What is the recommended dosage and treatment guidelines for Polymyxin B (Polymyxin B) in patients with multidrug-resistant gram-negative bacterial infections and Impaired renal function?

Polymyxin B Dosing and Treatment Guidelines for Multidrug-Resistant Gram-Negative Infections with Renal Impairment

For patients with multidrug-resistant gram-negative infections and impaired renal function, administer polymyxin B with a loading dose of 2-2.5 mg/kg followed by maintenance dosing of 1.5-3 mg/kg/day divided into two doses, without dose adjustment for renal impairment, as polymyxin B clearance is not significantly influenced by renal function. 1, 2

Loading Dose (Critical for All Patients)

• Administer 2-2.5 mg/kg loading dose to all patients regardless of renal function 1, 2
• The loading dose achieves optimal plasma levels on the first day and should never be omitted, even in patients with severe renal dysfunction 1
• Calculate based on actual body weight, not adjusted body weight 3

Maintenance Dosing Strategy

For Patients with Renal Impairment (CrCL <80 mL/min)

• Fixed maintenance dose of 60 mg every 12 hours is recommended 4
• This fixed dosing achieves ≥90% probability of target attainment against organisms with MIC ≤2 mg/L 4
• Alternative weight-based dosing: 1.5-3 mg/kg/day divided into two doses 1, 2
• No dose adjustment is necessary for patients on continuous renal replacement therapy (CRRT) 1, 2

For Patients with Normal Renal Function (CrCL ≥80 mL/min)

• Weight-based maintenance dose of 1.25 mg/kg every 12 hours 4
• Total daily dose should not exceed 3 mg/kg/day 1
• Recent pharmacokinetic studies demonstrate comparable polymyxin B exposures between patients with normal and impaired renal function at standard dosing 3

Key Pharmacokinetic Principles

Polymyxin B clearance is poorly correlated with creatinine clearance, distinguishing it from colistin. 3, 5

• Polymyxin B is administered as the active drug, not as a prodrug like colistin methanesulfonate 1
• Plasma concentrations are not significantly influenced by renal function 1
• Mean polymyxin B clearance is approximately 1.75 L/h, with renal function as a significant but modest covariate 5
• The FDA-approved label recommending dose reduction for renal impairment contradicts current pharmacokinetic evidence 6, 3

Combination Therapy Recommendations

Polymyxin B combination therapy is strongly preferred over monotherapy for multidrug-resistant infections. 1, 2

Specific Combination Strategies

• For carbapenem-resistant Enterobacterales (CRE): Combine with tigecycline, meropenem, or aminoglycosides 1
• For carbapenem-resistant Acinetobacter baumannii (CRAB): If meropenem MIC ≤32 mg/L, combine with high-dose extended-infusion meropenem (2g over 3 hours every 8 hours) 1, 2
• For CRE with meropenem MIC ≤8 mg/L: Polymyxin-carbapenem combination with extended-infusion meropenem 1, 2
• Combination therapy reduces treatment failure by approximately 119 cases per 1000 patients compared to monotherapy 1, 2
• Mortality reduction with combination therapy: 35.7% vs 55.5% with monotherapy (OR 0.46,95% CI 0.30-0.69) 1

Nephrotoxicity Risk Management

Nephrotoxicity occurs in approximately 14% of patients with normal baseline renal function, significantly lower than colistin. 1, 7

Independent Risk Factors for Nephrotoxicity

• Higher daily dose by actual body weight (HR 1.73) 8
• Concurrent vancomycin use (HR 1.89) 8
• Concurrent contrast media exposure (HR 1.79) 8
• Older age (mean 76 vs 59 years in those developing renal failure) 7

Monitoring and Prevention

• Avoid concurrent nephrotoxic or ototoxic drugs 1, 2
• Monitor renal function throughout treatment, with median onset of nephrotoxicity at 9 days 8
• Therapeutic drug monitoring (TDM) is strongly encouraged when available 1, 2
• Mortality increases to 57% in patients who develop renal failure during treatment 7

Dosing Conversion Reference

Critical dosing unit conversions to prevent medication errors: 1, 2

• Polymyxin B sulfate: 1 mg = 10,000 units 1, 2
• For comparison with colistin: 1 million IU colistin = 80 mg CMS = 33 mg colistin base activity 1, 2

Administration Considerations

• Continuous infusion may be suitable as an alternative to intermittent dosing 1, 2
• Extended 4-hour infusions optimize PK/PD properties 1
• For intermittent hemodialysis: Use normal loading dose; no supplemental dosing needed post-dialysis 1

Clinical Efficacy Data

• Microbiologic clearance achieved in 88% of patients 7
• Overall mortality 20% in treated patients 7
• Clinical cure rates comparable between polymyxin B and colistin, but with lower nephrotoxicity (15.3% vs 33%) 1