Neonatal Sepsis

Overview

• Early-onset sepsis (EOS): Occurring within 0-72 hours of birth (some definitions use <7 days)

• Late-onset sepsis (LOS): Occurring >72 hours after birth (up to 28 days, or up to 90 days in preterm infants)

• EOS: 0.5-2 per 1,000 live births in developed countries; higher in developing countries

• LOS: 2-6 per 1,000 live births; much higher in preterm and VLBW infants (up to 20-25%)

• EOS: 3-10% overall; higher in preterm infants

• LOS: 2-6% in term infants; 18-36% in preterm infants

Aetiology

Early-Onset Sepsis (EOS)

• Group B Streptococcus (GBS) - Streptococcus agalactiae (most common in many countries)

• Escherichia coli (most common in preterm infants, often associated with higher mortality)

• Other Gram-negative bacteria:
• Klebsiella species
• Enterobacter species
• Pseudomonas aeruginosa
• Haemophilus influenzae

• Listeria monocytogenes (less common)

• Enterococcus species

• Coagulase-negative staphylococci (CoNS)

• Streptococcus pneumoniae

• Staphylococcus aureus

• Group A Streptococcus

• Anaerobes

• GBS colonization (vaginal/rectal)

• Chorioamnionitis (fever, uterine tenderness, foul discharge)

• Prolonged rupture of membranes (PROM >18 hours)

• Intrapartum fever (>38°C)

• Urinary tract infection during pregnancy (especially GBS bacteriuria)

• Previous infant with GBS disease

• Sexually transmitted infections

• Prematurity (<37 weeks, especially <32 weeks)

• Prolonged labour

• Multiple vaginal examinations

• Fetal scalp electrodes or other invasive monitoring

• Instrumental delivery (forceps, vacuum)

• Low birth weight (<2,500 g, especially <1,500 g)

• Prematurity

• Male gender (slightly higher risk)

• Multiple gestation

• Birth asphyxia

• Meconium-stained liquor (if aspirated)

Late-Onset Sepsis (LOS)

• Coagulase-negative staphylococci (CoNS) - most common (often catheter-related)

• Staphylococcus aureus (including MRSA)

• Gram-negative bacteria:
• E. coli
• Klebsiella species
• Enterobacter species
• Pseudomonas aeruginosa
• Serratia species

• Enterococcus species

• Candida species (fungal sepsis, especially in VLBW infants on prolonged antibiotics)

• E. coli

• Klebsiella species

• Streptococcus pneumoniae

• Salmonella species

• Viruses: HSV, CMV, enteroviruses

• GBS (late-onset GBS disease)

• Prematurity (<32 weeks)

• Very low birth weight (<1,500 g)

• Immature immune system

• Prolonged NICU stay

• Central venous catheters (umbilical or peripherally inserted)

• Endotracheal intubation and mechanical ventilation

• Total parenteral nutrition (TPN)

• Frequent blood sampling

• Surgical procedures

• Prolonged antibiotic use (increases fungal infection risk)

• Overcrowding in NICU

• Poor hand hygiene practices

• Necrotising enterocolitis (NEC)

• Immunodeficiency disorders

Pathophysiology

• Organisms breach physical barriers (skin, mucosa, respiratory tract)

• In EOS: ascending infection from birth canal or transplacental transmission

• In LOS: via skin breach (lines, venepuncture), respiratory tract, or GI tract

• Neonatal immune system is immature:
• Reduced neutrophil function
• Decreased complement activity
• Impaired cell-mediated immunity
• Limited antibody production

• Overwhelming bacterial load → systemic inflammatory response

• Release of endotoxins and cytokines (TNF-α, IL-1, IL-6)

• Activation of coagulation cascade

• Endothelial dysfunction and increased vascular permeability

• Hypotension, poor perfusion, metabolic acidosis

• Multi-organ dysfunction

• Meningitis (20-30% of GBS sepsis, 20-40% of E. coli sepsis)

• Disseminated intravascular coagulation (DIC)

• Acute respiratory distress syndrome (ARDS)

• Shock and circulatory failure

• Renal failure

• Death

Clinical Features

General signs:

• Temperature instability:
• Fever (>38°C) or hypothermia (<36.5°C) - hypothermia more common in preterm

• Poor feeding

• Lethargy, reduced activity

• Irritability or high-pitched cry

• Hypotonia or hypertonia

• Mottled skin, pallor, or cyanosis

Respiratory:

• Tachypnoea (>60 breaths/min)

• Apnoea (especially in preterm)

• Grunting, flaring, retractions

• Increased oxygen requirement

• Respiratory distress or failure

Cardiovascular:

• Tachycardia (>160 bpm) or bradycardia (<100 bpm)

• Prolonged capillary refill time (>3 seconds)

• Weak pulses

• Hypotension

• Shock (cold or warm)

Gastrointestinal:

• Vomiting

• Abdominal distension

• Feeding intolerance

• Hepatomegaly

• Jaundice (especially within first 24 hours - pathological)

Neurological:

• Seizures

• Altered consciousness

• Bulging fontanelle (meningitis)

• Neck stiffness (rare in neonates, even with meningitis)

Metabolic:

• Hypoglycaemia (<2.6 mmol/L)

• Hyperglycaemia

• Metabolic acidosis

Skin:

• Petechiae or purpura

• Sclerema (hardening of skin - poor prognostic sign)

• Pustules or abscesses

• Omphalitis (umbilical inflammation)

Other:

• Bleeding (DIC)

• Oliguria (renal impairment)

Remember: The threshold for investigating sepsis in neonates should be very low due to non-specific presentation and rapid deterioration.

Investigations

Screening tests (performed early, guide initial management):

• Full blood count:
• White cell count: <5 or >20 × 10⁹/L suspicious
• Absolute neutrophil count: Neutropenia (<1.5) or neutrophilia
• Immature to total neutrophil ratio (I:T ratio) >0.2 suggests sepsis
• Thrombocytopenia (<150 × 10⁹/L)

• C-reactive protein (CRP):
• Often normal in first 6-12 hours (takes time to rise)
• Repeat at 24 hours if initial suspicion high
• CRP >10 mg/L suggestive; >40 mg/L strongly suggestive
• Serial CRP useful for monitoring response to treatment

• Procalcitonin (PCT):
• May be elevated earlier than CRP
• PCT >2 ng/mL suggestive
• Useful for antibiotic stewardship (stop if low and blood cultures negative)

• Hypoglycaemia or hyperglycaemia

• Metabolic acidosis (base deficit >10)

• Lactate elevation

• If DIC suspected (prolonged PT/APTT, low fibrinogen, elevated D-dimer)

Diagnostic tests (definitive):

• Blood culture (at least 1 mL blood) - gold standard
• May be negative in 50-70% of clinically suspected sepsis
• Takes 24-48 hours for results

• Cerebrospinal fluid (CSF) culture:
• Lumbar puncture indicated if:
• Positive blood culture
• Strong clinical suspicion of meningitis
• Seizures or neurological signs
• Clinically unstable after initial stabilization
• May defer LP if infant too unstable initially
• CSF analysis:
• Cell count, protein, glucose
• Gram stain
• Culture
• Consider PCR for HSV if suspected

• Urine culture:
• Not routine in EOS (low yield)
• Consider in LOS >72 hours (suprapubic aspirate or catheter specimen)

• Surface swabs:
• Ear, umbilicus, gastric aspirate (limited value, indicates colonization not infection)

• Viral PCR (HSV, CMV, enterovirus) if clinically indicated

• Fungal cultures if high risk (prolonged antibiotics, TPN, VLBW)

Imaging:

• If respiratory signs present

• May show pneumonia, RDS, or other pathology

• Screening for IVH, especially in preterm

• Limited for detecting meningitis (use CT/MRI if needed)

• If abdominal distension or NEC suspected

Management

Immediate management:

• Airway: Ensure patent airway, suction if needed

• Breathing: Oxygen therapy, respiratory support (CPAP, intubation if needed)

• Circulation:
• IV access (peripheral or umbilical venous catheter)
• Fluid resuscitation if shocked (10-20 mL/kg boluses of normal saline)
• Inotropes if poor response (dopamine, dobutamine)

• Blood culture, FBC, CRP, blood gas, glucose (before antibiotics)

• Lumbar puncture if stable enough

• Other investigations as indicated

• START IMMEDIATELY after cultures taken (do not wait for results)

• Choice depends on local guidelines and epidemiology

Antibiotic regimens:

Early-Onset Sepsis:

• Benzylpenicillin (Penicillin G):
• <7 days: 50,000 units/kg/dose IV every 12 hours

7 days: 50,000 units/kg/dose IV every 8 hours

• PLUS Gentamicin:
• Weight-based and age-based dosing (e.g., 4-5 mg/kg once daily)
• Monitor levels (peak and trough)
• Monitor renal function

• Ampicillin + Gentamicin

• Cefotaxime (avoid ceftriaxone in neonates due to bilirubin displacement and risk of kernicterus)

• Add Ampicillin (covers Listeria better than penicillin)

• Higher doses of antibiotics

• Add Cefotaxime to penicillin + gentamicin regimen

• Consider Ampicillin for Listeria coverage

Late-Onset Sepsis:

• Flucloxacillin or Vancomycin (for Staph coverage including CoNS)

• PLUS Gentamicin or Cefotaxime (for Gram-negative coverage)

• Adjust based on local resistance patterns

• Similar to EOS regimen (Penicillin/Ampicillin + Gentamicin)

• Amphotericin B or Fluconazole

Duration of antibiotics:

• Stop antibiotics after 36-48 hours (if CRP normal or low)

• Some advocate for 5 days if strong initial clinical suspicion

• 10-14 days for uncomplicated sepsis

• 14-21 days for meningitis (Gram-negative may need longer)

• Guided by clinical response and CRP normalization

Supportive care:

• Oxygen therapy (target SpO₂ 90-95%)

• CPAP or mechanical ventilation as needed

• Treat underlying lung pathology

• Maintain adequate blood pressure and perfusion

• Fluid management (balance between adequate perfusion and fluid overload)

• Inotropic support if needed

• Correct hypoglycaemia

• Maintain electrolyte balance

• Correct acidosis (optimize ventilation and perfusion; consider bicarbonate if severe)

• Blood transfusion if anaemic and symptomatic

• Platelet transfusion if severe thrombocytopenia (<20-30 × 10⁹/L or if bleeding)

• FFP, cryoprecipitate if DIC with bleeding

• Enteral feeding may need to be withheld initially

• Total parenteral nutrition (TPN) if prolonged

• Resume feeds when stable

• Maintain normothermia (36.5-37.5°C)

• Incubator or radiant warmer

• Anticonvulsants if seizures (phenobarbital, phenytoin)

• Continuous cardiorespiratory monitoring

• Regular vital signs, fluid balance

• Serial CRP (daily until downtrending)

• Repeat cultures if poor response

Complications

• Meningitis (20-30% of sepsis cases)

• Septic shock

• Disseminated intravascular coagulation (DIC)

• Acute kidney injury

• Respiratory failure (ARDS)

• Necrotising enterocolitis (NEC)

• Pulmonary hypertension

• Multi-organ dysfunction syndrome (MODS)

• Death

• Neurodevelopmental impairment (especially with meningitis):
• Cerebral palsy
• Hearing loss (especially with Gram-negative meningitis)
• Visual impairment
• Developmental delay
• Epilepsy
• Intellectual disability

• Chronic lung disease (bronchopulmonary dysplasia)

• Growth impairment

Prognosis

• EOS: 3-10% overall (higher in preterm and with Gram-negative organisms)

• LOS: 2-6% in term; 18-36% in preterm

• Meningitis: 10-15% mortality; 20-50% neurodevelopmental sequelae

• Prematurity and low birth weight

• Gram-negative organisms (especially E. coli)

• Delayed diagnosis and treatment

• Meningitis

• Severe complications (shock, DIC, ARDS)

• Multi-organ dysfunction

• Term infant

• Early recognition and treatment

• Gram-positive organisms (especially CoNS)

• Good response to initial therapy

• No meningitis or complications

Prevention

Prevention of Early-Onset Sepsis:

• GBS screening: Vaginal-rectal swab at 35-37 weeks gestation

• Intrapartum antibiotic prophylaxis (IAP):
• Indicated if:
• GBS colonization detected in current pregnancy
• GBS bacteriuria during current pregnancy
• Previous infant with invasive GBS disease
• Unknown GBS status with risk factors (preterm labour <37 weeks, PROM ≥18 hours, intrapartum fever ≥38°C)
• Antibiotic: Penicillin G or Ampicillin IV (at least 4 hours before delivery)

• Treatment of maternal infections (UTI, STIs)

• Good antenatal care

• Aseptic technique during delivery

• Avoid unnecessary invasive procedures (scalp electrodes)

• Minimize prolonged rupture of membranes

• Hand hygiene before handling newborn

• Delayed cord clamping (unless resuscitation needed)

• Skin-to-skin care

• Early and exclusive breastfeeding (provides passive immunity)

Prevention of Late-Onset Sepsis:

• Strict hand hygiene (most important)

• Aseptic technique for all procedures

• Minimize invasive procedures and devices

• Remove central lines as soon as possible

• Isolation of infected infants

• Cohorting of infants by gestational age

• Adequate staffing ratios

• Environmental cleaning

• Breast milk (provides immunological protection)

• Donor breast milk if mother's milk unavailable

• Probiotic supplementation (may reduce NEC and sepsis in preterm - evidence evolving)

• Rational antibiotic use (avoid prolonged or unnecessary courses)

• Antimicrobial stewardship

• Immunoprophylaxis (GBS vaccine in development)

• Monoclonal antibodies against GBS

Neonatal Sepsis Risk Calculators

• Uses maternal risk factors and infant clinical presentation

• Helps identify low-risk infants who may not need antibiotics

• Reduces unnecessary antibiotic use

• Risk-based algorithms

• Clinical examination-based algorithms

Use in conjunction with clinical judgment, not as sole decision-making tool.

Key Points: Neonatal sepsis is a medical emergency with non-specific presentation. Early recognition and prompt antibiotic therapy are crucial. GBS and *E. coli are the most common causes of EOS. CoNS is the most common cause of nosocomial LOS. Always perform blood cultures before starting antibiotics. Meningitis occurs in 20-30% of sepsis cases. Prevention strategies* include GBS screening, IAP, and strict hand hygiene in NICU.