What are the considerations for using Colistin and Polymyxin B (antibiotics) for treating infections caused by multidrug-resistant gram-negative bacteria?

Considerations for Using Colistin and Polymyxin B for Multidrug-Resistant Gram-Negative Infections

Colistin and polymyxin B should be used as last-resort antibiotics for multidrug-resistant gram-negative bacterial infections, with polymyxin B generally preferred over colistin due to lower nephrotoxicity and better pharmacokinetic properties. 1, 2

Indications and Spectrum of Activity

• Both colistin and polymyxin B are effective against carbapenem-resistant gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacterales 1, 3
• Polymyxin B is indicated for serious infections caused by susceptible strains of P. aeruginosa, H. influenzae (meningeal infections), E. coli (urinary tract infections), Aerobacter aerogenes (bacteremia), and Klebsiella pneumoniae (bacteremia) 3
• These agents should be reserved for situations where less potentially toxic drugs are ineffective or contraindicated 3, 1

Dosing Considerations

• For colistin, a loading dose of 9 MU (5 mg/kg) followed by maintenance dose of 4.5 MU twice daily is recommended for critically ill patients 1
• Careful attention to unit conversion for colistin is essential: 1 million U = 80 mg colistin methanesulfonate = 33 mg colistin base activity 4
• Dose adjustment is required in patients with renal impairment 1, 3
• Therapeutic drug monitoring is recommended when available to optimize dosing and minimize toxicity 1, 5

Monotherapy vs. Combination Therapy

• For severe carbapenem-resistant P. aeruginosa (CRPA) infections, combination therapy with two in vitro active drugs (including a polymyxin) is suggested 5, 2
• For carbapenem-resistant A. baumannii (CRAB) infections:
  • If susceptible to sulbactam, ampicillin-sulbactam is preferred over polymyxins due to better safety profile 1, 4
  • For sulbactam-resistant CRAB, polymyxin-based combination therapy is recommended over monotherapy 4
  • Colistin-carbapenem combinations are suggested for CRAB infections if meropenem MIC is ≤32 mg/L 4
• For non-severe or low-risk infections, monotherapy may be appropriate, selected according to the source of infection 2

Polymyxin B vs. Colistin: Key Differences

• Polymyxin B is administered as its active form, while colistin is administered as an inactive prodrug (colistin methanesulfonate) 6
• Polymyxin B demonstrates significantly lower MICs than colistin against K. pneumoniae, A. baumannii, and P. aeruginosa 7
• Nephrotoxicity appears to be less common with polymyxin B compared to colistin (adjusted HR 2.27,95% CI 1.35-3.82) 5, 2
• Both agents have similar antibacterial spectrum but differ in one amino acid in their structure 7, 8

Toxicity and Monitoring

• Nephrotoxicity is the most significant adverse effect of polymyxins, occurring in 10.9-53.7% of patients 1
• Risk factors for nephrotoxicity include pre-existing renal impairment, older age, and concomitant nephrotoxic medications 1
• Regular monitoring of renal function is strongly recommended during treatment 1, 2
• Neurotoxicity can also occur, especially when used concurrently with neuromuscular blocking agents 3, 8

Special Considerations for Respiratory Infections

• For respiratory tract infections, adding aerosolized polymyxin to intravenous therapy may improve clinical outcomes 2, 4
• Colistin methanesulfonate is preferred for inhalation therapy 4

Clinical Pearls and Pitfalls

• Source control should always be a priority to optimize outcomes and shorten antibiotic treatment durations 5
• Follow-up cultures are recommended in case of treatment failure to detect resistance development 5
• For pan-resistant gram-negative bacteria, select antibiotics with the lowest MICs relative to breakpoints 5
• Avoid concurrent use of neurotoxic drugs (ether, tubocurarine, succinylcholine, gallamine, decamethonium, sodium citrate) which may precipitate respiratory depression 3
• Superinfection with non-susceptible organisms, including fungi, may occur during therapy 3
• Testing against polymyxins is recommended for carbapenem-resistant gram-negative bacteria that are resistant to all β-lactams 5

Emerging Resistance Considerations

• Acquired resistance to polymyxins is still relatively rare but increasing with their more widespread use 9, 10
• Combination therapy may help prevent emergence of resistant sub-populations 2, 10
• Polymyxins should be used judiciously as part of antibiotic stewardship programs to preserve their effectiveness 5, 1