The febrile neonate (28 days of age or younger): Initial management

INTRODUCTION — 

The management of febrile neonates (≤28 days old) undergoing outpatient evaluation is discussed in this topic.

For a discussion of the outpatient evaluation of the febrile neonate; the evaluation and management of febrile infants 29 to 90 days old; the definition of fever in the young infant; the diagnosis, evaluation, and initial management of neonatal sepsis; and the approach to the ill-appearing infant without fever, refer to the following topics:

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

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

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

●(See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at or after 35 weeks gestation" and "Neonatal bacterial sepsis: Treatment, prevention, and outcome in neonates born at or after 35 weeks gestation".)

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

TERMINOLOGY

●Fever – We define fever in neonates as a rectal temperature of ≥38°C (100.4°F). This is the standard for detecting fever in neonates because most studies establishing the risk of serious infections in neonates have relied upon rectal temperatures. (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 is 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 (IBI) – For this topic, IBI refers to bacteremia or bacterial meningitis. IBI replaces the previously used term "serious bacterial infection" (SBI), which includes urinary tract infection (UTI), the most common bacterial infection in febrile neonates. However, urinalysis and urine cultures remain an integral part of a comprehensive evaluation for IBIs because some patients with UTIs also have bacteremia.

APPROACH — 

For febrile neonates, management is determined by age, appearance, and, for neonates 22 to 28 days old who undergo stepwise evaluation, the results of initial ancillary studies.

ILL-APPEARING — 

Regardless of age or degree of highest measured temperature, neonates who are ill appearing, have a weak cry, or have other abnormal behaviors are at higher risk of invasive bacterial infection (IBI) with sepsis and herpes simplex virus (HSV) [1,2]. In addition, neonates 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 over 10 percent of ill-appearing young infants may have IBIs [3-5], 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 1). (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Rapid recognition' and "Children with sepsis 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 neonates warrant a full evaluation for sepsis (table 1).

●Empiric antimicrobial therapy – 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 be given without delay.

Empiric therapy in ill-appearing neonates (table 2) consists of (see "Neonatal bacterial sepsis: Treatment, prevention, and outcome in neonates born at or after 35 weeks gestation", section on 'Admitted from the community' and "Skin and soft tissue infections in neonates: Evaluation and management", section on 'Antimicrobial therapy'):

•Ampicillin and

•Ceftazidime or cefepime or cefotaxime (if available) or gentamicin and

•Acyclovir

•Add vancomycin for infants with septic shock or, in regions with a high prevalence (>10 percent) of methicillin-resistant S. aureus (MRSA), suspicion of selected focal sites of infection outlined below or evidence of focal skin and soft tissue infection in the neonate or a household member (especially the mother)

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

WELL-APPEARING — 

There is no consensus definition for what constitutes a "well-appearing" febrile neonate. 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 with which this topic is in general accord should not be applied when clinicians are uncertain as to whether an infant is well appearing [6]. Furthermore, clinicians should adapt their approach if an infant's appearance deteriorates.

Neonates <7 days old — The management of febrile neonates <7 days old with sepsis, including neonates hospitalized since birth and those admitted from the community, is discussed separately. (See "Neonatal bacterial sepsis: Treatment, prevention, and outcome in neonates born at or after 35 weeks gestation".)

Neonates 7 to 21 days old — Well-appearing, febrile neonates 7 to 21 days old are at substantial risk for invasive bacterial infection (IBI) and, after a comprehensive evaluation for sepsis, should receive empiric treatment with antimicrobial agents (table 2) followed by admission to a hospital with nurses and staff experienced with caring for neonates (algorithm 2) [6]. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation", section on '7 to 21 days old'.)

Empiric antimicrobial treatment is determined by preliminary findings of the evaluation:

●No obvious source of infection – In neonates with no obvious source of infection suggested by initial evaluation, empiric antimicrobial regimens that provide coverage for E. coli, group B Streptococcus (GBS), Enterococcus species, L. monocytogenes, and other potential pathogens are indicated pending culture results (see "Neonatal bacterial sepsis: Treatment, prevention, and outcome in neonates born at or after 35 weeks gestation", section on 'Admitted from the community'):

•Ampicillin and gentamicin or

•Ampicillin and ceftazidime or cefepime (or cefotaxime, if available)

The combination of ampicillin and ceftazidime or cefepime (or cefotaxime, if available) is preferred in regions where there are high rates of gentamicin-resistant organisms, especially E. coli [7]. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Definition and risk factors'.)

Patients at risk due to exposure (maternal active genital lesions) should also undergo evaluation for herpes simplex virus (HSV) infection and receive acyclovir (algorithm 3). (See "Neonatal herpes simplex virus (HSV) infection: Management and prevention", section on 'Initial antiviral therapy'.)

●Suspected urinary tract infection (UTI) – The combination of parenteral ampicillin and gentamicin provides coverage for most common bacterial pathogens. However, with increasing reports of resistant organisms, local surveillance of pathogens and antibiotic susceptibility patterns may be important to determine appropriate initial antibiotic therapy. (See "Urinary tract infections in neonates", section on 'Empiric therapy'.)

●Abnormal cerebrospinal fluid (CSF), traumatic tap, or dry tap – Neonates with CSF results that suggest bacterial meningitis (table 3) or are uninterpretable (traumatic or dry lumbar puncture) warrant treatment with ampicillin, ceftazidime, and gentamicin. (See "Bacterial meningitis in the neonate: Treatment and outcome".)

CSF pleocytosis is also an indication for acyclovir administration prior to virologic confirmation in otherwise well-appearing neonates. For neonates with a traumatic or dry tap, expert opinion differs. Regardless, if empiric acyclovir is given, then a comprehensive evaluation for HSV should be performed prior to acyclovir administration. (See "Neonatal herpes simplex virus (HSV) infection: Management and prevention", section on 'Initial antiviral therapy'.)

●Focal infection – Empiric antibiotics are given according to the specific type of infection. (See 'Focal infection' below.)

The estimated risk for invasive bacterial infection in febrile, well-appearing neonates 0 to 21 days of age is high (bacteremia 3 to 5 percent (figure 1), meningitis 1.1 to 2.7 percent) [6,8,9]. The risk for UTI is higher (16 to 28 percent) [8,10]. Furthermore, clinical decision rules have insufficient ability to stratify neonates 7 to 21 days into lower versus higher risk groups. Empiric parenteral antibiotics in these patients mitigate progression of invasive bacterial illness and the potential development of sepsis.

In addition, indirect evidence for the efficacy of empiric antibiotics in febrile neonates 7 to 21 days old is supported by observational data demonstrating the substantial reduction in sepsis-related infant mortality in the pre- and post-antibiotic eras, although other factors such as secular trends also contribute [11]. Additional support comes from the observation that sepsis-related infant mortality is considerably lower in resource-rich regions where febrile neonates are routinely treated with antibiotics soon after presentation compared with resource-limited countries where timely access to antibiotic therapy may be limited, and initiation of antibiotics in febrile neonates is often delayed [12].

Neonates 22 to 28 days old — Based upon declines in sepsis and bacterial meningitis due to peri-partum GBS prophylaxis and the availability of more rapid blood culture results (typically within 24 to 36 hours), the 2021 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) offers the opportunity to do less treatment in well-appearing, febrile neonates 22 to 28 days old [6]. Our approach to the evaluation of well-appearing febrile neonates 22 to 28 days old is consistent with to the AAP CPG (algorithm 4). For these patients, we suggest use of the Pediatric Emergency Care Applied Research Network (PECARN) low risk rule [13].

Management is determined by results of the evaluation:

●Any IM abnormal – Neonates 22 to 28 days old with any abnormal inflammatory marker (IM) (table 4) and CSF pleocytosis require empiric parenteral antimicrobial agents (table 2) and admission to an inpatient setting with personnel experienced in managing neonates until cultures and other pertinent pathogen testing are final. Patients in whom CSF is not interpretable (bloody tap) or is not obtained (dry tap) also require parenteral antimicrobial agents and inpatient admission.

Patients who have abnormal IM and interpretable CSF studies that show no CSF pleocytosis also require empiric parenteral antimicrobial agents. For these patients, we suggest parenteral administration of empiric antimicrobials and hospital admission until cultures are final. Alternative approaches after shared decision-making with the parent/primary caregiver include:

•Observation in the hospital with or without antimicrobial therapy until blood, urine, and CSF cultures, and other pertinent pathogen testing are complete.

•Administration of intramuscular ceftriaxone in the emergency department and discharge home for observation. This option may occur only when the parents/primary caregivers and clinician agree that:

-The family has reliable phone and transportation to return if pending blood or CSF cultures become positive.

-The caregiver is willing and able to observe the infant for deterioration.

-Follow-up and administration of a second dose of intramuscular ceftriaxone within 24 hours of the first dose is ensured.

For patients who receive intramuscular ceftriaxone and discharge home, another consideration is that ceftriaxone alone is not adequate coverage for infection by L. monocytogenes or Enterococcus species.

●All IMs normal – If procalcitonin (PCT), C-reactive protein (CRP), and absolute neutrophil count (ANC) are normal, further evaluation and management should involve shared decision-making with the parent/primary caregiver. Further management depends upon whether the clinician performs a lumbar puncture (LP) and obtains interpretable CSF:

•CSF studies not obtained – For patients who do not have CSF studies obtained, we suggest hospital observation with or without empiric antibiotics.

Evidence suggests that the risk of IBI (primarily bacteremia) in such patients is very low (0.2 to 0.7 percent) [6,14-16]. Furthermore, clinical decompensation prior to the availability of blood and urine culture results during hospital observation appears to be rare [5,8,12,15,17,18]. Thus, clinicians may reasonably choose to withhold antibiotics while awaiting culture results. In general, CSF studies are recommended prior to initiating antibiotics, although in these patients, the risk of partially treated meningitis is low.

•CSF studies obtained – Options in neonates 22 to 28 days old with normal IM who have CSF obtained include:

-Normal CSF results – As determined by shared decision-making with the parents/primary caregivers, hospital observation with or without empiric antimicrobials (table 2) or intramuscular ceftriaxone and home observation as described above for neonates 22 to 28 days old with abnormal blood IMs. The same conditions apply for home observation as described above for patients with abnormal IMs and no CSF pleocytosis.

-Traumatic lumbar puncture (>10,000 red blood cells (RBCs)/mm³) – Hospital observation with or without empiric antibiotics based upon shared decision-making.

-CSF not obtained (dry tap) – Hospital observation with or without empiric antibiotics.

•Positive urinalysis (UA) – Febrile neonates 22 to 28 days old whose UA is positive require antibiotics while awaiting urine culture results. We also suggest that the clinician admit these patients to an inpatient unit with personnel experienced in managing neonates for observation until blood and, if obtained, CSF culture results are complete. (See "Urinary tract infections in infants older than one month and children younger than two years: Acute management, imaging, and prognosis", section on 'Inpatient management'.)

However, administration of intramuscular ceftriaxone in the emergency department and discharge home for observation is an acceptable alternative if:

-The family has reliable phone and transportation to return if pending blood or CSF cultures become positive

-The caregiver is willing and able to observe the infant for deterioration

-Follow-up and administration of a second dose of intramuscular ceftriaxone within 24 hours of the first dose is ensured

A prediction rule has been validated using data from over 1000 well-appearing febrile infants ≤90 days of age in Europe [19]. Well-appearing febrile infants ≤90 days of age at low risk for IBI were identified despite a positive urine dipstick based upon age >15 days, normal procalcitonin (<0.6 ng/mL) and C-reactive protein (<20 mg/L) with a negative predictive value of 100 percent (95% CI 97.3-100 percent, IBI prevalence 4.9 percent). However, only a limited number of neonates 22 to 28 days of age were included in this analysis.

FOCAL INFECTION — 

Febrile neonates with a focal infection require empiric parenteral antimicrobial therapy designed to cover perinatal pathogens and organisms commonly associated with the specific focal infection and hospitalization in a unit with nurses and staff experienced with caring for neonates. For those not familiar with the treatment of neonatal infections, consultation with a pediatric infectious disease specialist is encouraged.

Initial empiric regimens for selected focal infections and additional considerations are described separately:

●Abscess, cellulitis, osteomyelitis, or bacterial arthritis (see "Neonatal bacterial sepsis: Treatment, prevention, and outcome in neonates born at or after 35 weeks gestation", section on 'Coverage for focal sources of infection')

●Omphalitis (see "Care of the umbilicus and management of umbilical disorders in children", section on 'Omphalitis')

●Mastitis (see "Mastitis and breast abscess in infants younger than two months", section on 'Antimicrobial therapy')

●Pneumonia (see "Neonatal pneumonia", section on 'Initial empiric therapy')

VIRAL INFECTION

Herpes simplex virus infection — Febrile neonates with clinical suspicion for (herpes simplex virus) HSV infection should undergo a full sepsis evaluation, receive empiric acyclovir and antibiotics, and be admitted to the hospital (table 5). Appropriate testing for HSV should be obtained before the initiation of acyclovir whenever possible. Patients with suspected ocular involvement require ophthalmology consultation.

Testing for and management of HSV infection in neonates are discussed in detail separately. (See "Neonatal herpes simplex virus (HSV) infection: Clinical features and diagnosis", section on 'Detection of HSV' and "Neonatal herpes simplex virus (HSV) infection: Management and prevention".)

Influenza — Neonates with influenza warrant antiviral therapy (table 6), as discussed separately. (See "Seasonal influenza in children: Management".)

Other viral infections — Neonates 7 to 28 days of age with diagnosed viral infections still have a significant risk for invasive bacterial infection (IBI) (bacteremia or meningitis) and warrant treatment as if the viral infection is not present. (See 'Neonates 7 to 21 days old' above and 'Neonates 22 to 28 days old' above.)

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 – For febrile neonates, management is determined by age, appearance, and, for neonates 22 to 28 days old who undergo stepwise evaluation, the results of initial ancillary studies. Admitted patients should receive care in units with nurses and ancillary staff experienced in the care of neonates.

●Ill-appearing – Ill-appearing febrile neonates require treatment for sepsis and septic shock (algorithm 1) in an intensive care unit. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric regimens' and "Neonatal bacterial sepsis: Treatment, prevention, and outcome in neonates born at or after 35 weeks gestation", section on 'Admitted from the community'.)

●Well-appearing – The management of well-appearing neonates varies by age:

•Neonates ≤21 days old – For well-appearing, febrile neonates ≤21 days old, we recommend empiric parenteral antimicrobial therapy (table 2 and algorithm 2) (Grade 1B). These patients also require hospital admission. (See 'Neonates 7 to 21 days old' above.)

•Neonates 22 to 28 days old – For well-appearing, febrile neonates 22 to 28 days old with abnormal inflammatory markers, we suggest empiric parenteral antimicrobial therapy and hospital admission pending culture (Grade 2C).

However, for patients with normal blood inflammatory markers, initial urine testing, and (if obtained) cerebrospinal fluid (CSF) studies, alternative approaches as suggested by expert guidelines including outpatient management are reasonable (algorithm 4). (See 'Neonates 22 to 28 days old' above.)

However, outpatient management may occur only when the parents/primary caregivers and clinician agree that:

-The family has reliable phone and transportation to return if pending blood or CSF cultures become positive

-The caregiver is willing and able to observe the infant for deterioration

-Follow-up and administration of a second dose of intramuscular ceftriaxone within 24 hours of the first dose is ensured

For patients who receive intramuscular ceftriaxone and discharge home, another consideration is that ceftriaxone alone is not adequate coverage for infection by L. monocytogenes or Enterococcus species.

●Additional considerations:

•Focal bacterial infections (pneumonia, skin, breast, bone, or joint) – Febrile neonates with focal infections should receive empiric parenteral antimicrobial therapy appropriate to provide broad coverage of the specific infection and undergo hospital admission. For those not familiar with the treatment of neonatal infections, consultation with a pediatric infectious disease specialist is encouraged. (See 'Focal infection' above.)

•Viral infection – Neonates 7 to 28 days of age diagnosed with other viral infections still have a significant risk for invasive bacterial infection (IBI) and warrant empiric antibiotic treatment as if the viral infection is not present. (See 'Other viral infections' above.)

In addition, febrile neonates with the following viral infections require antiviral therapy:

-Herpes simplex virus (HSV) – Febrile neonates with clinical suspicion of HSV infection should also receive empiric acyclovir; patients with suspected ocular involvement require ophthalmology consultation (table 5). (See "Neonatal herpes simplex virus (HSV) infection: Management and prevention".)

-Influenza – Neonates with influenza warrant antiviral therapy (table 6), as discussed separately. (See "Seasonal influenza in children: Management".)