What is the recommended dose and potential interactions of Polymyxin B (antibiotic) for treating multidrug-resistant gram-negative bacterial infections, particularly with regards to Impaired renal function?

Polymyxin B Dosing and Interactions for Multidrug-Resistant Gram-Negative Infections

For multidrug-resistant gram-negative bacterial infections, polymyxin B should be dosed at 15,000-25,000 units/kg/day in patients with normal renal function, with dose reduction required in renal impairment, and should be used in combination therapy rather than monotherapy to improve efficacy while monitoring for nephrotoxicity.

Recommended Dosing

Standard Dosing

• Normal renal function: 15,000-25,000 units/kg/day divided every 12 hours 1
• Loading dose: 5 mg/kg colistin base activity recommended 2
• Maintenance dose: 2.5 mg CBA × (1.5 × CrCl + 30) every 12 hours 2

Special Populations

• Renal impairment: Dose should be reduced from 15,000 units/kg/day downward 1
• Infants with normal renal function: May receive up to 40,000 units/kg/day 1
• Pediatric patients: Loading dose of 0.15 MU/kg followed by maintenance dose of 0.075 MU/kg every 12 hours 2

Important Dosing Considerations

• Dose conversion: 1 million units = 80 mg mass CMS = 33 mg colistin base activity (CBA); polymyxin B sulfate: 1 mg = 10,000 units 3
• Contrary to traditional belief: Polymyxin B dosing does not need adjustment based on renal function as previously thought, as studies have shown comparable drug exposures in patients with normal and impaired renal function 4
• Administration: Dissolve 500,000 polymyxin B units in 300 to 500 mL of 5% Dextrose Injection for continuous drip 1

Combination Therapy

Polymyxin B should be used in combination therapy rather than monotherapy for treating multidrug-resistant gram-negative bacterial infections:

• Strong recommendation with moderate-quality evidence for polymyxin combination therapy over monotherapy 3
• Combination therapy results in:
  • Fewer treatment failures (119 fewer per 1000 patients) 3
  • Better pathogen eradication (74 fewer eradication failures per 1000 patients) 3
  • Shorter time to microbiological clearance 3

Recommended Combinations

• For CRE: Polymyxin + carbapenem when meropenem MIC is ≤8 mg/L 3, 2
• For CRAB: Polymyxin + carbapenem when meropenem MIC is ≤32 mg/L 3, 2
• Extended-infusion of meropenem for 3 hours is recommended when used in combination 3

Potential Interactions and Monitoring

Drug Interactions to Avoid

• Nephrotoxic drugs: Avoid concurrent use with other nephrotoxic agents 3
• Specific concerns:
  • Vancomycin (increases nephrotoxicity risk, HR = 1.89) 5
  • Contrast media (increases nephrotoxicity risk, HR = 1.79) 5

Risk Factors for Nephrotoxicity

• Higher daily dose by actual body weight (HR = 1.73) 5
• Older age (76 vs 59 years significantly associated with renal failure) 6
• Underlying diabetes mellitus (AOR = 1.81) 7
• Low serum albumin levels 7

Monitoring Requirements

• Renal function: Mandatory monitoring during treatment 3, 2
• Therapeutic drug monitoring: Encouraged where available due to high interpatient variability 2
• Onset of nephrotoxicity: Typically occurs around day 9 of therapy 5

Clinical Pearls and Pitfalls

• Nephrotoxicity incidence: 45.8% overall prevalence rate 5, with polymyxin B (38%) having lower nephrotoxicity than colistin (48%) 7
• Patient weight influence: Weight notably influences exposure and required dose - higher weight patients may require lower mg/kg dosing 8
• Storage: Solutions for parenteral use should be refrigerated, and unused portions discarded after 72 hours 1
• Newer alternatives: When available and susceptible, newer agents (ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam) are preferred over polymyxins due to better safety profiles 2

By following these evidence-based recommendations for polymyxin B dosing and being vigilant about potential interactions, clinicians can optimize treatment efficacy while minimizing toxicity in patients with multidrug-resistant gram-negative infections.