What is the recommended use of polymyxin (antibiotic) combined with imipenem (carbapenem antibiotic) for treating multi-drug resistant bacterial infections?

Polymyxin Combined with Imipenem for Multi-Drug Resistant Bacterial Infections

Based on high-quality evidence, polymyxin-carbapenem combination therapy is not recommended for carbapenem-resistant Acinetobacter baumannii (CRAB) infections, as it shows no benefit over polymyxin monotherapy for mortality or clinical outcomes.

Evidence Against Polymyxin-Carbapenem Combinations

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2022 guidelines provide strong recommendations against specific polymyxin combinations:

• For CRAB infections: Strong recommendation against polymyxin-meropenem combination therapy (high certainty evidence) and polymyxin-rifampin combination therapy (moderate certainty evidence) 1

• The AIDA randomized controlled trial showed no significant difference between colistin monotherapy and colistin-meropenem combination therapy for CRAB infections regarding:

  • Clinical failure at day 14 (RR 0.97,95% CI 0.87-1.09)
  • 14-day mortality (RR 1.11,95% CI 0.82-1.52) 1

• The OVERCOME trial similarly found no mortality benefit at 28 days between colistin monotherapy (46%) and colistin-meropenem combination (42%) for carbapenem-resistant infections 1

Specific Recommendations for Different Pathogens

For Carbapenem-Resistant Acinetobacter baumannii (CRAB)

1. Avoid polymyxin-carbapenem combinations (strong recommendation) 1

2. For severe and high-risk CRAB infections:

   • Consider combination therapy with two in vitro active antibiotics among polymyxins, aminoglycosides, tigecycline, or sulbactam combinations (conditional recommendation) 1

3. Special case: For CRAB with meropenem MIC <8 mg/L only:

   • Consider carbapenem combination therapy using high-dose extended-infusion carbapenem dosing 1

For Difficult-to-Treat Resistant Pseudomonas aeruginosa (DTR-PA)

1. First choice: Ceftolozane-tazobactam if active in vitro (conditional recommendation) 1

2. For severe CRPA infections when using polymyxins, aminoglycosides, or fosfomycin:

   • Use two in vitro active drugs (conditional recommendation) 1
   • No specific combination is recommended over others

3. For non-severe CRPA infections:

   • Consider monotherapy with in vitro active antibiotics 1

4. Novel agents to consider:

   • Ceftazidime-avibactam, ceftolozane-tazobactam, or imipenem-cilastatin-relebactam (weak recommendation) 1

For Carbapenem-Resistant Enterobacterales (CRE)

1. Polymyxin-based combination therapy is recommended for CRE bloodstream infections (weak recommendation) 1

   • Tigecycline was the most commonly used combination agent

2. Newer agents preferred when available:

   • Ceftazidime-avibactam 2.5g IV q8h (3-hour infusion)
   • Meropenem-vaborbactam 4g IV q8h (3-hour infusion)
   • Imipenem-cilastatin-relebactam 1.25g IV q6h 1

Practical Considerations

• Dosing for colistin (in normal renal function):

  • Loading dose: 300 mg CMS (9 MU) infused over 0.5-1 hour
  • Maintenance: 300-360 mg CMS (9-10.9 MU) divided in two doses 1

• Nephrotoxicity concerns:

  • Colistin has higher RIFLE-defined nephrotoxicity compared to polymyxin B (adjusted HR 2.27) 1
  • Nephrotoxicity with polymyxin B occurs in approximately 10% of patients 2

• Resistance development:

  • Breakthrough infections with polymyxin-resistant organisms can occur during treatment 3
  • Approximately 45% of patients may develop new CRKP infections after polymyxin B treatment 3

Clinical Efficacy

• Polymyxin B monotherapy for CRKP infections has shown clinical cure rates of 73% in retrospective studies 3

• Polymyxin B in combination with other antimicrobials for MDR Gram-negative respiratory tract infections has shown:

  • End-of-treatment mortality: 21%
  • Overall mortality at discharge: 48% 2

• Risk factors for treatment failure with polymyxin B include baseline renal insufficiency (6-fold increased risk) 3

In conclusion, while in vitro studies have suggested synergy between polymyxins and carbapenems, high-quality clinical evidence does not support this combination for most carbapenem-resistant infections. Treatment should be guided by susceptibility testing, with newer agents preferred when available and appropriate combination therapy considered for severe infections based on resistance patterns.