Neonatal sepsis is a life-threatening systemic infection occurring within the first 28 days of life, classified as early-onset sepsis (EOS, ≤72 hours) or late-onset sepsis (LOS, >72 hours), with distinct pathogenesis, microbiology, and management implications. [1-2] Presentations are notoriously nonspecific, and a high index of suspicion is critical — the threshold to initiate workup and empiric antibiotics should be low.
1. History
- Feeding: Poor feeding, refusal to feed, or feeding intolerance — the single most sensitive clinical sign (sensitivity ~56%) and strongest predictor of both culture-confirmed sepsis and mortality [3]
- Activity level: Decreased movement, lethargy, irritability, inconsolability, weak/absent cry
- Breathing: Apnea episodes, grunting, tachypnea, increased work of breathing
- Temperature: Fever (≥38°C) or hypothermia (<35.5°C) — neonates may present with either; hypothermia is more common in preterm infants [1]
- Timing of onset: Age at symptom onset determines EOS vs LOS classification and guides empiric therapy [4]
- Birth history: Gestational age, birth weight, mode of delivery, duration of rupture of membranes, maternal fever, GBS status, intrapartum antibiotics
- Important negatives: Absence of rash, no vomiting/diarrhea, no seizures, no cyanosis
2. Alarm Features
- Weak, abnormal, or absent cry — strongest association with mortality (OR 20.48) [3]
- Not able to feed at all (OR 18.32 for mortality) [3]
- Drowsiness or unconsciousness (OR 12.46 for mortality) [3]
- Prolonged capillary refill (OR 12.06 for mortality; OR 3.59 for culture-confirmed sepsis) — not currently in WHO IMCI but strongly predictive [3]
- Central cyanosis (OR 7.35 for clinical sepsis; specificity 98.2%) [3]
- Bulging fontanelle — suggests meningitis (OR 6.79) [3]
- Seizures/convulsions
- Hypotension, mottled skin, poor perfusion — signs of septic shock
- Petechiae/purpura — suggests DIC or meningococcemia [1]
- Apnea — may be the sole presenting sign in neonates [1]
3. Medications
Empiric Therapy — EOS (≤72 hours)
- Ampicillin + gentamicin is the standard first-line regimen [5-7]
- Ampicillin: 150 mg/kg/day IV divided q8h (meningitis dosing: 300 mg/kg/day divided q6h) [8]
- Gentamicin: 4 mg/kg/dose IV q24h [8]
- If meningitis suspected: Ampicillin + ceftazidime (or cefotaxime where available) [8-9]
- Add acyclovir if HSV is suspected (vesicles, seizures, CSF pleocytosis, maternal history) [8]
Empiric Therapy — LOS (>72 hours)
- Flucloxacillin (or nafcillin) + gentamicin — guided by local susceptibility data [2][4]
- Add vancomycin if CoNS or MRSA suspected (e.g., central line in situ) [4]
- Broader-spectrum agents (carbapenems) reserved for ESBL-producing organisms [5]
Contraindicated/Cautions
- Avoid routine empiric third-generation cephalosporins due to risk of Candida superinfection and resistance emergence [5]
- Cephalosporins do not cover Listeria or Enterococcus — ampicillin must be included when these are suspected [8]
- Monitor aminoglycoside levels for nephrotoxicity and ototoxicity [10]
4. Diet
- NPO initially if hemodynamically unstable, significant respiratory distress, or concern for NEC
- Breast milk is preferred when feeding is resumed — provides passive immunity (IgA, lactoferrin)
- Maintain normoglycemia — both hyperglycemia and hypoglycemia are associated with sepsis and should be monitored [4]
- IV fluids: Dextrose-containing maintenance fluids with close glucose monitoring
- Gradual reintroduction of enteral feeds as clinical status improves
5. Review of Systems
- Neurological: Seizures, lethargy, irritability, bulging fontanelle, abnormal tone
- Respiratory: Apnea, tachypnea (RR ≥60), grunting, nasal flaring, chest indrawing, oxygen requirement [1]
- Cardiovascular: Tachycardia, bradycardia, hypotension, prolonged capillary refill, mottling [3]
- GI: Feeding intolerance, vomiting, abdominal distension (consider NEC), diarrhea
- Dermatologic: Jaundice, petechiae, pustules, periumbilical erythema/purulence, sclerema [1]
- Musculoskeletal: Erythema/edema overlying bones or joints (osteomyelitis, septic arthritis)
- Genitourinary: Urine output — oliguria suggests renal hypoperfusion
6. Collateral History and Family History
- Maternal history: GBS colonization status, chorioamnionitis, intrapartum fever, UTI, prolonged/premature rupture of membranes (>18 hours), intrapartum antibiotic administration and timing [6][11]
- Maternal HSV history: Active genital lesions, primary infection near delivery
- Birth history: Gestational age, birth weight, Apgar scores, resuscitation required, instrumented delivery
- Siblings/household contacts: Sick contacts, viral illness exposure
- Social context: Home birth vs hospital, NICU stay, indwelling devices
- Family history: Immunodeficiency syndromes, recurrent infections
7. Risk Factors
EOS
- Prematurity and low birth weight — most significant risk factors (82% of EOS in preterm, 81% in LBW infants) [6]
- Maternal GBS colonization [5][11]
- Chorioamnionitis / maternal intrapartum fever [6]
- Prolonged rupture of membranes >18 hours [5-6]
- Premature rupture of membranes [6]
- Inadequate or absent intrapartum antibiotic prophylaxis [2]
- Multiple gestation, meconium aspiration [6]
LOS
- Prematurity (especially VLBW/ELBW)
- Central venous catheters and other indwelling devices [2]
- Prolonged NICU stay
- Prolonged parenteral nutrition
- Prolonged antibiotic exposure (risk of fungal sepsis) [2]
- Surgical procedures (e.g., NEC requiring intervention)
8. Differential Diagnosis
- Meningitis — may coexist with sepsis; LP essential in symptomatic neonates [1]
- Necrotizing enterocolitis (NEC) — abdominal distension, bloody stools, pneumatosis on imaging
- Congenital heart disease — cyanosis, poor feeding, murmur; consider prostaglandin-dependent lesions
- Inborn errors of metabolism — lethargy, poor feeding, metabolic acidosis, hyperammonemia
- Neonatal HSV — vesicles, seizures, hepatitis, CSF pleocytosis; mortality high if untreated [8]
- Congenital viral infections (CMV, enterovirus, parechovirus) — hepatitis, rash, thrombocytopenia
- Transient tachypnea of the newborn / RDS — respiratory symptoms without infectious signs
- Non-accidental trauma — irritability, altered consciousness, unexplained bruising
- Congenital adrenal hyperplasia — salt-wasting crisis mimicking septic shock
- Intestinal obstruction (malrotation/volvulus) — bilious vomiting, distension
9. Past Medical History
- Gestational age and birth weight
- NICU admission history, duration of hospitalization
- Previous episodes of suspected or proven sepsis
- Prior antibiotic exposure (impacts resistance patterns and fungal risk)
- Surgical history (e.g., abdominal surgery, VP shunt)
- Chronic lung disease, congenital anomalies
- Immunization status (Hepatitis B at birth)
10. Physical Exam
Vital Signs
- Temperature: Fever ≥38°C or hypothermia <35.5°C [1]
- Heart rate: Tachycardia (>160–180 bpm) or bradycardia (<100 bpm)
- Respiratory rate: Tachypnea ≥60 breaths/min
- Blood pressure: Hypotension (MAP < gestational age in weeks as rough guide)
- SpO₂: Desaturation
Focused Exam
- General: Tone (hypotonia), activity level, cry quality, color (pallor, mottling, cyanosis, jaundice)
- Fontanelle: Bulging (meningitis) vs sunken (dehydration)
- Skin: Petechiae, purpura, pustules, periumbilical erythema, sclerema, capillary refill time (>3 seconds is concerning) [3]
- Respiratory: Grunting, nasal flaring, retractions, chest indrawing
- Cardiovascular: Perfusion, pulse quality, murmur
- Abdomen: Distension, tenderness, hepatosplenomegaly
- Musculoskeletal: Joint swelling, erythema, pseudoparalysis (osteomyelitis/septic arthritis)
- Neurological: Seizure activity, tone, reflexes
11. Lab Studies
Core Workup
- Blood culture (minimum 0.5–1 mL from two sites; ideally peripheral + central if line present) — gold standard [1-2]
- CBC with differential: WBC (leukocytosis or leukopenia), I:T ratio (immature-to-total neutrophil ratio), ANC, platelet count [4]
- CRP: Serial measurements at 0 and 24–48 hours; >20 mg/L considered abnormal [8]
- Procalcitonin: >0.5 ng/mL abnormal; rises earlier than CRP; useful for risk stratification and guiding antibiotic duration [8][12]
- Blood glucose: Hyper- or hypoglycemia associated with sepsis [4]
- Blood gas: Metabolic acidosis, lactate
- Urinalysis and urine culture (catheterized specimen)
- CSF analysis: Cell count, glucose, protein, Gram stain, bacterial culture, enterovirus PCR (if available) — LP should be performed in all symptomatic neonates [1][8]
Additional as indicated
- Coagulation studies (PT, PTT, fibrinogen) if DIC suspected
- Liver function tests (ALT) if HSV suspected [8]
- HSV PCR (blood and CSF), surface swabs if HSV concern
Expected Abnormalities
- 90% of positive blood cultures grow pathogen by 24 hours; >94% by 36 hours [2][13]
- Thrombocytopenia, neutropenia, elevated I:T ratio support diagnosis [4]
12. Imaging
- Chest X-ray: First-line if respiratory symptoms present; evaluate for pneumonia, RDS, pneumothorax [14]
- Abdominal X-ray: If abdominal distension or concern for NEC — look for pneumatosis intestinalis, portal venous gas, free air
- Cranial ultrasound: If meningitis confirmed or suspected — evaluate for ventriculitis, abscess, intraventricular hemorrhage
- Echocardiography: If persistent hemodynamic instability, murmur, or concern for endocarditis or congenital heart disease
- Imaging is generally unnecessary in the absence of focal signs; the prevalence of occult pneumonia in febrile infants <3 months without respiratory symptoms is only ~1–3% [14]
13. Special Tests
Scoring Systems / Calculators
- Kaiser Permanente Neonatal EOS Calculator (kp.org/eoscalc): Multivariable risk estimate using gestational age, maternal temperature, GBS status, ROM duration, and intrapartum antibiotics — endorsed by AAP as an alternative framework for EOS risk assessment [2][15-16]
- Step-by-Step Approach to Febrile Infants: Sequential algorithm for infants ≤90 days using Pediatric Assessment Triangle, age, leukocyturia, procalcitonin, CRP/ANC to stratify risk [8]
- WHO IMCI 7-sign algorithm: Sensitivity 79%, specificity 77% for identifying sick infants requiring hospitalization [17]
Point-of-Care Tests
- Rapid viral panels (RSV, influenza, enterovirus) — a positive viral test may modify management in well-appearing older neonates [13]
- Multiplex PCR on positive blood cultures for rapid pathogen identification [1]
Biomarkers Under Investigation
14. ECG
- Indications: Persistent tachycardia or bradycardia, arrhythmia, hemodynamic instability
- Findings in sepsis: Sinus tachycardia most common; reduced heart rate variability may be an early sign
- Dangerous patterns: Bradycardia with poor perfusion (pre-arrest), ST changes (myocardial dysfunction in septic shock)
- ECG is not part of the routine sepsis workup but should be obtained if cardiac pathology is in the differential
15. Assessment
Classification
- EOS (≤72 hours): Vertical transmission — GBS (#1 in term infants), E. coli (#1 cause of mortality and most common in preterm), Listeria [5][9]
- LOS (>72 hours): Horizontal/nosocomial — CoNS (most common in NICU), S. aureus, Klebsiella, E. coli, Candida [4]
Severity Stratification
- Well-appearing with risk factors only → risk-stratified approach using EOS calculator or inflammatory markers [2]
- Symptomatic but hemodynamically stable → full sepsis workup + empiric antibiotics + admission
- Ill-appearing / septic shock → immediate resuscitation, empiric antibiotics, NICU admission
Complications
16. Treatment Plan
Initial Stabilization
- ABCs: Secure airway, supplemental O₂, intubation if needed
- IV access (consider IO if unable)
- Fluid resuscitation: NS 10–20 mL/kg boluses; reassess after each bolus
- Correct hypoglycemia, hypothermia, metabolic acidosis
- Empiric antibiotics within 1 hour of clinical suspicion — do not delay for LP if unstable
Empiric Antibiotic Regimens (per AAP): [8]
Duration
- Culture-negative, clinically well: Reassess at 36 hours — discontinue antibiotics if cultures negative and clinical improvement [5][13]
- Culture-positive sepsis without meningitis: 7–10 days [5]
- Meningitis: 14–21 days (GBS) or 21 days (Gram-negative) [6]
- Procalcitonin-guided duration may safely reduce antibiotic exposure in suspected EOS [12]
Supportive Care
- Vasopressors (dopamine, epinephrine) for fluid-refractory shock
- Respiratory support as needed (CPAP, mechanical ventilation)
- Thermoregulation, glucose monitoring, electrolyte correction
17. Disposition
Admission Criteria (all neonates <28 days with fever or suspected sepsis should be admitted):
- All infants ≤21 days with fever ≥38°C — full sepsis workup + admission + empiric antibiotics regardless of appearance [8]
- Ill-appearing infant of any neonatal age
- Abnormal inflammatory markers (elevated procalcitonin, CRP, ANC) [8]
- Positive urinalysis
- CSF pleocytosis or abnormal Gram stain
NICU Admission
- Hemodynamic instability / septic shock
- Respiratory failure requiring mechanical ventilation
- Seizures, altered consciousness
- Preterm or VLBW infants
Observation (may apply to select 29–60 day old well-appearing infants):
- Normal inflammatory markers, negative urinalysis, no CSF pleocytosis
- Reliable follow-up within 24 hours
- Per AAP guidelines, some well-appearing 29–60 day olds with normal markers may be managed with observation ± antibiotics [8]
Specialist Consultation Triggers
- Pediatric infectious disease: Culture-positive sepsis, meningitis, HSV concern, unusual organisms
- Neonatology: All preterm infants, critically ill neonates
- Pediatric surgery: Suspected NEC, surgical abdomen
18. Follow Up / Return Precautions
Follow-Up Timing
- If discharged after observation: 24-hour follow-up with pediatrician for clinical reassessment and culture review
- After completed antibiotic course: Follow-up within 1–2 weeks for clinical assessment
- Hearing screen: Repeat if aminoglycosides used (ototoxicity risk) [10]
- Neurodevelopmental follow-up for confirmed meningitis or complicated sepsis
Return Precautions (counsel caregivers)
- Return immediately for: fever or hypothermia, poor feeding or refusal to feed, decreased activity/lethargy, color changes (pale, blue, mottled), fast or difficult breathing, seizures, rash (especially petechiae/purpura)
- Emphasize that neonates can deteriorate rapidly and any concern warrants immediate evaluation
Expected Recovery
- Culture-negative suspected sepsis: Typically improves within 24–48 hours; antibiotics discontinued at 36 hours if cultures negative [13]
- Culture-positive uncomplicated bacteremia: Clinical improvement expected within 48–72 hours of appropriate therapy
- Meningitis: Prolonged course; risk of neurodevelopmental sequelae requiring long-term follow-up
The following forest plot from a 2026 meta-analysis illustrates the pooled associations between clinical signs and culture-confirmed sepsis in young infants, highlighting that feeding-related signs, prolonged capillary refill, and altered consciousness are the strongest predictors:
References
1. Neonatal Sepsis. — Shane AL, Sánchez PJ, Stoll BJ. Lancet. 2017.
2. Neonatal Bacterial Sepsis. — Strunk T, Molloy EJ, Mishra A, Bhutta ZA. Lancet. 2024.
3. Clinical Signs Associated With Mortality and Sepsis in Young Infants. — Driker S, Mathias S, Fung A, et al. JAMA Pediatrics. 2026.
4. Antibiotic Regimens for Late-Onset Neonatal Sepsis. — Korang SK, Safi S, Nava C, et al. The Cochrane Database of Systematic Reviews. 2021.
5. Shorter Versus Longer Duration Antibiotic Regimens for Treatment of Suspected Neonatal Sepsis. — Legge AA, Middleton JL, Fiander M, et al. The Cochrane Database of Systematic Reviews. 2024.
6. Antibiotic Regimens for Early-Onset Neonatal Sepsis. — Korang SK, Safi S, Nava C, et al. The Cochrane Database of Systematic Reviews. 2021.
7. Management of Infants at Risk for Group B Streptococcal Disease. — Puopolo KM, Lynfield R, Cummings JJ. Pediatrics. 2019.
8. Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old. — Pantell RH, Roberts KB, Adams WG, et al. Pediatrics. 2021.
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11. Hospital Admissions After Early-Onset Neonatal Bacterial Infection Management Guidelines in France. — Paucard L, Varga B, Kermorvant-Duchemin E, Huynh BT, Watier L. JAMA Network Open. 2025.
12. Procalcitonin-Guided Decision Making for Duration of Antibiotic Therapy in Neonates With Suspected Early-Onset Sepsis: A Multicentre, Randomised Controlled Trial (NeoPIns). — Stocker M, van Herk W, El Helou S, et al. Lancet. 2017.
13. Evaluation and Management of Febrile Children: A Review. — Cioffredi LA, Jhaveri R. JAMA Pediatrics. 2016.
14. ACR Appropriateness Criteria® Fever Without Source or Unknown Origin-Child: 2024 Update. — Cooper ML, Iyer RS, Chan SS, et al. Journal of the American College of Radiology : JACR. 2025.
15. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. — Kuzniewicz MW, Puopolo KM, Fischer A, et al. JAMA Pediatrics. 2017.
16. Neonatal Early-Onset Infections: Comparing the Sensitivity of the Neonatal Early-Onset Sepsis Calculator to the Dutch and the Updated NICE Guidelines in an Observational Cohort of Culture-Positive Cases. — Snoek L, van Kassel MN, Krommenhoek JF, et al. EClinicalMedicine. 2022.
17. Diagnostic Accuracy of Clinical Sign Algorithms to Identify Sepsis in Young Infants Aged 0 to 59 Days: A Systematic Review and Meta-Analysis. — Fung A, Shafiq Y, Driker S, et al. Pediatrics. 2024.
18. Diagnostic Performance of Biomarkers Tumor Necrosis Factor-Α, Interleukin-6, and Procalcitonin in Neonatal Sepsis: A Case-Control Study. — Kumar D, Kumar D, Sharma N, et al. Journal of Interferon & Cytokine Research : The Official Journal of the International Society for Interferon and Cytokine Research. 2025.