptoms are unclear. Transplacental
transfer of maternal antibodies (also in breastmilk) to the mother’s own vaginal flora
may play a role in determining which exposed infants become infected, especially in
the case of GBS infections. In case of nosocomial spread, the pathogenesis is related
to the underlying illness and debilitation of the infant, the flora in the neonatal
intensive care (NICU) environment, and invasive monitoring and other techniques
used in the NICU, especially the use of peripherally inserted central catheters
(PICCs). Breaks in the natural barrier function of the skin and intestine allow
opportunistic organisms to invade and overwhelm the neonate. Infants, especially
the premature, have an increased susceptibility to infection because of underlying
illnesses and immature immune defenses that are less efficient at localizing and
clearing bacterial invasion.
A. Microbiology. The pathogens that cause LOS or nosocomial sepsis tend to vary
in each nursery; however, coagulase-negative staphylococci (CONS), especially
Staphylococcus epidermidis, are the most predominant (53% of cases in NICHD-
NRN). Other microorganisms causing LOS include gram-negative rods (including
Pseudomonas, Klebsiella, Serratia, E coli, and Proteus), S aureus (both methicillin-
susceptible and methicillin-resistant), GBS, and fungal microorganisms.
B. Antibiotic resistance.  Antibiotics resistance, especially to Enterobacteriaceae
such as E coli, is an emerging problem in many NICUs. Multiple mechanisms
of resistance may be present simultaneously. Resistance resulting from produc-
tion of chromosomally encoded or plasmid-derived AmpC β-lactamases or from
plasmid-mediated extended-spectrum β-lactamases (ESBLs) occurs primarily in
E coli, Klebsiella species, and Enterobacter species but has been reported in many
other gram-negative species. Resistant gram-negative infections have been associ-
ated with nursery outbreaks, especially in VLBW infants. Organisms that produce
ESBLs typically are resistant to penicillins, cephalosporins, and monobactams and
can be resistant to aminoglycosides. Carbapenemase-producing Enterobacteriaceae
(CPE) also have emerged, especially Klebsiella pneumoniae, Pseudomonas aeru-
ginosa, and Acinetobacter species. ESBL- and carbapenemase-producing bacteria
often carry additional plasmid-borne genes that encode for high-level resistance to
aminoglycosides, fluoroquinolones, and trimethoprim-sulfamethoxazole.
IV. Risk factors of neonatal late-onset sepsis 
A. Prematurity and low birthweight. Prematurity (<37 weeks’ gestation) is the single
most significant factor correlated with sepsis. The risk increases in proportion to
the decrease in birthweight and GA (GA <25 weeks: 41%; GA 25–28 weeks: 21%;
GA 29–32 weeks: 10%). Being small for gestational age increases the risk further.
1186 INFECTIOUS DISEASES

B. Invasive procedures/devices. Intravascular catheterization (PICC and umbilical

catheters) and respiratory (endotracheal intubation) or metabolic support (total
parenteral nutrition) are important risk factors for LOS. Mechanical ventilation
and continuous positive airway pressure have been associated with an increased
risk of LOS in VLBW infants.
C. Risk factors for extended-spectrum β-lactamase infection and carbapenemase-
producing Enterobacteriaceae. Additional risk factors associated with neonatal
ESBL infection include prolonged mechanical ventilation, extended hospital stay,
use of invasive devices, and use of antimicrobial agents. Infants born to mothers
colonized with ESBL-producing E coli are themselves at an increased risk of acquir-
ing colonization with ESBL-producing E coli.
D. Other factors. Bottle feeding (as opposed to breast feeding) predisposes to infec-
tion. Black African descent has been found as an independent risk factor for GBS
sepsis (both EOS and LOS). Reasons for the disproportionately high disease burden
among black populations cannot be fully explained by prematurity or socioeco-
nomic status. NICU staff and family members are often vectors for the spread of
microorganisms, primarily as a result of improper or lack of hand washing. The
risk of infection correlates with length of stay in the NICU.
V. Clinical presentation of neonatal late-onset sepsis. Because the initial diagnosis of
sepsis is, by necessity, a clinical one, it is crucial to begin treatment before the results
of cultures are available. Clinical signs and symptoms of sepsis are nonspecific, and the
differential diagnosis is broad. Some signs are subtle or insidious, and therefore, a high
index of suspicion is required to identify and evaluate infected neonates. Clinical signs
and symptoms most often mentioned include the following:
A. Temperature irregularity. Hypothermia is more common than fever as a present-
ing sign for bacterial sepsis in premature infants. Hyperthermia is more common
in full-term infants beyond the first 24 hours of life and if viral agents (eg, herpes)
are involved.
B. Change in behavior. Lethargy, irritability, or change in tone.
C. Skin.  Poor peripheral perfusion, cyanosis, mottling, pallor, petechiae, rashes,
sclerema, and jaundice singularly or in combinations are known signs of sepsis.
D. Feeding problems. Feeding intolerance, vomiting, diarrhea, or abdominal disten-
tion with or without visible bowel loops.
E. Cardiopulmonary. Tachypnea, respiratory distress (grunting, flaring, and retrac-
tions), new onset of apnea, bradycardia and desaturation episodes (ABD [apnea,
bradycardia, desaturation] spells), tachycardia, and hypotension singularly or in
combinations should suggest sepsis. Hypotension tends to be a late sign.
  Reduced variability and transient decelerations in heart rate (HR) may be present
in the hours to days before diagnosis of LOS. These abnormal HR characteristics
(HRC) in response to systemic infection and inflammation have been character-
ized mathematically, and the resulting HRC index can be computed in real time
and displayed continuously at the bedside. Some studies suggest that monitoring
the HRC index in high-risk premature infants may result in improved outcomes
and decreased mortality (through early warning with diagnosing early sepsis and
prompt treatment with antibiotics).
F. Metabolic. Metabolic findings include hypoglycemia, hyperglycemia, or metabolic
acidosis.
G. Focal infections. These may precede or accompany LOS. Look for cellulitis, impe-
tigo, soft tissue abscesses, omphalitis, conjunctivitis, otitis media, meningitis, or
osteomyelitis.
VI. Diagnosis of neonatal late-onset sepsis 
A. Differential diagnosis. Because signs and symptoms of neonatal sepsis are nonspe-
cific, noninfectious etiologies need to be considered. If the infant is presenting with
cardiorespiratory symptoms, aspiration pneumonia, patent ductus arteriosus, or
other congenital heart diseases need to be considered. If the infant is showing CNS
146: SEPSIS 1187

symptoms, then intracranial hemorrhage, drug withdrawal, and inborn errors of

metabolism are considered. Patients with feeding intolerance and bloody stool may
have necrotizing enterocolitis (NEC), gastrointestinal perforation, or obstruction.
Some nonbacterial infections such as disseminated herpes simplex virus can be
indistinguishable from bacterial sepsis and should be considered in the differential
diagnosis, especially if the infant has fever. Postnatal cytomegalovirus (acquired
through breast milk or blood transfusion) is another agent that is increasingly being
recognized as a cause of sepsis-like illness in extremely low birth weight infants
beyond the first week of life. Other viral agents that need to be considered include
respiratory syncytial virus (RSV) and Enterovirus/Parechovirus.
B. Laboratory studies of neonatal late-onset sepsis 
1. Cultures. Blood and other normally sterile body fluids (urine, spinal fluid, and
occasionally tracheal aspirate) should be obtained for culture. Body surface cul-
tures are not recommended unless the infant has pustules or a characteristic
rash (eg, candida).
a. Blood cultures. Computer-assisted automated blood culture systems identify
up to 94% to 96% of all microorganisms by 36 to 48 hours of incubation. The
minimum volume for blood culture is 1 mL (some have suggested weight-
based criteria; 1 mL for infants weighing <1.5 kg, 2 mL for infants weighing
1.5–3 kg, and 3 mL for infants >3 kg). Two blood cultures (1 from PICC
and 1 peripheral) are recommended. In many clinical situations, infants
are treated for “presumed” sepsis despite negative cultures, if clinical and
laboratory findings are suggestive of infection and no other etiology is found
to explain the clinical deterioration.
b. Lumbar puncture. LP should be part of the routine evaluation for LOS. Men-
ingitis is likely to happen without sepsis in VLBW infants, and therefore, LP
is mandatory.
c. Urine culture must be obtained as part of evaluation for LOS. Urine specimen
should be obtained by either a suprapubic tap (see Chapter 29) or catheterized
specimen (see Chapter 30). Bag urine samples should not be used to diagnose
UTI in neonates.
d. Tracheal cultures may be considered in intubated neonates with a clinical
picture suggestive of pneumonia, especially when the quality and volume of
tracheal secretions change substantially. However, it is often hard to differ-
entiate tube colonization from true infection.
2. Gram stain of various fluids. Gram staining is especially helpful for the study
of CSF. A Gram stain of tracheal aspirate fluid may suggest an inflammatory
process if numerous WBCs, together with bacteria, are identified.
3. Molecular testing. See prior discussion under EOS of this chapter (page 1177).
4. Other laboratory tests 
a. Complete blood count with differential. See prior discussion under EOS
of this chapter. LOS is associated with both low and high WBC (<1000/mm3
and >50,000/mm3), high absolute neutrophil count (>17,670/mm3), elevated
I/T ratio (>0.2), and low platelet count (<50,000/mm3). It is also important to
note that neutropenia has been described commonly as an incidental finding
in otherwise healthy growing VLBW infants.
b. Acute-phase reactants.  See prior discussion under EOS section of this
chapter. Serial CRP determinations are helpful in ruling out infection when
normal (high negative predictive value). PCT may be better than CRP in the
diagnosis and follow-up of neonatal sepsis secondary to CONS.
C. Imaging and other studies 
1. Chest radiograph. A chest radiograph should be obtained in cases with respira-
tory symptoms, although it is often difficult to differentiate changes associated
with true bacterial pneumonia from those associated with bronchopulmonary
dysplasia, simple aspiration, or atelectasis.
1188 INFECTIOUS DISEASES

2. Urinary tract imaging. Imaging with renal ultrasound, renal scan, and possibly
voiding cystourethrogram should be considered when UTI accompanies sepsis.
VII. Management of neonatal late-onset sepsis. Isolation precautions for all infectious dis-
eases, including maternal and neonatal precautions, breast feeding, and visiting issues,
can be found in Appendix F.
A. Prevention of neonatal nosocomial late-onset sepsis.  A subset of nosocomial
sepsis is central line–associated bloodstream infections (CLABSIs). Although
primary prevention of CLABSI relies on minimizing the use of central lines, novel
technologies such as antiseptic- and antimicrobial-impregnated catheters in addition
to meticulous care during PICC insertion and maintenance are key factors in
preventing CLABSIs. Quality improvement initiatives that focus on adherence to best
practices of catheter insertion and maintenance (NICU Central Catheter Bundles)
have resulted in widespread reduction in CLABSIs across different NICUs. Some of
those bundles were adopted and disseminated through statewide collaboratives such
as the California Perinatal Quality Care Collaborative (CPQCC). Hand hygiene is the
single most important strategy for avoiding transmission of contagions in the NICU.
Fresh maternal milk contains a number of substances responsible for innate immune
and humoral responses against pathogens; therefore, promotion of breast feeding
is considered a key step in the prevention of NICU infections. Medical stewardship
of antibiotics, steroids, and H2 blockers is mandatory; indiscriminate use of these
agents has been associated with increased nosocomial sepsis. Enhancement of the
enteric microbiome composition with the possible use of probiotics may restore gut
immune function and help prevent NEC and sepsis. In a recent meta-analysis of 37
trials, probiotics were associated with a small, but statistically significant, reduction in
the risk of LOS compared with placebo or no treatment. Use of bioactive substances
with known anti-infective properties such as lactoferrin may be helpful. A recently
published Cochrane review that included 6 trials suggested that lactoferrin
supplementation to enteral feeds with or without probiotics may decrease LOS
and NEC in preterm infants. However, no recommendations can be made until
ongoing trials that enrolled >6000 preterm neonates are completed. Finally, specific
and targeted pharmacologic prophylactic interventions have been used with some
success. For example, specific antifungal prophylaxis with fluconazole has been
associated with significant reduction in invasive fungal infection; it is recommended
in NICUs that experience high rates of invasive candidiasis. However, the use of
pagibaximab, a recombinant monoclonal antibody targeting staphylococcal species,
does not appear to offer protection against gram-positive CLABSIs in the NICU.
B. Empiric antibiotic therapy. Treatment is most often begun before a definite caus-
ative agent is identified. In nosocomial sepsis, the flora of the NICU must be con-
sidered in choosing antibiotics; however, staphylococcal coverage with vancomycin
plus an aminoglycoside such as gentamicin or amikacin is usually begun. Some
NICUs use a cefazolin or nafcillin for staphylococcal coverage instead of vanco-
mycin. The empirical treatment for suspected LOS in a neonate admitted from the
community is ampicillin and gentamicin; cefotaxime can be added only when there
is a concern for meningitis. Dosages are presented in Chapter 155.
C. Continuing therapy is based on culture and sensitivity results, clinical course, and
other serial laboratory studies (eg, CRP or PCT). If an ESBL-producing organism,
such as K pneumoniae, is suspected or identified, then carbapenem is the drug
of choice (with aminoglycoside for double coverage). Of the aminoglycosides,
amikacin retains the most activity against ESBL-producing strains. An aminogly-
coside or cefepime can be used if the organism is susceptible, because cefepime
does not induce chromosomal AmpC enzymes. Monitoring for antibiotic toxicity
is important, as well as monitoring levels of aminoglycosides and vancomycin.
D. Complications and supportive therapy are reviewed under the EOS section of this
chapter (page 1184). In particular, administration of intravenous immunoglobulin
to neonates with suspected or proven LOS does not result in reduction in mortality
147: SYPHILIS 1189

during hospital stay or major disability at 2 years of age. Similarly, administration of

colony-stimulating factors, namely G-CSF and GM-CSF, does not result in reduced
mortality or better neurodevelopmental outcome at 2 and 5 years. However, there
might be a place for using G-CSF in cases of severe infection complicated by severe
neutropenia (absolute neutrophil count <500/mm3) and/or in the presence of
specific hematologic diseases causing severe neutropenia.
E. Future developments. Intensive research continues in the development of vac-
cines as well as synthetic monoclonal antibodies to the specific pathogens caus-
ing neonatal LOS. Research is also ongoing into blocking some of the body’s own
inflammatory mediators that result in significant tissue injury, including endotoxin
inhibitors, cytokine inhibitors, nitric oxide synthetase inhibitors, and neutrophil
adhesion inhibitors. Finally, recent research is showing prebiotics, probiotics, and
lactoferrin to be promising agents in the prevention of LOS and NEC.
VIII. Prognosis. Neonatal LOS remains a major cause of death in VLBW infants, with a
reported mortality rate of approximately 18%. Mortality due to gram-negative infections
is higher than that due to gram-positive infections. Risk factors for LOS mortality
include endotracheal intubation, administration of vasopressors, hypoglycemia,
thrombocytopenia, and development of NEC. VLBW infants who survive LOS are at
risk for long term neurodevelopmental impairment including cerebral palsy.

147 Syphilis
I. Definition. Syphilis is a sexually transmitted infection caused by Treponema pallidum,
which is a thin, motile spirochete that is extremely fastidious, surviving only briefly
outside the host. The Centers for Disease Control and Prevention (CDC) issued a
case definition of congenital syphilis (CS) in 2018 as follows: a condition caused by
infection in utero with T pallidum. A wide spectrum of severity exists, from inap-
parent infection to severe cases that are clinically apparent at birth. Laboratory cri-
teria for diagnosis entail demonstration of T pallidum by: (1) darkfield microscopy
of lesions, body fluids, or neonatal nasal discharge; or (2) polymerase chain reaction
(PCR) or other equivalent direct molecular methods of lesions, neonatal nasal dis-
charge, placenta, umbilical cord, or autopsy material; or (3) immunohistochemistry or
special stains (eg, silver staining) of specimens from lesions, placenta, umbilical cord,
or autopsy material. Cases are classified as confirmed (by laboratory diagnosis) or
probable. Probable CS is a condition affecting an infant whose mother had untreated
or inadequately treated syphilis at delivery, regardless of signs in the infant, or an infant
or child who has a reactive nontreponemal test for syphilis (Venereal Disease Research
Laboratory [VDRL], rapid plasma reagin [RPR], or equivalent serologic methods) and
any 1 of the following: (1) any evidence of CS on physical examination; (2) any evidence
of CS on radiographs of long bones; (3) a reactive cerebrospinal fluid (CSF) VDRL test;
(4) an elevated CSF leukocyte (white blood cell [WBC]) count or protein (without other
cause) in a nontraumatic lumbar puncture. Suggested parameters for abnormal CSF
WBC and protein values include the following: during the first 30 days of life, a CSF
WBC count of >15 WBC/mm3 or a CSF protein >120 mg/dL is abnormal; after the
first 30 days of life, a CSF WBC count of >5 WBC/mm3 or a CSF protein >40 mg/dL is
abnormal, regardless of CSF serology. Adequate treatment is defined as completion of
a penicillin-based regimen, in accordance with CDC treatment guidelines, appropriate
for stage of infection, initiated ≥30 days before delivery.