What are the empiric antibiotic choices for sepsis?

Empiric Antibiotic Choices for Sepsis

For adults with sepsis or septic shock, administer broad-spectrum intravenous antibiotics within 60 minutes of recognition, using combination therapy with an anti-pseudomonal β-lactam (such as piperacillin-tazobactam, cefepime, or a carbapenem) PLUS either an aminoglycoside or fluoroquinolone to cover all likely gram-negative and gram-positive pathogens. 1, 2

Timing is Critical

• Intravenous antimicrobials must be initiated within one hour of sepsis or septic shock recognition, as this is the single most critical intervention for reducing mortality 1, 2
• Obtain at least two sets of blood cultures (aerobic and anaerobic) before antibiotics, but never delay antimicrobials beyond 45 minutes waiting for cultures 2

First-Line Empiric Regimens for Adults

Combination Therapy (Preferred for Septic Shock)

• Use an anti-pseudomonal β-lactam PLUS either an aminoglycoside OR a fluoroquinolone for patients with septic shock 2

• Specific β-lactam options include:

  • Piperacillin-tazobactam 2
  • Cefepime 2
  • Imipenem-cilastatin 3
  • Meropenem 2

• Combination therapy with different mechanisms of action reduces mortality compared to monotherapy (34% vs 40% mortality, P=0.042) 4

• Aminoglycosides (particularly gentamicin) offer broader coverage than fluoroquinolones and increase appropriate initial therapy rates significantly 5, 6

Add MRSA Coverage When Indicated

• Add vancomycin or linezolid if MRSA is suspected, such as in healthcare-associated infection, known MRSA colonization, or severe skin/soft tissue infection 2
• For late-onset nosocomial sepsis (>72 hours), coagulase-negative staphylococci become more common and vancomycin should be considered 7

Add Antifungal Coverage for High-Risk Patients

• Add anidulafungin or caspofungin if risk factors for invasive candidiasis exist, including immunosuppression, prolonged ICU stay, total parenteral nutrition, or broad-spectrum antibiotic exposure 2

Specific Pathogen Considerations

• For Pseudomonas aeruginosa with respiratory failure and septic shock: Use extended-spectrum β-lactam PLUS aminoglycoside or fluoroquinolone 2
• For bacteremic Streptococcus pneumoniae with septic shock: Use β-lactam PLUS macrolide combination 2
• For suspected gram-negative sepsis: An antipseudomonal β-lactam with or without an aminoglycoside is recommended 8

Dosing Optimization

• Use loading doses for vancomycin (25-30 mg/kg actual body weight) to rapidly achieve therapeutic levels in septic shock due to expanded extracellular volume from fluid resuscitation 2
• Consider extended or continuous infusions of β-lactams after initial bolus to maximize time above MIC, particularly for resistant organisms 2

De-escalation Strategy (Critical to Prevent Resistance)

• Reassess antimicrobial therapy daily for potential narrowing once pathogen identification and sensitivities are available 1, 2
• Discontinue combination therapy within 3-5 days in response to clinical improvement and/or evidence of infection resolution 1, 2
• Narrow to the most appropriate single therapy once susceptibility profile is known 1
• Use procalcitonin or similar biomarkers to guide discontinuation of empiric antibiotics when no evidence of infection is found 1

Duration of Therapy

• 7-10 days is adequate for most serious infections associated with sepsis and septic shock 1, 2
• Longer courses are appropriate for:
  • Slow clinical response 1, 2
  • Undrainable foci of infection 1, 2
  • Staphylococcus aureus bacteremia 1, 2
  • Fungal and viral infections 1, 2
  • Immunodeficiency including neutropenia 1, 2

Pediatric and Neonatal Sepsis

Early-Onset Neonatal Sepsis (First 72 Hours)

• Benzylpenicillin (or ampicillin) PLUS gentamicin is the first-line empirical treatment 7
• Third-generation cephalosporins (e.g., cefotaxime) represent a reasonable alternative to an aminoglycoside 7

Late-Onset Neonatal Sepsis (>72 Hours to 1 Month)

• For coagulase-negative staphylococci: Vancomycin 7
• For GBS, E. coli, enterococci: Cefotaxime or piperacillin-tazobactam 7
• If gram-negative bacterial sepsis is suspected, add cefotaxime or another antibiotic active against gram-negative bacteria 7

Older Children with Suspected Sepsis

• Ceftriaxone (plus ampicillin or amoxicillin in neonates up to 3 months) 7

Common Pitfalls to Avoid

• Delayed administration: Mortality increases with each hour delay in appropriate antibiotic administration 1
• Inappropriate initial antimicrobial therapy (IIAT): Associated with significantly higher mortality (51.7% vs 36.4%, P<0.001) 5
• Monotherapy in septic shock: Combination therapy is associated with lower rates of IIAT (22.2% vs 36.0%, P<0.001) 5
• Failure to de-escalate: Continuing broad-spectrum therapy unnecessarily increases resistance risk 1
• Overlooking source control: Identify and address infection source within 12 hours when possible 1
• Routine use of vancomycin and antifungal therapy: Should be discouraged unless specific risk factors are present 8

Evidence Quality Note

The evidence strongly supports combination therapy over monotherapy for septic shock, with multiple guidelines from the Surviving Sepsis Campaign, Society of Critical Care Medicine, and European Society of Intensive Care Medicine all recommending this approach 1, 2. The most recent high-quality evidence (2024 WHO guidelines and 2025 Praxis summaries) consistently emphasizes the importance of rapid administration, broad-spectrum coverage, and timely de-escalation 7, 1, 2.