What is the recommended management for a newborn presenting with fever and no other signs or symptoms?

Management of a Febrile Newborn Without Other Signs or Symptoms

All well-appearing febrile newborns (≤28 days old) require immediate comprehensive evaluation including urinalysis with culture, blood culture, and lumbar puncture for CSF analysis, followed by hospitalization and empiric parenteral antibiotics (ampicillin plus gentamicin) until cultures are negative at 24-36 hours. 1, 2

Age-Based Risk Stratification

Neonates (0-28 days)

• Highest risk group with invasive bacterial infection rates of 8-13%, requiring the most aggressive approach 3, 4, 2
• Group B Streptococcus (GBS) and Escherichia coli are the leading pathogens in this age group 1, 5
• Even well-appearing neonates warrant full sepsis evaluation, as only 58% of infants with bacteremia or bacterial meningitis appear clinically ill 2

Infants 29-60 days

• Lower risk than neonates but still require careful evaluation 1
• Risk of bacteremia is 0.1% for well-appearing infants 29-60 days with negative screening tests 1
• Management can be stratified based on clinical appearance and laboratory findings 1

Mandatory Diagnostic Evaluation

Urine Testing (All Ages)

• Obtain urine by catheterization or suprapubic aspiration for both urinalysis and culture 1
• Urinalysis has 94% sensitivity for UTI (97.6-100% when associated with bacteremia) and 99% negative predictive value 1
• UTIs are the most common serious bacterial infection in febrile infants (8-13% prevalence) 3, 2
• Critical pitfall: Never use bag specimens for diagnosis—they are unreliable and lead to false positives 3

Blood Culture

• Obtain at least 1 mL of blood in a single aerobic blood culture bottle before starting antibiotics 1, 5
• Bacteremia occurs in 1.1-2.2% of all febrile infants and 5-10% of those with UTI 1
• Critical pitfall: Administering antibiotics before cultures may obscure diagnosis 3

Cerebrospinal Fluid Analysis

• Mandatory for all neonates ≤28 days regardless of appearance 1, 3, 2
• For infants 29-60 days, perform lumbar puncture if:
  • Infant appears ill 1
  • Any inflammatory markers are abnormal 1
  • Urinalysis is positive 1
  • Blood culture is positive 1
• If CSF cannot be obtained or is uninterpretable, parenteral antibiotics must be administered 1

Inflammatory Markers

• Consider obtaining CRP and/or procalcitonin to aid risk stratification 1, 3
• Important caveat: A normal WBC count does not rule out bacterial infection, especially in neonates 3
• Biomarkers alone should not guide antibiotic decisions but may be part of an algorithm 5

Empiric Antibiotic Therapy

Neonates (≤28 days)

• Ampicillin plus gentamicin is the first-line regimen 1, 6, 7, 8, 5, 9
• Ampicillin dosing for neonates with suspected meningitis/septicemia: 6
  • Gestational age ≤34 weeks, postnatal age ≤7 days: 100 mg/kg/day divided every 12 hours
  • Gestational age ≤34 weeks, postnatal age 8-28 days: 150 mg/kg/day divided every 12 hours
  • Gestational age >34 weeks, postnatal age ≤28 days: 150 mg/kg/day divided every 8 hours
• Gentamicin provides synergy against GBS and enterococcal species 1, 7

Infants 29-60 days (if antibiotics indicated)

• Ampicillin plus gentamicin or ceftriaxone/cefotaxime 1, 9
• If meningitis suspected: add vancomycin to cover resistant S. pneumoniae (discontinue if another organism identified) 1

When Antibiotics Can Be Withheld or Discontinued

Antibiotics NOT Required if ALL of the following are met: 1

1. CSF analysis (if obtained) is normal or enterovirus-positive
2. Urinalysis is negative
3. No inflammatory markers obtained are abnormal
4. Infant remains well-appearing

Discontinue Antibiotics at 24-36 hours if: 1, 5

1. All bacterial cultures are negative
2. Infant is clinically well or improving (fever resolved, feeding well)
3. No other infection requiring treatment (e.g., otitis media)

Critical consideration: Recent data suggest prolonged empirical antibiotic treatment (≥5 days) in preterm infants increases risks of late-onset sepsis, necrotizing enterocolitis, and mortality 8

Hospitalization Decisions

Mandatory Hospitalization

• All neonates ≤28 days with fever require hospitalization 1, 4, 2
• Infants 29-60 days who are high-risk based on clinical appearance or abnormal laboratory findings 1

Potential Outpatient Management (29-60 days only)

• May consider for well-appearing infants with: 1
  • Normal urinalysis
  • Normal inflammatory markers
  • Normal CSF analysis (if obtained)
• Must administer parenteral antimicrobial therapy (e.g., IM ceftriaxone) even if managed at home 1
• Requires close follow-up within 24 hours and reliable caregiver 1

Duration of Therapy for Proven Infections

• Positive bacterial pathogens in urine, blood, or CSF require targeted antimicrobial therapy for duration consistent with the organism and clinical response 1
• Minimum 48-72 hours beyond when patient becomes asymptomatic or bacterial eradication is documented 2, 6
• Group A beta-hemolytic streptococcal infections require minimum 10 days to prevent rheumatic fever or glomerulonephritis 1

Critical Pitfalls to Avoid

• Never rely on clinical appearance alone in neonates—threshold for full workup must be low 2
• Recent antipyretic use can mask fever severity—do not be falsely reassured 4, 2
• Viral infection does not exclude bacterial co-infection—approximately 75% have viral infections, but bacterial infection can coexist 2
• Do not delay antibiotics if CSF suggests bacterial meningitis or is unavailable 1
• Avoid unnecessary prolonged antibiotics when cultures are negative to minimize antimicrobial resistance and microbiome disruption 1, 8, 5