According to the neonatal manual of care, how are early‑onset (within 72 hours) and late‑onset (after 72 hours) neonatal sepsis defined, what are the recommended empiric antibiotic choices and treatment plans for each, and what are the rationales for these regimens?

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Last updated: February 27, 2026 • View editorial policy

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Neonatal Sepsis: Definitions, Antibiotic Choices, and Management

Defining Early-Onset vs. Late-Onset Sepsis

Early-onset sepsis (EOS) is defined as sepsis occurring within the first 72 hours of life, while late-onset sepsis (LOS) occurs after 72 hours of life. 1

  • EOS is traditionally acquired peripartum from the maternal genital tract, classically caused by Group B Streptococcus and enteric Gram-negative bacteria 1
  • LOS arises from pathogens acquired during hospitalization, with very low birth weight and early gestational age as strong risk factors 1
  • However, this traditional distinction is increasingly outdated, particularly in low- and middle-income countries where Gram-negative and hospital-associated infections predominate in both EOS and LOS 1

Early-Onset Sepsis (EOS): Empiric Antibiotic Regimen

First-Line Treatment

Ampicillin plus gentamicin is the standard first-line empiric treatment for early-onset neonatal sepsis. 1, 2

  • This combination provides coverage against Group B Streptococcus, E. coli, Listeria monocytogenes, and other Enterobacteriaceae 3, 2
  • The WHO, American Academy of Pediatrics, and NICE all recommend this regimen as first-line therapy 1, 2
  • Alternative: Third-generation cephalosporins (e.g., cefotaxime) represent a reasonable alternative to aminoglycosides per the American Academy of Pediatrics 1

Dosing Recommendations

  • Ampicillin: 150–200 mg/kg/day IV divided every 6–8 hours 3
  • Gentamicin: 3–7.5 mg/kg/day IV 3

When to Escalate or Modify

  • Add cefotaxime (or another antibiotic active against Gram-negative bacteria) when there is evidence or strong suspicion of Gram-negative sepsis 1, 2
  • If Gram-negative infection is confirmed, stop benzylpenicillin/ampicillin 1
  • Escalate therapy immediately if no clinical improvement occurs after 48-72 hours of initial empiric therapy 3, 2

Critical Timing

  • Initiate antibiotics within 1 hour for septic shock, within 3 hours for sepsis without shock 3, 2
  • Obtain blood cultures before antibiotic administration, but never delay treatment waiting for results 3, 2

Reassessment and De-escalation

  • If blood cultures remain negative and the infant shows clinical improvement within 48-72 hours, discontinue antibiotics to avoid unnecessary exposure and limit antimicrobial resistance 3, 2
  • Adjust therapy based on blood culture results and antimicrobial susceptibility testing 2

Late-Onset Sepsis (LOS): Empiric Antibiotic Regimen

Critical Distinction: Community-Acquired vs. Nosocomial

The choice of empiric antibiotics for LOS depends critically on whether the infection is community-acquired or hospital-acquired (nosocomial). 3

Community-Acquired LOS (Days 4-28, No Prolonged Hospitalization)

  • First-line: Ampicillin plus gentamicin 3
  • Pathogens: Group B Streptococcus, E. coli, Listeria monocytogenes 3
  • This is the same regimen as EOS because the pathogen profile is similar 3

Nosocomial/Hospital-Acquired LOS

For hospital-acquired neonatal infections, amikacin plus cloxacillin is the WHO-recommended first-line therapy. 3, 2

  • This regimen provides coverage against resistant staphylococci (including coagulase-negative staphylococci) and Gram-negative bacteria 3, 2
  • Pathogens: Coagulase-negative staphylococci, Staphylococcus aureus (including MRSA), resistant Gram-negative bacteria, and enterococci 1, 3

When to Use Vancomycin-Based Regimens

Vancomycin plus ceftazidime should replace amikacin plus cloxacillin when methicillin-resistant organisms are suspected. 3, 2

  • Specific indications: Central venous catheters, prolonged NICU stays, or known MRSA colonization 1, 3
  • In developed countries, coagulase-negative staphylococci is the leading cause of LOS, followed by GBS and Gram-negative bacteria 1
  • For coagulase-negative staphylococci: vancomycin 1
  • For GBS, E. coli, enterococci: cefotaxime or piperacillin-tazobactam 1

Escalation Algorithm

  • If no clinical improvement after 48-72 hours on ampicillin plus gentamicin, immediately escalate to amikacin plus cloxacillin (or vancomycin if MRSA suspected) 3
  • If Gram-negative sepsis is strongly suspected, add cefotaxime to the regimen 1, 3

Rationales for Antibiotic Choices

Why Ampicillin Plus Gentamicin for EOS?

  • Ampicillin provides excellent coverage against Group B Streptococcus and Listeria monocytogenes, the traditional EOS pathogens in high-income countries 1, 2
  • Gentamicin adds Gram-negative coverage, particularly against E. coli and other Enterobacteriaceae 1, 2
  • This combination has been the standard of care for decades and is supported by all major guidelines 1, 2

Why Different Regimens for Nosocomial LOS?

  • Nosocomial infections have a completely different pathogen profile dominated by staphylococci (particularly coagulase-negative staphylococci) and resistant Gram-negative bacteria 1, 3
  • Amikacin demonstrates better sensitivity than gentamicin in many nosocomial settings with high resistance rates 3
  • Cloxacillin provides anti-staphylococcal coverage, while vancomycin is reserved for methicillin-resistant organisms 3, 2

The Growing Problem of Resistance

In low- and middle-income countries, 97% of Gram-negative isolates show ampicillin resistance, and only 28.5% remain susceptible to ampicillin-gentamicin combinations. 2

  • Gram-negative bacteria account for 60% of neonatal sepsis in LLMICs, with high rates of resistance against WHO-recommended empirical antibiotics 1
  • Klebsiella species account for 38% of Gram-negative neonatal sepsis in LLMICs, followed by E. coli (15%) 1
  • 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) 2

Plan of Care: Step-by-Step Algorithm

Step 1: Immediate Actions Upon Suspicion of Sepsis

  1. Obtain blood cultures immediately (and CSF if meningitis suspected) 3, 2
  2. Initiate empiric antibiotics within 1 hour for septic shock, within 3 hours for sepsis without shock 3, 2
  3. Never delay antibiotic administration waiting for culture results 3, 2

Step 2: Choose Initial Empiric Regimen

For EOS (≤72 hours of life):

  • Ampicillin plus gentamicin 1, 2

For Community-Acquired LOS (>72 hours, no prolonged hospitalization):

  • Ampicillin plus gentamicin 3

For Nosocomial/Hospital-Acquired LOS:

  • Amikacin plus cloxacillin 3, 2
  • OR vancomycin plus ceftazidime if central venous catheter present or MRSA suspected 3

Step 3: Reassess at 48-72 Hours

If cultures negative and clinical improvement evident:

  • Discontinue antibiotics to avoid unnecessary exposure 3, 2

If no clinical improvement:

  • Escalate therapy immediately 3, 2
  • For EOS or community-acquired LOS: switch to amikacin plus cloxacillin (or vancomycin if MRSA suspected) 3
  • For nosocomial LOS already on amikacin plus cloxacillin: escalate to vancomycin plus ceftazidime or broader-spectrum agents based on local antibiogram 3, 2

If Gram-negative sepsis confirmed or strongly suspected:

  • Add cefotaxime (or another antibiotic active against Gram-negative bacteria) 1, 3, 2

Step 4: Adjust Based on Culture Results

  • De-escalate to the narrowest effective spectrum once culture results and susceptibility testing are available 3, 2
  • Adjust therapy based on antimicrobial susceptibility testing 2
  • Duration of treatment should be determined by site of infection, etiological organism, and clinical response 2

Common Pitfalls and How to Avoid Them

Pitfall 1: Ignoring Local Resistance Patterns

Local antibiotic resistance patterns must dictate empiric therapy choices. 2

  • The WHO recommendations may be inadequate in many LLMICs due to high resistance rates 1
  • Consult your institution's antibiogram before selecting empiric therapy 2

Pitfall 2: Failing to Distinguish Community-Acquired from Nosocomial LOS

  • Community-acquired LOS has a pathogen profile similar to EOS (GBS, E. coli, Listeria) and should be treated with ampicillin plus gentamicin 3
  • Nosocomial LOS is dominated by staphylococci and resistant Gram-negative bacteria, requiring amikacin plus cloxacillin or vancomycin-based regimens 3, 2

Pitfall 3: Delaying Antibiotic Initiation

  • Delaying antibiotic initiation while awaiting culture results increases mortality risk 3
  • Always obtain cultures first, but never delay treatment 3, 2

Pitfall 4: Not Reassessing at 48-72 Hours

  • Failing to adjust therapy based on culture results and clinical response leads to treatment failure 2
  • If no improvement by 48-72 hours, escalate immediately 3, 2

Pitfall 5: Overusing Antibiotics When Cultures Are Negative

  • If cultures are negative and clinical improvement is evident at 48-72 hours, discontinue antibiotics 3, 2
  • Unnecessary antibiotic exposure promotes resistance and increases adverse effects 3, 2

Pitfall 6: Missing Meningitis

  • Blood cultures can be sterile in up to 15% of newborns with meningitis 2
  • Perform lumbar puncture if clinically feasible when sepsis is suspected 2
  • If lumbar puncture is deferred and empiric therapy continues beyond 48 hours due to clinical instability, obtain CSF for analysis 2

Special Considerations

Infants with Central Venous Catheters

  • Use vancomycin instead of cloxacillin due to high risk of coagulase-negative staphylococci and MRSA 3

Premature Infants (<37 Weeks)

  • All premature infants should be treated with broad-spectrum antibiotics if there is a history of chorioamnionitis, prolonged rupture of membranes >18 hours, or inadequate GBS intrapartum antimicrobial prophylaxis 1

Infants Born to Mothers with Suspected Chorioamnionitis

  • All asymptomatic infants born to women with suspected chorioamnionitis should receive broad-spectrum antibiotics 1

High-Risk Settings (LLMICs)

  • In areas with high resistance to aminoglycosides, consider the combination of third-generation cephalosporins with ampicillin 2
  • Robust antimicrobial resistance surveillance and reporting is necessary to develop region-specific empirical antibiotic recommendations 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Guideline

Neonatal Sepsis Treatment Guidelines

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

3
Guideline

Management of Late Onset Neonatal Sepsis

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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