The febrile infant (29 to 90 days of age): Management

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

The outpatient evaluation of febrile infants younger than 90 days of age; the definition of fever in the young infant; the diagnosis, evaluation, and initial management of fever and early-onset sepsis in neonates (younger than seven days of age); and the approach to an ill-appearing infant are discussed separately:

●(See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

●(See "The febrile infant (younger than 90 days of age): Definition of fever".)

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

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

TERMINOLOGY

Fever — Rectal temperatures are the standard for detecting fever in infants younger than three months of age, and most 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) as fever in infants ≤90 days of age. (See "The 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 "The febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

Invasive bacterial infection — For this topic, invasive bacterial infection (IBI) refers to bacteremia or meningitis.

Well-appearing — There is no consensus definition for what constitutes a "well-appearing" febrile young infant. The distinction between "well" and "ill" may not be clear cut, and an infant's appearance may change rapidly. Because of the difficulties in assessing well appearance, the clinical practice guideline (CPG) for well-appearing, febrile infants 29 to 60 days with which this topic is in general accord should not be applied when clinicians are uncertain as to whether an infant is well appearing [1]. Furthermore, clinicians should adapt their approach if an infant's appearance deteriorates.

MANAGEMENT — The age and the results of initial ancillary studies stratify the level of risk for invasive bacterial infection (IBI; bacteremia or meningitis) and determine the management of febrile young infants 29 to 90 days old.

Well-appearing

Infants 29 to 60 days old — In accordance with the 2021 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG), our approach is to manage well-appearing febrile infants 29 to 60 days old without a focal infection on examination based upon the level of risk for IBI (bacteremia or meningitis) (algorithm 1). (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on '29 to 60 days old'.)

Increased risk for invasive bacterial infection — In otherwise well-appearing febrile infants 29 to 60 days old without a focal infection, management of those with an increased risk for IBI (table 1) includes a full evaluation for sepsis (table 2). Further management depends upon the results of the evaluation:

●Risk factors for IBI or abnormal inflammatory markers – For febrile infants with known risk factors for IBI (table 1) or abnormal inflammatory markers (table 3) but no obvious source of infection, we suggest empiric parenteral antibiotics (eg, ceftriaxone or, if available, cefotaxime) (table 4). Cerebrospinal fluid (CSF) should be obtained for testing, if not already performed, prior to antibiotic administration in these patients whenever possible. However, antibiotics should not be delayed if lumbar puncture cannot be accomplished in a timely manner. The initial dose of empiric antibiotics should be sufficient to treat meningitis until the results of CSF testing are available.

Because of the higher risk for IBI, infants 29 to 60 days of age with significant comorbidities (eg, congenital disease, prematurity, or technology dependence), CSF pleocytosis, or a finding on chest radiograph (if obtained) suggesting a bacterial pneumonia require admission to a hospital with nurses and staff experienced with young infants [2].

Many physicians may also prefer to admit infants with historical risk factors (table 1) or abnormal inflammatory markers (table 3) pending blood and CSF culture results [1]. For patients with a single risk factor of antibiotic therapy in the past three days, an alternative approach is to give a single dose of intramuscular (IM) ceftriaxone (50 mg/kg) and discharge the patient to home with ensured follow-up within 24 hours for a second IM dose of ceftriaxone, pending culture results.

These recommendations are based upon observational studies that provide test characteristics for combined clinical features and laboratory tests [2]. Based upon studies that include febrile infants evaluated prior to widespread use of conjugate vaccines, the range of positive predictive values is wide for clinical features, basic laboratory tests alone, or a combination of the two (3 to 71 percent). More recent evidence indicates that the estimated baseline prevalence for IBI is low (approximately 1 to 2 percent for bacteremia and 0.25 percent for meningitis) [1]. In a multicenter study of over 900 febrile infants, IBI occurred in approximately 3 percent of infants with an elevated C-reactive protein or absolute neutrophil count and in 8 percent of patients with an elevated procalcitonin [3].

●CSF pleocytosis – In patients who undergo lumbar puncture, those with CSF pleocytosis require empiric treatment for bacterial meningitis (table 5) and admission to a hospital with nurses and staff experienced in caring for young infants. Although central nervous system herpes virus infection is rare in this age group, patients with a history of active maternal genital herpes lesions at birth or signs of herpes virus infection (table 6) should also receive acyclovir. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Initial antiviral therapy'.)

For patients who have positive and highly accurate CSF testing for enterovirus (eg, reverse transcriptase polymerase chain reaction [RT-PCR]) and no other findings suggesting bacterial infection (including any abnormal inflammatory markers), antibiotics may be discontinued [1]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Laboratory diagnosis'.)

Suspected urinary tract infection — The approach to well-appearing infants 29 to 60 days old who have abnormal urine studies (ie, positive dipstick for nitrites or leukocytes, uncentrifuged sample with a positive Gram stain or >10 white blood cells [WBCs]/mm³, or centrifuged sample with >5 WBCs/high-power field) varies by degree of fever and risk status:

●Risk factors for IBI – For infants 29 to 60 days old, lumbar puncture for testing (if not already performed), empiric parenteral antibiotics, and hospital admission to a unit with nurses and other staff experienced with young infants are warranted if any one of the following are present:

•Any risk factors for IBI (table 1)

•Any abnormal inflammatory marker (table 3)

Because the risk of meningitis in well-appearing infants 29 to 60 days old with a urinary tract infection (UTI) is low, the choice to obtain cerebrospinal fluid (CSF) studies should be a shared decision with the family after discussing risks and benefits of the procedure and incorporating the caregivers' values and preferences [1]. For otherwise healthy infants with elevated inflammatory markers, we suggest not obtaining CSF (see "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Low-risk, well-appearing infants'). The suggested empiric antibiotic regimens for treatment of a UTI in infants younger than 60 days of age are discussed separately. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Parenteral antibiotics'.)

Alternatively, these patients may receive a single dose of IM ceftriaxone (50 mg/kg) and can be discharged to home with ensured follow-up within 24 hours for a second IM dose of ceftriaxone, pending culture results, if all of the following criteria are met:

•Lumbar puncture completed and CSF shows no pleocytosis and a negative Gram stain

•No neutropenia (absolute neutrophil count >500/mm³)

•Chest radiograph (if obtained because of respiratory findings) shows no infiltrate suggesting a bacterial pneumonia

Additional imaging to identify urinary tract abnormalities is also warranted in follow-up for infants with a UTI. The type of study and timing for performance are discussed separately. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Imaging'.)

●Without risk factors for IBI – We suggest that otherwise low-risk, well-appearing infants 29 to 60 days old with abnormal urine studies receive oral antibiotics and close follow-up as an outpatient. These patients should have normal inflammatory markers, and no other risk factors for IBI (algorithm 1). Treatment is guided by local prevalence and patterns of resistance to Escherichia coli. Some physicians may choose to give the first dose of antibiotic parenterally prior to discharge. Some experts admit these patients for parenteral antibiotics. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Parenteral antibiotics' and "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Preferred empiric oral regimens'.)

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/high-power field, do not necessarily indicate a higher risk for bacterial meningitis in well-appearing infants [4-6]. In addition, sterile CSF pleocytosis (usually fewer than 20 cells/microliter), occurs in up to 29 percent of infants with a UTI, which may complicate hospital management and lead to unnecessary and prolonged antibiotic therapy for patients who undergo a lumbar puncture for this indication [5,7,8]. Thus, many experts recommend not obtaining CSF in these patients if they are otherwise at low risk and regardless of results of inflammatory markers [6,9-11]. If the provider feels that CSF should be obtained, this should be a shared decision with the family after discussing risks and benefits of the procedure and incorporating their values and preferences. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on '29 to 60 days old'.)

Timely imaging to identify urinary tract abnormalities is also warranted in follow-up for infants with a UTI. The type of study and timing for performance are discussed separately. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Imaging'.)

Limited evidence from retrospective observational studies supports outpatient management of low-risk, well-appearing infants 29 to 60 days old [10,11]. Such infants are unlikely to have progression of illness after treatment. This alternative approach may be offered to families of infants who meet these additional criteria.

Low risk for IBI — For low-risk, well-appearing febrile infants 29 to 60 days old, we suggest close observation as an outpatient without antimicrobial therapy (algorithm 1). Low-risk findings include:

●No risk factors for IBI (table 1)

●Normal inflammatory markers (table 3)

●Normal urine dipstick or urinalysis

●If obtained, no findings of pneumonia on chest radiograph

●If obtained, CSF with no pleocytosis and a negative Gram stain (although CSF studies are not required to classify the patient as low risk)

Reliable follow-up must be arranged within 24 hours (by return visit to the treating physician or primary care provider). If the social situation suggests that follow-up within 24 hours is problematic (eg, transportation problems, no phone, inability to assess severity of illness, or other concerns regarding parental adherence), then the infant should be admitted to the hospital for observation.

Some experts suggest that infants who are followed as outpatients receive empiric treatment with IM ceftriaxone (50 mg/kg in a single dose) pending culture results. Observational evidence suggests that the risk of IBI in this population is approximately 0.4 to 1.4 percent [2,12]. Thus, approximately 71 to 250 infants would need to receive empiric antibiotics to prevent delayed treatment of one case of bacteremia or meningitis [2]. However, delayed treatment is unlikely with automated blood culture techniques [1].

In addition to ensured follow-up within 24 hours, caregivers must understand that worsening respiratory distress, ill appearance, or inability to feed warrant emergency return for medical care. As an example, rapidly progressive Staphylococcus aureus pneumonia has been described in infants and children with influenza and should be suspected if other members of the family have had or have S. aureus infection. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Clinical spectrum' and "Seasonal influenza in children: Clinical features and diagnosis", section on 'S. pneumoniae or S. aureus coinfection'.)

The risk of IBI (bacteremia or bacterial meningitis) in well-appearing febrile infants 29 to 60 days of age with a temperature <38.6°C (101.5°F) and a normal evaluation is approximately 0.4 percent [2]. Multiple prospective studies that included over 11,000 febrile infants have reported that patients who are at low risk of serious bacterial infection (SBI; bacteremia, meningitis, and other infections such as UTI, pneumonia, or bacterial gastroenteritis) based upon history, physical examination, and whatever laboratory testing has been performed can be safely managed as outpatients [13-15]. In several observational studies, CSF studies were not obtained at the initial evaluation in most febrile infants with no major adverse events reported. In a large administrative database study that evaluated the outcomes of over 49,000 febrile infants 29 to 56 days of age and compared risk of adverse events in hospitals with more versus less CSF testing, there was no increase in adverse events, including delayed diagnosis of meningitis, among the hospitals with less CSF testing (approximately 3 percent unadjusted adverse events for both groups, adjusted difference 0.3 percent [95% CI -0.2 to 0.9]) [16].

Infants 61 to 90 days old — The management of well-appearing infants 61 to 90 days old without focal infection depends upon whether other risk factors for IBI (table 1) are present:

●Risk factors for IBI – For infants who have comorbidities (eg, tracheostomy, in-dwelling central line, or significant congenital anomalies) that raise the risk of IBI, we suggest urine testing, blood inflammatory markers, blood culture, and, if respiratory symptoms are present, chest radiograph.

For patients in whom any blood inflammatory markers are abnormal (table 3), we suggest parenteral antibiotics and admission to the hospital.

Patients with findings of bacterial pneumonia warrant empiric antibiotic therapy (table 7) and hospital admission as discussed separately. (See "Pneumonia in children: Inpatient treatment".)

●No risk factors for IBI – The suggested evaluation for well-appearing febrile infants 61 to 90 days old without risk factors for IBI includes urine dipstick or microscopic urinalysis and urine culture. Management varies by the results of initial urine studies:

•For previously healthy and well-appearing febrile infants 61 to 90 days of age with no risk factors for IBI who have normal preliminary urine testing (negative dipstick for leukocytes and nitrites, <5 WBCs/high-power field on spun urine, or <10 WBCs/mm³ and negative Gram stain of unspun urine), we suggest outpatient observation with close follow-up with their primary care provider.

Patients who have preliminary urine findings indicative of a UTI warrant oral antibiotics and close follow-up as an outpatient. Blood or CSF studies need not be obtained prior to initiating antibiotics. Additional imaging to identify urinary tract abnormalities is warranted in infants with urine cultures results demonstrating a UTI. The type of study and timing for performance are discussed separately. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Imaging'.)

This approach acknowledges the low prevalence of bacteremia and meningitis and the possible low utility of further studies in these patients as discussed below. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Preferred empiric oral regimens'.)

Some contributors to this topic also recommend blood inflammatory markers and blood culture in selected patients, primarily when there is concern about the caregiver's ability to identify progression of illness or when close follow-up is not possible. If obtained, then it is reasonable to treat patients with abnormal urine testing and elevated blood inflammatory markers with parenteral antibiotics either as an outpatient when close follow-up is ensured or in the hospital while awaiting blood culture results. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on '61 to 90 days old' and "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Parenteral antibiotics'.)

The risk of bacteremia for well-appearing febrile infants 61 to 90 days of age is estimated at 0.4 to 1 percent with a risk for meningitis of <0.1 percent [2,17]. This risk is similar to that of older infants. As an example, in a prospective observational study (conducted after the initiation of routine immunization of infants with conjugated pneumococcal vaccine) describing febrile infants 57 to 180 days of age, there was no significant difference in the incidence of bacteremia between those who were 57 to 89 days of age and those who were older (0.9 percent for both) [18]. At this threshold, the measurement of a WBC count, inflammatory markers (eg, C-reactive protein or procalcitonin), and blood culture have limited utility and may lead to unnecessary treatment. For example, the risk of blood culture contamination (approximately 2 percent) exceeds the frequency of bacteremia. However, some experts think the risk of bacteremia in well-appearing infants 61 to 90 days of age is high enough to warrant routine blood culture [17].

Ill-appearing — Regardless of age or degree of highest measured temperature, infants who are ill-appearing, have a weak cry, or have other abnormal behaviors have a higher risk of IBI with sepsis and, from birth through about six weeks of age, herpes simplex virus (HSV) infection [19,20]. In addition, infants who are ill appearing but have normal or low temperature are also at significant risk for infection.

Because over 10 percent of ill-appearing young infants may have IBIs [3,21,22], such infants should undergo the following treatment:

●Identify and treat septic shock – Many ill-appearing infants have sepsis and require resuscitation according to the 2020 Surviving Sepsis Campaign international guidelines (algorithm 2). (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Rapid recognition' and "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", 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 and rapid evaluation for sepsis (table 2).

●Empiric antimicrobial – Empiric antimicrobial therapy using dosing for severe infections, meningitis, or sepsis 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; in such cases, antimicrobial therapy should not be withheld or delayed.

Initial empiric therapy for immunocompetent patients varies by age as follows (see "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric regimens'):

•29 to 60 days of age:

-Ceftriaxone or, if available, cefotaxime and

-Ampicillin (to cover group B Streptococcus [GBS], Enterococcus species, and Listeria monocytogenes) and

-Vancomycin (to cover Streptococcus pneumoniae or S. aureus that is not susceptible to cefotaxime or ceftriaxone)

-Add acyclovir for those infants with vesicular rash and/or laboratory findings suggestive of HSV infection (eg, elevated liver enzyme studies), which is unusual beyond four weeks of age and exceeding unlikely beyond six 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 S. pneumoniae or S. aureus that is not susceptible to cefotaxime or ceftriaxone)

In addition to these regimens, suggested antibiotics in individuals with a suspected genitourinary or gastrointestinal source or who are immunosuppressed are discussed separately. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric regimens'.)

●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 in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Resuscitation' and "Septic shock in children in resource-abundant settings: Ongoing management after resuscitation".)

Viral infections

Herpes simplex virus — Febrile young infants with clinical findings that suggest HSV infection (table 6) or a maternal history of active genital lesions at birth should undergo a full sepsis evaluation, receive empiric acyclovir and antibiotics, and be admitted to the hospital. For an otherwise well-appearing infant >28 days old with CSF pleocytosis (mononuclear cell predominant) and no other risk factors or clinical findings for/signs of HSV infection, we typically do not give acyclovir. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Initial antiviral therapy'.)

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'.)

Among young infants undergoing outpatient evaluation with clinical findings of HSV infection, the overall prevalence of HSV infection is approximately 1 percent but peaks in the second week of life and declines significantly after four weeks of age. Despite the low prevalence of HSV in febrile infants >28 days old in this setting, testing and empiric treatment for HSV is warranted in those with findings suspicious for HSV because early treatment has been shown to improve survival and reduce long-term sequelae. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Incidence and prevalence' and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

Respiratory syncytial virus bronchiolitis or influenza — Febrile infants 29 to 90 days of age with respiratory syncytial virus (RSV) bronchiolitis or influenza have a markedly reduced risk of IBI that permits modification of their evaluation and treatment (see "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Patients with recognizable viral infections'):

●RSV bronchiolitis – Febrile infants 29 to 90 days of age with RSV bronchiolitis and normal urine testing should receive care according to the severity of their bronchiolitis (algorithm 3). They do not require empiric antibiotics. (See "Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

Patients 29 to 60 days of age with abnormal initial urine testing warrant additional laboratory evaluation and management as described separately (see "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on '29 to 60 days old' and 'Suspected urinary tract infection' above).

●Influenza – Febrile infants 29 to 90 days of age with influenza by highly accurate testing (eg, polymerase chain reaction [PCR]) during a period of high seasonal prevalence warrant antiviral therapy (table 8) and, as determined by the results of urine testing, treatment for UTI (table 9 and algorithm 4). (See "Seasonal influenza in children: Management", section on 'Antiviral therapy'.)

Otherwise, they should be managed according to appearance and age as described above. (See 'Ill-appearing' above and 'Well-appearing' above.)

Coronavirus disease 2019 — In young infants, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause fever without any other manifestations, including respiratory symptoms and signs [23,24]. Thus, coronavirus disease 2019 (COVID-19) testing of young infants who require hospital admission for possible IBI is warranted to prevent transmission in the hospital setting. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Criteria for COVID-19 testing'.)

The treatment of COVID-19 in infants is discussed in detail separately. (See "COVID-19: Management in children".)

Enterovirus — RT-PCR for enterovirus in cerebrospinal fluid distinguishes viral from bacterial meningitis in febrile young infants and, for patients with a positive test, permits shorter duration of antibiotic administration and hospitalization. (See "Viral meningitis in children: Clinical features and diagnosis", section on 'Cerebrospinal fluid studies' and "Viral meningitis in children: Clinical features and diagnosis", section on 'Distinguishing viral from bacterial meningitis'.)

A positive blood PCR for enterovirus may also be associated with a reduced risk of IBI in febrile young infants. For example, in a secondary analysis of a single-center registry that included over 700 febrile infants ≤90 days old with blood PCR testing for enterovirus, none of the 174 infants with a positive test had an IBI (0 percent, 95% CI 0-2.1 percent) compared with 2.6 percent (95% CI 1.5-4.4 percent) of infants with a negative test [25]. Approximately 25 percent of positive blood PCR tests occurred outside of the typical enteroviral season. These findings suggest that blood PCR for enterovirus along with clinical findings and other tests may be helpful in determining the risk of IBI in febrile young infants and guide management decisions. However, confirmation in a large multicenter study is necessary before this testing becomes routine.

Other viruses — Testing panels for other viral pathogens such as human rhinovirus, adenovirus, non-SARS-CoV-2 coronavirus, parainfluenza, and/or human metapneumovirus exist but are not always readily available and may be cost prohibitive depending upon the setting. Evidence suggests that IBI is less common in febrile young infants with positive PCR testing for these respiratory viruses but not to the extent that the evaluation or management should be different after consideration of age, appearance, other risk factors, and, if obtained, inflammatory markers. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'PCR positive for other viral infections'.)

Focal bacterial infection (pneumonia, skin, breast, bone, or joint) — 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 "The febrile infant (29 to 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 these infections in young infants, consultation with a pediatric infectious disease specialist is encouraged.

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

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

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

●Omphalitis – Vancomycin and gentamicin or, in regions with substantial (>10 percent) gentamicin-resistant E. coli, ceftazidime or (if available) 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'.)

●Mastitis – Febrile infants warrant empiric parenteral antibiotics tailored to the prevalence of methicillin-resistant S. aureus (MRSA) isolates in the community. Drainage of the abscess should accompany antibiotic treatment. Suggested regimens for infants with uncomplicated mastitis are similar to treatment of abscesses and are provided in the table (table 10). Antimicrobial therapy for patients with severe complications (eg, extensive cellulitis, fasciitis, osteomyelitis, and/or shock) are discussed separately. (See "Mastitis and breast abscess in infants younger than two months", section on 'Antimicrobial therapy'.)

●Pneumonia – The treatment regimen is determined by age, clinical findings, and MRSA isolates in the community. In regions with high MRSA prevalence (generally considered to be >10 percent of isolates), the preferred regimens include:

•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 hospital-associated 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 in well-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 percent.

Acute otitis media — Well- appearing febrile infants 29 to 90 days old with acute otitis media should receive treatment based upon their age, risk for IBI, and the results of the initial evaluation. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Acute otitis media'.):

●Elevated risk of IBI or suspected UTI – For patients with findings that make them at elevated risk for IBI or who have abnormal urine results, management is based upon age as described above for infants 29 to 60 days old (see 'Increased risk for invasive bacterial infection' above and 'Suspected urinary tract infection' above) and for infants 61 to 90 days old. (See 'Infants 61 to 90 days old' above.)

●Low risk for IBI – For patients at low risk for IBI based upon lack of IBI risk factors at all ages and, in infants 29 to 60 days old, results of initial studies, we suggest outpatient management with oral antibiotics to treat otitis media (eg, amoxicillin) with close follow-up pending culture results. (See 'Low risk for IBI' above and 'Infants 61 to 90 days old' above and "Acute otitis media in children: Treatment".)

For all patients, outpatient treatment of young infants with acute otitis media must include extensive parental counseling regarding warning signs of more serious infection and close follow-up. The repeat evaluation should ensure that the fever resolves by 48 hours and that the patient remains well appearing.

Special situations

Traumatic or dry lumbar puncture — A traumatic lumbar puncture can cause small amounts of bleeding into the CSF that can interfere with interpretation of the CSF cell count. Certain formulas have been used to aid in the interpretation of the cell count when the lumbar puncture is traumatic. When the CSF is not grossly bloody, we subtract 1 WBC for every 1000 red blood cells (RBCs)/microL in young infants [26,27]. However, none of the formulas to "correct" the CSF WBC can be used with total confidence to exclude meningitis when the lumbar puncture is traumatic (see "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on 'Predicted WBC count after traumatic tap'). A dry tap occurs when no CSF is obtained.

If interpretable CSF cannot be obtained in febrile infants 29 to 90 days of age, then the patient should receive meningitic doses of parenteral antibiotics, and if indicated (eg, active maternal genital lesions at birth or clinical findings of HSV infection (table 6)), acyclovir while awaiting culture results. Most of these patients also warrant admission. However, for well-appearing infants who do not require empiric acyclovir treatment, close observation at home with ensured follow-up for repeated parenteral antibiotics with 24 hours is a reasonable option because, despite abnormal blood inflammatory markers, the risk of meningitis is low (algorithm 1) [1]. (See 'Increased risk for invasive bacterial infection' above and "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation'.)

Further management is based upon culture results and whether CSF was obtained during initial evaluation:

●Traumatic lumbar puncture – Patients with positive blood culture, CSF culture, or HSV testing warrant further care as discussed separately. (See "Bacterial meningitis in children older than one month: Treatment and prognosis" and "Neonatal herpes simplex virus infection: Management and prevention".)

After initial treatment, the infant with a traumatic lumbar puncture who has done well and has negative blood, urine, and CSF cultures at 48 hours typically does not require a repeat lumbar puncture. Infants receiving acyclovir for possible HSV should receive treatment until all HSV cultures and/or PCR are negative. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Viral culture'.)

●CSF not obtained – Repeat lumbar puncture is required in infants in whom CSF was not obtained and who have positive blood culture, urine culture, or HSV testing because the presence of CSF pleocytosis may necessitate a prolonged course of parenteral antibiotics or acyclovir. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Treatment duration' and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Duration of therapy'.)

Management of infants with negative blood and urine cultures at 48 hours and, if indicated, other testing for HSV depends upon the patient's clinical course during observation. Well-appearing patients who defervesce and whose inflammatory markers normalize may be candidates for additional observation off antibiotics either in the hospital or at home.

Once the physician decides to perform a lumbar puncture, every reasonable attempt should be made to obtain interpretable CSF for studies and culture. However, this task frequently cannot be accomplished in infants ≤90 days old [1]. For example, success rates for obtaining CSF with <10,000 RBCs/mm³ on the first attempt in children range from 45 to 74 percent [28,29], and age <90 days is an important risk factor for not obtaining CSF despite multiple lumbar puncture attempts [29]. If the lumbar puncture is traumatic, the tube in which the CSF is clearest should be sent for a cell count.

Receiving antibiotics — Based upon the half-life of oral antibiotics in young infants, a well-appearing, febrile young infant 29 to 60 days old on prophylactic antibiotics or who has received antibiotics within the previous three days, usually for a urinary tract abnormality, may have an IBI masked by negative culture results. In these patients, we prefer to perform a complete sepsis evaluation with the understanding that, regardless of the results, these patients cannot be classified as "low risk" for IBI. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Definition and risk factors'.)

Further management depends upon the results:

●Abnormal CSF, urine testing, and/or elevated blood inflammatory markers (eg, procalcitonin or C-reactive protein) – Manage as previously described (see 'Increased risk for invasive bacterial infection' above)

●Normal results – Admit to the hospital for observation that includes repeated vital signs and clinical reassessment off antibiotics

OUTPATIENT FOLLOW-UP — Well-appearing infants 29 to 90 days old who are sent home must have follow-up in a clinical setting within 24 hours at which time preliminary culture results (if available) are reviewed. Further treatment should be based upon clinical presentation, laboratory features, and culture results.

Infants who are no longer febrile and a normal physical examination may continue to be observed as an outpatient until culture results are final as can well-appearing febrile infants who have a documented viral source (eg, respiratory syncytial virus [RSV] bronchiolitis or influenza).

Any of the following circumstances warrants additional evaluation and hospitalization for empiric antibiotic therapy (see 'Management' above):

●Any deterioration in clinical status (eg, no longer well appearing or increasing height of fever from prior evaluation)

●A positive blood culture not thought to be a contaminant

●A positive urine culture in an infant who remains febrile

For an infant 29 to 90 days of age with a positive urine culture who is afebrile and well-appearing less than 24 hours after parenteral ceftriaxone, options include a second dose of parenteral ceftriaxone at 24 hours or initiation of oral antibiotics and continued outpatient follow-up. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Choice of antibiotics'.)

DISCHARGE CRITERIA FOR ADMITTED PATIENTS — Early discharge at 24 to 36 hours is feasible in hospitals with continuously monitored blood culture instruments [1]. These systems identify between 77 and 87 percent of all cultures with pathogens [30,31] and 95 percent of critical pathogens (eg, S. pneumoniae, Salmonella and other Enterobacteriaceae, Neisseria meningitidis, groups A and B Streptococcus) within 24 hours [30]. The length of hospitalization for admitted infants whose cultures remain negative depends upon the clinical course of the patient:

●Afebrile and well-appearing – Admitted patients who remain well-appearing during hospitalization and become afebrile are eligible for discharge at 36 hours of negative cultures [13]. In addition, 24-hour discharge may be appropriate for well-appearing patients who have positive viral testing (eg, respiratory syncytial virus [RSV], influenza, or enterovirus) regardless of the presence of fever [1].

Patients sent home before bacterial cultures have been negative for 48 hours must have follow-up within 24 hours either by phone or by visit, at which time preliminary culture results are reviewed. If antibiotics were given in the hospital and diagnostic testing does not identify a viral etiology, then the child should receive an additional dose of antibiotics (eg, ceftriaxone 50 mg/kg daily) until all cultures are final and negative.

●Febrile and well-appearing – For some admitted infants, fever may persist after cultures are negative at 48 hours. For the patient whose clinical condition has improved, a period of observation in the hospital off antimicrobial therapy is a reasonable option. The child who remains ill or who does not improve as expected should be carefully re-evaluated, and further testing, consultation, and treatment options should be pursued.

Use of early discharge criteria has been associated with reduced length of stay without an increase [13]. As an example, implementation of a care plan that permitted discharge at 24 hours for infants 29 to 90 days old with positive viral testing for enterovirus or respiratory viruses, other than rhinovirus (eg, RSV, influenza), and negative bacterial cultures or discharge at 36 hours if both viral testing and bacterial cultures were negative, resulted in a clinically significant decrease in length of stay across a large hospital system without an increase in readmissions for bacterial illness.

CLINICAL PRACTICE GUIDELINES — The 2021 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) for evaluation and management of well-appearing febrile infants 8 to 60 days of age provides a summary of the evidence and multidisciplinary consensus guidance [1].

The use of evidence-based clinical practice guidelines (CPGs) can help standardize care among individual physicians and various institutions. As an example, outcomes for well-appearing febrile infants cared for in four hospitals, including a children's hospital, were assessed before (over 4500 febrile episodes) and after (almost 3000 febrile episodes) the implementation of an evidence-based care process model (EB-CPM) that was derived from the Rochester Criteria (table 11) [13,32]. EB-CPM implementation was associated with significantly increased adherence to recommended diagnostic testing (13 percent increased measurement of complete blood count, urinalysis, and blood and urine culture; 8 percent increase in viral testing for admitted infants) and recommended antibiotic selection (15 percent increased use of recommended antibiotics), a 16-hour decrease in hospital length of stay for admitted patients, and a significantly lower cost per admitted infant.

However, when evidence is still evolving and not definitive, CPGs that promote additional testing in febrile infants may not always have an associated clinical benefit. For example, in a large administrative database study that evaluated the outcomes of over 49,000 febrile infants 29 to 56 days of age, 65 percent of infants treated in hospitals with CPGs recommending routine cerebrospinal fluid (CSF) testing underwent lumbar puncture compared with 48 percent in hospitals without such guidelines [16]. However, the increased CSF testing was not associated with improved clinical outcomes for infants treated in hospitals with CPGs, and adverse events (including delayed diagnosis of meningitis) were not increased in hospitals where fewer lumbar punctures were performed (approximately 3 percent unadjusted adverse events for both groups, adjusted difference 0.3 percent [95% CI -0.2 to 0.9]). Thus, the CPGs that promoted additional testing may have led to more costly care without clinical benefit.

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 5^th to 6^th 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 10^th to 12^th 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

●Approach – The level of risk for invasive bacterial infection (IBI) determines management of febrile young infants 29 to 90 days old. Admitted patients should receive care in units with nurses and staff who are experienced with young infants. (See 'Management' above and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Management'.)

●Well-appearing

•Infants 29 to 60 days old – Well-appearing infants 29 to 60 days of age without a focal bacterial infection on examination should be managed based upon the level of risk for IBI identified by the initial evaluation (algorithm 1) (see 'Infants 29 to 60 days old' above):

-Increased risk for IBI – For well-appearing febrile infants with a risk factor for IBI (table 1) or abnormal inflammatory markers (table 3), we suggest empiric parenteral antibiotics (Grade 2C). For these patients, we suggest ceftriaxone or, if available, cefotaxime rather than other antibiotics (Grade 2C); selected patients may need additional antibiotics (table 4). The antibiotic dose should be sufficient to treat meningitis. Most of these infants warrant admission. (See 'Increased risk for invasive bacterial infection' above.)

-Cerebrospinal fluid (CSF) pleocytosis – Infants with CSF pleocytosis require empiric treatment for bacterial meningitis (table 5) and hospital admission, as discussed separately. (See "Bacterial meningitis in children older than one month: Treatment and prognosis", section on 'Empiric therapy'.)

Patients with CSF pleocytosis and risk factors for herpes simplex virus (HSV) infection (table 6) should also receive acyclovir, as discussed separately. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Initial antiviral therapy'.)

-Abnormal urine studies – For infants 29 to 60 days old with abnormal urine studies and any one of the following: other risk factors for IBI, or temperature ≥38.6°C (101.5°F); we suggest empiric parenteral antibiotics and hospital admission (Grade 2C). Such patients warrant a lumbar puncture, if not already performed. (See 'Suspected urinary tract infection' above and "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Parenteral antibiotics'.)

For infants 29 to 60 days of age with abnormal urine studies who are at low risk for IBI, we suggest oral antibiotics and home observation (Grade 2C). (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Preferred empiric oral regimens'.)

-Low risk for IBI – For well-appearing infants who have undergone appropriate evaluation as summarized in the algorithm (algorithm 1) and who lack the risk factors and laboratory abnormalities discussed in the previous bullets, we suggest close outpatient observation without antimicrobial therapy (Grade 2C), provided that the infant is discharged to a reliable caregiver and follow-up within 24 hours is ensured. (See 'Low risk for IBI' above.)

•Infants 61 to 90 days old – For previously healthy and well-appearing febrile infants 61 to 90 days of age with no risk factors for IBI and who have normal preliminary urine testing, we suggest outpatient observation with close follow-up with their primary care provider (Grade 2C). (See 'Infants 61 to 90 days old' above.)

Patients who have preliminary urine findings indicative of a urinary tract infection (UTI) warrant oral antibiotics and close follow-up as an outpatient, as discussed separately. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Preferred empiric oral regimens'.)

For infants who have comorbidities (eg, tracheostomy, in-dwelling central line, or significant congenital anomalies) that raise the risk of IBI, treatment depends upon results of the evaluation as described separately (see "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on '61 to 90 days old'). For patients in whom any blood inflammatory marker is abnormal (table 3), we suggest parenteral antibiotics and admission to the hospital (Grade 2C).

●Ill-appearing – Ill-appearing febrile infants 29 to 90 days old require a full sepsis evaluation (table 2) and treatment for sepsis and septic shock, as summarized in the figure (algorithm 2) and discussed in detail separately. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric regimens'.)

The evaluation should also identify and treat other causes of ill appearance in young infants as discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)".)

●Recognizable infections – For infants with a recognizable viral infection (eg, HSV, bronchiolitis, influenza) or evidence of a focal bacterial infection, the extent of evaluation depends upon the specific infection, as discussed separately. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Patients with recognizable viral infections' and "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Focal infection'.)

Detailed management of these conditions is provided in separate topic reviews:

•(See "Neonatal herpes simplex virus infection: Management and prevention".)

•(See "Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

•(See "Seasonal influenza in children: Management".)

•(See "COVID-19: Management in children".)

•(See "Pneumonia in children: Inpatient treatment" and "Community-acquired pneumonia in children: Outpatient treatment".)

•(See "Skin and soft tissue infections in children >28 days: Evaluation and management".)

•(See "Acute otitis media in children: Treatment".)

•(See "Hematogenous osteomyelitis in children: Management".)