What are the recommended adult dosing, administration routes, and toxicity precautions for Polymyxin B, including dose adjustments for renal impairment?

Polymyxin B Dosing and Administration

Standard Adult Dosing Regimen

Administer polymyxin B with a loading dose of 2-2.5 mg/kg followed by maintenance dosing of 1.5-3 mg/kg/day (or 2.5-3.0 mg/kg/day) divided into two daily intravenous doses every 12 hours, with NO dose reduction required for renal impairment. 1, 2, 3

Loading Dose Protocol

• Always initiate therapy with a loading dose of 2-2.5 mg/kg to rapidly achieve therapeutic plasma concentrations on the first day, regardless of renal function status 1, 2
• The loading dose must be given to all patients, including those with severe renal dysfunction or on continuous renal replacement therapy (CRRT) 1, 2
• For a 70 kg patient, this translates to 140-175 mg as the loading dose 2

Maintenance Dosing

• Standard maintenance regimen: 1.5-3 mg/kg/day divided into two doses (every 12 hours) 4, 1, 2
• Alternative dosing from guidelines: 2.5-3.0 mg/kg/day divided in 2 daily IV doses 4, 3
• For a 70 kg patient, maintenance dose is 105-210 mg/day divided into two doses 1, 2

Critical Renal Function Considerations

Polymyxin B does NOT require dose adjustment for renal impairment—this is the most important distinction from colistin and contradicts older FDA labeling. 1, 2, 5

Key Renal Dosing Principles

• Do not reduce doses in patients with renal impairment—maintain standard dosing of 1.5-3 mg/kg/day even in severe renal dysfunction 1, 2
• Polymyxin B clearance is not significantly influenced by renal function, unlike colistin 2, 5
• No dose adjustment is necessary for patients on CRRT 1, 2
• Research confirms comparable polymyxin B exposures (AUC 63.5 vs 56.0 mg·h/L, p=0.42) in patients with normal versus impaired renal function receiving standard dosing 5

FDA Label Discrepancy

• The FDA label recommends dose reduction for renal impairment (from 15,000-25,000 units/kg/day downward), but this recommendation is outdated and contradicted by current pharmacokinetic evidence 6, 1, 2
• Current guidelines based on pharmacokinetic studies demonstrate that renal function does not significantly affect polymyxin B clearance 2, 5

Administration Routes

Intravenous (Primary Route)

• Dissolve 500,000 polymyxin B units in 300-500 mL of 5% Dextrose Injection for continuous drip 6
• Infusions may be given every 12 hours 6
• Note: 1 mg polymyxin B = 10,000 units 4

Intramuscular

• Not recommended routinely because of severe pain at injection sites, particularly in infants and children 6

Intrathecal (for CNS Infections)

• For patients >2 years: 50,000 units (≈5 mg) intrathecally once daily for 3-4 days, then every other day for at least 2 weeks after CSF cultures become negative 1, 6
• For children <2 years: 20,000 units once daily for 3-4 days, then 25,000 units every other day 6
• Dissolve 500,000 units in 10 mL of 0.9% Sodium Chloride for 50,000 units/mL 6

Combination Therapy Requirements

Polymyxin B should be used in combination therapy rather than monotherapy for carbapenem-resistant infections. 1, 3

Recommended Combinations

• For ventilator-associated pneumonia (VAP) or hospital-acquired pneumonia (HAP) with multidrug-resistant gram-negative pathogens: combine with an antipseudomonal β-lactam (piperacillin-tazobactam 4.5g IV q6h, cefepime 2g IV q8h, or meropenem 1g IV q8h) 4, 3
• For carbapenem-resistant Enterobacterales bloodstream infections: consider combination with tigecycline or meropenem (extended infusion) 1
• For VAP/HAP caused by carbapenem-resistant pathogens sensitive only to polymyxins: combine IV polymyxin B with adjunctive inhaled colistin (not inhaled polymyxin B) 1

Rationale for Combination Therapy

• Polymyxins should be reserved for settings with high prevalence of multidrug resistance and local expertise 4
• Combination therapy improves outcomes and reduces resistance development 4, 1

Nephrotoxicity Risk Management

Polymyxin B has significantly lower nephrotoxicity than colistin (11.8% vs 39.3%). 1, 3

Strategies to Minimize Nephrotoxicity

• Avoid concurrent nephrotoxic agents: aminoglycosides, NSAIDs, diuretics, ACE inhibitors/ARBs 2, 3
• Monitor renal function closely during therapy 2
• Consider therapeutic drug monitoring to optimize dosing and minimize toxicity 4, 1

Therapeutic Drug Monitoring

Target a steady-state average concentration (Css,avg) of approximately 3.35 mg/L. 1, 3

TDM Parameters

• Optimal AUCss,24h target: 50-100 mg·h/L 1, 3
• TDM is encouraged to optimize dosing, improve clinical efficacy, and reduce adverse reactions 4, 1
• International consensus recommends TDM for clinical use of polymyxins 4

PK/PD Target

• The pharmacodynamic target is AUC/MIC ratio of 50-100 for bacterial eradication 7, 8

Duration of Therapy

• For HAP/VAP: 7-day course of antimicrobial therapy 1
• For carbapenem-resistant Enterobacterales bloodstream infections: 7-14 day course 1

Common Pitfalls and How to Avoid Them

Critical Errors to Avoid

1. Do not reduce doses in renal impairment based on outdated FDA labeling—current evidence shows no need for adjustment 1, 2, 5

2. Do not omit the loading dose—failure to load results in subtherapeutic levels for the first 24-48 hours 1, 3

3. Do not confuse polymyxin B with colistin dosing—they have different unit conversions (polymyxin B: 1 mg = 10,000 units; colistin dosing is based on colistin base activity) 4, 1

4. Do not use as monotherapy for carbapenem-resistant infections when combination therapy is feasible 1, 3

5. Do not exceed 25,000 units/kg/day (2.5 mg/kg/day) total systemic dose per FDA labeling, though higher doses up to 3 mg/kg/day are recommended in some guidelines 6, 4

Special Population Considerations

• Critically ill patients with normal renal function (CrCL ≥80 mL/min): may require higher maintenance doses (1.25 mg/kg q12h) to achieve therapeutic targets 7
• Patients with renal impairment (CrCL <80 mL/min): a fixed maintenance dose of 60 mg q12h may be optimal, balancing efficacy and reduced toxicity risk 7
• Renal transplant patients: dosing adjustment based on creatinine clearance may be beneficial; a 75 mg loading dose with 50 mg maintenance dose showed optimal outcomes for MIC ≤1 mg/L 8