Evaluation and management of fever in the neonate and young infant (younger than three months of age)

7/29/15, 19:06Evaluation and management of fever in the neonate and young infant (younger than three months of age)
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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: Hannah F Smitherman, MD Nothing to disclose. Charles G Macias, MD, MPH Nothing to disclose. Stephen J
Teach, MD, MPH Grant/Research Support: Novartis [Asthma (Omalizumab)]. Sheldon L Kaplan, MD Grant/Research/Clinical Trial
Support: Pfizer [vaccine (PCV13)]; Forest Lab [antibiotic (Ceftaroline)]; Optimer [antibiotic (fidaxomicin)]. Consultant/Advisory
Boards: Pfizer [vaccine (PCV13)]. James F Wiley, II, MD, MPH Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately
referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
Evaluation and management of fever in the neonate and young infant (younger than three months of age)
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2015. | This topic last updated: Aug 26, 2014.
INTRODUCTION — 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 separately. (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)".)
In addition, the diagnosis and treatment of specific infections, including meningitis, pneumonia, and urinary tract
infections and the evaluation of infants and children 3 to 36 months of age are discussed elsewhere. (See "Bacterial
meningitis in children older than one month: Clinical features and diagnosis" and "Community-acquired pneumonia in
children: Clinical features and diagnosis" and "Urinary tract infections in neonates" and "Fever without a source in
children 3 to 36 months of age".)
RATIONALE — Although most neonates (younger than 28 days of age) and young infants (29 to 90 days of age)
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, or 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 the past, most of these 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]. Subsequently, criteria have been developed that can identify young infants with fever who are at low risk for
serious bacterial illness and can be safely managed as outpatients (algorithm 1). (See "Strategies for the evaluation
of fever in neonates and infants (less than three months of age)", section on 'Traditional strategies'.)
HISTORY — A thorough history is an essential component of the evaluation of all neonates and young infants with
fever (T ≥38ºC or 100.4°F). 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 "Neonatal herpes simplex virus infection: Clinical features
and diagnosis", section on 'Epidemiology and transmission' and "Management of the infant whose mother has
●

PHYSICAL EXAMINATION — The physical examination must quickly identify the ill-appearing infant who requires
immediate resuscitation and treatment. Specific finding to note are the following:
ANCILLARY STUDIES — 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 urinary tract infection, bacteremia and meningitis in young infants [16-18], especially neonates [19]. For
this reason, we suggest that the decision to perform a urinalysis, urine culture, blood culture, or cerebrospinal fluid
studies not be based solely upon the WBC count.
Blood culture — Blood culture does not help with the immediate assessment of fever but should be obtained
routinely in the infant <60 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 [20]. This is particularly helpful in infants managed as outpatients [3].
Inflammatory mediators — Although no single test is sufficient to rule in or exclude SBI in febrile young infants,
evidence from observational studies suggests that elevation of procalcitonin (PCT) or C-reactive protein (CRP) level
mays be a better marker of SBI than WBC count, and PCT may best indicate invasive bacterial illness (IBI):
received group B streptococcal chemoprophylaxis", section on 'Overview of management'.)
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 central nervous system (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].
●
In a multicenter observational study of 1112 well-appearing febrile infants (26 percent with a SBI [urinary tract
infection, bacterial gastroenteritis, bacteremia, or bacterial meningitis] and 2 percent with an IBI [bacteremia or
bacterial meningitis]), a PCT ≥0.5 ng/mL was the only marker independently associated with IBI (adjusted OR
22) [18]. A PCT <0.5 ng/mL was better than WBC, absolute neutrophil count, and C-reactive protein for ruling
out an IBI and reduced the posttest probability of IBI to 0.4 percent among infants with fever and normal urine
dipstick results. A CRP ≤20 mg/L and >40 mg/L was similar in accuracy for ruling out or ruling in SBI (most
commonly, a urinary tract infection), respectively, when compared to a PCT level of <0.5 ng/mL (rule out SBI) or
≥2 ng/mL (rule in SBI). Either procalcitonin or CRP measurements were superior to WBC in accuracy for
identifying young febrile infants with SBI.
●
In a separate analysis of well-appearing febrile infants included in the above study who had a urine dipstick,●

Thus, individual and combined measurements of CRP and PCT appear to complement and enhance the ability to
detect SBI and IBI in young febrile infants when used along with urine dipstick, WBC, and ANC. However, use of
these markers alone has limited ability to exclude SBI or IBI.
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 [24]. 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.
Molecular assays — Although early results are promising, molecular assays based upon polymerase chain
reaction, detection of bacterial 16S ribosomal RNA genes, or identification of host RNA signatures need further
validation before they can be clinically implemented [25].
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 [11,26,27]. (See "Urinary tract infections in children:
Epidemiology and risk factors", section on 'Prevalence'.)
A urine specimen for culture should be obtained by urethral catheterization or suprapubic aspiration, as bag
collections frequently are contaminated [28]. (See "Urine collection techniques in infants and children with suspected
urinary tract infection" and "Urinary tract infections in neonates", section on 'Urine culture'.)
A negative urine dipstick or urinalysis alone does not exclude UTI [19]; pyuria is absent on initial urinalysis in up to 20
percent of febrile infants with pyelonephritis [29]. Thus, urine culture should be performed on all specimens.
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.
Cerebrospinal fluid studies — We recommend that lumbar puncture always be performed in febrile infants with the
following indications (see 'Evaluation and management' below):
CRP and procalcitonin level obtained, a Lab-score was computed as follows: 2 points for PCT ≥0.5 ng/mL or
CRP ≥40 mg/L, 4 points for PCT ≥2 ng/mL or CRP ≥100 mg/L, and 1 point for positive urine dipstick (either
positive leukocyte esterase, positive nitrites, or both) [21]. A Lab-score ≥3 had a sensitivity of 52 percent and
specificity of 95 percent for SBI (1012 febrile infants), a sensitivity of 70 percent and specificity of 84 percent for
IBI (1098 infants), and post-test probabilities of 80 percent for SBI and 8 percent for IBI.
An observational study of 234 young infants found that a cutoff value for procalcitonin of 0.12 ng/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 [22].
●
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 ng/mL, respectively). In this study, a cut off value of 0.12 ng/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 [23].
●
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●

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 [26].
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
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'.)
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 [28]. This was illustrated in a meta-analysis of 617 febrile infants less than three
months of age [30]. 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 [31]. 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
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)".)
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●

However, the use of evidence-based guidelines could help standardize care among, not only individual physicians,
but various institutions as well. As an example, outcomes for well-appearing febrile infants cared for in four hospitals,
including a children’s hospital, were assessed before (4524 febrile episodes) and after (2987 febrile episodes) the
implementation of an evidence-based care process model (EB-CPM) that was derived from the Rochester criteria
[32,33]. EB-CPM implementation was associated with significantly increased adherence to recommended diagnostic
testing (13 percent increased measurement of complete blood count, urinalysis, blood and urine culture; 8 percent
increase in viral testing for admitted infants), recommended antibiotic selection (15 percent increased use of
recommended antibiotics), a 16 hour decrease in hospital length of stay for admitted patients, and a significantly
lower cost per admitted infant.
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 ≥38°C have blood, urine, and CSF cultures performed regardless of clinical
appearance [34,35]. 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 with empiric 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 approximately 12 percent of febrile neonates [36].
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 [37]. Other organisms
that cause SBI in neonates include Escherichia coli and other gram negative rods, enterococcus, and Listeria
monocytogenes [38,39]. 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 cefotaxime or ampicillin and gentamicin are potential regimens that will
provide empiric coverage for these organisms until culture results are available (table 2). The combination of
ampicillin and cefotaxime is preferred in regions where there are high rates of gentamicin-resistant organisms [40].
(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, have a maternal history of genital herpesvirus (HSV) infection, 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", section on 'Acyclovir therapy' 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 cerebrospinal fluid for HSV
should be obtained before the initiation of acyclovir. HSV antigen may be detected using direct fluorescent antibody
(DFA) tests of scrapings from the base of vesicles. In addition, CSF should be sent for HSV DNA polymerase chain
reaction (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
≥38.5°C have a higher risk of SBI [41,42]. 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).
●

Well-appearing infants
29 to 60 days — For well-appearing infants with a rectal temperature ≥38.0°C, laboratory testing is necessary to
help determine which patients may be at high risk for a serious bacterial infection (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 a 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:
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 [44,45]. 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 as long as the
infant is well-appearing, does not have a high risk past medical history, and has normal peripheral band and absolute
neutrophil counts [45,46].
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
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:
●
Ampicillin (to cover Listeria up to six to eight weeks of age).•
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●
Urinary tract infections (UTIs) are common in this age group, particularly in uncircumcised boys and in girls
[27]. 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,
reliable 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) [30,43].
●

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 a SBI as well as the more common but typically less
severe risks associated with parenteral antibiotic administration. We recommend that CSF for culture 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 [47]. (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
'Well-appearing'). 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 cerebrospinal fluid (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.)
Ill-appearing infants with an abnormal urinalysis should receive parenteral antibiotics after obtaining CSF and be
admitted to the hospital. However, well-appearing infants, over two months of age, can be treated orally as long as
oral intake is tolerated without obtaining CSF. The choice of antibiotic is discussed in more detail separately. (See
"Urinary tract infections in infants and children older than one month: Acute management, imaging, and prognosis",
section on 'Oral therapy'.)
As with infants 29 to 60 days of age, the clinician must consider the risk of not treating a 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
'Cerebrospinal fluid studies' 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:
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 neonates".)
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●

Discharge criteria for admitted patients — The length of hospitalization depends upon the clinical course of the
patient and the type of culture system in use. Early discharge is feasible in hospitals with continuously monitored
blood culture instruments, These systems identify between 77 and 87 percent of all cultures with pathogens [48,49]
and 95 percent of critical pathogens (eg, S. pneumoniae, Salmonella and other Enterobacteriaceae, N. meningitidis,
groups A and B streptococcus) within 24 hours [48].
Admitted patients over 28 days of age, who remain well-appearing during hospitalization and become afebrile are
eligible for discharge at 36 hours of negative cultures [32]. In addition, 24 hour discharge may be appropriate for
well-appearing patients who have positive viral testing regardless of the presence of fever. Patients sent home
before bacterial 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 and diagnostic
testing do not identify a viral etiology, then the child should receive two additional doses of antibiotics (eg, ceftriaxone
50 mg/kg daily) until all cultures are final and negative.
For some admitted infants, 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 is a reasonable option. 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.
Of note, neonates (0 to 28 days of age) by definition are not low risk and would not be eligible for early discharge.
These patients typically receive inpatient care and parenteral antibiotics until all cultures are negative for at least 48
hours. Furthermore, 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", section on 'Acyclovir therapy'.)
Use of early discharge criteria has been associated with reduced length of stay. As an example, implementation of a
care plan that allowed discharge at 24 hours for infants with positive viral testing for enterovirus or respiratory
viruses, other than rhinovirus, (eg, respiratory syncytial virus, influenza) and negative bacterial cultures or discharge
at 36 hours if both viral testing and bacterial cultures were negative resulted in a clinically significant decrease in
length of stay across a large hospital system without an increase in readmissions for bacterial illness [32].
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 or traumatic lumbar puncture — When the decision is made to perform a lumbar puncture (LP), every
reasonable attempt should be made to obtain cerebrospinal fluid (CSF) for studies and culture. However, this cannot
always be accomplished and either no CSF (dry LP) or bloody CSF (traumatic LP) may be obtained. In this
circumstance, at a minimum, cultures of blood and urine should be obtained.
If the LP is traumatic, the tube in which the CSF is clearest should be sent for a cell count. For patients with a
peripheral white blood cell (WBC) count that is in the normal range, one rule of thumb is to subtract one WBC for
every 500 to 1500 red blood cells. A predicted CSF WBC count can also be used and its calculation is discussed in
detail separately. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on
'Predicted WBC count after traumatic tap'.)
The possibility of meningitis cannot be excluded when the CSF cell count is not available or is not interpretable. In
this situation, the infant should be admitted and treated with meningitic doses of antibiotics until the CSF culture is
negative at 48 hours or the clinical picture warrants discharge.
When no CSF culture is obtained, 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. A repeat lumbar puncture after admission, or observing the infant in the hospital off antibiotics after the
cultures are negative at 48 hours, are two acceptable approaches, especially in infants under 29 days of age.

In contrast, the infant with a traumatic LP who has done well and has negative blood, urine, and CSF cultures at 48
hours typically does not require a repeat lumbar puncture. In selected instances, infants over 28 days of age may be
discharged without a repeat LP or observation off antibiotics if they are well-appearing and afebrile in addition to
having negative blood and urine cultures.
However, a repeat lumbar puncture should be performed if either the blood or urine culture is positive in patients with
a dry LP because the finding of CSF pleocytosis may necessitate a prolonged course of parenteral antibiotics,
depending upon the organism isolated. (See "Bacterial meningitis in children older than one month: Treatment and
prognosis", section on 'Duration of therapy' and "Bacterial meningitis in children older than one month: Clinical
features and diagnosis", section on 'Diagnosis'.)
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 a 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 [50,51].
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 "Seasonal influenza in children: Clinical features and diagnosis", 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 infection (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]) [52]. 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

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had or have S. aureus infection. (See "Seasonal influenza in children: Clinical features and diagnosis", section on
'Bacterial coinfection' and "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and
clinical spectrum", section on 'Clinical spectrum'.)
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 [52]. Extrapolation from studies of febrile neonates with concomitant
RSV infection suggests that those with influenza infection may remain at high risk for a 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 [50,53-64]. However, the risk of SBI among neonates (0 to 28 days of age) is substantial
and does not appear to be altered by the presence of RSV infection [50,64].
UTI is the most common SBI seen in febrile infants with bronchiolitis [63]. Bacteremia may be found in up to 1
percent of these patients [50]. No cases of meningitis have been described in febrile infants with concomitant clinical
bronchiolitis [63].
These findings suggest that it may be reasonable to limit laboratory testing in well-appearing 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 a 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: Diagnosis", section on 'Diagnosis' and "Acute otitis media in children:
Epidemiology, microbiology, clinical manifestations, and complications", section on 'Clinical manifestations'.)
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 [65]. None of the afebrile
infants with AOM or the febrile infants who were otherwise determined to be at low risk developed a 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 [66]. Two febrile
infants had a 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 a 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 5 to 6 gradeth th

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
10 to 12 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.)
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 ≥38°C or 100.4°F) 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)
Ill-appearing infants (29 to 90 days)
th th
Basics topic (see "Patient information: Fever in children (The Basics)")●
Beyond the Basics topic (see "Patient information: Fever in children (Beyond the Basics)")●
We recommend that all neonates with a rectal temperature ≥38°C have blood, urine, and cerebrospinal fluid
(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 cefotaxime or ampicillin and gentamicin are potential regimens that will provide empiric coverage
for these organisms until culture results are available (table 2). The combination of ampicillin and cefotaxime is
preferred in regions where there are high rates of gentamicin-resistant organisms. (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.)
●
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).
●

Well-appearing
Infants 29 to 60 days of age
Infants 61 to 90 days of age
(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".)
•
We suggest that well-appearing infants 29 to 60 days of age with a rectal temperature ≥38.0°C 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
recommend 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 under 60 days of age with an abnormal urinalysis also be admitted for a
period of observation (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 a
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.)
●
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 'Cerebrospinal fluid studies' 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
"Urinary tract infections in infants and children older than one month: Acute management, imaging, and
prognosis", section on 'Overview'.)
●

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