Polymyxin B in Renal Impairment

Key Pharmacokinetic Differences

• Polymyxin B has critical advantages in renal impairment, including administration as the active drug, with its plasma concentration not influenced by renal function, and it requires no dose adjustment during continuous renal replacement therapy (CRRT) 1

Nephrotoxicity Evidence

• The incidence of renal failure is lower with polymyxin B than colistin, with polymyxin B causing nephrotoxicity in 11.8% of patients versus 39.3% with colistin 1

Dosing Recommendations

• For polymyxin B in renal impairment, a loading dose of 2-2.5 mg/kg is recommended, regardless of renal function, with a maintenance dose of 1.5-3 mg/kg/day and no adjustment needed for CRRT 1
• For colistin, if polymyxin B is unavailable, a loading dose of 6-9 million IU is recommended, regardless of renal function, with maintenance dose individually adjusted according to creatinine clearance 2, 1

Clinical Pitfalls to Avoid

• Acute kidney injury during colistin treatment is a major factor related to clinical failure and mortality, highlighting the importance of careful dosing and monitoring 2

Monitoring Requirements

• Renal function must be closely monitored during therapy with either agent, with colistin nephrotoxicity being dose-dependent and most nephrotoxicity being reversible within one week 2

Colistin and Polymyxin B Differences

Pharmacokinetics and Administration

• One million international units (IU) of colistin is equivalent to 80 mg of colistimethate sodium (CMS) 3
• Colistin requires a loading dose of 9 million IU regardless of renal function, followed by maintenance doses of 4.5 million IU every 12 hours in patients with normal renal function 3
• Polymyxin B requires less dose adjustment than colistin in renal impairment 4

Dosing and Nephrotoxicity

• Polymyxin B may be a suitable alternative for patients on continuous renal replacement therapy, as it doesn't require dose adjustment during CRRT 4
• Colistin-associated nephrotoxicity occurs earlier and is more frequent than with polymyxin B 5

Clinical Implications

• For inhaled administration, colistin is preferred over polymyxin B based on clinical evidence from controlled studies 6, 7, 8
• In hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) caused by carbapenem-resistant pathogens sensitive only to polymyxins, either agent can be used intravenously, with a suggestion for adjunctive inhaled colistin 6, 7, 8

Monitoring

• Both drugs require close monitoring of renal function during therapy 3, 4

Comparative Effectiveness of Polymyxin B and Colistin

Efficacy and Nephrotoxicity Considerations

• The Infectious Diseases Society of America recommends considering the use of ceftolozane-tazobactam over polymyxin/aminoglycoside combinations for mixed MDR/XDR infections, due to its superiority and lower nephrotoxicity (adjusted OR 0.08, 95% CI 0.03-0.22) 9
• For carbapenem-resistant Pseudomonas aeruginosa (CRPA), very low-certainty evidence shows no mortality difference between polymyxin B and colistin 9
• A before-after study in critically ill patients showed higher RIFLE-defined nephrotoxicity with colistin (adjusted HR 2.27, 95% CI 1.35-3.82) 9

Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections

First-Line Therapy Selection

• The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) conditionally recommends ceftolozane-tazobactam for severe multidrug-resistant Pseudomonas aeruginosa infections when active in vitro, based on very low certainty evidence 10, 11
• Ceftolozane-tazobactam demonstrates superior clinical outcomes compared to polymyxin-based regimens, with clinical cure rates significantly higher (adjusted OR 2.63, 95% CI 1.31-5.30) 11
• The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) reserve polymyxins for settings with high prevalence of multidrug resistance and local expertise 12, 13

Renal Function Considerations

• A before-after study showed colistin has higher RIFLE-defined nephrotoxicity (adjusted HR 2.27, 95% CI 1.35-3.82) compared to polymyxin B 10, 11

Combination Therapy Recommendations

• The ESCMID guidelines suggest treatment with two in vitro active drugs when using polymyxins, aminoglycosides, or fosfomycin (conditional recommendation, very low certainty) 10, 14
• No recommendation exists for or against combination therapy with ceftolozane-tazobactam for multidrug-resistant Pseudomonas aeruginosa infections 10, 15

Infection-Specific Considerations

• The ASPECT-NP trial showed clinical cure in 4/10 patients with extensively drug-resistant Pseudomonas aeruginosa treated with ceftolozane-tazobactam versus 2/5 with meropenem 10, 11