What are the guidelines for treating neonatal sepsis?

Neonatal Sepsis Treatment Guidelines

First-Line Empiric Therapy for Early-Onset Sepsis

The WHO recommends ampicillin plus gentamicin as the standard first-line empiric treatment for early-onset neonatal sepsis, providing coverage against Group B Streptococcus, E. coli, and Listeria monocytogenes. 1, 2, 3

Dosing Considerations

• Ampicillin dosing for neonates ≤28 days varies by gestational and postnatal age 4:

  • Gestational age ≤34 weeks, postnatal age ≤7 days: 100 mg/kg/day divided every 12 hours 4
  • Gestational age ≤34 weeks, postnatal age 8-28 days: 150 mg/kg/day divided every 12 hours 4
  • Gestational age >34 weeks, postnatal age ≤28 days: 150 mg/kg/day divided every 8 hours 4

• Gentamicin is indicated for serious gram-negative infections including neonatal sepsis, with dosing adjusted for gestational and postnatal age 5

• In neonates with suspected bacterial sepsis, a penicillin-type drug is usually indicated as concomitant therapy with gentamicin 5

Critical Timing Requirements

Antibiotics must be initiated within 1 hour for septic shock and within 3 hours for sepsis without shock. 1, 2

• Blood cultures should be obtained before antibiotic administration, but never delay treatment waiting for results 1, 2

• Empiric therapy should be started immediately after cultures are obtained without awaiting results 6

Late-Onset and Hospital-Acquired Sepsis

For hospital-acquired neonatal infections, the WHO recommends amikacin plus cloxacillin as first-line therapy, providing coverage against resistant staphylococci and gram-negative bacteria. 1, 3

• Vancomycin plus ceftazidime should replace the above when methicillin-resistant staphylococci or resistant gram-negative bacteria are suspected 1

• Hospital-acquired pathogens include coagulase-negative staphylococci, enterococci, and Pseudomonas aeruginosa 6

When to Escalate or Modify Therapy

Add cefotaxime when there is evidence or strong suspicion of gram-negative sepsis. 1, 2, 3

• Escalate therapy immediately if no clinical improvement occurs after 48-72 hours of initial empiric therapy 1, 2

• Adjust therapy based on blood culture results and antimicrobial susceptibility testing 2, 6

• For bacterial meningitis, increase ampicillin dosing to 150-200 mg/kg/day in divided doses every 3-4 hours 4

Regional Resistance Patterns: A Critical Caveat

In low- and middle-income countries, 97% of gram-negative isolates show ampicillin resistance, and only 28.5% of gram-negative isolates remain susceptible to ampicillin-gentamicin combinations. 7

• Less than one-quarter of neonates globally receive WHO-recommended first- or second-line antibiotics, with meropenem being the most commonly prescribed empiric antibiotic in LMICs (15.9% of regimens) 7, 1

• Resistance to gentamicin and ceftriaxone is similarly concerning across all key groups of gram-negative bacteria in LMICs 7

• Local antibiotic resistance patterns must dictate empiric therapy choices 1, 2

Duration of Therapy and Discontinuation

Discontinue antibiotics after 48 hours if blood cultures are negative and the infant remains asymptomatic with low probability of sepsis. 1, 8, 9

• Time to positivity (TTP) of blood cultures with pathogenic organisms is <48 hours in 100% of cases, with mean TTP of 17.7 hours versus 80.5 hours for contaminants 8

• For proven sepsis with minimal or absent focal infection, continue therapy for 10-14 days 6, 10

• Treatment should continue for a minimum of 48-72 hours beyond clinical improvement or bacterial eradication 4

• For Group A beta-hemolytic streptococcal infections, treat for minimum 10 days to prevent acute rheumatic fever or glomerulonephritis 4

Common Pitfalls to Avoid

• Prolonged empiric treatment (≥5 days) with broad-spectrum antibiotics in preterm infants increases risks of late-onset sepsis, necrotizing enterocolitis, and mortality 9

• Failing to adjust therapy based on culture results and clinical response leads to treatment failure 2, 3

• Ignoring local antimicrobial resistance patterns when selecting empiric therapy is a critical error 1, 2

• More rapid intravenous administration of ampicillin than recommended (faster than 10-15 minutes for 1-2g doses) may result in convulsive seizures 4

Special Considerations for Meningitis

• When clinical signs suggest sepsis, perform lumbar puncture if feasible, as blood cultures can be sterile in up to 15% of newborns with meningitis 7

• If lumbar puncture is deferred and empiric therapy continues beyond 48 hours due to clinical instability, obtain CSF for analysis 7

• Bacterial meningitis requires higher ampicillin dosing (150-200 mg/kg/day) and may require initiation with intravenous therapy for at least 3 days 4