Is the combination of meropenem with colistin a preferred treatment option for severe infections caused by multidrug-resistant Gram-negative bacteria?

Meropenem with Colistin Combination Therapy for Multidrug-Resistant Gram-Negative Infections

The combination of meropenem with colistin is not recommended for the treatment of severe infections caused by multidrug-resistant Gram-negative bacteria, particularly for carbapenem-resistant Acinetobacter baumannii (CRAB) infections. 1, 2

Evidence Against Meropenem-Colistin Combination

• High-quality randomized controlled trials (RCTs) have demonstrated no benefit of colistin-meropenem combination therapy over colistin monotherapy for CRAB infections 1, 3
• The OVERCOME trial, a double-blind RCT, showed no significant difference in 28-day mortality between colistin monotherapy (43%) and colistin-meropenem combination therapy (37%) for carbapenem-resistant Gram-negative infections 2
• The AIDA trial, including 406 patients (mostly with CRAB infections), found no significant difference in clinical failure at 14 days between colistin monotherapy (79%) and colistin-meropenem combination (73%) 3
• The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) makes a strong recommendation against polymyxin-meropenem combination therapy for CRAB infections, with high certainty of evidence 1

Specific Pathogen Considerations

For Carbapenem-Resistant Acinetobacter baumannii (CRAB):

• Colistin monotherapy is preferred over colistin-meropenem combination for CRAB infections 1, 4
• A meta-analysis of studies comparing colistin monotherapy versus colistin plus meropenem showed comparable efficacy and safety profiles for CRAB infections 4
• For CRAB with meropenem MIC <8 mg/L, high-dose extended-infusion carbapenem combinations may be considered, but this is a good practice statement rather than an evidence-based recommendation 1

For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA):

• For severe CRPA infections, combination therapy with two in vitro active drugs (which could include a polymyxin) is suggested, but specific combinations cannot be definitively recommended 1, 5
• The ESCMID suggests treatment with two in vitro active drugs for severe CRPA infections, but this is a conditional recommendation with very low certainty of evidence 1

Clinical Implications and Monitoring

• When using colistin (or polymyxin B), optimal dosing is critical: a loading dose of 9 MU (5 mg/kg) followed by maintenance dose of 4.5 MU twice daily for critically ill patients 6, 5
• Nephrotoxicity appears less common with polymyxin B compared to colistin (adjusted HR 2.27,95% CI 1.35-3.82) 1, 5
• Regular monitoring of renal function is strongly recommended during treatment with polymyxins 6, 5
• Source control should always be prioritized to optimize outcomes and shorten antibiotic treatment durations 1, 7

Situations Where Combination Therapy May Be Considered

• For severe and high-risk CRAB infections, combination therapy including two in vitro active antibiotics among available options (polymyxin, aminoglycoside, tigecycline, sulbactam combinations) may be considered 1, 7
• For respiratory tract infections, adding aerosolized polymyxin to intravenous therapy may improve clinical outcomes 6, 5

Laboratory Considerations

• In vitro synergism between colistin and meropenem via checkerboard method does not translate into clinical benefit 8
• Follow-up cultures are recommended in case of treatment failure to detect resistance development 7, 6

In conclusion, current high-quality evidence does not support the routine use of meropenem-colistin combination therapy for multidrug-resistant Gram-negative infections, particularly for CRAB. For non-severe infections, monotherapy with an appropriate agent is preferred, while for severe infections, combination therapy with two active agents may be considered, though specific combinations cannot be definitively recommended.