Evaluation and management of fever in the neonate and
young infant (less than three months of age)
Authors
Hannah F Smitherman, MD
Charles G Macias, MD, MPH
Section Editors
Stephen J Teach, MD, MPH
Sheldon L Kaplan, MD
Deputy Editor
James F Wiley, II, MD, MPH
Disclosures
Last literature review version 19.2: May 2011 | This topic last updated: March 17,
2011 (More)
INTRODUCTION — Although most neonates and young infants with fever have a benign
viral illness, the goal of the evaluation is to identify those children who are at high risk for
serious bacterial illness (eg, bacteremia, urinary tract infection, meningitis, bacterial
gastroenteritis, pneumonia), and who therefore require empiric antimicrobial therapy and
possibly hospitalization.
The young febrile infant may demonstrate few, if any, interpretable clues to the underlying
illness [1]. The limitations of the history and physical examination in neonates and young
infants with fever traditionally have led to an aggressive laboratory evaluation, even for
patients who were previously healthy, are well-appearing, and have no focal infection. In
addition, most of the patients have been admitted to the hospital for antibiotic treatment
pending negative cultures. This practice is expensive and can result in iatrogenic morbidity
for a substantial number of infants [2].
The evaluation of neonates and young infants younger than three months with fever is
discussed below. The definition and etiology of fever in this age group, as well as traditional
strategies for evaluating young infants with fever, are discussed elsewhere. (See "Definition
and etiology of fever in neonates and infants (less than three months of age)" and
"Strategies for the evaluation of fever in neonates and infants (less than three months of
age)".)
The evaluation of infants and children age 3 to 36 months is discussed elsewhere. In
addition, the diagnosis and treatment of specific infections, including meningitis,
pneumonia, and urinary tract infections, is discussed elsewhere. (See "Fever without a
source in children 3 to 36 months of age" and "Clinical features and diagnosis of acute
bacterial meningitis in children older than one month of age" and "Clinical features and
diagnosis of community-acquired pneumonia in children" and "Urinary tract infections in
newborns".)
HISTORY — A thorough history is an essential component of the evaluation of all neonates
and young infants with fever (T ≥38ºC or 100.4ºF). The history should address the
following clues to the etiology of the fever:

Associated symptoms (respiratory, gastrointestinal) and behaviors (feeding,
irritability, activity)

Exposures to sick contacts (siblings, babysitters, day care)

Any previous illness, or antibiotic use

Birth history, including perinatal factors that suggest an increased risk of vertically
transmitted infection such as maternal fever; the mother's group B streptococcus
status and prophylaxis; maternal history of sexually transmitted infections such as
herpes simplex virus, gonorrhea, and chlamydia; prolonged rupture of membranes,
and the infant's nursery course. (See "Management of the infant whose mother has
received group B streptococcal chemoprophylaxis" and "Neonatal herpes simplex
virus infection: Management and prevention" and "Neonatal herpes simplex virus
infection: Clinical features and diagnosis", section on 'Epidemiology and
transmission'.)
PHYSICAL EXAMINATION — The physical examination must quickly identify the illappearing infant who requires immediate resuscitation and treatment. Specific finding to
note are the following:

Abnormal vital signs, including pulse oximetry, which may be a better predictor of
pulmonary infection than respiratory rate [3,4]

Toxic appearance including characteristics such as irritability, inconsolability, poor
perfusion, poor tone, decreased activity, or lethargy

Signs of localized infection such as omphalitis, arthritis, or limb swelling and
inflammation, and skin lesions, including skin or mucus membrane lesions,
consistent with a herpetic etiology

Signs and symptoms associated with bacterial meningitis may be minimal or absent
altogether. Subtle clues include altered sleep patterns, decreased oral intake,
hyperthermia, hypothermia, or paradoxical irritability (infant more irritable when
being held than when lying still). A bulging fontanelle classically presents late in the
disease process. Other meningeal signs and symptoms gradually localize to the CNS
only as the infant matures. Nuchal rigidity is present in only 27 percent of infants
aged zero to six months with bacterial meningitis, compared with 95 percent of
patients 19 months or older [5].
LABORATORY TESTS — Studies that have included cohorts of infants younger than three
months without an obvious source of fever on physical examination have used a variety of
laboratory studies to identify infants at low risk of serious bacterial infection (SBI) [6-15].
WBC count — The white blood cell (WBC) count has been a standard part of the evaluation
in virtually all studies of fever in young infants. In most studies, low-risk criteria included a
WBC count <15,000/microL, although in one study, low risk was defined as WBC count
<20,000/microL [9], and in another, 5000 to 15,000/microL [11]. The number of bands on
differential should be no higher than 1.5 x 10(9) cells/L (1500/microL) [11]. (See
"Strategies for the evaluation of fever in neonates and infants (less than three months of
age)".)
Despite its common use, observational studies report that WBC count has poor sensitivity
and specificity for identifying bacteremia and meningitis in young infants [16,17]. For this
reason, we suggest that the decision to perform a blood culture or a lumbar puncture not be
based solely on the WBC count.
Inflammatory mediators — Preliminary evidence from small single center observational
studies suggests that elevation of procalcitonin level may be a better marker of SBI than
WBC in febrile infants [18,19].

An observational study of 234 young infants found that a cutoff value for
procalcitonin of 0.12 nanograms/mL had a sensitivity of 95 percent (95% CI 83-99
percent), a specificity of 26 percent (95% CI 20-32 percent), and a negative
predictive value of 96 percent (95% CI 85-99 percent) for serious bacterial illness
[18].

An observational study of 271 young infants found that young infants with SBI and
immunized febrile young infants had higher median procalcitonin levels than
unimmunized febrile young infants without serious bacterial infection (0.53, 0.29,
and 0.17 nanograms/mL, respectively). In this study, a cut off value of 0.12
nanograms/mL had a sensitivity of 96 percent (95% CI 83-99 percent), a specificity
of 23 percent (95% CI 18-29 percent), and a negative predictive value of 96 percent
(95% CI 86-99 percent) for detecting serious bacterial infection [19].
In most clinical settings, PCT has limited availability. In addition, questions exist regarding
the reliability of the bedside procalcitonin assay used in these studies because of variation in
results by age, type of infection, and pathogen [20]. Further study is needed to better
define the utility of procalcitonin for identifying febrile young infants (under 90 days of age)
with serious bacterial infection.
Data concerning C-reactive protein in febrile infants (less than 90 days) is more limited.
(See "Fever without a source in children 3 to 36 months of age", section on 'Inflammatory
mediators'.)
Urine examination — We recommend that a urinalysis and urine culture be obtained
because the incidence of urinary tract infection (UTI) is high among febrile young infants
[11,21,22]. (See "Epidemiology and risk factors for urinary tract infections in children".)
A negative urine dipstick or urinalysis alone does not exclude UTI; pyuria is absent on initial
urinalysis in up to 20 percent of febrile infants with pyelonephritis [23]. Thus, urine culture
should be performed on all specimens.
A urine specimen for culture should be obtained by urethral catheterization or suprapubic
aspiration, as bag collections frequently are contaminated [24]. (See "Urinary tract
infections in newborns", section on 'Urine collection' and "Urine collection techniques in
children".)
Stool examination — Not all studies of febrile neonates and young infants included
evaluation of the stool for WBCs in patients with diarrhea. One study found the presence of
≥5 WBCs per high-power field to be a predictor of occult Salmonella infection, including
bacteremia [11]. However, a Wright stain of the stool for WBCs may not be readily
available. A stool culture is suggested when there is blood and/or mucus in the stool, or for
the infant with diarrhea when a Wright stain is not available.
Lumbar puncture — We recommend that lumbar puncture always be performed in febrile
infants with the following indications (see 'Evaluation and management' below):

Age ≤28 days

Ill appearance

Diagnostic evaluation identifies a high risk for bacterial infection (see "Strategies for
the evaluation of fever in neonates and infants (less than three months of age)")

Prior to administration of empiric antibiotics

Clinically evident invasive infection (eg, cellulitis, abscess, mastitis, omphalitis,
osteomyelitis) (see "Evaluation and management of suspected methicillin-resistant
Staphylococcus aureus skin and soft tissue infections in children", section on 'Severe
SSTI')

Seizures
The cerebrospinal fluid should be sent for cell count, glucose, protein, and bacterial culture.
In addition, viral studies (viral culture, polymerase chain reaction [PCR]) should be sent if
the clinical picture suggests viral meningitis (table 1). (See "Viral meningitis: Clinical
features and diagnosis in children", section on 'CSF studies'.)
Several observational studies suggest that infants at low risk of SBI can be identified
without performing a lumbar puncture [6,7,11,13,14]. Based on these reports, some
consider lumbar puncture optional in a generally well-appearing infant who is over 28 days
of age, particularly if the infant has a low-grade fever [21].
However, the significant morbidity and mortality associated with bacterial meningitis may
outweigh the low incidence of this infection in making the decision whether or not to
perform a lumbar puncture. (See "Strategies for the evaluation of fever in neonates and
infants (less than three months of age)".)
We recommend that lumbar puncture be performed if empiric antibiotics are prescribed [3].
Otherwise, if the child returns for further evaluation and lumbar puncture at that time
reveals CSF pleocytosis, it will not be clear whether a negative culture result is due to
partially treated bacterial meningitis or aseptic meningitis. This uncertainty may result in
the infant receiving an unnecessary course of antibiotics.
Seizures may be a sign of meningitis, and we recommend that a lumbar puncture be
performed in all neonates and young infants who have had a seizure. Appropriate CSF
studies to identify possible viral etiologies may be useful diagnostically (table 1). (See "Viral
meningitis: Clinical features and diagnosis in children", section on 'Virology'.)
Blood culture — Blood culture does not help with the immediate assessment of fever but
should be obtained routinely in the infant <28 days old or in older infants prescribed empiric
antibiotics. Rapid detection of bacterial pathogens is possible with automated blood culture
techniques, allowing the identification of positive culture results often within 24 hours. This
is particularly helpful in infants managed as outpatients [3].
Chest radiograph — Not all studies of febrile neonates and young infants have included a
chest radiograph as part of the initial evaluation. A chest radiograph is helpful in identifying
a source of infection in infants with at least one clinical sign of pulmonary disease [24]. This
was illustrated in a meta-analysis of 617 febrile infants under three months of age [25]. All
361 infants who had no clinical evidence of pulmonary disease (defined as respiratory rate
>50 breaths/min, rales, rhonchi, retractions, wheezing, coryza, grunting, stridor, nasal
flaring, or cough) had normal chest radiographs. In contrast, 85 of 256 infants (33 percent)
with at least one of these signs had an abnormal chest radiograph.
Even when the chest radiograph reveals pneumonia, a viral etiology is most likely, given
that nonbacterial pneumonias comprise the majority of cases of pneumonia in children [26].
A bacterial process is more likely if alveolar disease (consolidation and air bronchograms) or
bronchopneumonia (diffuse bilateral pattern with increased peribronchial markings and
small fluffy infiltrates) is present.
EVALUATION AND MANAGEMENT — A cautious approach to neonates (0 to 28 days) and
young infants (29 to 90 days) with fever is prudent, given the risk and potentially adverse
consequences of unrecognized and/or untreated serious bacterial infection (SBI). Multiple
approaches to the evaluation of these infants, with varying inclusion and exclusion criteria,
have been proposed and studied, including protocols from Boston, Philadelphia, and
Rochester [9-11]. While these approaches have a high negative predictive value (ability to
remove patients with SBI from the low-risk group), each suffers from a relatively low
positive predictive value, resulting in many infants undergoing unnecessary laboratory
testing, hospitalization, and exposure to unnecessary antibiotics. (See "Strategies for the
evaluation of fever in neonates and infants (less than three months of age)".)
The predictors of SBI used to classify febrile infants into risk subsets aid in the assessment
of risk, but they do not eliminate risk. There is a lack of definitive data to guide patient
evaluation, and some categories that define high-risk groups such as age and white blood
cell (WBC) count are arbitrary. Consequently, each patient and each clinical situation must
be evaluated individually. (See "Strategies for the evaluation of fever in neonates and
infants (less than three months of age)".)
Neonates (0 to 28 days) — The available guidelines and approaches to fever in young
infants do not perform well in neonates 28 days of age and younger compared with older
infants [1]. Consequently, most experts recommend that all neonates with a rectal
temperature ≥38ºC have blood, urine, and CSF cultures performed regardless of clinical
appearance [27,28]. A chest radiograph should be obtained in those with any sign or
symptom of pulmonary disease. These neonates should be admitted to the hospital and
treated presumptively with antibiotics (table 2). (See "Strategies for the evaluation of fever
in neonates and infants (less than three months of age)", section on 'Limitations in
neonates'.)
Antibiotic therapy — Serious bacterial illness is present in 12 percent of febrile neonates
[29]. Group B Streptococcus, a common pathogen in this age group, causes high rates of
meningitis (39 percent) and sepsis (9 percent). Prior to routine antibiotic administration to
intrapartum mothers and to febrile neonates, the case fatality rate approached 50 percent
in babies with early onset group B Streptococcal infection [30]. Other organisms that cause
SBI in neonates include Escherichia coli and other gram negative rods, enterococcus. and
Listeria monocytogenes [31,32]. In addition, Streptococcus pneumoniae, Haemophilus
influenzae, and Neisseria meningitidis cause disease in the slightly older neonate.
Because of the high rates of serious bacterial infection and high risk of mortality if
untreated, we recommend empiric treatment with antibiotics. Ampicillin and gentamicin or
ampicillin and cefotaxime will provide empiric coverage for these organisms until culture
results are available (table 2). (See "Definition and etiology of fever in neonates and infants
(less than three months of age)".)
Acyclovir — Although acyclovir should not be used routinely in the management of febrile
neonates, those who are ill-appearing, have mucocutaneous vesicles, or have seizures
should be treated with acyclovir (60 mg/kg per day divided three times daily). In addition,
elevated liver enzymes may be an early indicator of disseminated HSV in neonates less than
two weeks of age. Controversy exists regarding the use of empiric acyclovir in neonates who
have CSF pleocytosis without other clinical features suggestive of HSV. We suggest that
such patients receive acyclovir empirically pending the results of bacterial CSF culture and
CSF HSV DNA polymerase chain reaction (PCR). (See "Neonatal herpes simplex virus
infection: Management and prevention" and "Neonatal herpes simplex virus infection:
Clinical features and diagnosis", section on 'Clinical manifestations'.)
Cultures of skin vesicles (if present), oropharynx, conjunctivae, urine, blood, stool, and CSF
for HSV should be obtained before the initiation of acyclovir. HSV antigen may be detected
using direct fluorescent antibody tests of scrapings from the base of vesicles. In addition,
CSF should be sent for HSV DNA PCR. (See "Definition and etiology of fever in neonates and
infants (less than three months of age)".)
Ill-appearing infants (29 to 90 days) — Infants who are ill-appearing, have an abnormal
cry, or temperatures ≥38.5ºC have a higher risk of SBI [33,34]. Because up to 45 percent
of ill-appearing young infants may have SBI [1], such infants should undergo the following
treatment:

Full laboratory evaluation including blood, urine, and CSF

Chest radiograph if signs or symptoms of pulmonary disease are present (respiratory
rate >50 breaths/min, rales, rhonchi, retractions, wheezing, coryza, grunting,
stridor, nasal flaring, or cough).

Empiric antibiotic therapy (with cefotaxime or ceftriaxone), regardless of the initial
laboratory results. Empiric therapy should also be adjusted based on specific clinical
findings as follows:

Vancomycin should be given to those infants with evidence of soft tissue infection.
(See "Evaluation and management of suspected methicillin-resistant Staphylococcus
aureus skin and soft tissue infections in children", section on 'Severe SSTI'.)

Vancomycin should be given to those infants with CSF pleocytosis to treat meningitis
caused by S. pneumoniae that is not susceptible to cefotaxime or ceftriaxone and, in
infants 29 to 60 days of age, ampicillin should also be given to cover Listeria
monocytogenes (table 2). (See "Treatment, prognosis, and prevention of Listeria
monocytogenes infection".)

Hospital admission
Well-appearing infants
29 to 60 days — For well-appearing infants with a temperature ≥38.0ºC, laboratory
testing is necessary to determine which patients are at high risk for an SBI [11]. A complete
history and physical examination with appropriate laboratory evaluation including CBC,
blood culture, urinalysis and culture, and CSF for cell count and culture should be performed
in most patients. Infants without CSF pleocytosis, a WBC count 5000 to 15,000/microL, and
a normal urinalysis are at low risk for an SBI.
Some clinicians may elect to perform fewer laboratory tests. There are, however, no
guidelines for the minimal evaluation of fever in well-appearing infants ages 29 to 60 days.
The following factors should be considered:

Urinary tract infections (UTIs) are common in this age group, particularly in
uncircumcised boys and in girls [22]. Consideration always should be given to
performing a urinalysis with culture.

A WBC count 5000 to 15,000/microL with less than 1500 bands/microL suggests a
lower risk of SBI.

A stool culture should be performed if diarrhea is present.

Lumbar puncture may not be necessary in some well-appearing infants who have
knowledgeable caregivers, transportation, and well-established follow-up. However,
a lumbar puncture should always be performed whenever empiric antibiotics are
prescribed.

A chest radiograph should be obtained in infants with at least one clinical sign of
pulmonary disease (respiratory rate >50 breaths/min, rales, rhonchi, retractions,
wheezing, coryza, grunting, stridor, nasal flaring, or cough) [25,35].
Infants 29 to 60 days of age with CSF pleocytosis or a peripheral WBC ≥20,000/microL
should be admitted to the hospital for treatment with empiric parenteral antibiotics. Many
clinicians may also prefer to admit infants with WBC ≤5000/microL and WBC
≥15,000/microL. We also suggest that those with an abnormal urinalysis be treated with
parenteral antibiotics as inpatients. (See "Strategies for the evaluation of fever in neonates
and infants (less than three months of age)".)
However, some experts treat well-appearing infants with an abnormal urinalysis with
parenteral antibiotics as outpatients [36]. Limited data from a retrospective review of the
hospital course of febrile infants <60 days of age with UTI demonstrated that progression of
illness was unlikely and lends some support to this strategy [37].
Multiple prospective studies have reported that infants who are at low risk of SBI based on
history, physical examination, and whatever laboratory testing has been performed can be
safely managed as outpatients. Reliable follow-up must be arranged within 24 hours (either
by phone or by return visit to the clinician). If the social situation suggests that follow-up
within 24 hours is problematic (eg, transportation problems or other concerns regarding
parental adherence), then the infant should be admitted to the hospital. (See "Strategies for
the evaluation of fever in neonates and infants (less than three months of age)", section on
'Traditional strategies'.)
Infants who are followed as outpatients may be treated presumptively with ceftriaxone (50
mg/kg in a single dose), pending culture results. In making the decision whether or not to
prescribe empiric antibiotic therapy, the clinician must consider both the potentially severe
risk of not treating an SBI as well as the more common but typically less severe risks
associated with parenteral antibiotic administration. We suggest that CSF be obtained if
antibiotics are given empirically.
61 to 90 days — Data regarding the incidence of serious bacterial infection (SBI) among
infants 61 to 90 days of age with fever (as compared with younger infants) on which to
base definitive guidelines are limited. The risk of SBI for this age group may be similar to
that for older febrile infants. In a prospective observational study (conducted after the
initiation of routine immunization of infants with conjugated pneumococcal vaccine)
describing febrile infants 57 to 180 days of age, there was no significant difference in the
incidence of SBI between those who were 57 to 89 days of age and those who were older
[38]. (See "Fever without a source in children 3 to 36 months of age".)
Since infants less than three months of age have not yet been fully immunized against
pneumococcus and Haemophilus influenzae type b, most experts recommend a CBC,
urinalysis, and cultures of blood and urine be obtained in those who are well-appearing.
(See "Fever without a source in children 3 to 36 months of age", section on 'Wellappearing'.)Those who have signs of pulmonary disease should have a chest radiograph as
well.
Despite its poor ability to identify young infants with bacteremia or meningitis, a WBC
outside of the normal range of 5000 to 15,000/microL suggests the need for lumbar
puncture followed by treatment with parenteral antibiotics until all cultures are final (table
2). For outpatient therapy in patients with normal CSF and urinalysis, ceftriaxone (50
mg/kg) is the preferred drug because of its antimicrobial spectrum and long duration of
action (see 'WBC count' above).
Infants with an abnormal urinalysis should receive parenteral antibiotics. Some experts
suggest that these infants be admitted to the hospital, regardless of clinical appearance.
(See "Acute management, imaging, and prognosis of urinary tract infections in children".)
As with infants 29 to 60 days of age, the clinician must consider the risk of not treating an
SBI as well as the risks associated with parenteral antibiotic administration in deciding
whether or not to prescribe empiric antibiotic therapy (ceftriaxone 50 mg/kg in a single
dose). We suggest that CSF be obtained if empiric antibiotics are prescribed (see 'Lumbar
puncture' above).
Follow-up for outpatient treatment — Well-appearing infants ages 29 to 90 days who
are sent home must have follow-up within 24 hours either by phone or by visit, at which
time preliminary culture results (if obtained) are reviewed. Patients who received parenteral
antibiotics at the initial visit should return for a second intramuscular dose (eg,
ceftriaxone 50 mg/kg) pending final culture results.
Any of the following circumstances warrants extensive evaluation and hospitalization for
empiric antibiotic therapy with cefotaxime, ceftriaxone, or other antibiotics, as indicated:

Any deterioration in clinical status or worsening of fever

A positive blood culture not thought to be a contaminant

A positive urine culture in an infant who remains febrile
For an infant with a positive urine culture who is afebrile and well-appearing less than 24
hours after parenteral ceftriaxone, it may be reasonable to give a second dose of parenteral
ceftriaxone at 24 hours and continue outpatient follow-up. (See "Urinary tract infections in
newborns".)
Discharge criteria for admitted patients — Neonates and young infants who remain
well-appearing or who rapidly improve may either be treated with or observed off antibiotics
while in the hospital, until bacterial cultures have been negative for 24 to 48 hours.
The length of hospitalization depends on the type of culture system in use. For example,
continuously monitored blood culture instruments identify between 77 and 87 percent of all
cultures with pathogens [39,40] and 95 percent of critical pathogens (eg, S. pneumoniae,
Salmonella and other Enterobacteriaceae, N. meningitidis, groups A and B streptococcus)
within 24 hours [39]. Patients sent home before cultures have been negative for 48 hours
must have follow up within 24 hours either by phone or by visit, at which time preliminary
culture results are reviewed. If antibiotics were given in the hospital, then the child should
receive two additional doses of antibiotics (eg, ceftriaxone 50 mg/kg daily) until all cultures
are final and negative.
Initial treatment with acyclovir implies significant clinical concern for herpes infection. It
would seem prudent then to continue to treat the infant with acyclovir until the PCR result
of CSF specimen is available. (See "Neonatal herpes simplex virus infection: Management
and prevention".)
Fever may persist after cultures are negative at 48 hours. For the patient whose clinical
condition has improved, a period of observation in the hospital off antimicrobial therapy
would be reasonable. The child who remains ill or who does not improve as expected should
be carefully reevaluated, and further testing, consultation, and treatment options should be
pursued.
DIFFICULT CLINICAL SITUATIONS — Some clinical situations arise that do not fit neatly
into treatment guidelines. Until more definitive information becomes available, these
circumstances should be considered on an individual basis, using clinical judgment.
Dry lumbar puncture — When the decision is made to perform lumbar puncture, every
reasonable attempt should be made to obtain CSF. However, this cannot always be
accomplished. In this circumstance, cultures of blood and urine should be obtained. Infants
28 days of age or younger should be admitted to the hospital and treated with meningitic
doses of antibiotics pending those results.
Negative blood and urine culture results in a baby who does well would be reassuring,
although the true incidence of meningitis in patients who have negative blood and urine
cultures is not known. In addition, a brief period of inpatient observation off of antibiotics
could be considered.
On the other hand, a repeat lumbar puncture should be performed to obtain CSF if either
the blood or urine culture is positive. The finding of CSF pleocytosis would necessitate a
prolonged course of parenteral antibiotics. (See "Clinical features and diagnosis of acute
bacterial meningitis in children older than one month of age" and "Treatment and prognosis
of acute bacterial meningitis in children older than one month of age", section on 'Duration
of therapy'.)
For an infant 29 days or older in this situation, a similar approach is sensible. However, the
young infant in this age group who does well and has negative blood and urine cultures
probably does not need an inpatient observation period off antibiotics.
Traumatic lumbar puncture — A traumatic lumbar puncture is not unusual in young
infants. The tube in which the CSF is clearest should be sent for the cell count. The
interpretation of results from traumatic lumbar puncture is discussed elsewhere. (See
"Lumbar puncture: Indications, contraindications, technique, and complications in
children" and "Cerebrospinal fluid: Physiology and utility of an examination in disease
states".)
The possibility of meningitis cannot be excluded when the CSF cell count is uninterpretable.
In this situation, the infant should be treated with meningitic doses of antibiotics until the
CSF culture is negative at 48 hours. A repeat lumbar puncture after admission, or observing
the infant in the hospital off antibiotics after the cultures are negative at 48 hours, may be
helpful when there is uncertainty regarding the possibility of meningitis. The infant who has
done well and has negative CSF cultures at 48 hours may not require a repeat lumbar
puncture.
When the CSF culture is negative and a pathogen grows from the blood or urine, a normal
CSF white blood cell (WBC) count would be reassuring in the child who has persistent fever
or is not well-appearing.
Patient on antibiotics — A young infant on prophylactic antibiotics, usually for a urinary
tract abnormality, may have a serious bacterial illness masked by negative culture results.
CBC, UA, CSF cell count, and cultures of blood, urine, and CSF should be obtained with the
understanding that regardless of the laboratory evaluation, these patients cannot be
classified as "low risk" for serious bacterial infection (SBI), since they have an underlying
condition that places them at risk for SBI. Neonates should be admitted to the hospital and
treated empirically with ampicillin and gentamicin or ampicillin and cefotaxime, at least until
cultures have been negative for 48 hours. For well-appearing infants ≥29 days, it would be
reasonable to consider admission to the hospital and empiric antibiotic therapy, or at least
observation in the hospital off of antibiotics.
Concomitant viral infections — Despite the concern for SBI, most young infants with
fever have a viral illness. The presence of upper respiratory symptoms does not rule in a
viral etiology, nor conversely rule out an SBI. However, infants with a "recognizable viral
syndrome," such as bronchiolitis, croup, varicella, or stomatitis, have a markedly lower risk
for bacteremia, although UTI remains a significant concomitant infection in those with
bronchiolitis and influenza [41,42].
Influenza — Rapid diagnostic tests for the detection of viral neuraminidase are
commercially available for influenza A and B viruses and can be used for rapid point of care
testing. However, test performance is variable. False positive results occur and are of
particular concern if rapid influenza testing is used to limit further laboratory evaluation in
young febrile infants. As a result, rapid influenza testing should only be relied upon for
clinical management during the time of regional high prevalence for influenza infection,
since high prevalence will raise the positive predictive value. (See "Clinical features and
diagnosis of influenza in children", section on 'Laboratory diagnosis'.)
In a multicenter trial of 844 febrile infants ≤60 days of age who were tested for influenza, a
significantly lower rate of serious bacterial illness (SBI) was noted in the 123 infants who
were influenza-positive compared with the 721 infants who were influenza-negative (2.5
percent versus 11.7 percent, relative risk 0.19 [95% CI 0.06-0.59]) [43]. The three infants
with SBI in the influenza-positive group all had a urinary tract infection (UTI); none had
bacteremia or meningitis. In contrast, SBIs in influenza-negative patients included 77 with
UTIs, 16 with bacteremia, and 6 with meningitis.
Although bacteremia was not identified in any of the 123 febrile infants with influenza, we
suggest that a complete blood count (CBC) with differential, blood culture, urinalysis, urine
culture, and, in children with clinical signs of pneumonia, a chest radiograph be obtained. If
the CBC and urinalysis do not suggest bacterial infection, lumbar puncture can be omitted in
well-appearing febrile infants who are older than 28 days of age, have a positive rapid
influenza test, and no evidence of bacterial infection on physical examination. This approach
should only be considered if the rapid influenza test in use has high specificity and is
obtained during a time of high prevalence of influenza infection in the region, thereby
maximizing the positive predictive value.
Parents of infants more than 28 days of age who are discharged home from the emergency
department should understand that worsening respiratory distress, ill appearance, or
inability to feed warrant emergent return for medical care. In addition, these patients should
have assured follow-up with their primary care provider within 24 hours for possible
worsening disease. As an example, rapidly progressive Staphylococcus aureus pneumonia
has been described in infants and children with influenza and should be suspected if other
members of the family have had or have S. aureus infection. (See "Clinical features and
diagnosis of influenza in children", section on 'Bacterial coinfection' and "Epidemiology and
clinical spectrum of methicillin-resistant Staphylococcus aureus infections in children".)
Current evidence is insufficient to identify the risk of SBI in febrile neonates ≤28 days of
age with influenza infection, as only 36 such patients were in the above trial [43].
Extrapolation from studies of febrile neonates with concomitant RSV infection suggest that
those with influenza infection may remain at high risk for an SBI and should undergo a full
evaluation followed by inpatient observation with antibiotic therapy. (See
'Bronchiolitis' below.)
Bronchiolitis — Multiple retrospective and prospective observational studies demonstrate
that the incidence of SBI is 1.1 to 7 percent among febrile infants with bronchiolitis as
opposed to 10 to 17 percent in high risk febrile infants without bronchiolitis [41,44-53].
However, the risk of SBI among neonates (0 to 28 days of age) is substantial and was not
altered by the presence of RSV infection in one large prospective multicenter observational
study [41].
UTI is the most common SBI seen in febrile infants with bronchiolitis. Bacteremia may be
found in up to 1 percent of these patients [41]. No cases of meningitis have been described
in febrile infants with concomitant clinical bronchiolitis.
These findings suggest that it may be reasonable to limit laboratory testing in wellappearing febrile infants older than 28 days of age with bronchiolitis to CBC, blood culture,
urinalysis, and urine culture. If the CBC and urinalysis do not suggest bacterial infection,
then these children may be managed without antibiotics according to the degree of illness
caused by their bronchiolitis. (See "Bronchiolitis in infants and children: Treatment;
outcome; and prevention", section on 'Indications for hospitalization'.)
Febrile neonates (0 to 28 days) with bronchiolitis remain at high risk for an SBI and should
have a full evaluation and inpatient observation with antibiotic therapy.
Otitis media — Acute otitis media (AOM) is diagnosed infrequently in neonates and young
infants. Nevertheless, the infant who presents with otitis media, with or without fever, can
present a diagnostic and management challenge. (See "Acute otitis media in children:
Epidemiology, microbiology, clinical manifestations, and complications" and "Acute otitis
media in children: Diagnosis".)
The Rochester [11] and Boston criteria [9] specifically exclude patients with ear infections
from low-risk groups, and the Philadelphia protocol only considers low-risk those cases with
an "unremarkable exam" [8]. On the other hand, one study found that none of the 13
infants excluded from the low-risk group for only otitis media had systemic infections [12],
and in a second report no infant excluded from the low-risk group because of otitis media
had a systemic infection [11]. (See "Strategies for the evaluation of fever in neonates and
infants (less than three months of age)".)
Similarly, a report of 130 patients 60 days and younger with AOM confirmed by
tympanocentesis found that the presence of AOM did not predict a higher risk for SBI in
either febrile or afebrile patients [54]. None of the afebrile infants with AOM or the febrile
infants who were otherwise determined to be at low risk developed an SBI. On the other
hand, 14 percent of high-risk infants with AOM also had a serious bacterial illness.
Finally, in a study of 40 infants zero to eight weeks of age with isolated otitis media who
underwent a full sepsis evaluation and tympanocentesis, all afebrile infants had negative
cultures of blood, urine, and CSF [55]. Two febrile infants had an SBI.
These findings suggest that febrile infants with AOM should be evaluated and managed
similarly to febrile infants without AOM. The decision to forego a full sepsis evaluation in
afebrile infants with AOM should be made with caution. The practitioner must consider the
possibility of masking an SBI and the difficult situation that will arise if the infant becomes
febrile and ill-appearing.
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 information: Fever in children (The Basics)")

Beyond the Basics topics (see "Patient information: Fever in children")
SUMMARY AND RECOMMENDATIONS — Given the risk and potentially adverse
consequences of unrecognized and/or untreated serious bacterial infection (SBI), a cautious
approach to neonates (0 to 28 days) and young infants (29 to 90 days) with fever (T ≥
38ºC or 100.4ºF) is prudent. (See "Definition and etiology of fever in neonates and infants
(less than three months of age)".)
Definitive data to guide patient evaluation are lacking, and some categories that define
high-risk groups such as age and white blood cell (WBC) count are arbitrary. (See
"Strategies for the evaluation of fever in neonates and infants (less than three months of
age)".)
Consequently, each patient and each clinical situation must be evaluated individually.
Bearing in mind that the predictors of SBI used to classify febrile infants into risk subsets
aid in the assessment of risk, but do not eliminate risk, we offer the following
recommendations:
Neonates (0 to 28 days)

We recommend that all neonates with a rectal temperature ≥38ºC have blood, urine,
and CSF cultures performed regardless of clinical appearance. We recommend a
chest radiograph be obtained in those with any sign or symptom of pulmonary
disease. We recommend that these neonates be admitted to the hospital (Grade
1B). Because of the high rates of serious bacterial infection and high risk of mortality
if untreated, we recommend empiric treatment with antibiotics (Grade 1B) (table 2).
(See 'Neonates (0 to 28 days)' above.)

Ampicillin and gentamicin or ampicillin and cefotaxime provide adequate empiric
therapy for the pathogens that are common in this age group. (See 'Neonates (0 to
28 days)' above.)

Infants ≤28 days who are ill-appearing and lethargic, demonstrate mucocutaneous
vesicles, have had seizures, display a CSF pleocytosis, or exhibit elevated liver
transaminases may have a CNS or disseminated herpes simplex virus (HSV)
infection. In this select population of infants, we suggest initiating treatment with
acyclovir (60 mg/kg per day divided three times daily) (Grade 2B). For patients who
are not initially treated with acyclovir, we suggest adding it if the bacterial cultures
remain negative at 48 to 72 hours, and the patient has not improved clinically
(Grade 2C). Routine use of acyclovir is not indicated in the management of febrile
neonates. Laboratory studies to confirm the diagnosis of HSV should be sent prior to
the initiation of acyclovir. (See 'Neonates (0 to 28 days)' above.)
Ill-appearing infants (29 to 90 days)

We recommend that infants who are ill-appearing have a full laboratory evaluation
including blood, urine, and CSF cultures and receive parenteral antibiotics. Those
who have signs of pulmonary disease should also receive a chest radiograph. We
recommend that these patients receive empiric antibiotic therapy with cefotaxime or
ceftriaxone and be admitted to the hospital for ongoing parenteral antibiotic therapy
(Grade 1B). (See 'Ill-appearing infants (29 to 90 days)' above.)

Empiric antibiotic therapy should also be adjusted based on specific clinical findings
as follows (see 'Ill-appearing infants (29 to 90 days)' above):

Vancomycin should be given to those infants with evidence of soft tissue infection.
(See "Evaluation and management of suspected methicillin-resistant Staphylococcus
aureus skin and soft tissue infections in children", section on 'Severe SSTI'.)

Vancomycin should be given to those infants with CSF pleocytosis to treat meningitis
caused by S. pneumoniae that is not susceptible to cefotaxime or ceftriaxone and, in
infants 29 to 60 days of age, ampicillin should also be given to cover Listeria
monocytogenes (table 2). (See "Treatment, prognosis, and prevention of Listeria
monocytogenes infection".)
Well appearing
Infants 29 to 60 days of age

We suggest that well-appearing infants 29 to 60 days of age with a temperature
≥38.0ºC undergo a complete history and physical examination with appropriate
laboratory evaluation including CBC, blood culture, urinalysis and culture, and CSF
for cell count and culture. Although lumbar puncture may not be necessary in some
well-appearing infants, including those with bronchiolitis or a positive rapid test for
influenza, we suggest that lumbar puncture be performed if empiric antibiotics are
prescribed, including in infants who have an abnormal urinalysis or otitis media. A
stool culture is suggested if diarrhea is present. (See '29 to 60 days' above.)

We suggest that a chest radiograph be obtained only in infants with at least one
clinical sign of pulmonary disease (respiratory rate >50 breaths/minute, rales,
rhonchi, retractions, wheezing, coryza, grunting, stridor, nasal flaring, or cough).
(See '29 to 60 days' above.)

Infants who have an abnormal urinalysis, CSF pleocytosis, or an abnormal chest
radiograph require presumptive antibiotic therapy (table 2). Infants with pneumonia
or meningitis should be admitted to the hospital. We suggest that infants with an
abnormal urinalysis also be admitted (Grade 2C). (See '29 to 60 days' above.)

Infants 29 to 60 days of age who are well-appearing and have a normal laboratory
evaluation and chest radiograph, when one is performed, can be sent home as long
as reliable follow-up within 24 hours can be arranged (either by phone or by return
visit to the clinician). We suggest treatment with parenteral antibiotics (Grade 2C).
Ceftriaxone (50 mg/kg in a single dose) is preferred because of its antimicrobial
spectrum and long duration of action. This recommendation emphasizes the small
but potentially severe risk of not treating an SBI as opposed to the more common
but typically less severe risks associated with parenteral antibiotic administration.
We suggest that CSF be obtained if antibiotics are given empirically. (See '29 to 60
days' above.)
Infants 61 to 90 days of age

We suggest that a CBC, urinalysis, and cultures of blood and urine be obtained in
well-appearing infants. Those who have signs of pulmonary disease should receive a
chest radiograph as well. In addition, WBC outside of the normal range of 5000 to
15,000/microL suggests the need for lumbar puncture followed by treatment with
parenteral antibiotics until all cultures are final (table 2). we suggest that CSF be
obtained when empiric antibiotics are prescribed. (See 'Lumbar puncture' above and
'61 to 90 days' above.)

Infants with an abnormal urinalysis should be treated for urinary tract infection. (See
'61 to 90 days' above and "Acute management, imaging, and prognosis of urinary
tract infections in children".)
Use of UpToDate is subject to the Subscription and License Agreement.
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GRAPHICS
Cerebrospinal fluid (CSF) patterns and diagnosis of viral meningitis
WBC
(cells/mm3)
RBC
Glucose
(mg/dL)
Protein
(mg/dL)
Enterovirus
100-1000
None
NL/SL↓
<160
Cell culture: NP,
rectal, CSF;
PCR: CSF
Herpes simplex
virus
~100
None
or ↑
~
~100 or
higher
Cell culture: skin
or mucosal
lesion; PCR:
CSF; Brain
biopsy
Epstein Barr virus
↑
None
NL
↑
Cell culture and
PCR: CSF
(research
laboratories)
Cytomegalovirus
↑
None
↓
↑
Pathogen
Viral
diagnosis
Cell culture as
CSF
PCR
Lymphocytic
choriomeningitis
virus
↑
None
NL/SL↓
NL/SL ↑
Serology, cell
culture and PCR
Influenza
NL/SL↑
None
NL
NL/SL↑
Cell culture: NP
and CSF
Arboviruses
<200
None
NL
↑
Eastern equine
encephalitis
400-4000
Western equine
encephalitis
(WEE)
≤2000
West Nile virus
<200
Up to 900
St. Louis
encephalitis
virus
<200
~200
Serum serology
testing
Cell culture:
research
laboratories
WEE virus: PCR:
CSF
NL: normal; SL: slightly; NP: nasopharyngeal aspirate; PCR: polymerase chain reaction; ↓: decrease; ↑:
increase. Data from: Feigin RD, Shackelford PG. Value of repeat lumbar puncture in the differential diagnosis
of meningitis. N Engl J Med 1973;289: 571 and Negrini B, Kelleher KJ, Wald ER. Cerebrospinal fluid findings
in aseptic versus bacterial meningitis. Pediatrics 2000; 105:316 and Rotbart HA. Viral meningitis. Semin
Neurol 2000; 20:277 and Sawyer MH. Enterovirus infections: diagnosis and treatment. Pediatr Infect Dis J
1999; 18:1033 and Simko JP, Caliendo AM, Hogle K, Versalovic J. Differences in laboratory findings for
cerebrospinal fluid specimens obtained from patients with meningitis or encephalitis due to herpes simplex
virus (HSV) documented by detection of HSV DNA. Clin Infect Dis 2002; 35:414.
Empirical treatment of suspected SBI in febrile infants less than 90
days of age*
Age
Most likely organism
Neonate -
Common: Group B Streptococcus, E. coli
(≤28 days)
Less common: Listeria monocytogenes,
Enterococcus, S. aureus, other Gram negative
organisms, Herpes simplex virus
Infant - (29
to 90 days)
Empiric treatment
Ampicillin & cefotaxime OR
ampicillin & aminoglycoside• &
acyclovir,Δ as indicated (see
footnotes)
Common: S. pneumoniae, H. influenzae, N.
meningiditis
Well-appearing, no CSF
pleocytosis:
Less common: Group B Streptococcus, E. coli,
S. aureus, Enterococcus, Listeria
monocytogenes, Pseudomonas sp., other
Gram negative organisms
Ceftriaxone OR cefotaxime
CSF pleocytosis or illappearing:
Vancomycin & ampicillin &
ceftriaxone OR cefotaxime◊
* Broad spectrum coverage is prudent until an organism is identified.
• The choice of regimen should be based on local susceptibility patterns of E. coli and likelihood of L.
monocytogenes infection.
Δ Acyclovir is indicated in infants ≤28 days with ill-appearance, mucocutaneous vesicles, seizures, or CSF
pleocytosis.
◊ This regimen does not include an aminoglycoside and may not optimally cover infection with L.
monocytogenes or resistant Gram negative organisms, especially when meningitis is present. Antibiotic
therapy should be adjusted accordingly if infection with these pathogens is identified.