What are the symptoms, diagnostic approach, causes, and treatment of neonatal sepsis?

Neonatal Sepsis: Comprehensive Clinical Overview

Definition and Epidemiology

Neonatal sepsis is a life-threatening bloodstream infection occurring in infants ≤3 months of age, representing the third leading cause of neonatal mortality globally with approximately 1.3 million cases annually and 203,000 deaths per year. 1 The condition carries mortality rates of 11-19% in high-income countries, but up to 40 times higher incidence in middle-income countries. 2

Classification by Timing

• Early-Onset Sepsis (EOS): Occurs within 72 hours to 7 days of birth, traditionally acquired peripartum from maternal genital tract organisms. 2
• Late-Onset Sepsis (LOS): Develops after the first week up to 28 days of life, typically hospital-acquired with very low birth weight and early gestational age as strong risk factors. 2, 1

Clinical Presentation and Symptoms

Newborn-Specific Signs (Suspect septic shock with ANY of the following):

• Cardiovascular: Tachycardia, reduced perfusion, poor color, capillary refill >2 seconds. 2
• Respiratory: Tachypnea, respiratory distress, increased work of breathing. 2
• Feeding/Gastrointestinal: Poor feeding, poor tone, diarrhea. 2
• Neurological: Altered mental status (irritability, inappropriate crying, somnolence, lethargy, poor interaction). 3
• Metabolic: Hypoglycemia, hypocalcemia. 2
• Maternal Risk Factors: History of chorioamnionitis or prolonged rupture of membranes. 2

Critical Differential Diagnoses to Rule Out:

• Ductal-dependent congenital heart disease: Check for hepatomegaly, cyanosis, cardiac murmur, differential upper/lower extremity blood pressures or pulses—start prostaglandin infusion immediately until echocardiography rules this out. 2
• Inborn errors of metabolism: Obtain ammonia and glucose levels to exclude hyperammonemia or hypoglycemia. 2
• Persistent Pulmonary Hypertension of the Newborn (PPHN): Common complication with right ventricular failure, right-to-left shunting causing cyanosis. 2

Diagnostic Approach

Immediate Monitoring Requirements:

• Temperature monitoring continuously. 2
• Preductal AND postductal pulse oximetry (difference should be <5%). 2
• Intra-arterial blood pressure (umbilical or peripheral). 2
• Continuous electrocardiogram. 2
• Arterial pH, glucose, and ionized calcium concentrations. 2
• Urine output monitoring (goal >1 mL/kg/h). 2

Laboratory Investigations:

• Blood cultures: Obtain from normally sterile sites before antibiotics, though sensitivity may be only 21-71% and requires 2-5 days for results. 2, 4
• Cerebrospinal fluid culture: For suspected meningitis. 2
• Complete blood count: Look for thrombocytopenia, leukocytosis (nonspecific). 2
• C-reactive protein: Elevated but nonspecific for candidiasis or bacterial sepsis. 2
• Serum (1,3)-Beta-D-Glucan (BDG): For invasive candidiasis—at 80 pg/mL threshold: 89% sensitivity, 60% specificity; at 120 pg/mL: 81% sensitivity, 80% specificity. 2

Key Diagnostic Limitations:

Blood culture sensitivity is particularly poor in neonates because samples are often <1 mL, and clinical signs are nonspecific, especially in preterm infants. 2, 5 Therefore, empirical antibiotic therapy must begin immediately after cultures without awaiting results. 5, 6

Causative Organisms

Early-Onset Sepsis:

• Traditional pathogens: Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Enterobacteriaceae. 6
• Emerging pattern: Up to 64% now caused by Gram-negative and hospital-associated infections even in EOS. 2

Late-Onset Sepsis:

• Hospital-acquired pathogens: Staphylococci (coagulase-positive and negative), enterococci, Pseudomonas aeruginosa, Klebsiella, Enterobacter, Serratia, Citrobacter. 7, 6
• Fungal: Candida albicans and C. parapsilosis account for 80-90% of neonatal fungal infections, with 3-10% incidence in very low birth weight (1000-1500g) and 6-20% in extremely low birth weight (<1000g) neonates. 2

Antimicrobial Resistance Crisis:

In low- and lower-middle-income countries, only 28.5% of Gram-negative isolates remain susceptible to ampicillin-gentamicin combination, with 97% resistant to ampicillin alone. 2 An estimated 214,000 neonatal sepsis deaths annually are attributable to resistant pathogens. 2

Treatment Protocol

Therapeutic End Points (Goals of Resuscitation):

• Capillary refill ≤2 seconds. 2
• Normal pulses with no differential between peripheral and central. 2
• Warm extremities. 2
• Urine output >1 mL/kg/h. 2
• Normal mental status. 2
• Normal blood pressure for age. 2
• Normal glucose and calcium concentrations. 2
• Preductal-postductal O₂ saturation difference <5%. 2
• ≥95% arterial oxygen saturation. 2

Airway and Breathing Management:

Intubate and ventilate based on clinical diagnosis of increased work of breathing, inadequate respiratory effort, or marked hypoxemia. 2 Volume loading is often necessary before intubation because positive pressure ventilation reduces preload. 2

Empirical Antibiotic Therapy

First-Line for Early-Onset Sepsis:

Ampicillin (or penicillin) PLUS gentamicin to cover Group B Streptococcus, E. coli, and Listeria monocytogenes. 7, 6

• Gentamicin indications: Effective against Pseudomonas aeruginosa, Proteus species, E. coli, Klebsiella-Enterobacter-Serratia, Citrobacter, and Staphylococcus species. 7
• Critical caveat: In suspected staphylococcal sepsis or pneumonia, add a penicillinase-resistant penicillin (oxacillin, nafcillin) or vancomycin for methicillin-resistant strains. 7, 6

First-Line for Late-Onset Sepsis:

Same ampicillin-gentamicin combination initially, but consider netilmicin or amikacin for nosocomial infections. 6

• If vascular catheter present: Add antistaphylococcal agent. 6
• If Pseudomonas suspected (typical skin lesions): Use anti-Pseudomonas agents (piperacillin, azlocillin, ceftazidime, or cefoperazone). 6

Second-Line Therapy:

Ceftriaxone or cefotaxime as WHO-recommended second-line, though resistance rates are concerning. 2

• Cefotaxime coverage: Effective against Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, E. coli for CNS infections. 8
• Warning: Extensive cephalosporin use leads to rapid emergence of drug-resistant organisms; antagonistic interactions occur when combined with other beta-lactams. 6

Third-Line/Refractory Sepsis:

Meropenem is the most commonly prescribed empirical antibiotic in low- and middle-income countries (15.9% of regimens), reflecting local epidemiology of multidrug resistance. 2

Antibiotic Duration and Reassessment:

• If cultures negative and clinical improvement: Stop antibiotics after 2-3 days. 6
• If cultures positive or clinical sepsis confirmed: Continue 10-14 days for sepsis with minimal focal infection. 6
• Reevaluate antibiotics when culture and susceptibility results available. 7, 8, 6

Adjunctive Therapies

Hemodynamic Support:

• Fluid resuscitation: Restore circulation and perfusion first. 2
• Low cardiac output with high SVR: Add dobutamine or type III phosphodiesterase inhibitors (milrinone, enoximone). 2
• Low blood pressure with low SVR: Add norepinephrine to increase diastolic blood pressure and systemic vascular resistance. 2
• High cardiac output with low SVR: Use low-dose vasopressin, angiotensin, or terlipressin with cardiac output/ScvO₂ monitoring (may reduce cardiac output). 2

Hormone Replacement:

• Hydrocortisone: For adrenal or hypothalamic-pituitary-adrenal axis insufficiency; 7-day course reduces inotrope requirements in very low birth weight infants with septic shock. 2
• Thyroid hormone (triiodothyronine): For documented thyroid insufficiency. 2
• Calcium supplementation: Normalize ionized calcium (premature infants have relative parathyroid hormone deficiency). 2

PPHN-Specific Management:

• Metabolic alkalinization: Initial resuscitative strategy; PPHN can reverse when acidosis corrected. 2
• Inhaled nitric oxide: Treatment of choice for uncomplicated PPHN. 2
• Milrinone or inamrinone: Add to improve heart function as tolerated. 2
• ECMO: For refractory PPHN with sepsis (approximately 80% survival in neonates). 2

Refractory Shock—Rule Out Reversible Causes:

• Pericardial effusion (pericardiocentesis). 2
• Pneumothorax (thoracentesis). 2
• Hypoadrenalism (hormone replacement). 2
• Hypothyroidism (hormone replacement). 2
• Ongoing blood loss (transfusion/hemostasis). 2
• Increased intra-abdominal pressure (peritoneal catheter/abdominal release). 2
• Necrotic tissue (surgical debridement). 2
• Inadequate source control (remove nidus, use antibiotics with MIC <1, consider IV immunoglobulin for toxic shock). 2

Wound Care and Infection Prevention (for at-risk neonates):

• Monitor wounds closely for signs of infection: exudate, odor, pain, erythema, edema. 2
• Use antimicrobial soaks for nonsymptomatic positive wound cultures; rotate antimicrobials if long-term use. 2
• Neonatal sepsis requires urgent intervention due to risk of rapid deterioration, especially in severe subtypes. 2

Critical Pitfalls to Avoid

Antibiotic Stewardship Concerns:

Broad-spectrum antibiotics and prolonged empirical treatment are associated with adverse outcomes and increased antimicrobial resistance. 5 However, given high mortality risk, clinicians must balance early empirical treatment against stewardship principles. 5

Third-Generation Cephalosporin Overuse:

Do not use third-generation cephalosporins as routine first-line therapy—reserve for documented resistance or specific indications to prevent rapid emergence of resistant organisms. 6

Aminoglycoside Monitoring:

Monitor renal function carefully, especially with higher aminoglycoside dosages or prolonged therapy, due to nephrotoxicity and ototoxicity risk. 8 Potential nephrotoxicity may be potentiated when combined with cephalosporins. 8

ECMO Considerations:

ECMO survival is approximately 50% in pediatric septic shock; avoid flows >110 mL/kg/min to prevent hemolysis. 2 Normalize calcium in red blood cell pump prime (300 mg CaCl₂ per unit). 2

Regional Antibiotic Recommendations

Given alarming multidrug resistance rates (particularly in low- and middle-income countries), region- or country-specific empirical antibiotic regimens are essential based on structured antimicrobial resistance surveillance. 2 Less than 25% of neonates globally receive WHO-recommended first- or second-line antibiotics, reflecting clinicians' adaptation to local resistance patterns. 2