What is the best course of action for a patient with worsening sepsis and septic shock who is already being treated with Polymyxin B (Polymyxin B) and Meropenem (Meropenem)?

Management of Worsening Septic Shock Despite Polymyxin B and Meropenem

You must immediately reassess for source control, add empiric coverage for additional resistant pathogens (particularly MRSA and resistant gram-positives), optimize antimicrobial dosing strategies, and consider adjunctive therapies while obtaining urgent cultures to guide de-escalation. 1

Immediate Priority Actions

Source Control Assessment

• Identify and eliminate any uncontrolled infectious source within 12 hours - this is the single most critical intervention when patients deteriorate on appropriate antibiotics 1
• Obtain urgent imaging to identify drainable collections, undrained abscesses, infected devices, or necrotic tissue 1
• Remove any intravascular access devices that could be infected and replace them at new sites 1
• Consider surgical consultation for any potentially drainable focus, choosing the least physiologically invasive intervention (percutaneous drainage over open surgery when feasible) 1

Expand Antimicrobial Coverage

Add vancomycin immediately (15-20 mg/kg loading dose) to cover MRSA and resistant gram-positive organisms that your current regimen does not adequately address 2

Consider adding an aminoglycoside or fluoroquinolone for synergistic gram-negative coverage, as the Surviving Sepsis Campaign specifically recommends combination therapy for septic shock with difficult-to-treat multidrug-resistant pathogens like Pseudomonas and Acinetobacter 1

The rationale: While polymyxin B and meropenem provide broad gram-negative coverage, worsening clinical status suggests either:

• Inadequate source control 1
• Resistant gram-positive organisms (particularly MRSA) 2
• Polymyxin-resistant gram-negatives requiring additional agents 1
• Subtherapeutic drug levels 1, 3

Optimize Current Antibiotic Dosing

Ensure meropenem is dosed at 2g IV every 8 hours as an extended infusion (over 3 hours) rather than standard dosing, as critically ill septic shock patients frequently have altered pharmacokinetics that result in subtherapeutic β-lactam concentrations with standard dosing 4, 3

Research demonstrates that 75% of patients achieved target concentrations with meropenem, but only when appropriately dosed - standard dosing fails in the early phase of severe sepsis 3

Consider therapeutic drug monitoring if available, as septic shock patients have abnormal volumes of distribution from aggressive fluid resuscitation and fluctuating renal function 1

Diagnostic Workup

Obtain Cultures Immediately

• Draw at least two sets of blood cultures (one percutaneous, one from each vascular access device if present >48 hours) before adding new antibiotics if this causes no significant delay 1
• Obtain site-specific cultures: respiratory (if pneumonia suspected), urine, wound, or any other potential source 2
• Consider fungal cultures if the patient has been on broad-spectrum antibiotics, has central lines, or is immunocompromised 1

Consider Resistant Pathogens

The combination of polymyxin B and meropenem suggests you're already treating highly resistant gram-negatives, but worsening status requires consideration of:

• Carbapenem-resistant Enterobacteriaceae (CRE) - may require ceftazidime-avibactam 5
• MRSA or vancomycin-resistant enterococci - requires vancomycin or alternative gram-positive coverage 2
• Invasive fungal infections - particularly Candida in patients with prolonged broad-spectrum therapy 1

Adjunctive Considerations

Polymyxin B Hemoperfusion

If the patient has gram-negative abdominal sepsis with high endotoxin burden, polymyxin B hemoperfusion (not just IV polymyxin B) showed mortality reduction from 53% to 32% in the EUPHAS trial, with improved hemodynamics and organ dysfunction scores 6, 7

This is distinct from systemic polymyxin B administration and involves extracorporeal blood purification 6

Daily Management Strategy

Reassessment Protocol

• Reassess antimicrobial regimen daily for potential de-escalation once culture results return 1
• Plan for 7-10 days total duration for most serious infections, though longer courses may be needed with slow clinical response, undrainable foci, or S. aureus bacteremia 1
• De-escalate combination therapy within 3-5 days once clinical improvement occurs or sensitivities are known 1

Monitoring Parameters

• Track Sequential Organ Failure Assessment (SOFA) scores daily 4
• Monitor vasopressor requirements and mean arterial pressure trends 6
• Assess for clinical improvement: fever curve, white blood cell count, lactate clearance 2

Critical Pitfalls to Avoid

Failure to identify and control the source is the most common reason for antibiotic failure in septic shock - no antibiotic regimen will succeed without source control 1

Inadequate MRSA coverage in patients already on broad gram-negative therapy is frequently overlooked 2

Subtherapeutic dosing of β-lactams occurs in up to 66-84% of septic shock patients receiving standard doses in the early phase 3

Delayed addition of appropriate coverage - every hour of inappropriate therapy increases mortality, so empiric broadening should occur immediately while awaiting cultures 1, 2

Prolonged broad-spectrum therapy without de-escalation increases risk of C. difficile, resistant organisms, and fungal superinfection 1