What clinical signs, risk factors, and laboratory findings define the diagnosis of neonatal sepsis and determine the initial empiric antibiotic regimen?

Neonatal Sepsis Diagnostic Criteria

Definition and Clinical Framework

Neonatal sepsis is defined as infants up to 3 months of age presenting with clinical signs and/or laboratory evidence of infection, requiring immediate empiric antibiotic therapy after obtaining blood cultures. 1

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Temporal Classification

Early-Onset Sepsis (EOS)

• Timing: Within 72 hours of birth (some definitions extend to 7 days) 1
• Pathogen acquisition: Peripartum transmission from maternal genital tract 1
• Common organisms: Group B Streptococcus, E. coli, Listeria monocytogenes 2, 3

Late-Onset Sepsis (LOS)

• Timing: After 72 hours to 28 days of life 1
• Pathogen acquisition: Hospital-acquired or community-acquired 4
• Common organisms: Coagulase-negative staphylococci, Staphylococcus aureus, resistant gram-negative bacteria, enterococci 4

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Clinical Signs Defining Sepsis

Nonspecific Presenting Features

• Temperature instability (hypothermia or fever) 5
• Respiratory distress (tachypnea, apnea, increased oxygen requirement) 1
• Cardiovascular compromise (tachycardia, poor perfusion, hypotension) 1
• Feeding intolerance (poor feeding, vomiting, abdominal distension) 1
• Neurological changes (lethargy, irritability, hypotonia, seizures) 1
• Jaundice (particularly when unexplained or severe) 1

Critical pitfall: These signs are highly nonspecific and overlap with numerous non-infectious conditions, requiring a low threshold for evaluation. 5, 6

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Risk Factors Triggering Evaluation

Maternal Risk Factors

• Maternal chorioamnionitis (clinical or histologic) 2
• Prolonged rupture of membranes (>18 hours) 1, 2
• Inadequate Group B Streptococcus intrapartum prophylaxis 1, 2
• Maternal fever during labor (≥38°C) 2
• Maternal colonization with GBS without adequate prophylaxis 2

Neonatal Risk Factors

• Prematurity (<37 weeks, especially <35 weeks) 2, 7
• Very low birth weight (<1500g) 1
• Extremely low birth weight (<1000g) 1
• Central venous catheter presence 4
• Prolonged NICU hospitalization 4
• Mechanical ventilation 1

Important caveat: The risk factor-based approach in asymptomatic infants has poor predictive value except for prematurity and leukopenia, and cannot be justified as sole indication for antibiotic treatment. 7 However, all preterm infants <35 weeks with high-risk delivery characteristics require empiric antibiotics. 2

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Laboratory Findings for Diagnosis

Blood Culture (Gold Standard)

• Obtain before antibiotic administration but never delay treatment waiting for results 2, 8
• Sensitivity limitation: Blood cultures can be sterile in up to 15% of newborns with meningitis 2
• Volume matters: Sensitivity is lower in neonates due to blood sample <1 mL 1
• Time to positivity: Usually 2-5 days 1

Complete Blood Count with Differential

• Leukopenia (most predictive risk factor) 7
• Leukocytosis (less specific) 1
• Thrombocytopenia (nonspecific but supportive) 1
• Bandemia (elevated immature neutrophils) 8
• Elevated I/T ratio (immature to total neutrophil ratio >0.2) 6

Inflammatory Markers

C-Reactive Protein (CRP)

• Later marker: Peaks at 24-48 hours after infection onset 6
• Useful for: Monitoring response to therapy and guiding antibiotic discontinuation 6
• Limitation: Not sensitive enough to withhold antibiotics based on normal value alone 6

Procalcitonin (PCT)

• Earlier marker than CRP 3, 6
• Useful in combination with other markers for antibiotic stewardship 6
• Limitation: Availability varies by institution 3

Interleukin-6 (IL-6) and Interleukin-8 (IL-8)

• Early markers: Rise within hours of infection 3, 6
• High sensitivity for early detection 3
• Limitation: Not widely available in all settings 3

Cell Surface Antigens (CD64, CD11b)

• Promising markers for early diagnosis 3, 6
• Current status: Still under investigation, not yet standard of care 3

Cerebrospinal Fluid Analysis

• Indication: Perform lumbar puncture if infant is hemodynamically stable and sepsis is suspected 2, 8
• Critical importance: Blood cultures can be negative in meningitis cases 2
• CSF findings: Elevated white blood cells, elevated protein, decreased glucose, positive Gram stain or culture 8

Additional Diagnostic Tests

• Urinalysis and urine culture (especially in late-onset sepsis >72 hours) 8
• Chest radiograph if respiratory symptoms present 5

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Diagnostic Algorithm for Antibiotic Initiation

Symptomatic Neonates

1. Immediate full sepsis workup: Blood culture, CBC with differential, CRP (or PCT if available), lumbar puncture if stable 2, 8
2. Initiate antibiotics within 1 hour for septic shock, within 3 hours for sepsis without shock 8, 4
3. Do not wait for laboratory results to start treatment 2, 8

Asymptomatic Neonates with Risk Factors

1. Preterm <35 weeks with high-risk characteristics: Empiric antibiotics required 2
2. Term infants with isolated risk factors: In-hospital observation for 48-72 hours may be reasonable alternative to empiric antibiotics 7
3. If antibiotics initiated: Discontinue at 48 hours if cultures negative and infant remains asymptomatic 2, 8

Critical pitfall: Continuing antibiotics beyond 48 hours despite negative cultures and clinical stability increases risks of late-onset sepsis, necrotizing enterocolitis, and mortality in preterm infants. 2

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Empiric Antibiotic Regimens Based on Criteria

Early-Onset Sepsis (First 72 Hours)

• First-line: Ampicillin plus gentamicin 1, 2
• Alternative if meningitis suspected: Ampicillin plus cefotaxime 1, 2
• Rationale: Covers Group B Streptococcus, E. coli, Listeria monocytogenes 2

Late-Onset Sepsis (>72 Hours)

Community-Acquired

• First-line: Ampicillin plus gentamicin 4
• Covers: GBS, Enterobacteriaceae, Listeria 4

Nosocomial/Hospital-Acquired

• First-line (WHO recommendation): Amikacin plus cloxacillin 4
• If MRSA suspected or central line present: Vancomycin plus ceftazidime 4
• Rationale: Covers resistant staphylococci and gram-negative bacteria 4

Specific Dosing (Day 2 of Life Example)

• Ampicillin: 150 mg/kg/day IV divided every 8 hours 8
• Gentamicin: 4 mg/kg IV every 24 hours for infants 8-21 days old 8

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Reassessment and Antibiotic Stewardship

48-72 Hour Evaluation

• If cultures negative and clinical improvement: Discontinue antibiotics 8, 4
• If cultures positive: Switch to targeted therapy based on sensitivities 8
• If no improvement on ampicillin-gentamicin: Escalate to amikacin plus cloxacillin (or vancomycin if MRSA suspected) 4

Duration of Therapy

• Uncomplicated sepsis: 10-14 days 5
• Meningitis: Longer duration based on organism and clinical response 5
• De-escalate to narrowest spectrum once culture results available 4

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Special Considerations

Fungal Sepsis (Neonatal Invasive Candidiasis)

• Risk factors: VLBW/ELBW, broad-spectrum antibiotics, central venous catheter, parenteral nutrition, mechanical ventilation 1
• Diagnostic marker: Serum (1,3)-Beta-D-Glucan at 80 pg/mL threshold has 89% sensitivity and 60% specificity 1
• At 120 pg/mL threshold: 81% sensitivity and 80% specificity 1

Gram-Negative Resistance in Low-Resource Settings

• Emerging concern: Increasing multidrug resistance in low- and lower-middle-income countries 1
• WHO recommendations may not be adequate in areas with high resistance 1
• Local antibiograms essential for appropriate empiric selection 4

Common Pitfalls to Avoid

• Never use ceftriaxone in neonates: Displaces bilirubin causing kernicterus; use cefotaxime instead 2
• Do not delay lumbar puncture indefinitely: Blood cultures alone miss 15% of meningitis cases 2
• Avoid third-generation cephalosporins as first-line: Rapid emergence of resistance and potential antagonism with penicillins 5
• Do not ignore local resistance patterns: Resistance varies significantly between institutions 4