What are polymyxins?

Polymyxins: Last-Line Antibiotics for Multidrug-Resistant Gram-Negative Infections

Polymyxins are cyclic polypeptide antibiotics that serve as a critical last-line therapy against multidrug-resistant gram-negative bacteria, including carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii (CRAB), and Pseudomonas aeruginosa (CRPA). 1

Structure and Types

• Polymyxins are amphipathic molecules that interact with lipopolysaccharide in the bacterial outer membrane, disrupting membrane integrity and causing bacterial cell death 2, 3
• Two main clinically used polymyxins are:
  • Polymyxin B (administered as polymyxin B sulfate) - used in its active form 4
  • Colistin (polymyxin E) - administered as colistimethate sodium (CMS), an inactive prodrug that converts to active colistin in the body 5, 4

Antimicrobial Spectrum

• Effective against many multidrug-resistant gram-negative bacteria including:
  • Pseudomonas aeruginosa (including carbapenem-resistant strains) 5, 6
  • Acinetobacter baumannii (including carbapenem-resistant strains) 1, 6
  • Klebsiella pneumoniae and other Enterobacterales (including carbapenem-resistant strains) 1
  • Escherichia coli 5
  • Enterobacter species 5
• Not effective against:
  • Gram-positive bacteria 2
  • Proteus species 2
  • Serratia species 2
  • Burkholderia cepacia 2

Clinical Applications

• Primary use: Treatment of infections caused by multidrug-resistant gram-negative bacteria when other options are limited 1, 6
• Specific indications:
  • Carbapenem-resistant Enterobacterales (CRE) infections 1
  • Carbapenem-resistant Acinetobacter baumannii (CRAB) infections 1, 6
  • Carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections 6
• Route of administration:
  • Intravenous for systemic infections 5
  • Aerosolized for respiratory tract infections (as adjunctive therapy) 1, 6

Dosing Considerations

• Colistin (as CMS):
  • Loading dose of 9 MU (5 mg/kg) followed by maintenance dose of 4.5 MU twice daily for critically ill patients 6
  • Dose adjustment required in renal impairment 5
• Polymyxin B:
  • Typically dosed at 1.5-2.5 mg/kg/day in two divided doses 2
  • Less renal elimination compared to colistin, requiring fewer dose adjustments in renal impairment 7

Combination Therapy

• Polymyxin combination therapy is strongly recommended over monotherapy for treating CRGNB infections 1
• Benefits of combination therapy:
  • Reduced mortality (14 fewer deaths per 1000 patients) 1
  • Decreased treatment failure (119 fewer failures per 1000 patients) 1
  • Improved pathogen eradication (74 fewer eradication failures per 1000 patients) 1
  • Prevention of resistance development 1, 7
• Common combination partners:
  • Carbapenems (especially for CRE with meropenem MIC ≤8 mg/L) 1
  • Tigecycline (for CRE infections) 1
  • Rifampicin (for CRAB infections) 1
  • Sulbactam (for CRAB infections) 1

Toxicity and Monitoring

• Major adverse effects:
  • Nephrotoxicity (more common with colistin than polymyxin B) 6, 2
  • Neurotoxicity (including paresthesias, dizziness, and rarely neuromuscular blockade) 2
• Monitoring recommendations:
  • Regular renal function assessment 6
  • Therapeutic drug monitoring when available 1
  • Avoid concurrent use of other nephrotoxic agents when possible 1

Resistance Mechanisms

• Primary mechanism: Modification of lipopolysaccharide in the bacterial outer membrane, reducing polymyxin binding 3
• Regulated by bacterial two-component signal transduction systems 3
• Increasing prevalence due to expanded clinical use since the mid-1990s 7, 3

Current Challenges and Future Directions

• Limited pharmacokinetic/pharmacodynamic data for optimal dosing strategies 4, 7
• Toxicity concerns limiting dose escalation 7
• Development of novel, less toxic polymyxin derivatives 7
• Combination therapy approaches to maximize efficacy while minimizing resistance 7

Polymyxins remain crucial antimicrobials in our limited arsenal against multidrug-resistant gram-negative pathogens, but their use must be optimized through appropriate dosing, combination therapy, and careful monitoring to preserve their effectiveness and minimize toxicity 1, 7.