What are the recommended empiric antibiotics for sepsis?

Empiric Antibiotic Therapy for Sepsis

Administer broad-spectrum intravenous antibiotics within 60 minutes of recognizing sepsis or septic shock, using an anti-pseudomonal β-lactam (piperacillin-tazobactam, cefepime, or meropenem) combined with either an aminoglycoside or fluoroquinolone for septic shock, plus vancomycin if MRSA risk factors exist. 1, 2, 3

Critical Timing

• Initiate IV antimicrobials within one hour of sepsis recognition—this is the single most critical intervention for reducing mortality. 2, 3
• Obtain at least two sets of blood cultures before antibiotics, but never delay antimicrobials beyond 45 minutes waiting for cultures. 2, 3
• Each hour of delay in appropriate antibiotic administration increases mortality risk. 2

First-Line Empiric Regimens for Adults

Core β-Lactam Selection

Choose one of the following anti-pseudomonal β-lactams as your foundation:

• Piperacillin-tazobactam 4.5 g IV every 6-8 hours 1, 2, 4
• Cefepime 2 g IV every 8 hours 2, 5, 4
• Meropenem 1-2 g IV every 8 hours 1, 2, 4
• Imipenem-cilastatin 500 mg to 1 g IV every 6-8 hours 6, 4

The choice among these agents should be guided by local resistance patterns, with carbapenems (meropenem or imipenem) reserved for settings with high rates of extended-spectrum β-lactamase (ESBL) producing organisms. 1, 4

Combination Therapy for Septic Shock

• For septic shock, add either an aminoglycoside OR a fluoroquinolone to the β-lactam to ensure coverage of resistant gram-negative pathogens, particularly Pseudomonas aeruginosa. 1, 2, 3
• This dual coverage increases the probability that at least one active agent is administered when multidrug-resistant pathogens are present. 1

MRSA Coverage

Add vancomycin or linezolid when any of these risk factors exist: 2, 3

• Healthcare-associated infection
• Known MRSA colonization
• Severe skin/soft tissue infection
• Recent hospitalization or antimicrobial use

Vancomycin loading dose: 25-30 mg/kg actual body weight to rapidly achieve therapeutic levels in septic shock due to expanded extracellular volume from fluid resuscitation. 2, 3

Antifungal Coverage

Add anidulafungin or caspofungin if risk factors for invasive candidiasis exist: 1, 2, 3

• Immunosuppression (neutropenia, chemotherapy, transplant)
• Prolonged ICU stay (>7 days)
• Total parenteral nutrition
• Broad-spectrum antibiotic exposure
• Recent major abdominal surgery
• Multiple site Candida colonization

Pathogen-Specific Considerations

Pseudomonas aeruginosa with Respiratory Failure

• Use extended-spectrum β-lactam PLUS aminoglycoside or fluoroquinolone for patients with respiratory failure and septic shock when P. aeruginosa is suspected. 1, 2, 3

Streptococcus pneumoniae Bacteremia

• Use β-lactam PLUS macrolide combination for septic shock from bacteremic S. pneumoniae. 1, 2, 3

Dosing Optimization Strategies

• Consider extended or continuous infusions of β-lactams after initial bolus to maximize time above MIC, particularly for resistant organisms. 2, 3
• Optimize all antibiotic dosing based on pharmacokinetic/pharmacodynamic principles, accounting for altered volumes of distribution and clearance in septic shock. 1, 2

De-escalation Protocol

• Reassess antimicrobial therapy daily for potential narrowing once pathogen identification and sensitivities are available. 1, 2, 3
• Discontinue combination therapy within 3-5 days in response to clinical improvement and/or evidence of infection resolution. 1, 7
• Narrow to the most appropriate single therapy once susceptibility profile is known. 1, 7
• Failure to de-escalate continuing broad-spectrum antibiotics beyond 3-5 days when culture results are available increases antimicrobial resistance risk. 7

Duration of Therapy

• 7-10 days is adequate for most serious infections associated with sepsis and septic shock. 1, 2, 3, 7

Indications for Longer Courses

Extend therapy beyond 10 days for: 1, 2, 3, 7

• Slow clinical response to initial therapy
• Undrainable foci of infection
• Staphylococcus aureus bacteremia
• Fungal and viral infections
• Immunologic deficiencies, including neutropenia

Indications for Shorter Courses

Consider shorter courses for: 1

• Rapid clinical resolution following effective source control
• Uncomplicated pyelonephritis with appropriate source control
• Intra-abdominal or urinary sepsis with successful drainage

Site-Specific Modifications

The empiric regimen must be adjusted based on the anatomic site of infection: 1

• Intra-abdominal infections: Add metronidazole to β-lactam for anaerobic coverage if using cefepime (which lacks anaerobic activity), or use piperacillin-tazobactam, meropenem, or imipenem which provide adequate anaerobic coverage. 1, 5, 6
• Pneumonia: Ensure coverage for atypical pathogens (Legionella) by adding a macrolide or fluoroquinolone if not already included. 1
• Urinary tract source: May use narrower spectrum if no shock present, but maintain broad coverage for septic shock. 1

Critical Pitfalls to Avoid

• Never use antimicrobial agents in patients with severe inflammatory states determined to be of noninfectious cause (e.g., severe pancreatitis without infection, sterile burn injury). 1, 7
• Do not continue combination therapy beyond 3-5 days—this increases resistance without improving outcomes. 1, 7
• Do not overlook source control—identify and address the infection source within 12 hours when possible, as antibiotics alone are insufficient without drainage of abscesses or removal of infected devices. 2
• Avoid cefepime monotherapy for suspected ESBL-producing organisms even when reported as susceptible, as this is associated with delayed clinical stability and potentially worse outcomes compared to carbapenems. 8, 9

Risk Stratification for Resistant Organisms

Assess these risk factors that mandate broader empiric coverage: 1

• Prolonged hospital or chronic care facility stay
• Recent antimicrobial use (within 3 months)
• Prior hospitalization
• Prior colonization or infection with multidrug-resistant organisms
• Presence of invasive devices (central lines, urinary catheters)
• Immunocompromise (diabetes, chronic liver/renal failure, HIV, neutropenia)

When these risk factors are present, empiric regimens must include coverage for multidrug-resistant pathogens including MRSA, ESBL-producing Enterobacterales, and resistant Pseudomonas/Acinetobacter species. 1, 9