What are the recommendations for using Polymyxin B (Polymyxin B) and Meropenem combination therapy for Carbapenem-Resistant Acinetobacter baumannii (CRAB) infections?

Polymyxin B and Meropenem Combination Therapy for CRAB Infections

Polymyxin B combined with high-dose extended-infusion meropenem is recommended for treating moderate to severe carbapenem-resistant Acinetobacter baumannii (CRAB) infections when the meropenem MIC is ≤32 mg/L. 1

Evidence-Based Recommendations for CRAB Treatment

First-line Treatment Options

• For CRAB infections with meropenem MIC ≤32 mg/L:

  • Polymyxin B + high-dose extended-infusion meropenem (strong recommendation, moderate quality evidence) 1
  • Consider adding a third agent for severe infections (conditional recommendation) 1

• For CRAB infections with meropenem MIC >32 mg/L:

  • Polymyxin B + alternative in vitro active agent (aminoglycoside, tigecycline, or sulbactam combinations) 1
  • Avoid polymyxin-meropenem combination when meropenem MIC >32 mg/L (strong recommendation against, high quality evidence) 1

Dosing Considerations

• Meropenem dosing:

  • High-dose extended-infusion: 2g every 8 hours administered as 3-hour infusion 1
  • Consider escalating to 6-8g/day in severe infections for enhanced bacterial killing 2

• Polymyxin B dosing:

  • Standard dosing: 1.5-2.5 mg/kg/day divided every 12 hours 1
  • Pay attention to correct dose conversion: 1 mg polymyxin B sulfate = 10,000 units 1

Special Considerations for Respiratory Infections

• For CRAB respiratory tract infections:
  • Consider adding aerosolized polymyxin to intravenous therapy (weak recommendation, low quality evidence) 1
  • Aerosolized polymyxin should not be used alone 1
  • Monitor for bronchospasm with inhaled therapy 1

Efficacy and Rationale

The rationale for polymyxin B-meropenem combination therapy is based on:

1. Synergistic effects: In vitro studies demonstrate that polymyxin B drastically decreases the meropenem concentration needed for activity against meropenem-resistant populations 2

2. Clinical outcomes: Combination therapy shows:

   • 119 fewer treatment failures per 1000 patients (RR = 0.82,95% CI 0.72-0.93) 1
   • 74 fewer cases of pathogen eradication failure per 1000 patients (RR = 0.81,95% CI 0.67-0.98) 1
   • Shorter time to microbiological clearance 1

3. Resistance prevention: Colistin-based combinations have been shown to prevent emergence of resistant sub-populations 1

Important Caveats and Limitations

• Mortality benefit is modest: Only approximately 14 fewer deaths per 1000 patients with combination therapy (RR = 0.97,95% CI 0.84-1.13) 1

• Avoid polymyxin-rifampin combination: Strong recommendation against this combination (high/moderate quality evidence) 1

• Meropenem MIC threshold is critical: The efficacy of combination therapy depends on meropenem MIC, with benefit primarily seen when MIC ≤32 mg/L 1

• Adverse effects: Monitor for:

  • Nephrotoxicity (though combination may reduce incidence of mild renal failure compared to polymyxin monotherapy) 1
  • Increased incidence of diarrhea with combination therapy (27% vs 16%) 1

• Pharmacodynamic optimization: Extended or continuous infusion of meropenem improves efficacy by maximizing time above MIC, especially important for CRAB with elevated MICs 2

Alternative Approaches

For CRAB resistant to polymyxins or when polymyxins are unavailable:

• Consider triple therapy with minocycline, sulbactam, and polymyxin B for enhanced killing and resistance prevention 3

• Ampicillin-sulbactam may be considered for CRAB susceptible to sulbactam 1

• For polymyxin shortages, combinations of meropenem with gentamicin and sulbactam have shown in vitro synergy against 75% of CRAB isolates 4

By following these evidence-based recommendations and considering the meropenem MIC of the isolate, clinicians can optimize treatment outcomes for patients with CRAB infections while minimizing the development of further resistance.