The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management

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

For a discussion of the 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): Management".)

●(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" and "Management and outcome of sepsis in term and late preterm neonates".)

●(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 meningitis. IBI supplants the previously used term "serious bacterial infection" (SBI), which includes urinary tract infection (UTI).

●Neonatal sepsis – Febrile neonates with a positive blood culture for a bacterial pathogen meet criteria for neonatal sepsis. Sepsis is further defined by the infant's age at the onset of symptoms (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Terminology'):

•Early-onset sepsis is defined either as the onset of symptoms before 72 hours of age or infections with onset at <7 days of life.

•Late-onset sepsis is often defined as the onset of symptoms at ≥72 hours of age. Like early-onset sepsis, there is variability in the definition, ranging from an onset at >72 hours of life to ≥7 days of age.

ETIOLOGY

Viral infection — Viral infection is a common cause of fever in neonates undergoing outpatient evaluation [1-4]. However, neonates with viral infection remain at high risk for concomitant invasive bacterial infection (IBI). Viruses that can cause serious illness in febrile neonates include:

●Herpes simplex virus (HSV) (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis")

●Varicella-zoster virus (see "Varicella-zoster infection in the newborn")

●Some enteroviruses (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention")

●Influenza virus (see "Seasonal influenza in children: Clinical features and diagnosis", section on 'Clinical features')

●Some adenoviruses (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection")

●Respiratory syncytial virus (RSV) (see "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children")

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age')

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

Invasive bacterial infection

Risk factors for IBI — Risk factors for IBI in neonates undergoing outpatient evaluation include (table 1):

●Age – Traditionally, 28 days of age has been used as the threshold for a full sepsis evaluation in neonates with fever [5-9]. More recent evidence from large observational studies indicate that the highest risk for IBI occurs in febrile neonates ≤21 days old (bacteremia 3 to 5 percent, meningitis 1.1 to 2.7 percent) [10,11]. However, the risk for IBI in neonates 22 to 28 days old is still substantial [11]. Febrile neonates evaluated in primary care offices have rates of bacteremia and meningitis of 3 and 1.1 percent, respectively [12].

●Ill appearance – Ill appearance, including lethargy, irritability, respiratory distress, or poor perfusion, significantly increases the risk of IBI in febrile neonates undergoing outpatient evaluation [12-14]. However, signs of IBI may be subtle and difficult to identify.

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

●Maternal group B Streptococcus (GBS) infection – Potential findings that increase the risk for early-onset sepsis in neonates <14 days old include:

•Maternal fever

•Chorioamnionitis typically caused by prolonged rupture of membranes

•Maternal colonization with GBS

GBS screening and maternal intrapartum antibiotic prophylaxis reduce the risk of early-onset GBS infection but do not eliminate it. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors' and "Prevention of early-onset group B streptococcal disease in neonates".)

●Comorbidities or chronic illness – Historically, studies of IBI in young infants have excluded patients with the following comorbidities who are considered at higher risk for IBI [5,11]:

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

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

●Received antibiotics within the prior three to seven days – Because of the long half-lives of antibiotics in neonates, administration from three up to seven days prior to evaluation may mask signs and symptoms of IBI.

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

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

•Limited access to a medical home for questions and/or follow-up

•Lack of transportation

•Language and other communication limitations

Infection source and common pathogens — Urinary tract infection (UTI) accounts for most bacterial infections in neonates undergoing outpatient evaluation for fever [6,9,14]. Bacteremia, cellulitis, meningitis, pneumonia, and osteomyelitis constitute other important but less common infection sources.

Escherichia coli is the most common pathogen causing bacteremia (neonatal sepsis) and bacterial meningitis in febrile neonates presenting for outpatient evaluation, followed by GBS [11,15-18]. E. coli also causes the majority of UTIs in this age group. Other bacterial pathogens include [19-21]:

●Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus (MRSA), usually association with skin, bone, or joint sites of involvement

●Streptococcus pneumoniae

●Enterococcus faecalis

●Gram-negative bacteria such as Enterobacter cloacae, Moraxella catarrhalis, Klebsiella species, and Citrobacter species

●Salmonella species may also cause bacteremia in neonates with diarrhea [22,23]

●Listeria monocytogenes (sporadic cause of late-onset sepsis and meningitis) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Epidemiology')

EVALUATION — The febrile neonate demonstrates few, if any, interpretable clues to the underlying cause of fever on physical examination despite evaluation by experienced clinicians or the use of an observation scale score [11,24,25]. The risk of sepsis and invasive bacterial infection (IBI) remains elevated for all neonates, especially those ≤21 days old [11]. Furthermore, fever may be the only manifestation of late-onset sepsis prior to decompensation. It should be noted that approximately 50 percent of infants presenting with neonatal sepsis are normothermic or hypothermic. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

Stabilization — Unstable neonates who have respiratory or circulatory compromise (eg, apnea, respiratory distress, or signs of shock [eg, tachycardia with poor perfusion]) must be quickly identified and treated (table 2 and algorithm 1). (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Initial stabilization'.)

These ill-appearing patients are at high risk for IBI and warrant a complete evaluation for sepsis (table 3) and prompt administration of empiric antibiotics. (See "Management and outcome of sepsis in term and late preterm neonates".)

In addition to respiratory or circulatory compromise, ill-appearing infants may display irritability, poor tone, or lethargy. A careful physical examination may identify a pattern of clinical features that suggests the etiology of an infant's symptoms and warrants further studies in addition to a sepsis evaluation. (See "Approach to the ill-appearing infant (younger than 90 days of age)", section on 'Evaluation'.)

History — For the febrile neonate, history should focus on identifying risk factors for IBI and on subtle signs and symptoms of illness, including:

●Poor feeding (eg, decreased frequency, amount, or length of feeding; and, for breastfeeding infants, weak sucking)

●Lethargy (eg, increased sleeping or difficulty waking the infant)

●Increased crying

●Weak cry

●Difficulty breathing

For neonates in whom fever is the only presenting symptom reported by caregivers, the clinician should determine how the temperature was taken and the exact reading. Rectal temperatures are the standard for detecting fever in neonates. (See "The febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

Perinatal history should identify maternal risk factors that indicate a higher risk for late-onset neonatal sepsis or herpes simplex virus (HSV) infection:

●Late-onset sepsis (most applicable to neonates <14 days old) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors'):

•Maternal fever

•Maternal colonization with group B Streptococcus (GBS) and/or administration of antibiotic prophylaxis at delivery

•Chorioamnionitis typically caused by prolonged rupture of membranes

●HSV infection (applicable to all neonates) (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Epidemiology and transmission'):

•Active genital lesions at the time of delivery

•Maternal history of sexually transmitted infections (STIs) such as HSV, gonorrhea, and chlamydia

Neonates with the following risk factors also remain at significant risk of IBI and sepsis:

●History of prematurity (gestational age younger than 37 weeks)

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

●Antibiotic administration in the past seven days due to potential masking of a partially treated IBI

Physical examination

Appearance — Ill-appearing neonates require emergency stabilization, comprehensive sepsis evaluation (table 3), and treatment. (See 'Ill-appearing' below.)

For most neonates, comprehensive sepsis evaluation is required despite well appearance. However, selected neonates 22 to 28 days old may undergo a stepwise evaluation (see '22 to 28 days old' below) [11]. Identifying a young infant as well-appearing relies heavily upon the clinician's pediatric knowledge and experience. Prior to the development of a social smile at approximately six weeks of age, this task is especially challenging.

In addition to a careful physical examination, determination that a neonate is well requires observation over time to ensure that the infant feeds well, remains vigorous, maintains normal vital signs, and does not develop new findings suggestive of bacterial illness (eg, tachypnea, tachycardia, pulmonary rales, focal bone or joint tenderness, abdominal tenderness, petechiae, or purpura).

Degree of fever — For most neonates, the height of the fever does not change further evaluation or management.

However, for well-appearing neonates 22 to 28 days old with rectal temperatures ≥38°C (100.4°F) and no obvious source of infection on physical examination, the likelihood of IBI (bacteremia or meningitis) and urinary tract infection (UTI) increases with higher fevers. A rectal temperature >38.5°C (101.3°F) is the recommended threshold for performing more comprehensive evaluation for IBI in these patients [11].

Signs of focal infection — During physical examination, the clinician should look for focal infection as indicated by the following signs:

●Focal bacterial infections

•Acute suppurative otitis media – Bulging and inflammation of the tympanic membrane (picture 1) or perforation of the tympanic membrane with acute purulent otorrhea (rare in neonates) (see "Acute otitis media in children: Clinical manifestations and diagnosis", section on 'Otoscopic evaluation')

•Pneumonia – Tachypnea, respiratory distress (including grunting, flaring, and retractions), decreased oxygen saturation, cough, crackles, or decreased breath sounds on auscultation (see "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical evaluation')

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

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

•Osteomyelitis – Decreased movement of a limb with localized swelling or erythema (see "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Birth to three months')

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

•Mastitis – Unilateral breast redness, tenderness, and induration that may have fluctuance or purulent nipple discharge (see "Mastitis and breast abscess in infants younger than two months")

•Meningitis – Irritability, lethargy, decreased or increased tone on examination, bulging fontanelle (late finding), and nuchal rigidity (rare finding in neonates) (see "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Clinical findings')

●Serious viral infections

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

-Mucocutaneous vesicles (picture 5 and picture 6)

-Seizures, which typically consist of facial automatisms (eg, lip smacking or pursing), eye deviation, or unresponsiveness rather than tonic-clonic motor activity

-Focal neurologic signs

-Respiratory distress, apnea, or progressive pneumonitis

-Conjunctivitis, excessive tearing, or painful eye symptoms

-Sepsis-like illness (fever or hypothermia, irritability, lethargy, respiratory distress, apnea, abdominal distension, hepatomegaly, or ascites)

•Bronchiolitis – Tachypnea, copious nasal discharge, cough, auscultation demonstrating rales and/or wheezing, or apnea (see "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Clinical features')

Ancillary studies

Ill-appearing — Regardless of age, young neonates who are ill appearing are at high risk for IBI and warrant a full evaluation for sepsis (table 3) [9,24,26].

In addition to diagnostic testing to identify IBI and UTI, diagnostic testing for viral etiologies may be warranted in selected patients:

●HSV – Infants with clinical suspicion for HSV infection (table 4) warrant additional blood and cerebrospinal fluid (CSF) studies, surface viral cultures, and scraping from skin vesicles or mucous membranes for additional testing as described separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Neonatal HSV'.)

●Respiratory syncytial virus (RSV) – Ill-appearing infants with clinical findings of bronchiolitis warrant rapid testing for respiratory viruses (eg, RSV) to permit proper infection control measures during hospitalization. However, empiric antibiotics are still indicated. (See 'Other viral infections' below and "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Approach to testing'.)

●Influenza – During high seasonal prevalence, testing for influenza using highly accurate testing (table 5) is helpful for determining the need for continued contact precautions and antiviral treatment in neonates. However, laboratory confirmation is not necessary before initiation of these measures and should not delay their initiation in patients in whom they are indicated. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Whom to test'.)

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – Coronavirus disease 2019 (COVID-19) can cause fever with or without ill appearance in young infants. Therefore, SARS-CoV-2 viral testing (nasal or nasopharyngeal swab for nucleic acid amplification testing [NAAT], which includes polymerase chain reaction [PCR] testing) is indicated for infection control and COVID-19-specific treatment in all hospitalized patients. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age' and "COVID-19: Management in children".)

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

Focal infection — All febrile neonates with focal infections (eg, acute otitis media, cellulitis, abscess, mastitis, pneumonia, osteomyelitis, bacterial arthritis, or omphalitis) require a complete sepsis evaluation (table 3).

For well-appearing, afebrile neonates with acute otitis media, the appropriate evaluation prior to administration of empiric antibiotics is unclear, and clinical practice varies [27]. It is important to be certain that physical findings of acute otitis media (eg, bulging tympanic membrane (picture 1)) are present. For these patients, we suggest obtaining a blood culture before beginning empiric oral antibiotics. Although the absence of fever in such patients is reassuring, it does not completely exclude a systemic process. The decision to forego any evaluation in afebrile neonates prior to administering empiric antibiotics for acute otitis media should be made with caution. It is important to weigh the risk of masking an IBI and the difficult situation that will arise if the infant subsequently becomes febrile or ill appearing. (See "Acute otitis media in children: Clinical manifestations and diagnosis", section on 'Tympanic membrane findings'.)

In a multicenter, retrospective study of 1637 afebrile young infants with acute otitis media (including 100 neonates), none of the 278 patients with blood cultures had bacteremia (0 percent, 95% CI 0-1.4 percent), and none of the 102 infants with CSF cultures had meningitis (0 percent, 95% CI 0-3.6 percent) [27]. The diagnosis of acute otitis media was not routinely verified by subspecialist consultation or tympanocentesis. Two neonates with 30-day follow-up had an adverse event requiring hospitalization, but cultures of blood, urine, and CSF were negative in both patients.

Diagnosed with viral infections — For febrile neonates diagnosed with a viral infection, including RSV bronchiolitis, influenza, COVID-19, or other respiratory viral infections (eg, human rhinovirus, adenovirus, non-SARS-CoV-2 coronavirus, parainfluenza, and/or human metapneumovirus), we recommend a full sepsis evaluation (table 3) for neonates ≤21 days old. We suggest it for neonates 22 to 28 days old. Neonates with a viral infection remain at substantial risk for an IBI that does not appear to differ from neonates with negative testing for viral infection [4,5,28-30]. For example, in a retrospective study of over 287 neonates who tested positive for respiratory viruses, up to 2.1 percent also had an IBI [4]. The risk of concomitant bacterial infection decreases with advancing age in neonates.

Testing panels for viral pathogens such as human rhinovirus, adenovirus, non-SARS-CoV-2 coronavirus, parainfluenza, and/or human metapneumovirus are not always readily available and may be cost prohibitive depending upon the setting.

Evidence regarding the risk of IBI in neonates with SARS-CoV-2 infection is limited [31]. All febrile young infants warrant testing for SARS-CoV-2 regardless of their exposure history as part of the initial evaluation. Furthermore, chest radiographs are strongly encouraged for patients who are positive for SARS-CoV-2, regardless of respiratory symptoms. For those who are well appearing but have positive radiographic findings, hospital admission is advised, especially if oxygen saturation is consistently <95 percent on room air, work of breathing is increased, or feeding is poor. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'In infants <12 months of age' and "COVID-19: Clinical manifestations and diagnosis in children", section on 'Laboratory tests for SARS-CoV-2'.)

Well-appearing — Age and risk factors for bacterial or HSV infection are the primary determinants for the evaluation of well-appearing febrile young neonates. The risk of IBI for otherwise low-risk, febrile neonates is highest in the first three weeks of life and then decreases in the fourth week [11].

<8 days old — The evaluation of neonates <8 days old with possible early-onset sepsis, which includes individuals with fever, is discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

8 to 21 days old — We recommend that all febrile neonates 8 to 21 days of age undergo a full evaluation for sepsis, including studies to detect HSV for neonates with risk factors or physical examination findings for this infection (table 3). (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.)

These patients also warrant empiric antibiotics (table 6) and hospital admission to a unit with nurses and ancillary staff experienced in caring for neonates. (See 'Neonates 8 to 21 days old' below and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Symptomatic neonates'.)

The 2021 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) provides an algorithm for the evaluation and management of well-appearing, 8- to 21-day-old febrile neonates (algorithm 2) [11]. Due to the low risk of UTI in patients with normal urine results, the AAP CPG recommends sending a urine culture (obtained by bladder catheterization or suprapubic aspiration [SPA]) only when the urinalysis is positive (leukocyte esterase present on dipstick, >5 white blood cells (WBCs)/high-power field [centrifuged urine], or >10 WBCs/mm³ [uncentrifuged urine]) [11]. However, it is reasonable for clinicians to send a urine culture obtained by catheterization or SPA in all febrile neonates younger than 21 days old in settings with documented low rates of specimen contamination and with timely specimen processing because false positives are less likely in such settings. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Urine examination'.)

Based upon observational studies performed in febrile neonates presenting to the emergency department or pediatric provider office, the estimated risk for bacterial infection in febrile, well-appearing neonates 0 to 21 days of age is high (bacteremia 3 to 5 percent, meningitis 1.1 to 2.7 percent) [10,11]. The risk for UTI is higher (16 to 28 percent) [10,32]. However, a full sepsis evaluation was not performed in all febrile neonates in these studies; patients who did not undergo testing were assumed to have negative cultures based upon follow-up. Thus, these estimates may be low and may not be precise or generalizable. Nevertheless, the benefit of early detection and treatment of bacterial meningitis or HSV meningoencephalitis outweighs the risks of lumbar puncture. In addition, the ability to rapidly test for enterovirus as the cause of pleocytosis permits earlier discontinuation of antibiotics and hospital discharge.

22 to 28 days old — Neonates with risk factors for IBI (table 1) warrant a full sepsis evaluation (table 3).

The 2021 AAP CPG provides an algorithm for the evaluation and management of well-appearing, low-risk 22- to 28-day-old febrile neonates (algorithm 3) [11]. Our approach to evaluation differs because we consider the height of fever or positive urine studies as risk factors that require a complete sepsis evaluation even if other inflammatory markers (procalcitonin, C-reactive protein, or absolute neutrophil count) are normal:

●Temperature >38.5°C (101.3°F) – For otherwise low-risk, well-appearing, febrile neonates 22 to 28 days old with a rectal temperature >38.5°C, we suggest a full sepsis evaluation (table 3).

●Temperature ≤38.5°C – For low-risk, well-appearing, febrile neonates 22 to 28 days old with a rectal temperature ≤38.5°C, we suggest a full sepsis evaluation. However, a stepwise evaluation is an acceptable option for patients with normal blood inflammatory markers (table 7) [11]:

•Full sepsis evaluation – Traditionally, a full sepsis evaluation has been recommended in all febrile neonates regardless of age because of the poor ability to identify patients with IBI based upon appearance and results of blood and urine studies. However, there is growing evidence that neonates 22 to 28 days of age have a lower risk of IBI when inflammatory markers and urine studies are normal and can be safely managed without CSF studies being performed during the initial evaluation as discussed below [11] (see 'Neonates 22 to 28 days old' below). For this reason, the decision to perform a lumbar puncture in well-appearing febrile infants in this age group should be made as a shared decision between the clinician and family with a mutual understanding of the risks and benefits and with consideration of the family's values and preferences.

•Stepwise evaluation – With a stepwise approach, CSF studies are not obtained unless one or more inflammatory markers is abnormal (eg, procalcitonin, C-reactive protein, or absolute neutrophil count (table 8); rectal temperature >38.5°C (101.3°F) is considered an abnormal inflammatory marker if procalcitonin is not rapidly available). If inflammatory markers and urine studies are normal, clinicians and parents or caregivers may elect not to perform a lumbar puncture. Evidence suggests that the risk of IBI (primarily bacteremia) in such patients is 0.2 to 0.7 percent, which means that interpretable CSF studies would have to be performed in approximately 140 to 500 patients to diagnose one case of meningitis [14,33,34]. For some experts, this risk is low enough to not routinely perform a lumbar puncture in neonates 22 to 28 days old as long as close observation in the hospital is ensured until blood culture results are final [11].

Due to the lower risk of UTI in these patients, the 2021 AAP CPG recommends sending a urine culture (obtained by bladder catheterization or SPA) only when the urinalysis is positive (leukocyte esterase present on dipstick, >5 WBCs/high-power field [centrifuged urine], or >10 WBCs^/mm³ [uncentrifuged urine]) [11]. However, it is reasonable for clinicians to send a urine culture obtained by catheterization or SPA in all febrile neonates younger than 22 to 28 days old in settings with documented low rates of specimen contamination and with timely specimen processing as false positives are less likely in such settings. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Urine examination'.)

Independent analysis of prospective, observational studies from the United States and Europe and a national surveillance study from England suggests that the prevalence of bacteremia in well-appearing, low-risk febrile neonates 22 to 28 days old is approximately 2 to 3 percent [11]. Based upon large United States health care system registry studies, the prevalence of bacterial meningitis is much lower in these neonates (0.3 to 0.4 percent) [32,35]. Given the low prevalence of bacterial meningitis, it is reasonable for clinicians to omit lumbar puncture for patients with normal urine studies, normal inflammatory markers, and no risk factors for HSV infection [11].

●Urine dipstick or urinalysis abnormal – For low-risk, well-appearing febrile neonates 22 to 28 days of age whose preliminary urine studies are abnormal, we suggest CSF studies be obtained regardless of the results of inflammatory markers. Evidence from observational studies suggests that the risk of bacterial meningitis in all neonates with positive urine studies is approximately 1 to 2 percent although the risk appears to be highest in neonates <21 days old [36-38].

Our approach differs from the AAP CPG. Although the AAP CPG recommends performing a lumbar puncture for patients with abnormal urine studies and one or more elevated inflammatory markers, it indicates lumbar puncture may or may not be performed if inflammatory markers are normal [11]. In other observational studies that have included well-appearing neonates 22 to 28 days of age, IBI has occurred in approximately 5 percent of all patients >21 days old with abnormal urine dipstick results (positive leukocyte esterase and/or nitrites); however, bacteremia has accounted for almost all IBIs in these patients, and meningitis has been rare (<1 percent) [39,40]. Based on these studies, the negative predictive value for IBI in patients with an abnormal urine dipstick but normal procalcitonin and C-reactive protein is 100 percent with the lower limit of the 95 percent confidence interval 97.3 to 97.5 percent. Nevertheless, given the difficulty in discerning well appearance in this age group, the lack of sensitive predictors of meningitis in neonates with UTIs, and the limited numbers of patients 22 to 28 days old included in these studies, we still suggest a full evaluation.

MANAGEMENT — Appearance, age, and (for neonates 22 to 28 days old who undergo stepwise evaluation) the results of initial ancillary studies determine management.

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) [9,26]. 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 [14,24,41], 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 "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 neonates warrant a full evaluation for sepsis (table 3).

●Empiric antimicrobial therapy – 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; in such cases, antimicrobial therapy should be given without delay.

Empiric therapy in ill-appearing neonates (table 9) (see "Management and outcome of sepsis in term and late preterm neonates", 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 "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".)

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.

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

●Abscess, cellulitis, osteomyelitis, or bacterial arthritis (see "Management and outcome of sepsis in term and late preterm neonates", section on 'Coverage for focal sources of infection'):

•Vancomycin and gentamicin or

•Vancomycin, nafcillin, and gentamicin (neonates with toxic appearance) or

•Vancomycin and an expanded-spectrum cephalosporin (eg, ceftazidime, cefepime, 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 (see "Care of the umbilicus and management of umbilical disorders", section on 'Omphalitis')

•Vancomycin and

•Gentamicin or, in regions with substantial (>10 percent) gentamicin-resistant E. coli, ceftazidime, cefepime, or, if available, cefotaxime

•In infants with foul-smelling umbilical discharge or those born to mothers with amnionitis, add metronidazole or clindamycin to cover anaerobic infection

●Mastitis – Drainage of any concomitant abscess should accompany antibiotic treatment. Suggested regimens for infants with uncomplicated mastitis are provided in the table (table 10). The clinician should tailor the empiric parenteral antibiotics to the prevalence of MRSA isolates in the community. 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 (see "Neonatal pneumonia", section on 'Initial empiric therapy'):

•<7 days old – Ampicillin and gentamicin

•≥7 days old:

-Ampicillin or, in regions with high MRSA prevalence (generally considered to be >10 percent of isolates), vancomycin plus

-Gentamicin or an extended-spectrum cephalosporin (ceftazidime, cefepime, or, if available, cefotaxime)

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 [11]. Furthermore, clinicians should adapt their approach if an infant's appearance deteriorates.

Neonates <8 days old — The management of febrile neonates <8 days old with sepsis, including neonates hospitalized since birth and those admitted from the community, is discussed separately. (See "Management and outcome of sepsis in term and late preterm neonates".)

Neonates 8 to 21 days old — Well-appearing, febrile neonates ≤21 days old are at substantial risk for IBI and, after a comprehensive evaluation for sepsis, should receive empiric treatment with antimicrobial agents (table 9) followed by admission to a hospital with nurses and staff experienced with caring for neonates (algorithm 2) [11]. (See '8 to 21 days old' above.)

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 "Management and outcome of sepsis in term and late preterm neonates", section on 'Admitted from the community'):

•Ampicillin and gentamicin or

•Ampicillin and ceftazidime or cefepime (cefotaxime if available)

The combination of ampicillin and ceftazidime or cefepime (cefotaxime if available) is preferred in regions where there are high rates of gentamicin-resistant organisms, especially E. coli [20]. (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 HSV infection and receive acyclovir (algorithm 4). (See "Neonatal herpes simplex virus 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 – For neonates with CSF results that suggest bacterial meningitis (table 11), treatment with ampicillin, ceftazidime, and gentamicin is warranted. Patients with CSF that is uninterpretable (traumatic or dry lumbar puncture) require the same antibiotic coverage. (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 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' above.)

While randomized trials evaluating antibiotic therapy in febrile neonates are lacking, the efficacy of this intervention is supported by the substantial reduction in sepsis-related infant mortality in the pre- and post-antibiotic eras [42]. 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 compared with resource-limited countries where timely access to antibiotic therapy may be limited [43].

Neonates 22 to 28 days old — Management of well-appearing neonates 22 to 28 days old has traditionally consisted of:

●Performing a full sepsis evaluation (table 3)

●Administering empiric parenteral antibiotics (table 9)

●Admitting the patient to the hospital

We prefer this traditional approach, and the 2021 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) acknowledges that this management is acceptable. However, the AAP CPG also suggests a modified evaluation in selected, well-appearing neonates 22 to 28 days old that uses the results of blood inflammatory markers and urine studies (urine dipstick and urinalysis) to make decisions about the need for lumbar puncture, urine culture, and further management (algorithm 3) [11]:

●Abnormal inflammatory markers with normal CSF and urine studies – According to the AAP CPG, all neonates 22 to 28 days old with any abnormal blood inflammatory marker (table 8) should undergo lumbar puncture; urine culture is performed if urine studies are abnormal. For patients with normal CSF and urine results, reasonable alternatives to the traditional approach provided by the AAP CPG include:

•Hospital observation without empiric antibiotics – For patients admitted to a hospital setting with nurses and ancillary staff experienced with managing neonates, empiric antimicrobials may be given although, per the AAP CPG, it is acceptable not to give antimicrobials pending blood, CSF, and (if obtained) urine culture results.

•Intramuscular (IM) ceftriaxone and home observation – Administration of an IM dose of ceftriaxone and discharge may occur only when the caregiver 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 IM ceftriaxone within 24 hours of the first dose is ensured

However, given the increased risk of IBI in neonates with any abnormal inflammatory marker, our preferred approach is for the patient to receive empiric antimicrobials and hospital admission. For patients who receive IM ceftriaxone and discharge home, another consideration is that ceftriaxone alone is not adequate coverage for infection by L. monocytogenes or Enterococcus species.

●Normal inflammatory markers and urine studies – According to the AAP CPG, neonates 22 to 28 days old with normal blood inflammatory markers and urinalysis may undergo a lumbar puncture, but the decision to perform a lumbar puncture should be made as a shared decision between the clinician and family with a mutual understanding of the risks and benefits and with consideration of the family’s values and preferences. Reasonable alternatives to the traditional approach include:

•Lumbar puncture performed – Further management as determined by CSF results:

-Normal CSF results – Hospital observation with or without empiric antibiotics or IM ceftriaxone and home observation as described above for neonates 22 to 28 days old with abnormal blood inflammatory markers.

Evidence suggests that the risk of IBI (primarily bacteremia) in such patients is very low (0.2 to 0.7 percent) [11,14,33,34]. Furthermore, clinical decompensation prior to the availability of blood and urine culture results during hospital observation appears to be rare [10,14,33,39,44,45]. Thus, clinicians may reasonably choose to withhold antibiotics while awaiting culture results.

-Traumatic lumbar puncture (>10,000 red blood cells (RBCs)/mm³) – Empiric parenteral antimicrobials (table 9) and hospital observation.

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

•Lumbar puncture not performed – Hospital observation with or without empiric antibiotics.

●Abnormal urine studies – For patients with abnormal urine studies or one abnormal inflammatory marker (including a rectal temperature >38.5°C [101.3°F] when procalcitonin measurement is not available), we suggest parenteral empiric antimicrobial treatment and hospital admission.

The optimal management of febrile neonates whose preliminary urine studies suggest a UTI (eg, positive nitrites on dipstick, uncentrifuged sample with a positive Gram stain or >10 white blood cells [WBCs]/mm³, or centrifuged sample with >5 WBCs/high-power field) is unclear. We still suggest a full evaluation including collection of CSF studies, empiric antibiotics, and hospitalization. (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'.)

A prediction rule has been validated using data from over 1000 well-appearing febrile infants ≤90 days of age in Europe [40]. 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 and 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.

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 AAP CPG offers the opportunity to do less evaluation and treatment in well-appearing, febrile neonates 22 to 28 days old [11].

Viral infection

Herpes simplex virus infection — Febrile neonates with clinical suspicion for HSV infection (table 4) 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 and management of HSV infection in neonates are discussed separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV' and "Neonatal herpes simplex virus infection: Management and prevention".)

Other viral infections — Neonates 7 to 28 days of age with diagnosed viral infections still have a significant risk for IBI (bacteremia or meningitis) and warrant treatment as if the viral infection is not present. (See '8 to 21 days old' above and '22 to 28 days old' above.)

DISCHARGE CRITERIA FOR ADMITTED PATIENTS — Admitted neonates (0 to 28 days of age) should receive inpatient care and parenteral antibiotics until all cultures are negative for at least 48 hours. Furthermore, initial treatment with acyclovir implies significant clinical concern for herpes simplex virus (HSV) infection, and acyclovir should be continued until the results of all HSV testing are negative. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV' and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Initial antiviral therapy'.)

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

●Fever definition – A rectal temperature ≥38°C (100.4°F) defines a fever in neonates. (See 'Terminology' above.)

●Evaluation – The febrile neonate has an elevated risk for invasive bacterial infection (IBI; bacteremia and/or meningitis) or herpes simplex virus [HSV] infection. (See 'Evaluation' above.)

•Stabilization – Unstable febrile neonates require rapid identification and treatment for septic shock (algorithm 1). (See 'Stabilization' above.)

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)".)

•History – History should focus on risk factors for IBI (table 1) and subtle findings of illness (eg, poor feeding, lethargy, or decreased activity). (See 'History' above.)

•Physical examination – Physical examination focuses on general appearance and signs of (see 'Physical examination' above):

-Focal bacterial infection

-HSV infection

-Bronchiolitis

Well appearance does not exclude the possibility of IBI. (See 'Appearance' above.)

●Ancillary studies – The risk of IBI guides further evaluation:

•Higher IBI risk – For all febrile neonates 8 to 21 days old, we recommend a full sepsis evaluation (table 3 and algorithm 2) (see 'Ancillary studies' above); the evaluation of inpatient neonates <8 days of age is discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

For febrile neonates 22 to 28 days old, we recommend a full sepsis evaluation in patients with:

-Ill appearance (see 'Ill-appearing' above)

-Focal bacterial infection (see 'Focal infection' above)

-Risk factors for IBI (table 4) (see '22 to 28 days old' above)

•Lower IBI risk – For low-risk, well-appearing, febrile neonates 22 to 28 days old with a rectal temperature ≤38.5°C, we suggest a full sepsis evaluation. The decision to perform a lumbar puncture should be made as a shared decision between the clinician and family with a mutual understanding of the risks and benefits and with consideration of the family's values and preferences. (See '22 to 28 days old' above.)

A stepwise evaluation (table 7) is also an acceptable option with cerebrospinal fluid (CSF) testing only in patients with (algorithm 3) (see '22 to 28 days old' above):

-Temperature >38.5°C (101.3°F) or

-One or more abnormal blood inflammatory markers (table 8)

If preliminary urine studies are abnormal, we suggest obtaining CSF studies regardless of inflammatory marker results; other experts only perform a lumbar puncture when one or more inflammatory markers are also abnormal. (See '22 to 28 days old' above.)

•Viral infection – For febrile neonates diagnosed with a viral infection, we recommend a full sepsis evaluation (table 3) for infants ≤21 days old and suggest it for infants 22 to 28 days old. All neonates with clinical features of HSV infection also require testing for HSV (table 4). (See 'Diagnosed with viral infections' above.)

●Management – 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 "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric regimens' and "Management and outcome of sepsis in term and late preterm neonates", section on 'Admitted from the community'.)

•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. (See 'Focal infection' above.)

•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 9) and hospital admission (algorithm 2) (Grade 1B). (See '8 to 21 days old' above.)

-Neonates 22 to 28 days old – For well-appearing, febrile neonates 22 to 28 days old, we suggest empiric parenteral antimicrobial therapy and hospital admission pending culture results for all patients (Grade 2C). However, for patients with normal blood inflammatory markers, initial urine testing, and (if obtained) CSF studies, alternative approaches as suggested by expert guidelines (algorithm 3) are reasonable alternatives. (See 'Neonates 22 to 28 days old' above.)

•Viral infection – Febrile neonates with clinical suspicion for HSV infection should receive empiric acyclovir in addition to antibiotics and undergo hospital admission as discussed separately. (See "Neonatal herpes simplex virus infection: Management and prevention".)

-Neonates 7 to 28 days of age diagnosed with other viral infections still have a significant risk for IBI and warrant treatment as if the viral infection is not present. (See 'Management' above.)

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

-Antiviral and other therapies for coronavirus disease 2019 (COVID-19) in pediatric patients are discussed separately. (See "COVID-19: Management in children".)