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Febrile infant (younger than 90 days of age): Outpatient


evaluation
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

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2019. | This topic last updated: Jun 18, 2019.

INTRODUCTION

The outpatient evaluation of febrile infants younger than 90 days of age is discussed in this topic.

For a discussion of the management of febrile infants younger than 90 days of age; definition of
fever in the young infant; the diagnosis, evaluation, and initial management of early-onset sepsis in
neonates; and the approach to the ill-appearing infant without fever, refer to the following topics:

(See "Febrile infant (younger than 90 days of age): Management".)

(See "Febrile infant (younger than 90 days of age): Definition of fever".)

(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants",
section on 'Evaluation and initial management'.)

(See "Approach to the ill-appearing infant (younger than 90 days of age)".)

DEFINITION OF FEVER

Rectal temperatures are the standard for detecting fever in infants younger than three months of
age; the majority of studies establishing the risk of serious infections in febrile young infants have
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relied upon rectal temperatures. We regard a rectal temperature of 38°C (100.4°F) or greater as
fever in infants 90 days of age and younger. (See "Febrile infant (younger than 90 days of age):
Definition of fever", section on 'Definition of fever'.)

Interpretation of other means of temperature measurement and caregiver reports of fever in young
infants are discussed in detail separately. (See "Febrile infant (younger than 90 days of age):
Definition of fever", section on 'Definition of fever'.)

ETIOLOGY

The ability to generalize data from prior studies of the infectious etiology of fever in young infants is
limited because many studies were conducted in an era when numerous vaccines that are now
included in routine childhood immunizations were unavailable (eg, pneumococcal conjugate
vaccine, Haemophilus influenzae type b vaccine, varicella vaccine, and rotavirus vaccine) and
perinatal prophylaxis for group B Streptococcus was less common. Additionally, the Advisory
Committee on Immunization Practices recommends influenza vaccine administration for all
children ≥6 months [1]. While vaccination for influenza does not directly impact the youngest
infants, older children serve as the most effective vectors of disease transmission in the
community. Consequently, the epidemiology of influenza in the youngest infants is likely affected
by the vaccination of older children and adult family members.

Viral infection — Surveillance for viral infection in the first year of life indicates that it occurs
commonly in young infants and that the first infection is often asymptomatic [2]. Viral infection is
also the most common cause of fever in young infants. Depending upon the specific pathogen and
type of diagnostic testing, viral infections have been documented in up to 58 percent of young
febrile infants while bacterial infections account for 10 to 15 percent of pathogens although
molecular testing may reflect prior asymptomatic disease rather than the causative pathogen for
some viruses [3-5]. Based upon one study of over 4000 febrile young infants undergoing molecular
respiratory virus testing, human rhinovirus is detected most frequently followed by respiratory
syncytial virus, influenza, and parainfluenza [5].

Neonates, less than 28 days of age, with viral infection remain at high risk for concomitant invasive
bacterial illness. Infants 29 to 90 days of age have a lower risk of invasive bacterial illness but still
remain at significant risk for urinary tract infection. (See 'Patients with recognizable viral infections'
below.)

Viruses that can cause serious illness in febrile young infants include:

Herpes simplex virus (see "Neonatal herpes simplex virus infection: Clinical features and
diagnosis")
Varicella-zoster virus (see "Varicella-zoster infection in the newborn")

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Enteroviruses (see "Enterovirus and parechovirus infections: Clinical features, laboratory


diagnosis, treatment, and prevention")
Influenza virus (see "Seasonal influenza in children: Clinical features and diagnosis", section
on 'Clinical features')
Some adenoviruses (see "Pathogenesis, epidemiology, and clinical manifestations of
adenovirus infection")
Respiratory syncytial virus (see "Respiratory syncytial virus infection: Clinical features and
diagnosis")

The neonate acquires viral infection through vertical transmission from the mother during delivery
and postnatally from sources such as family members and hospital personnel. Neonates and
young infants are more likely than older infants to experience morbidity from a viral infection, in
part because of a decreased responsiveness of T cell-mediated immunity. (See "Immunity of the
newborn".)

Invasive bacterial infection (IBI)

Definition — Many of the studies of fever in the young infant defined outcomes by the
occurrence of serious bacterial infection (SBI) defined as invasive infections such as bacteremia,
bacterial meningitis, bacterial pneumonia, skin and soft tissue infections, osteomyelitis, bacterial
gastroenteritis, septic arthritis, or urinary tract infection (UTI) [6]. Although not classically described
in the literature of the early 1990s, the attention to community-acquired Staphylococcus aureus
has made pustulosis a relevant disease entity to be considered in skin and soft tissue infections in
neonates [7].

More recently, the focus on the specific type infection (eg, UTI, bacteremia, or meningitis) has
replaced the general concept of SBI in terms of evaluation and management secondary to the
overall decreased prevalence of bacterial infections in the febrile infant and the unique nature of
risk attributed to the specific type of infection. IBI, which refers to bacteremia and meningitis, has
become the more common term. (See "Febrile infant (younger than 90 days of age):
Management", section on 'Management'.)

Risk factors — Risk factors for IBI in young infants include the following [6,8-13]:

Age, especially younger than 28 days – Observational studies performed after the
introduction of vaccination against Haemophilus influenzae type b and evaluating febrile
neonates 28 days of age and younger who presented to an emergency department have
reported a higher prevalence of IBI (9 to 19 percent) [6,8,14-16] compared with approximately
7 to 11 percent in infants 29 to 90 days of age [8,16]. Similarly, febrile neonates evaluated in
primary care physician offices have a higher rate of bacteremia and meningitis than older
febrile young infants as follows [9]:

• 3 and 1.1 percent, respectively, in infants 0 to 1 month of age


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• 1.4 and 0.4 percent, respectively, in infants from 1 to 2 months of age


• 0.7 and 0 percent, respectively, in infants from 2 to 3 months of age

Ill-appearance – Ill-appearance has consistently been associated with a higher risk of IBI
based upon clinical experience and multiple observational studies [9,10,17]. However, a
substantial number of previously healthy, well-appearing infants without a focus of infection on
physical examination can also have an IBI.

Rectal temperature ≥40°C (104°F) – Hyperpyrexia is rare among febrile infants younger than
3 months but is highly associated with IBI when it occurs [18]. As an example, in an
observational study of 98 infants younger than 90 days of age, patients with a temperature
≥40°C had a 29 percent absolute increase in the frequency of SBI (38 versus 9 percent) [12].

Rectal temperature ≥38.6°C (101.5°F) – The risk for bacterial etiology appears to increase
with increasing fever (historically defined in the literature for infants of >38.0°C or >38.5°C)
despite a decrease in the incidence of invasive disease across all ages following the
introduction of conjugate vaccines. (See 'Etiology' above.)

Although increasing temperatures may increase risk, thresholds merely represent cutoffs
described in the literature for the purposes of research; true risk is a continuum. Nevertheless,
many experts use fever ≥38.6°C (101.5°F) as an additional risk factor that requires a full
sepsis evaluation.

Unimmunized (have not received the first dose of pneumococcal and Hib vaccine) –
Immunization with conjugate pneumococcal vaccines has significantly decreased the rates of
bacteremia in young infants and children and, in young infants, it appears to both confer direct
and herd immunity benefits [11]. As an example, in an observational cohort study that
identified children 3 years of age or younger and included 50 immunized and 67 unimmunized
infants 0 to 90 days of age, the rates of bacterial infection were significantly higher among
unimmunized febrile young infants 0 to 90 days of age (7 percent unimmunized versus 0
percent, respectively). In addition, there were no cases of pneumococcal bacteremia in any of
the infants who had received at least one dose of heptavalent pneumococcal vaccine or the
22 unimmunized infants younger than 28 days.

Prematurity (gestational age younger than 37 weeks) – Because of their immature immune
protective mechanisms, premature infants are at a much higher risk for IBI. For example,
premature infants have rates of sepsis that are approximately 10 to 12 times that of term
infants, including late-onset sepsis. Thus, febrile young infants who are premature should be
regarded as being at an increased risk for invasive bacterial infection. (See "Clinical features
and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on
'Incidence' and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm
infants", section on 'Epidemiology'.)

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However, excluding any comorbidities, former premature infants, once corrected for post-
conceptual age, have similar incidence of bacterial infection when compared with their term-
matched controls [19]. As an example, an infant who is eight weeks of age but was born at 34
weeks gestation (or six weeks early) is regarded as having a similar risk for SBI as a two-
week-old term infant.

Comorbidities or chronic illness – Historically, studies of IBI in young infants have excluded
the patients with the following comorbidities who are considered at higher risk for IBI [6]:

• Infants with a perinatal course that is complicated by surgery, infection, congenital or


chromosomal abnormalities
• Medically fragile patients who are dependent upon technology or specific therapies (eg,
home ventilator, home oxygen, or total parenteral nutrition)

Received antibiotics within the prior 3 to 7 days – Because of the long half-lives of
antibiotics in young infants, administration up to 7 days prior to evaluation may mask signs
and symptoms of IBI.

Risk of maternally transmitted infection – Potential findings that increase the risk for
neonatal infection include maternal fever, prolonged rupture of membranes, maternal culture
positive for group B Streptococcus (GBS), and maternal history of genital herpes. GBS
screening and maternal intrapartum antibiotic prophylaxis reduces the risk of early-onset GBS
infection but does not eliminate it. (See "Clinical features, evaluation, and diagnosis of sepsis
in term and late preterm infants", section on 'Maternal risk factors' and "Neonatal group B
streptococcal disease: Prevention".)

Social barriers to follow-up – Although it has not been shown to be a direct risk factor for
IBI, factors that negatively impact the ability to reevaluate a young febrile infant on an
outpatient basis pose a risk for safe management:

• Limited skills by the caregiver to assess severity of diseases/educational barriers


• Limited access to a medical home for questions and/or follow-up
• Lack of transportation
• Language and other communication limitations

Bacterial pathogens — Escherichia coli and group B Streptococcus are the pathogens most
likely to cause bacteremia and bacterial meningitis in febrile infants younger than 3 months of age
[13,20-22]. E. coli is the most common pathogen and also causes the majority of UTIs in this age
group.

Listeria monocytogenes is still an important cause of bacterial meningitis, but its overall prevalence
as a pathogen in febrile infants is becoming rare [23]. It is primarily isolated in neonates younger
than 28 days of age and premature infants.

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Other potential etiologies of SBI in febrile young infants include S. aureus, Streptococcus
pneumoniae, Salmonella species, Enterococcus faecalis, Enterobacter cloacae, Moraxella
catarrhalis, Klebsiella species, and Citrobacter species [24-26]. Of these, S. aureus is the most
frequent isolate from skin and soft tissue infections and osteomyelitis.

Source of infections — UTI accounts for most bacterial infections in infants under 90 days of
age; occurring in approximately 80 percent of 440 febrile infants with IBIs in one series [27].
Bacteremia, cellulitis, meningitis, and pneumonia constitute other important sources of infection
[4,28]. Additional studies indicate the importance of UTI as a source of infection in febrile young
infants as follows:

In a multicenter study of SBI among 3066 febrile infants ages 3 months and younger, who
were evaluated in the primary care office setting rather than the emergency department, UTI
occurred much more frequently than bacteremia and meningitis (5.4 versus 0.4 percent,
respectively) [9]. These numbers are likely underestimates, as only slightly more than 50
percent of infants had a urine test performed.

In a prospective, multicenter observational study of 1025 febrile young infants 60 days of age
or younger who were evaluated for fever ≥38°C, UTI was diagnosed in 9 percent of patients
[29]. UTI was diagnosed in 21 percent of uncircumcised males and was significantly
associated with fever ≥39°C.

The risk of UTI in uncircumcised male infants is discussed in detail separately. (See "Urinary tract
infections in children: Epidemiology and risk factors", section on 'Lack of circumcision'.)

Salmonella is a consideration in young infants with fever, particularly in those who also have
diarrhea or blood in the stool. A relatively small percent of these infants will have associated
bacteremia [30,31]. Salmonella meningitis should be excluded in young infants with Salmonella
bacteremia. (See "Nontyphoidal Salmonella bacteremia", section on 'Incidence' and "Nontyphoidal
Salmonella bacteremia", section on 'Risk factors'.)

EVALUATION

When evaluating the febrile young infant, the goal is to identify infants who are at high risk for
invasive bacterial infection (IBI; ie, bacteremia and/or meningitis) or serious viral infection (eg,
herpes simplex virus [HSV] infection) and who therefore require empiric antimicrobial therapy and
hospitalization. The young febrile infant may demonstrate few, if any, interpretable clues to the
underlying illness on physical examination despite evaluation by experienced physicians or the use
of an observation scale score [32,33]. However, careful assessment and judicious use of ancillary
studies can identify patients at both high and low risk of IBI.

Our approach — We recommend a full sepsis evaluation for the following febrile young infants:

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All ill-appearing infants regardless of age (see 'Ill-appearing infants' below)

Neonates younger than 28 days of age including neonates with a recognizable or testable viral
infection (eg, bronchiolitis, croup, influenza, or enterovirus) or a focal bacterial infection (see
'Neonates (28 days of age and younger)' below and 'Focal infection' below)

Any infant with findings suggesting HSV infection upon examination (eg, mucocutaneous
vesicles, seizures, or focal neurologic findings), especially those with maternal risk factors for
vertical transmission (see "Neonatal herpes simplex virus infection: Clinical features and
diagnosis", section on 'Clinical suspicion')

Infants 29 to 60 days of age (corrected for prematurity as indicated) with any one of the
following risk factors for IBI (see 'Infants 29 to 60 days of age' below):

• Rectal temperature ≥38.6°C


• Congenital or chromosomal defects, particularly those known to be associated with an
increased risk of infection
• Technology dependent (eg, home oxygen, home ventilator, indwelling central line)
• Antibiotic therapy in past 3 to 7 days

Infants 29 to 90 days of age with a focal infection (eg, cellulitis, abscess, osteomyelitis,
bacterial arthritis, or bacterial pneumonia) and abnormal white blood cell (WBC) count,
absolute band count (ABC), inflammatory markers (procalcitonin [PCT] and/or C-reactive
protein [CRP] but only if rapidly available), or urinalysis. Traditionally, a full sepsis evaluation
has been suggested for all well-appearing febrile young infants with focal infections. However,
evidence regarding the risk of IBI in febrile patients with focal infections who are older than 28
days of age is limited. The authors of this topic prefer to evaluate the extent of the focal
infection, results of preliminary blood and urine studies, and determine the need for a full
sepsis evaluation on a case-by-case basis (see 'Focal infection' below)

We suggest that well-appearing febrile infants 29 to 60 days of age (corrected for prematurity)
who do not have a focal bacterial infection, clinical findings of HSV infection, and other risk
factors for IBI and who have a rectal temperature <38.6°C (101.5°F) undergo the following
evaluation (algorithm 1):

Complete blood count (CBC) with differential


PCT (only if results are rapidly available [eg, within 60 minutes])
CRP (only if results are rapidly available [eg, within 60 minutes])
Blood culture
Urinalysis
Urine culture (by transurethral bladder catheterization or suprapubic aspiration)
Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or
abnormal breath sounds)

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These patients should also undergo a lumbar puncture with collection of cerebrospinal fluid
(CSF) studies if they have any one of the following results and are thus candidates for empiric
antibiotic therapy (see "Febrile infant (younger than 90 days of age): Management", section on
'Infants 29 to 60 days of age'):

• WBC count ≤5000/microL, ≥15,000/microL)


• ABC >1500/microL
• Immature to mature neutrophil (band to poly) ratio >0.2
• PCT >0.5 ng/mL
• CRP >20 mg/L (2 mg/dL)
• If obtained, findings of pneumonia on chest radiograph

We also suggest a similar evaluation, but without blood studies or a lumbar puncture in every case,
for well-appearing febrile infants 29 to 90 days of age with a recognizable or testable viral infection
(eg, bronchiolitis, croup, influenza, or enterovirus). (See 'Patients with recognizable viral infections'
below.)

We suggest that well-appearing febrile infants 61 to 90 days of age (corrected for prematurity) with
temperature ≤38.6°C undergo urinalysis and urine culture only, although some experts would
recommend a CBC and blood culture, particular for infants who have not received the first
immunization with conjugated vaccines. (See 'Infants 61 to 90 days of age' below.)

The expert contributors to this topic vary on their approach to infants 42 to 90 days of age who
have a fever within 48 hours of an immunization. Options for evaluation of these patients are
discussed separately. (See 'Recently immunized' below.)

History — A thorough history is an essential component of the assessment of young febrile


infants. The physician should first determine if the report of fever represents a true and reliably
measured elevation in body temperature. Rectal temperatures are the standard for detecting fever
in infants, 90 days of age. (See "Febrile infant (younger than 90 days of age): Definition of fever",
section on 'Definition of fever'.)

The physician should also identify findings that may indicate a higher risk for IBI (see 'Risk factors'
above):

A significant change in behavior (eg, decreased feeding, irritability, lethargy, or increased


sleeping) that may represent subtle symptoms of bacterial meningitis or HSV encephalitis

Documented rectal temperature ≥38.6°C (101.5°F)

Antibiotic administration in the past 7 days

History of prematurity (gestational age younger than 37 weeks)

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Increased risk of vertically transmitted infection (applicable to neonates younger than 28 days
of age):

• Maternal fever

• Maternal colonization with group B streptococcus (GBS) and/or administration of antibiotic


prophylaxis at delivery (see "Management of the infant whose mother has received group
B streptococcal chemoprophylaxis", section on 'Management of the neonate')

• Maternal history of sexually transmitted infections such as HSV, gonorrhea, and


chlamydia (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis",
section on 'Epidemiology and transmission')

• Prolonged rupture of membranes

Comorbidities or chronic illness including infants whose perinatal course was complicated by
surgery, infection, congenital or chromosomal anomalies or who are medically fragile (eg,
receiving home ventilator therapy, home oxygen, or total parenteral nutrition)

Unimmunized (infants who have not received the first dose of pneumococcal and
Haemophilus influenzae type b [Hib] vaccine)

In addition, the history should assess:

Associated symptoms (eg, rhinorrhea, cough, wheezing, vomiting, diarrhea, blood or mucus in
the stool, or rash [eg, vesicular rash suggesting HSV infection])

Exposures to sick contacts (caregivers, siblings, babysitters, or other children at day care)

Social barriers to outpatient management (limited caregiver skills or confidence to assess


severity or progression of disease, limited access to a medical home, lack of transportation,
and language limitations)

Physical examination — Infants who have respiratory or circulatory compromise (eg, apnea,
respiratory distress, or signs of shock [eg, tachycardia with poor perfusion]) must be quickly
identified and their conditions stabilized. These ill-appearing patients are at high risk for IBI and
warrant a complete evaluation for sepsis and prompt administration of empiric antibiotics. (See
"Febrile infant (younger than 90 days of age): Management", section on 'Ill-appearing' and "Septic
shock in children: Rapid recognition and initial resuscitation (first hour)", section on
'Resuscitation'.)

In addition to respiratory or circulatory compromise, ill-appearing infants may display irritability,


poor tone, or lethargy. A careful physical examination may identify a pattern of clinical features that
suggests the etiology of an infant's symptoms that, in addition to a sepsis evaluation, warrant

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further studies. (See "Approach to the ill-appearing infant (younger than 90 days of age)", section
on 'Evaluation'.)

Although the majority of young febrile infants have no obvious focus of infection on examination,
they should undergo a complete assessment to look for the following sources:

Bacterial infection:

• Acute suppurative otitis media – Bulging and inflammation of the tympanic membrane
(picture 1) (see "Acute otitis media in children: Diagnosis", section on 'Otoscopy')

• Pneumonia – Tachypnea, respiratory distress (including grunting, flaring, and retractions),


decreased oxygen saturation, cough, and crackles or decreased breath sounds on
auscultation (see "Community-acquired pneumonia in children: Clinical features and
diagnosis", section on 'Clinical evaluation')

• Omphalitis – Purulent drainage from the umbilical stump, circumferential erythema with
tenderness and/or induration around the umbilicus (picture 2 and picture 3) (see "Care of
the umbilicus and management of umbilical disorders", section on 'Omphalitis')

Occasionally these abnormal findings are accompanied by a foul odor.

• Bacterial arthritis – Swollen, painful, warm, and/or red joint with decreased range of
motion (picture 4A-B) (see "Bacterial arthritis: Clinical features and diagnosis in infants
and children", section on 'Neonates and infants')

• Osteomyelitis – Decreased use of a limb with localized swelling or erythema (see


"Hematogenous osteomyelitis in children: Clinical features and complications", section on
'Birth to three months')

• Cutaneous cellulitis or abscess – Redness, induration, warmth, and drainage from a skin
lesion which is often located in the scalp at the site of monitoring probe insertion

• Meningitis – Irritability, lethargy, decreased or increased tone on examination; bulging


fontanelle (late finding) and nuchal rigidity (rare finding in young infants) (see "Bacterial
meningitis in children older than one month: Clinical features and diagnosis", section on
'Meningeal signs')

Serious viral infection:

• HSV infection – Clinical findings concerning for HSV infection include (see "Neonatal
herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical
suspicion'):

- Mucocutaneous vesicles (picture 5 and picture 6)

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- Seizures which typically consist of facial automatisms (eg, lip smacking or pursing),
eye deviation, or unresponsiveness rather than tonic-clonic motor activity
- Focal neurologic signs
- Respiratory distress, apnea, or progressive pneumonitis
- Conjunctivitis, excessive tearing, or painful eye symptoms
- Sepsis-like illness (fever or hypothermia, irritability, lethargy, respiratory distress,
apnea, abdominal distension, hepatomegaly, or ascites)

• Bronchiolitis – Tachypnea, copious nasal discharge, cough, auscultation demonstrating


rales and/or wheezing or apnea (see "Bronchiolitis in infants and children: Clinical
features and diagnosis", section on 'Clinical features')

Suggested ancillary studies by risk group — In febrile young infants, ancillary studies provide a
way to stratify patients by risk of IBI based upon age and clinical findings. The suggested studies
for each risk group is provided here. The evidence supporting the ability of specific tests to identify
febrile young infants at lower or higher risk of IBI is discussed separately. (See 'Utility of ancillary
studies' below.)

Ill-appearing infants — Regardless of age, febrile and afebrile young infants who are ill-
appearing are at high risk for IBI and warrant a full evaluation for sepsis as follows [16,32,34]:

CBC with differential


Blood or serum glucose (to permit comparison with CSF glucose)
Inflammatory markers (eg, PCT and CRP, if rapidly available [eg, within 60 minutes])
Blood culture
Urinalysis
Urine culture (by bladder catheterization or suprapubic aspiration) (see "Urine collection
techniques in infants and children with suspected urinary tract infection")
Chest radiograph
Stool culture in infants with diarrhea or stool containing blood or mucus
CSF cell count with differential
CSF glucose and protein
CSF for bacterial culture and Gram stain
CSF polymerase chain reaction (PCR) as indicated based upon clinical risk:
• Enterovirus studies during time of high prevalence or in patients with CSF pleocytosis
• HSV in infants with clinical findings or increased risk of maternal HSV transmission
CSF for viral culture if there is pleocytosis; if there is a limited CSF sample, we prioritize PCR
over viral culture.

Additional studies are often obtained for patients with signs of septic shock (see "Systemic
inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology,
clinical manifestations, and diagnosis", section on 'Laboratory studies'):

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• Prothrombin time (PT), partial thromboplastin time (aPTT), international normalized ratio
(INR)
• Fibrinogen and D-dimer
• Serum lactate
• Serum total bilirubin and alanine aminotransferase
• Ionized calcium

Ill-appearing infants with clinical findings of bronchiolitis or, during a time of high regional
prevalence, influenza, warrant rapid testing for respiratory viruses (eg, respiratory syncytial
virus [RSV]) and influenza. However, these test results should not be used to determine the
need for antibiotics or anti-influenzal drugs in an ill-appearing infant. (See 'Patients with
recognizable viral infections' below.)

In addition, infants with findings of HSV infection (eg, mucocutaneous vesicles, seizures, or
focal neurologic findings) warrant the following studies (see "Neonatal herpes simplex virus
infection: Clinical features and diagnosis", section on 'Neonatal HSV'):

• Surface viral cultures from the conjunctivae, mouth, nasopharynx, and rectum
• Swab or scraping from skin vesicles or mucous membrane lesions for direct
immunofluorescence assay and viral culture
• Blood PCR for HSV
• Serum alanine transaminase and aspartate transaminase to identify elevation in
association with HSV-associated hepatitis; although these studies can also be elevated in
patients with disseminated enteroviral infection or in septic shock

Other causes of ill appearance in addition to sepsis include congenital heart disease, congenital
adrenal hyperplasia, inborn errors of metabolism, malrotation with volvulus, and a variety of other
conditions discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days
of age)", section on 'Causes'.)

Infants with clinical manifestations suggesting a diagnosis other than or in addition to serious
infection warrant additional studies based upon specific findings as discussed separately. (See
"Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Evaluation' and
"Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Targeted
Evaluation'.)

Focal infection — In patients with fever and focal infections (eg, cellulitis, abscess, pneumonia,
osteomyelitis, bacterial arthritis, or omphalitis), a full sepsis workup is recommended in all ill-
appearing infants and neonates younger than 28 days of age. (See 'Ill-appearing infants' above
and 'Neonates (28 days of age and younger)' below.)

We suggest that well-appearing febrile infants 29 to 90 days of age with a focal infection undergo
the following evaluation:

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CBC with differential


PCT (only if results are rapidly available)
CRP (only if results are rapidly available)
Blood culture
Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or
abnormal breath sounds)

In patients, other than those with cellulitis or abscess:

Urinalysis
Urine culture (by bladder catheterization or suprapubic aspiration) (see "Urine collection
techniques in infants and children with suspected urinary tract infection")

We suggest a lumbar puncture with collection of CSF studies for patients that have any one of the
following results (see "Febrile infant (younger than 90 days of age): Management", section on
'Infants 29 to 60 days of age'):

WBC count ≤5000/microL or ≥15,000/microL


Absolute band count >1500/microL
PCT >0.5 ng/mL (if rapidly available [eg, within 60 minutes])
CRP >20 mg/L (2 mg/dL, if rapidly available [eg, within 60 minutes])
Unspun urine WBC count >10 WBCs/high-power field (hpf), spun urine WBC count >5
WBCs/hpf, or urine Gram stain positive
If obtained, findings of pneumonia on chest radiograph

Because these patients will undergo empiric treatment with antibiotics, some experts advocate for
a lumbar puncture in all febrile infants 29 to 90 days of age with a focal infection to minimize the
risk of missing bacterial meningitis, especially patients with focal infections likely to be caused by
GBS, such as septic arthritis or osteomyelitis.

Evidence is lacking regarding the risk of bacteremia and meningitis in well-appearing febrile infants
with focal infections. In one retrospective study of 197 non-toxic infants younger than 2 months of
age with a focal infection (39 with a fever), a concomitant systemic infection was diagnosed in four
patients; three with a urinary tract infection (UTI) caused by E. coli and one with bacteremia
caused by S. pneumoniae [35]. Of the febrile infants with focal infections, 30 had a lumbar
puncture and none had meningitis. The most common focal infections included cellulitis, abscess,
impetigo, and acute otitis media.

Otitis media — We suggest that febrile infants with acute otitis media who are 60 days of
age and younger should be evaluated and managed similarly to febrile infants without acute otitis
media (AOM). (See 'Neonates (28 days of age and younger)' below and 'Infants 29 to 60 days of
age' below.)

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The expert contributors to this topic do not agree regarding the approach to well-appearing healthy
febrile infants older than 60 days of age with AOM and evidence is lacking. Some experts would
do no further studies while others would obtain urinalysis and urine culture alone or with a blood
culture prior to treatment. (See "Febrile infant (younger than 90 days of age): Management",
section on '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'.)

Limited evidence suggests that the risk of IBI in infants younger than 60 days of age is not
increased by the presence of AOM [36-39]. As an example, in a report of 130 patients 60 days and
younger with AOM confirmed by tympanocentesis, the presence of AOM did not predict a higher
risk for serious bacterial infection (SBI) in either febrile or afebrile patients [38]. 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 SBI.

The decision to forego evaluation in afebrile infants younger than 60 days of age with AOM who
are going to receive oral antibiotics should be made with caution. The definition of AOM indicates
the presence of erythema and serous fluid (as can be common in the neonate) or the presence of
purulent fluid behind a nonmobile tympanic membrane (picture 7). The physician should be
confident that the physical findings meet this definition before empiric treatment is prescribed.
Furthermore, it is important to weigh the risk of masking an IBI and the difficult situation that will
arise if the infant subsequently becomes febrile or ill-appearing.

Well-appearing infants (with no focus on exam) — Age and risk factors for infection are the
primary determinants for the evaluation of well-appearing febrile young infants.

Neonates (28 days of age and younger) — We recommend that all febrile neonates
younger than 28 days of age undergo a full evaluation for sepsis, as described above for ill-
appearing infants, including studies to detect herpes simplex virus for neonates with risk factors or
physical examination findings for this infection. (See 'Ill-appearing infants' above and "Neonatal
herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

As noted separately in this topic, neonates who are ill-appearing, have a focal infection, or a
recognizable viral illness (eg, bronchiolitis or influenza) have a substantial risk for IBI. (See 'Ill-
appearing infants' above and 'Focal infection' above and 'Patients with recognizable viral
infections' below.)

Well-appearing neonates also have considerable risk for IBI [6,40,41]. Based upon observational
studies performed since the introduction of conjugate vaccines, the estimated risk for bacterial

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infection in neonates 28 days of age and younger is as follows [40,41]:

Meningitis 0.3 to 3 percent


Bacteremia or sepsis 1 to 5 percent
UTI 16 to 28 percent

However, only about 60 percent of febrile neonates underwent full sepsis evaluations in these
studies; patients who did not undergo testing were assumed to have negative cultures based upon
follow-up. Thus, these estimates may not be precise or generalizable.

Furthermore, strategies for identifying the risk of IBI in well-appearing febrile young infants,
developed prior to the widespread availability of conjugate vaccines, can miss neonates with
invasive bacterial infection (table 1). (See 'Traditional criteria' below.)

In addition, more recent strategies that utilize appearance, CRP, and PCT, CBC, and urinalysis to
stratify risk of bacterial infection without the routine performance of a lumbar puncture still identify
some neonates with IBI as low risk [17,42]. (See 'Risk factors' above and 'Traditional criteria' below
and 'Step-by-step prediction rule' below.)

The approach to well-appearing febrile neonates (younger than 28 days of age) whose preliminary
urine studies suggest a UTI (eg, positive nitrites on dipstick, uncentrifuged sample with a positive
Gram stain or >10 WBCs/mm3, or centrifuged sample with >5 WBCs/hpf) is evolving. Evidence
from small observational studies, suggests that the risk of bacterial meningitis in all neonates with
positive urine studies is approximately 1 to 2 percent and is probably lower in well-appearing
neonates [43,44]. Nevertheless, given the difficulty in discerning well appearance in this age group
and the lack of sensitive predictors of meningitis in neonates with urinary tract infections, we and
most experts still recommend a full evaluation including collection of CSF studies in these patients.

However, one multicenter, prospective study of 766 febrile infants younger than 90 days of age
with an abnormal urinalysis demonstrated a negative predictive value for IBI of 100 percent (95%
CI 97.5-100 percent; prevalence of IBI in all patients, 6.5 percent) when all of the following findings
were present [45]:

Well appearance
Age >21 days
PCT ≤0.5 ng/mL
CRP ≤20 mg/L (2 mg/dL)

Infants 29 to 60 days of age — For former premature febrile infants 29 to 60 days of age,
we adjust the age (chronologic age in weeks – [40 – gestational age in weeks]), which may classify
them as neonates. (See 'Neonates (28 days of age and younger)' above.)

Our approach to the evaluation of well-appearing febrile infants 29 to 60 days of age who do not
have a bacterial focus for infection is described in the algorithm (algorithm 1).
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We recommend that febrile infants 29 to 60 days of age undergo a full sepsis evaluation, as
described for ill-appearing infants above, if they have risk factors for invasive bacterial illness (IBI)
or a rectal temperature ≥38.6°C (101.5°F). (See 'Ill-appearing infants' above.)

Patients with risk factors for IBI and those with rectal temperature ≥38.6°C (101.5°F) are
considered at higher risk for bacteremia and meningitis and have been excluded from most studies
designed to identify low risk criteria in well-appearing febrile infants [6]. (See 'Risk factors' above.)

The evaluation of infants 29 to 60 days of age with a focal bacterial infection is discussed
separately. (See 'Focal infection' above.)

We suggest that well-appearing infants with rectal temperature <38.6°C, no risk factors for IBI, no
infectious focus on examination, and who have not received an immunization within the previous
48 hours undergo the following evaluation:

CBC with differential


PCT (only if results are rapidly available [eg, within 60 minutes])
CRP (only if results are rapidly available [eg, within 60 minutes])
Blood culture
Urinalysis
Urine culture (by bladder catheterization or suprapubic aspiration) (see "Urine collection
techniques in infants and children with suspected urinary tract infection")
Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or
abnormal breath sounds)

These patients should also undergo a lumbar puncture with collection of CSF studies if they
have any one of the following results and are thus candidates for empiric antibiotic therapy
(see "Febrile infant (younger than 90 days of age): Management", section on 'Infants 29 to 60
days of age'):

• WBC count ≤5000/microL, ≥15,000/microL)


• Absolute band count >1500/microL
• PCT >0.5 ng/mL
• CRP >20 mg/L (2 mg/dL)
• If obtained, findings of pneumonia on chest radiograph

A combination of inflammatory markers, including PCT and CRP whenever rapidly available,
provides superior diagnostic accuracy for invasive bacterial infection. The white blood cell count
alone has very poor sensitivity [21]. (See 'Markers of inflammation' below.)

Preliminary urine studies that suggest a UTI such as a positive dipstick for nitrites and leukocytes,
uncentrifuged sample with a positive Gram stain or >10 WBCs/mm3, or centrifuged sample with >5
WBCs/hpf (table 2) do not necessarily indicate a higher risk for meningitis in well-appearing infants

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if all other studies are within normal limits. Some experts do not recommend obtaining CSF studies
in these patients [45].

Our approach to these patients varies among the expert contributors to this topic, options
include:

Obtain CSF. This option is especially appropriate for infants with a temperature >38.6°C or
with abnormal blood studies (WBC count, ABC, and, if rapidly available [eg, within 60 minutes]
elevated PCT or CRP).

Do not obtain CSF. This option is especially appropriate for infants with no abnormalities of
blood studies and a temperature ≤38.6°C.

If a lumbar puncture is planned in a well-appearing infant with signs of a UTI, normal blood studies
and a temperature ≤38.6°C, then the physician should inform the family of the risks and benefits
involved with this approach (eg, the benefit of identifying a rare case of meningitis versus the risks
of lumbar puncture, including a significant risk for a dry or traumatic tap), and include the family's
values and preferences before making the decision to proceed.

Treatment of febrile young infants with preliminary testing that suggests a UTI is discussed
separately. (See "Febrile infant (younger than 90 days of age): Management", section on 'Infants
29 to 60 days of age'.)

The evaluation of patients with clinical findings of bronchiolitis or influenza is discussed separately.
(See 'Patients with recognizable viral infections' below.)

Infants 61 to 90 days of age — For former premature febrile infants 61 to 90 days of age,
we adjust the age (chronologic age in weeks – [40 – gestational age in weeks]), which may classify
them as neonates or infants 29 to 60 days of age. (See 'Neonates (28 days of age and younger)'
above and 'Infants 29 to 60 days of age' above.)

We suggest that well-appearing infants 61 to 90 days of age with no bacterial focus for infection on
examination or a recognizable viral infection such as bronchiolitis or influenza have urine obtained
for culture and either urine dipstick or microscopic urinalysis (algorithm 2). This is especially
recommended for females and uncircumcised males based upon the elevated probability of a UTI
(table 3). Transurethral bladder catheterization is the preferred method for obtaining urine cultures.
Some experts recommend CBC and blood culture for infants in this age range, particularly if they
have not received conjugate vaccines. (See "Urine collection techniques in infants and children
with suspected urinary tract infection", section on 'Transurethral bladder catheterization'.)

Other approaches — Multiple approaches have been proposed for the evaluation of well-
appearing febrile young infants. Of these, the Pediatric Emergency Care Applied Research
Network (PECARN) clinical prediction rule and the step-by-step approach have undergone
multicenter validation [17,46]. Among the traditional approaches developed before the introduction
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of pneumococcal conjugate vaccines and Haemophilus influenzae type B (Hib) vaccines, the
Rochester and the modified Philadelphia criteria have shown the greatest potential for identifying
infants with a low risk for invasive bacterial illness without requiring routine lumbar puncture for all
patients [27,47].

PECARN prediction rule — The PECARN prediction rule was derived and validated to
identify well-appearing febrile infants younger than 60 days at low risk for SBI (eg, urinary tract
infection, bacteremia, and meningitis). In a prospective, observational study of over 1820 well-
appearing, febrile young infants, patients with a normal urinalysis (ie, negative for leukocyte
esterase and nitrite on dipstick and with <5 WBCs per high-powered field), procalcitonin ≤0.5
ng/mL and absolute neutrophil count ≤4,000/microL had a very low risk for SBI. For the validation
group, the negative likelihood ratio was 0.04 and the negative predictive value was 99.6 percent
(95% CI 98.4-99.9; prevalence of SBI: 9.3 percent) [46]. The rule also identified patients at high
risk for SBI with a sensitivity in the validation group of 97.7 percent (95% CI 91.3-99.6) and a
specificity of 60 percent (95% CI 56.6-63.3; positive likelihood ratio for the validation group: 2.24).
Of the 1820 patients in the cohort, the prediction rule misclassified three infants as low risk; two
with UTI and one with bacteremia. The prediction rule performance was similar when used to
predict invasive bacterial infection.

This prediction rule shows promise for identifying febrile young infants (29 to 60 days of age) who
are at low risk of SBI and who can be observed as outpatients without undergoing lumbar puncture
or receiving antibiotics. However, further evaluation of the prediction rule in a larger cohort is
warranted before widespread implementation of the rule [46]. Because of the higher risk of
invasive bacterial illness and herpes simplex meningitis in neonates (age ≤28 days), the
investigators advise a high degree of caution before use of the PECARN prediction rule in this
population; we do not support its use in neonates pending further study.

Step-by-step prediction rule — The recommended approach to evaluation presented in


this topic differs in important ways from the "step-by-step" approach: in some settings where the
results of CRP and PCT are readily available (eg, within 60 minutes), well-appearing infants 22 to
90 days of age do not routinely undergo lumbar puncture if the initial evaluation consisting of a
CBC, CRP, PCT, and urinalysis is normal [17,48]. These patients are observed for 24 hours without
receiving antibiotics and, are discharged if they remain well-appearing [49].

The “step-by-step” approach is based upon prospective observational studies in febrile infants 90
days of age and younger that indicate a low risk for meningitis (<0.2 percent) and bacteremia (<2
percent) when these criteria are met [17,40,42,45,48,49]. In a large multicenter prospective
observational study, the sensitivity and specificity of this approach for detecting bacteremia or
meningitis was 92 percent and 46 percent with a negative predictive value of 99.3 percent
(prevalence of bacteremia or meningitis: 4 percent) [17].

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However, among low risk patients, the prevalence of IBI was still approximately 1 percent and four
infants 22 to 28 days of age classified as low risk by the step-by-step approach had an IBI.
Furthermore, hospitalization rates for 24-hour observation is high among practitioners of this
approach. As an example, in the above study almost 60 percent of febrile infants were
hospitalized. Based on these findings, we urge practitioners to utilize the approach with caution in
infants 21 to 28 days of age. Furthermore, the step-by-step approach may be more resource
intensive than our approach which permits more outpatient management of febrile infants.

In summary, the step-by-step approach appears to identify febrile young infants older than 28 days
of age who are at low risk for IBI but often requires hospital observation for 24 hours in a large
proportion of patients in order to avoid lumbar puncture or empiric antibiotic administration.

Traditional criteria — Prior to the introduction of pneumococcal conjugate vaccines and


Haemophilus influenzae type b (Hib) vaccines, the "Boston," "Milwaukee," "Rochester," and
"Philadelphia" criteria were developed to identify febrile young infants who were at low risk of SBI
such as UTI, pneumonia, bacteremia, or meningitis, and who could be safely managed as
outpatients with or without empiric antibiotic treatment (table 1) [28,36,50,51]. In observational
studies that evaluated the frequency of SBI among well-appearing infants who were considered
low risk by one of the four criteria, SBI was reported in 2.2 percent (range 0 to 6.3 percent) [52].
When analysis was limited to studies that prospectively identified infants at low risk of SBI and
performed outpatient observation with no antibiotics (Philadelphia or Rochester criteria), the
frequency of SBI varied from 0.5 to 1.1 percent in studies that either did or did not include lumbar
puncture as part of the initial evaluation, respectively [53]. However, among febrile neonates (≤28
days of age) identified as low risk by these criteria, the risk of SBI was higher (approximately 3 to 6
percent) [14,15,54-56].

Overall, these four criteria have had high negative predictive values for SBI in febrile infants (94 to
100 percent when prevalence of SBI was approximately 15 percent) [6]. The range of sensitivity
and specificity for SBI utilizing the different criteria varies from 84 to 100 percent and 27 to 69
percent, respectively.

Although successful in identifying a low risk cohort when close outpatient follow-up was assured,
these criteria have had several limitations [6]:

The specificity of these strategies for identifying patients with SBI is poor. Therefore, with the
Boston, Rochester, and Milwaukee strategies large numbers of infants who do not have a
bacterial infection are considered high risk, receive broad-spectrum antibiotics, and may be
hospitalized [28,36]. With the Boston approach, fewer children are hospitalized, but all those
who are discharged receive ceftriaxone.

All of these approaches require extensive laboratory testing, increasing both patient
discomfort and expense.

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Studies performed after the wide availability of rapid viral testing (eg, influenza, RSV,
enterovirus, or respiratory virus panels) suggest that modification of these strategies may be
performed in selected infants with identified viral infections. (See 'Patients with recognizable
viral infections' below.)

Because these criteria fail to adequately identify neonates (≤28 days) at low risk for SBI, the
traditional approach is to perform a complete sepsis evaluation, administer empiric antibiotics,
and hospitalize all neonates [14,15,54-56].

The strategies were developed and tested in urban emergency departments and may not
apply in community primary care settings.

Guidelines that were developed based upon these low risk criteria for SBI in febrile infants have
been inconsistently followed [9,57-60]. As an example, in a prospective observational study of
3066 febrile infants 3 months and younger who had no other major comorbidities and were
evaluated in a pediatric office, practitioners followed the recommended guidelines in only 42
percent of patients; physicians hospitalized 36 percent of infants, performed laboratory testing in
75 percent, and initially treated 57 percent with antibiotics [9]. Despite a less aggressive approach
to testing, 61 of 63 infants (97 percent) with bacteremia/bacterial meningitis were treated with
antibiotics at the initial visit. UTI was diagnosed in 5 percent of patients. Only 4 of 1056 infants (0.4
percent) who were well-appearing, aged 25 days or older, and who had a fever of less than
38.6°C, had bacteremia and/or bacterial meningitis.

On the other hand, 96 percent of infants had more than one contact with their physician during the
illness (either by phone or office visit) indicating the importance of reliable follow-up when a
practitioner decides to forego invasive studies in a well-appearing young infant.

Several factors suggest that a less aggressive approach to testing is reasonable in selected well-
appearing infants at low risk of IBI who have assured follow-up within 12 to 24 hours (see 'Utility of
ancillary studies' below and 'Our approach' above):

Since development of the low risk criteria and publication of related guidelines in 1993 [10],
evidence suggests that the assessment of a combination of WBC count, absolute band count,
PCT, and CRP can identify well-appearing febrile infants 29 to 90 days of age at low risk for
invasive bacterial infection without the need to obtain CSF studies. (See 'Markers of
inflammation' below.)

The prevalence of bacterial meningitis appears to be declining with reported rates of 0 to 0.5
percent in studies performed since the widespread utilization of conjugate vaccines [48,61,62].

The availability of continuous monitoring of blood cultures permits more rapid identification of
bacteremia with an increased ability to intervene before the patient develops clinical
deterioration. (See 'Blood culture' below.)

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As an example, in a case-control study of febrile young infants evaluated from 2011 to 2016 that
included 135 infants with documented IBI, 118 with bacteremia alone, 17 with bacterial meningitis,
and 249 controls, a modification of the Philadelphia criteria that excluded cerebrospinal fluid testing
had a sensitivity of 92 percent and specificity of 35 percent, and all infants older than 28 days of
age with meningitis were classified as high risk [47].

Patients with recognizable viral infections — Despite the concern for invasive bacterial
illness, most young febrile infants have a viral infection (see 'Viral infection' above). Based upon
observational studies, infants 29 to 90 days of age with a "recognizable viral syndrome" or
identified viral infection by highly accurate testing such as human rhinovirus, RSV bronchiolitis,
influenza, enterovirus, or parainfluenza virus have a lower risk for bacteremia or meningitis,
although UTI remains a concern [4-6,63]. For example, in a retrospective study of almost 3000
febrile young infants 29 to 90 days of age who underwent respiratory polymerase chain reaction
panel testing, the risk of invasive bacterial illness was 4.0 percent for infants who tested negative
for respiratory viruses and 1.0 to 1.4 percent for those who tested positive [5]. Thus, evidence
supports limiting diagnostic testing for bacterial illness in well-appearing febrile infants 29 to 90
days of age for whom highly accurate rapid viral testing is positive. The greatest experience
involves evaluation of febrile infants with RSV bronchiolitis and influenza. Testing panels for other
viral pathogens such as human rhinovirus, adenovirus, coronavirus, parainfluenza, and/or human
metapneumovirus exist but are not always readily available and may be cost-prohibitive depending
upon the setting.

In neonates less than 28 days of age who test positive for respiratory viruses, the risk for invasive
bacterial infection remains high enough that full sepsis evaluation is still indicated. For example,
among over 287 neonates who tested positive for respiratory viruses, up to 2.1 percent also had
an invasive bacterial illness [5]. Risk of concomitant bacterial infection decreases with advancing
age and the risk continuum should be evaluated. The following guidelines are general.

Bronchiolitis — The approach to febrile infants younger than 90 days of age with
bronchiolitis, considered a clinically recognizable viral syndrome, depends upon the age of the
patient:

Neonates (28 days of age and younger) – Febrile neonates younger than 28 days of age
with bronchiolitis remain at substantial risk for an IBI and should have a full evaluation [64-66].

Infants older than 28 days of age – Evidence suggests a low prevalence for IBI (<0.01
percent) or UTI (0.5 percent) in well-appearing febrile infants 29 to 90 days of age with
bronchiolitis [67,68]. Thus, evaluation for these infections is not necessary unless there is
another indication (eg, infants with known or suspected urologic abnormality) (algorithm 1 and
algorithm 2) [68]. These patients should also receive further care based upon the degree of
respiratory compromise. (See "Bronchiolitis in infants and children: Treatment, outcome, and
prevention".)

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Multiple retrospective and prospective observational studies demonstrate that the incidence of
bacterial infection (including UTI, bacteremia, and meningitis) among febrile infants older than 28
days with bronchiolitis is lower than in febrile infants without bronchiolitis [4,6,64,65,67,69-77].
However, the risk of bacterial infection among neonates (0 to 28 days of age) is substantial and
does not appear to be altered by the presence of RSV infection [64-66].

UTI is the most common bacterial infection seen in febrile infants with bronchiolitis who are older
than 28 days. Previous studies had established a prevalence of UTI often exceeding the threshold
of 2 percent, at which evaluation for UTI is warranted [67]. However, a more recent meta-analysis,
which defined UTI by positive rapid urine testing (ie, positive urine dipstick or positive urinalysis)
and a positive urine culture, now demonstrates that the risk of UTI in this age group is well below
the threshold for evaluation [68]. Thus, a less aggressive approach to evaluating these patients for
UTI may be appropriate if there are no other indications. (See "Urinary tract infections in infants
and children older than one month: Clinical features and diagnosis", section on 'Decision to
obtain'.)

A systematic review of occult bacterial infection in young infants older than 28 days with clinical or
RSV-positive bronchiolitis indicates that bacteremia is uncommon, occurring in only 5 out of 1749
patients [67]. In addition, this systematic review identified no cases of meningitis.

Taken together, this evidence indicates that limiting laboratory testing in well-appearing febrile
infants older than 28 days of age with bronchiolitis is appropriate and has a low risk for missing
UTI, bacteremia, or meningitis.

Influenza — Similar to bronchiolitis and other clinically recognizable viral infection, we


recommend a full sepsis evaluation in febrile neonates ≤28 days of age regardless of the findings
of rapid influenza testing [6].

As with any other decision point of the fever work up algorithm, ill-appearing febrile infants 29 to 90
days of age also warrant a full sepsis evaluation. (See 'Ill-appearing infants' above.)

We suggest that well-appearing febrile infants 29 to 90 days of age with influenza diagnosed by
highly accurate influenza testing (eg, polymerase chain reaction [PCR] or influenza viral RNA or
nucleic acid detection (table 4)) have urine obtained by transurethral bladder catheterization or
suprapubic aspiration for urinalysis and urine culture. Additional testing is determined by the
patient's age and urine findings (algorithm 1 and algorithm 2). (See 'Infants 29 to 60 days of age'
above and 'Infants 61 to 90 days of age' above.)

Rapid diagnostic tests for the detection of viral neuraminidase or viral antigen are commercially
available for influenza A and B viruses and can be used for rapid point of care testing. However,
test performance is variable and less accurate than PCR or other molecular assays (table 4). 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, the authors of this topic only rely on

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these tests for guiding evaluation and management of febrile young infants during the time of
regional high prevalence for influenza infection, because high prevalence will raise the positive
predictive value. Further, some experts do not feel that rapid tests using viral neuraminidase or
viral antigen detection has sufficient accuracy to guide the evaluation of febrile young infants (see
"Seasonal influenza in children: Clinical features and diagnosis", section on 'Whom to test').
Clinicians must take into account their own laboratory’s method of testing in addition to the
seasonality and local prevalence of disease when making decisions regarding influenza as the
source of fever.

Evidence suggests that the risk of bacteremia and meningitis is also lower in infants with positive
rapid influenza testing that has less accuracy than PCR or other molecular assays [6,78]. For
example, in a multicenter trial of 844 febrile infants ≤60 days of age who were tested for influenza,
a significantly lower rate of SBI was noted in the 123 infants who were influenza-positive compared
with the 721 infants who were influenza-negative (2.5 versus 11.7 percent, relative risk 0.19 [95%
CI 0.06-0.59]) [79]. The three infants with SBI in the influenza-positive group all had a UTI; none
had bacteremia or meningitis. By contrast, SBI in influenza-negative patients included 77 with
UTIs, 16 with bacteremia, and 6 with meningitis. In another study of 218 infants younger than 3
months of age with laboratory confirmed influenza, SBI occurred in 5 infants (4 with UTIs [one also
with E. coli bacteremia] and 1 with Salmonella enteritidis bacteremia) [78]. If PCR is used, the rate
of concomitant bacterial infection would likely be even lower than described in these studies.

Recently immunized — Evidence is lacking regarding the best approach to well-appearing


febrile infants 42 to 90 days of age who have received immunizations within the previous 48 hours.
The expert contributors to this topic vary in their practice. The following options are suggested and
assume that the caregiver has the ability to identify worsening of condition and the capability to
adhere to close follow-up:

No testing with close follow-up to ensure that the fever resolves within 48 hours of vaccine
administration – This approach is most applicable to infants older than 60 days of age who are
seen <24 hours after immunization and who have a rectal temperature <38.6°C (101.5°F).

Urine testing including a culture obtained via catheter and subsequent and subsequent
empiric oral treatment for patients in whom preliminary studies suggest a UTI as described
above – This approach may be preferred in febrile infants older than 60 days of age who are
seen greater than 24 to 48 hours after immunizations.

Urine and blood testing as described for well-appearing infants 42 to 60 days of age with CSF
studies obtained if inflammatory markers are abnormal – This approach is favored by some
experts for all immunized infants younger than 60 days who have a rectal temperature
<38.6°C but no other risk factors for IBI. (See 'Infants 29 to 60 days of age' above.)

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Full evaluation for sepsis. This approach is favored by some experts for all immunized infants
younger than 60 days with a rectal temperature >38.6°C or other risk factor for IBI. (See
'Infants 29 to 60 days of age' above and 'Risk factors' above.)

The caregiver's values and preferences should be sought as well, given the lack of evidence to
identify the optimal approach.

Based upon one retrospective observational study of 213 recently immunized febrile infants 6 to 12
weeks of age, the frequency of SBIs (UTI, bacteremia, or meningitis) within 48 hours of
immunization is approximately 3 percent (95% CI 1-5 percent) and within 24 hours of immunization
is 0.6 percent (95% CI 0-2 percent) [80]. UTI was the only SBI reported in this study. Thus,
restricting evaluation initially to consideration of urine testing appears appropriate for well-
appearing febrile infants younger than 60 days of age who are seen within 48 hours of receiving
immunizations.

The evaluation of infants 61 to 90 days of age with ill appearance or focal infections is discussed
separately. (See 'Ill-appearing infants' above and 'Focal infection' above.)

MANAGEMENT

The management of febrile young infants (younger than 90 days of age) is discussed separately.
(See "Febrile infant (younger than 90 days of age): Management".)

UTILITY OF ANCILLARY STUDIES

Markers of inflammation — Studies that have included cohorts of infants younger than 3 months
without an obvious source of fever on physical examination have used a variety of inflammatory
markers to identify infants at low risk of serious bacterial infection (SBI; typically including urinary
tract infection [UTI], bacteremia, meningitis, and pneumonia) and invasive bacterial infection (IBI;
specifically, bacteremia and meningitis) [8,21,28,36,37,50,51,81-87].

Not all ancillary studies or markers of inflammation carry equal diagnostic weight; no single
inflammatory marker has adequate test characteristics to be used in isolation for this purpose
(table 5). Individual and combined measurements of C-reactive protein (CRP) and procalcitonin
(PCT) appear to complement and enhance the ability to detect SBI and IBI in young febrile infants
when used along with urine dipstick, white blood cell (WBC) count, or absolute band count (ABC)
[6,88]. Although a mainstay in years past, studies continue to show that the white blood cell count,
absolute neutrophil count, band to neutrophil ratio, and platelet count lack diagnostic accuracy for
IBI in healthy, well-appearing febrile infants [6,21]. A combination of inflammatory markers,
including procalcitonin and C-reactive protein whenever rapidly available, along with clinical risk
factors and clinical assessment, provides superior diagnostic accuracy for IBI.
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PCT has the best ability to discriminate for low risk of IBI in well-appearing febrile infants
[6,8,86,87,89]. In a multicenter observational study of 1112 well-appearing febrile infants (26
percent with a SBI [UTI, 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 odds ratio [OR] 22) [86]. A PCT <0.5 ng/mL was better
than WBC count, absolute band count, and CRP 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. In a
separate prospective multicenter study of over 2000 well-appearing febrile infants 7 to 91 days of
age, a PCT ≥0.3 ng/mL was optimal for detection of IBI with good discrimination in all ages (area
under the curve for receiver operator characteristic: 0.91) [89].

However, in some clinical settings, PCT has limited availability or a turnaround time that is too long
to influence initial evaluation and treatment. Any evaluation of risk in febrile infants that utilizes
PCT must take this availability into account.

Host RNA biosignatures — Preliminary results suggest that molecular assays using host
ribonucleic acid (RNA) biosignatures may outperform traditional blood markers of inflammation
(table 5) when used to identify febrile infants with bacterial infections. In a prospective, multicenter
study of 279 infants (89 with bacterial infections), 66 classifier genes identified the presence of
bacterial infection with a sensitivity of 87 percent (95% CI 73-95 percent) and specificity of 89
percent (95% CI 81-93 percent); 10 classifier genes distinguished the presence of bacteremia in
111 febrile patients (16 with bacteremia) with a sensitivity of 94 percent (95% CI 70-100 percent)
and specificity of 95 percent (95% CI 88-98 percent) [90]. The post-test negative probability for the
279 infants was 0.2 to 0.4 percent for bacteremia (prevalence 2.1 percent) and 0 percent for
meningitis (prevalence 0.4 percent). Application of a two-gene signature previously used in
children to the data set of infants with definitive bacterial diagnoses and proven viral infections
from the above study yielded similar results (sensitivity 89 percent, specificity 94 percent, area
under the receiver-operator curve 96 percent) [91].

Although early results are promising, molecular assays based upon host RNA biosignatures need
further validation and studies addressing their integration into emergency department to delineate
best practices before they can be clinically implemented.

Urine examination — Due to the high prevalence of UTI, we recommend that a urinalysis and
urine culture be obtained in all febrile young infants [9,29,36] (see "Urinary tract infections in
children: Epidemiology and risk factors", section on 'Prevalence'). Urine specimens should be
obtained by urethral catheterization or, less commonly, suprapubic aspiration. Diagnostic accuracy
is improved when testing is performed on catheterized urine rather than urines collected using a
bag, and urine cultures from bag urine collections are frequently contaminated [92]. (See "Urine
collection techniques in infants and children with suspected urinary tract infection" and "Urinary
tract infections in neonates", section on 'Urine culture'.)

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When UTI is defined as >50,000 colony-forming units (cfus) on urine culture, the urinalysis,
consisting of a dipstick for leukocyte esterase and nitrites and microscopy for WBCs, has high
diagnostic accuracy for UTIs in young febrile infants. In a secondary analysis of a prospective
observational study of over 4000 febrile infants 60 days of age or younger who were evaluated for
UTI (prevalence of UTI: 7 percent), a positive urinalysis consisting of any positive leukocyte
esterase or nitrites on dipstick or >5 WBC/high-power field on microscopy had a sensitivity of 94
percent and a specificity of 91 percent for UTI (table 6) [93]. The positive and negative predictive
values were 43 and 100 percent, respectively.

The urinalysis was more likely to be positive in febrile young infants with a UTI and bacteremia.
When the threshold for a positive urine culture was lowered to >10,000 cfus, the sensitivity
decreased to 87 percent (95% CI 83-90 percent), but the specificity was unchanged. Test
performance for urinalysis did not differ significantly between neonates and infants 29 to 60 days of
age. (See "Urinary tract infections in neonates", section on 'Urinalysis'.)

When UTI is defined as >10,000 cfus, other studies have reported lower sensitivities for urinalysis
ranging from 48 to 81 percent [16,94] and somewhat lower negative predictive values (90 to 98
percent with prevalence of UTI 7 to 10 percent) [6].

Regardless of findings on urinalysis, a urine culture should be sent for all patients because a
negative urine dipstick or urinalysis alone does not exclude a UTI [95,96].

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/hpf to be a
predictor of occult Salmonella infection, including bacteremia [36]. However, a Wright stain of the
stool for WBCs may not be readily available (eg, within 1 to 2 hours). 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.

Blood culture — Blood culture does not help with the immediate assessment of fever but should
be obtained depending upon patient characteristics, including age, risk factors for invasive
bacterial infection, and physical findings as described above. (See 'Our approach' above.)

Rapid detection of bacterial pathogens is possible with automated blood culture techniques,
permitting the identification of positive culture results often within 24 to 36 hours when the volume
of the blood sample is >1 mL and when the patient has not been exposed to antibiotics [97,98].
This is particularly helpful in infants managed as outpatients [53].

Cerebrospinal fluid studies — We recommend that lumbar puncture always be performed in


febrile infants with any one of the following indications:

Age 28 days or younger (see 'Neonates (28 days of age and younger)' above)
Ill appearance (see 'Ill-appearing infants' above)

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Diagnostic evaluation identifies a high risk for invasive bacterial infection (see 'Focal infection'
above and 'Infants 29 to 60 days of age' above)
Seizures

Cerebrospinal fluid (CSF) should be sent for cell count, glucose, protein, bacterial culture, and
Gram stain. In addition, viral studies (eg, PCR for herpes simplex virus [HSV] and enterovirus and
viral culture) should be sent if the clinical picture suggests viral meningitis or CSF pleocytosis is
present. (See "Viral meningitis: Clinical features and diagnosis in children", section on 'CSF
studies'.)

Several observational studies suggest that infants at low risk for meningitis can be identified
without performing a lumbar puncture [36,50,81,83,84,99]. In a retrospective study performed
during the post-conjugate vaccine era, bacterial meningitis was rare (1 of 1188 patients) and did
not occur in patients who met low risk criteria determined by past medical history, physical
examination, white blood cell count, band to neutrophil ratio, blood glucose, urinalysis, and, if
obtained, chest radiograph [99]. Based upon these reports, some experts feel that lumbar puncture
can be omitted in well-appearing infants older than 28 days of age who meet low risk criteria for
bacterial illness, particularly if the infant has a rectal temperature ≤38.6°C [9]. (See 'Infants 29 to
60 days of age' above.)

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 7). (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 [6]. A chest radiograph is helpful in identifying a source
of infection in infants with at least one clinical sign of pulmonary disease [92]. This was illustrated
in a meta-analysis of 617 febrile infants younger than three months of age [100]. All 361 infants
who had no clinical evidence of pulmonary disease (defined as respiratory rate >50
breaths/minute, rales, rhonchi, retractions, wheezing, coryza, grunting, stridor, nasal flaring, or
cough) had normal chest radiographs. By 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 [101]. 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. (See "Community-acquired pneumonia in children: Clinical features and
diagnosis", section on 'Etiologic clues'.)

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SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Febrile young infants (younger
than 90 days of age)".)

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 topic (see "Patient education: Fever in babies younger than 3 months (The Basics)")

Beyond the Basics topic (see "Patient education: Fever in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

We regard a rectal temperature of 38°C (100.4°F) or greater as fever in infants 90 days of age
and younger. (See 'Definition of fever' above.)

Viral infection is the most common cause of fever in young infants. However, invasive bacterial
infection (IBI) occurs in a significant proportion of febrile infants younger than 90 days of age.
Common bacterial sources in febrile young infants include urinary tract infection (UTI),
bacteremia, soft tissue infection, meningitis, and pneumonia. (See 'Etiology' above.)

The goal of the evaluation is to identify those infants who are at high risk for invasive bacterial
illness and/or herpes simplex virus (HSV) and who therefore require empiric antimicrobial
therapy and hospitalization. The young febrile infant may demonstrate few, if any, interpretable
clues to the underlying illness on physical examination. However, careful assessment and
judicious use of ancillary studies can identify patients at both high and low risk of serious
illness. (See 'Evaluation' above.)

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We recommend a full sepsis evaluation for the following febrile young infants (see 'Our
approach' above):

• All ill-appearing infants (eg, respiratory or circulatory compromise, irritability, poor tone, or
lethargy) (see 'Ill-appearing infants' above)

• Neonates younger than 28 days of age (see 'Neonates (28 days of age and younger)'
above)

• Any infant with findings suggesting HSV infection upon examination (eg, mucocutaneous
vesicles, seizures, or focal neurologic findings), especially those with maternal risk factors
for vertical transmission (see "Neonatal herpes simplex virus infection: Clinical features
and diagnosis", section on 'Clinical suspicion')

• Infants younger than 60 days of age (corrected for prematurity as indicated) with any one
of the following risk factors for IBI (see 'Infants 29 to 60 days of age' above):

- Rectal temperature ≥38.6°C


- Congenital or chromosomal defects known or suspected to increase the risk of
infection
- Technology dependent (eg, home oxygen, home ventilator, indwelling central line)
- Antibiotic therapy in past 3 to 7 days
- In neonates younger than 28 days of age, maternal factors (eg, peripartum fever,
prolonged rupture of membranes, or positive vaginal culture for group B
Streptococcus [GBS])

• Infants 29 to 90 days of age (corrected for prematurity as indicated) with a focal infection
(eg, cellulitis, abscess, osteomyelitis, bacterial arthritis, or bacterial pneumonia) and ill
appearance or abnormal white blood cell count, absolute band count (ABC), or
inflammatory markers (procalcitonin [PCT] and/or C-reactive protein [CRP]).

Because these patients will undergo empiric treatment with antibiotics, some experts
advocate for a lumbar puncture in all febrile infants 29 to 90 days of age with a focal
infection to minimize the risk of missing bacterial meningitis, especially patients with focal
infections likely to be caused by GBS, such as septic arthritis or osteomyelitis. (See 'Focal
infection' above.)

We suggest that well-appearing febrile infants 29 to 60 days of age who do not have a focal
bacterial infection, risk factors or findings of HSV infection, and other risk factors for invasive
bacterial infection and who have a rectal temperature <38.6°C (101.5°F) undergo the following
evaluation (algorithm 1):

• Complete blood count (CBC) with differential


• PCT (only if results are rapidly available [eg, within 60 minutes])
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• CRP (only if results are rapidly available [eg, within 60 minutes])


• Blood culture
• Urinalysis
• Urine culture (by transurethral bladder catheterization or suprapubic aspiration)
• Chest radiograph in patients with signs of respiratory illness (eg, cough, tachypnea, or
abnormal breath sounds)

These patients should also undergo a lumbar puncture with collection of cerebrospinal
fluid (CSF) studies if they have any one of the following results and are thus candidates
for empiric antibiotic therapy (see "Febrile infant (younger than 90 days of age):
Management", section on 'Infants 29 to 60 days of age'):

- White blood cell count ≤5000/microL, ≥15,000/microL


- ABC >1500/microL
- PCT >0.5 ng/mL (if obtained)
- CRP >20 mg/L (2 mg/dL, if obtained)
- If obtained, findings of pneumonia on chest radiograph

We also suggest a less extensive evaluation for the following patients as described above:

• Well-appearing febrile infants 28 to 90 days of age who have a recognizable viral infection
(eg, bronchiolitis, croup, influenza, or enterovirus) (algorithm 1 and algorithm 2) (see
'Patients with recognizable viral infections' above)

• Well-appearing febrile infants 61 to 90 days of age without a focal bacterial infection on


examination (algorithm 2) (see 'Infants 61 to 90 days of age' above)

Evidence is lacking regarding the best approach to well-appearing febrile infants 42 to 90 days
of age who have received immunizations within the previous 48 hours and febrile infants over
60 days of age with acute otitis media. The expert contributors to this topic vary in their
practice. Options for testing are provided above. (See 'Recently immunized' above and 'Otitis
media' above.)

Other causes of ill appearance in addition to sepsis include congenital heart disease,
congenital adrenal hyperplasia, inborn errors of metabolism, malrotation with volvulus, and a
variety of other conditions. Infants with clinical manifestations suggesting a diagnosis other
than or in addition to serious infection warrant additional studies based upon specific findings
as discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of
age)", section on 'Causes' and "Approach to the ill-appearing infant (younger than 90 days of
age)", section on 'Evaluation'.)

The management of febrile young infants 90 days of age and younger is discussed separately.
(See "Febrile infant (younger than 90 days of age): Management".)

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Topic 6072 Version 46.0

Contributor Disclosures
Hannah F Smitherman, MD Nothing to disclose Charles G Macias, MD, MPH Nothing to
disclose Stephen J Teach, MD, MPH Nothing to disclose Sheldon L Kaplan, MD Grant/Research/Clinical
Trial Support: Pfizer [Streptococcus pneumoniae (PCV13, linezolid)]; Merck [Staphylococcus aureus
(Tedizolid)]; Allergen [Osteomyelitis (Ceftaroline)]. Consultant/Advisory Board: Pfizer [Staphylococcus aureus
(PCV13, linezolid)]. Other Financial Interest: Pfizer [Speaker on PCV13, linezolid]; Medscape [Video
discussion on bacterial meningitis]; Elsevier [Co-editor (Feigin and Cherry Textbook of Pediatric Infectious
Diseases)]. 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
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