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

Authors:

Hannah F Smitherman, MD

Charles G Macias, MD, MPH

Section Editors:

Morven S Edwards, MD

Stephen J Teach, MD, MPH

Deputy Editor:

James F Wiley, II, MD, MPH

Contributor Disclosures

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

Literature review current through: Sep 2016. | This topic last updated: Sep 19, 2016.

INTRODUCTION — The management of febrile infants younger than 90 days of age is discussed in this topic.

For a discussion of the outpatient evaluation of febrile infants younger than 90 days of age; definition of fever in the young infant; the diagnosis, evaluation, and initial management of fever and early-onset sepsis in neonates (younger than 7 days of age); and the approach to an ill-appearing infant without fever refer to the following topics:

●(See "Febrile infants (younger than 90 days of age): Outpatient evaluation".)

●(See "Febrile young infants (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 less than 3 months of age and the majority of studies establishing the risk of serious infections in febrile young infants have 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 young infants (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 young infants (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

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 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 [1]. However, careful assessment and judicious use of ancillary studies can identify patients at both high and low risk of IBI. (See "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Our approach'.)

Our approach to the evaluation of febrile young infants is discussed separately. (See "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Our approach'.)

MANAGEMENT — The age and the results of the evaluation stratify the level of risk for serious bacterial or viral infection and determine the management of febrile young infants.

Ill-appearing — Regardless of age or degree of highest measured temperature, infants who are ill-appearing, have a weak cry, or other abnormal behaviors have a higher risk of bacterial infections such as urinary tract infection (UTI), pneumonia, bacterial gastroenteritis, bacteremia, and/or meningitis or herpes simplex virus (HSV) infection [2,3]. In addition, infants who are ill-appearing but have normal or low temperature are also at significant risk for infection as are those who are well-appearing with a low temperature.

Because up to 45 percent of ill-appearing young infants may have invasive bacterial infections (IBIs) [1], such infants should undergo the following treatment:

●Identify and treat septic shock – Many ill-appearing infants have sepsis and require resuscitation and goal-directed therapy. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Rapid recognition' and "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Resuscitation'.)

●Identify and treat other causes of ill appearance – Other causes of ill appearance in addition to sepsis include congenital heart disease, congenital adrenal hyperplasia, inborn errors of metabolism, malrotation with volvulus, or a variety of 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'.)

●Ancillary studies – Ill-appearing infants warrant a full evaluation for sepsis as described separately. (See"Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Ill-appearing infants'.)

●Empiric antimicrobial – Empiric antimicrobial therapy using dosing for severe infections, meningitis, or septicemia should be given as soon as possible regardless of the initial laboratory results. Some ill-appearing infants may be too unstable from a respiratory or hemodynamic standpoint to undergo a lumbar puncture (LP); in such cases, antimicrobial therapy should not be withheld or delayed.

Specific agents vary by age as follows (table 1):

•0 to 28 days of age:

-Ampicillin and

-Cefotaxime or gentamicin and

-Acyclovir

-Add vancomycin for those infants with septic shock or evidence of focal skin and soft tissue infections in regions with a high prevalence (>10 percent) of methicillin-resistant Staphylococcus aureus (MRSA). (See "Management and outcome of sepsis in term and late preterm infants", section on 'Late-onset sepsis' and "Suspected methicillin-resistant Staphylococcus aureus skin and soft tissue infections: Evaluation and management in children >28 days", section on 'Systemic antimicrobial therapy'.)

•29 to 60 days of age:

-Ceftriaxone or cefotaxime and

-Ampicillin (to cover Group B Streptococcus, Enterococcus species, and Listeria monocytogenes in susceptible infants) and

-Vancomycin (to cover meningitis and Streptococcus pneumoniae that is not susceptible tocefotaxime or ceftriaxone)

-Add acyclovir for those infants with vesicular rash and/or suggestive laboratory findings (eg, elevated liver enzyme studies) of HSV infection, which is unusual beyond 4 weeks of age and exceeding unlikely beyond 6 weeks. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations' and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

•61 to 90 days of age:

-Ceftriaxone or cefotaxime and

-Vancomycin (to cover meningitis and S. pneumoniae that is not susceptible to cefotaxime orceftriaxone)

●Hospital admission – Ill-appearing febrile infants are at higher risk of decompensation and may have early or established septic shock that requires acute and ongoing resuscitation. They typically warrant admission to a pediatric-capable intensive care facility. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Resuscitation'.)

Herpes simplex virus infection — Febrile young infants with clinical findings that suggest HSV infection should undergo a full sepsis evaluation, receive empiric acyclovir and antibiotics, and be admitted to the hospital.

Appropriate testing for HSV should be obtained before the initiation of acyclovir, whenever possible. Testing for HSV infection is discussed in greater detail separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV'.)

Indications for acyclovir therapy include:

●Laboratory proven HSV infection (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV')

●Clinically suspected HSV infection (figure 1), pending viral studies (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations')

●Selected asymptomatic neonates at risk due to exposure (maternal active genital lesions) (algorithm 1) (see "Neonatal herpes simplex virus infection: Management and prevention", section on 'Management of the asymptomatic exposed infant')

Other indications for initiation of empiric acyclovir are not standardized (see "Neonatal herpes simplex virus infection: Management and prevention", section on 'Indications'):

●Many experts recommend empiric treatment for ill-appearing neonates with fever or aseptic meningitis until results of HSV workup are known; we routinely give acyclovir to these patients in the first 4 weeks of life. (See 'Ill-appearing' above.)

●Evidence is lacking and expert opinions differ regarding the relative benefits, risks, and cost-effectiveness of empiric acyclovir before virologic confirmation in the following clinical situations:

•Cerebrospinal fluid (CSF) pleocytosis with a predominance of mononuclear cells in an otherwise well-appearing infant older than 28 days of age – In the absence of other risk factors for or signs of HSV infection we typically do not give acyclovir to these patients.

•Persistent or recurrent erythema or purulence/crusting at the site of a scalp electrode withoutvesicles – In the absence of other risk factors for or signs of HSV infection we typically do not giveacyclovir to these patients.

•Fever without localizing signs in an infant ≤21 days of age – In the absence of other risk factors for or signs of HSV infection (eg, hemodynamically stable patients with no cutaneous vesicles and normal liver enzymes, platelet count, and chest radiograph) it is controversial whether to start acyclovirpresumptively based upon age alone and infectious disease experts disagree on the best approach. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Indications'.)

If acyclovir is given, appropriate testing for HSV should be performed (table 2). The authors favor treating these patients pending results of HSV testing and when CSF shows a pleocytosis.

Focal infection

Otitis media — Febrile infants younger than 60 days of age with acute otitis media (AOM) should receive treatment based upon their age and the results of the initial evaluation. (See 'Neonates (28 days of age and younger)' below and 'Infants 29 to 60 days of age' below.)

Evidence suggests that the risk of IBI in infants younger than 60 days of age is not increased by the presence of AOM and that evaluation and treatment should be based upon other clinical features [4-7]. (See "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Otitis media'.)

The expert contributors to this topic differ in their management of well-appearing healthy febrile infants 61 to 90 days of age with AOM and evidence is lacking regarding the best management.

Options include:

●No testing and administration of oral antibiotics (eg, amoxicillin) – This approach may be most appropriate for infants approaching 90 days of age with rectal temperature ≤38.6°C.

●Obtain urinalysis and urine culture alone or with a blood culture prior to administration of oral antibiotics (eg, amoxicillin) – This approach may be most appropriate for infants closer to 60 days of age with rectal temperature ≥38.6°C.

The contributors do not suggest CSF studies in these patients, if they are otherwise well-appearing.

Regardless of approach, these patients require close follow-up to ensure that the fever resolves by 48 hours and that the patient remains well-appearing.

Evidence is limited regarding the incidence of IBI and pathogens isolated among previously healthy and well-appearing infants 61 to 90 days of age with fever and otitis media. In one observational study of 52 unimmunized infants younger than 3 months of age with AOM who underwent tympanocentesis, blood, urine, and CSF cultures were negative in all patients [8]. S. pneumoniae was the most frequent middle ear pathogen with 99 percent of isolates susceptible or intermediately susceptible to penicillin. Given the lack of impact of AOM on the frequency of IBI in infants younger than 60 days of age and the low risk of bacteremia in well-appearing infants 61 to 90 days of age without AOM, the measurement of a white blood cell (WBC) count, inflammatory markers (eg, C-reactive protein [CRP] or procalcitonin [PCT]), and blood culture likely has limited utility for management of these patients. (See 'Infants 61 to 90 days of age' below.)

Nevertheless, the presence of an AOM does not exclude the possibility of a UTI and the true prevalence of bacteremia in these infants is uncertain. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Younger children'.)

Other focal bacterial infections — The physician should tailor the diagnostic evaluation based upon the specific focal infection. The evaluation of febrile young infants with focal infection is discussed separately. (See"Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Focal infection'.)

Febrile young infants with a focal infection should receive an empiric antibiotic regimen designed to cover perinatal pathogens and organisms commonly associated with the specific focal infection and be hospitalized. For those not familiar with the treatment of neonatal infections, consultation with a pediatric infectious disease specialist is encouraged. (See "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Focal infection'.)

Our suggested initial empiric regimens by type of focal infection are as follows:

●Abscess, cellulitis, osteomyelitis, or bacterial arthritis – Vancomycin and cefotaxime.

Drainage and culture of any abscesses and, in ill-appearing infants with septic shock, surgical source control should accompany empiric antibiotic therapy. (See "Technique of incision and drainage for skin abscess" and "Septic shock: Ongoing management after resuscitation in children", section on 'Eradicate infection'.)

●Omphalitis – Vancomycin and gentamicin or, in regions with gentamicin-resistant Escherichia coli,cefotaxime; add metronidazole or clindamycin to cover anaerobic infection in infants with foul-smelling umbilical discharge or those born to mothers with amnionitis (see "Care of the umbilicus and management of umbilical disorders", section on 'Omphalitis'):

●Pneumonia – The treatment regimen is determined by age, clinical findings, and prevalence of methicillin-resistant Staphylococcus aureus isolates in the community (MRSA, oxacillin minimum inhibitory concentration [MIC ≥4 mcg/mL]). In regions with high prevalence (generally considered to be >10 percent of isolates), the preferred regimens include:

•Neonates 3 to 28 days of age (late-onset pneumonia) – Vancomycin and gentamicin (see "Neonatal pneumonia", section on 'Late-onset pneumonia')

•Infants 29 to 90 days of age with uncomplicated pneumonia – Ceftriaxone or cefotaxime (see"Pneumonia in children: Inpatient treatment", section on 'Uncomplicated bacterial pneumonia')

•Infants 29 to 90 days of age with complicated pneumonia – Vancomycin and ceftriaxone provide appropriate coverage in most cases, but the choice of antibiotic regimen is determined by severity of illness and potential for nosocomial infection (see "Pneumonia in children: Inpatient treatment", section on 'Empiric therapy')

Use of oxacillin, nafcillin, or clindamycin instead of vancomycin where specified above is appropriate only inwell-appearing infants cared for in regions with low prevalence of MRSA, However, some physicians may wish to administer vancomycin instead of alternative antistaphylococcal antibiotics despite a regional prevalence of MRSA that is 10 WBCs/mm3, or centrifuged sample with >5 WBCs/high-power field [hpf]) is evolving. We and most experts still suggest a full evaluation including collection of CSF studies in these patients, empiric antibiotics to cover typical urinary pathogens in this age group, and hospitalization. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Inpatient parenteral therapy'.)

Our approach acknowledges that criteria developed to stratify risk for IBI in febrile infants fail to adequately identify neonates (≤28 days) at low risk for serious bacterial infection (SBI) (table 3) [10-14]. (See "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Traditional approaches' and "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Step-by-step approach'.)

Infants 29 to 60 days of age — We suggest that febrile infants 29 to 60 days of age who are premature be managed according to their adjusted chronologic age which may reclassify them as neonates:

(Chronologic age [weeks] – (40 – gestational age [weeks]).

Well-appearing infants 29 to 60 days of age who do not have a focal infection on examination should be managed based upon the level of risk for IBI (bacteremia or meningitis) identified by the initial evaluation:

●High risk – The risk of IBI is determined by the presence of key historical risk factors and the results of ancillary testing including the WBC count, absolute band count (ABC), other inflammatory markers if obtained (eg, CRP and/or PCT), urine studies, and, if obtained, chest radiograph (see "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Utility of ancillary studies'):

•Historical risk factors, abnormal blood or CSF studies, or bacterial pneumonia – We recommend that well-appearing infants 29 to 60 days of age with significant historical risk factors, an abnormal WBC count, elevated ABC, elevated inflammatory markers, CSF pleocytosis (if obtained), or, if a chest radiograph is obtained, findings of bacterial pneumonia receive empiric parenteral antibiotics (cefotaxime or ceftriaxone) (table 1). CSF should be obtained for testing, if not already performed,prior to antibiotic administration in these patients. The initial dose of empiric antibiotics should be sufficient to treat meningitis until the results of CSF testing are available. (See "Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Infants 29 to 60 days of age' and"Febrile infants (younger than 90 days of age): Outpatient evaluation", section on 'Risk factors'.)

Because of the high risk for IBI, 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 until the results of cultures (blood and CSF) are available [15].

Many physicians may also prefer to admit infants with historical risk factors, a WBC ≤5000/microL, or a WBC ≥15,000/microL for inpatient antibiotic therapy pending blood and CSF culture results, especially if inflammatory markers (eg, CRP or PCT) are also abnormal.

These recommendations are based upon observational studies that provide test characteristics for combined clinical features and laboratory tests (table 3). Up to 40 percent of well-appearing febrile infants with an abnormal WBC count, ABC, elevated inflammatory markers, or chest radiograph suggesting bacterial pneumonia have bacteremia and up to 5 percent of such patient may have bacterial meningitis although the range of positive predictive values is wide and the estimated baseline prevalence for IBI is low (approximately 1 percent for bacteremia and 0.4 percent for meningitis) [15].

•Abnormal preliminary urine studies and other risk factors – We suggest that well-appearing infants 29 to 60 days of age who have abnormal urinalysis and also have abnormal blood studies, other risk factors for IBI, or a temperature ≥38.6°C (101.5°F) have CSF obtained for testing, if not already performed, and receive empiric parenteral antibiotics in the hospital pending culture results. Initial dosing should be sufficient to treat meningitis until the initial results of CSF testing are available. The suggested empiric regimens for treatment of a UTI in infants younger than 60 days are discussed separately. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Parenteral therapy'.)

Observational studies indicate that approximately 3 to 12 percent of well-appearing febrile infants 29 to 60 days of age with a culture-proven UTI have associated bacteremia [16-19]. Documented meningitis in such patients is rare [16,19].

●Low risk – We suggest that patients who have normal findings on evaluation not receive antibiotics and undergo close observation as an outpatient. Normal evaluation includes all of the following findings:

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

•ABC ≤1500/microL

•PCT 5 WBCs/hpf) but normal blood studies (eg, WBC, ANC, or, if obtained, inflammatory markers), no other risk factors for bacterial infection, and a temperature ................
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