What is the recommended administration protocol for polymyxin B in patients with severe infections caused by multidrug-resistant gram-negative bacteria and potential impaired renal function?

Polymyxin B Administration Protocol

Polymyxin B should be administered intravenously 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 every 12 hours, with dose adjustments based on patient weight rather than renal function. 1

Loading Dose Strategy

A loading dose is essential to achieve therapeutic plasma concentrations on the first day of treatment. 1

• Administer 2-2.5 mg/kg as a loading dose for all patients, including those with renal dysfunction 1
• Unlike colistin, polymyxin B does not require a delay to reach steady-state concentrations when a loading dose is used 1
• Recent high-quality evidence supports a 150 mg loading dose (approximately 2 mg/kg for a 75 kg patient) followed by 75 mg every 12 hours for critically ill patients with carbapenem-resistant infections 2

Maintenance Dosing

Daily maintenance doses should be calculated based on body weight, not renal function. 1

• Standard maintenance: 1.5-3 mg/kg/day divided into two doses every 12 hours 1
• FDA-approved dosing: 15,000-25,000 units/kg/day (equivalent to 1.5-2.5 mg/kg/day) for adults and children with normal kidney function 3
• Weight-based adjustments are critical: patients weighing 50 kg may require 2 mg/kg every 12 hours, while those weighing 100 kg may only need 1 mg/kg every 12 hours to achieve optimal exposure 4

Infusion Method

Administer polymyxin B as a 4-hour infusion to optimize pharmacokinetic/pharmacodynamic properties. 1

• Extended 4-hour infusion allows treatment of infections with MIC up to 8 mg/L 1
• Dissolve 500,000 units in 300-500 mL of 5% dextrose for continuous drip 3
• Continuous infusion may be suitable as an alternative administration method 1

Renal Function Considerations

Polymyxin B dosing does NOT require adjustment for renal impairment, including patients on renal replacement therapy. 1

• Plasma concentrations are not influenced by renal function 1
• No dose adjustment necessary for continuous renal replacement therapy (CRRT) 1
• This represents a major advantage over colistin, which requires complex renal dose adjustments 1
• Polymyxin B demonstrates lower nephrotoxicity compared to colistin (adjusted HR 2.27 for colistin versus polymyxin B) 5

Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) should be performed when available to optimize efficacy and minimize toxicity. 1

• Target steady-state AUC₀₋₂₄ of 50-100 mg·h/L 2
• TDM-guided dosing improves long-term survival and helps prevent acute kidney injury 2
• Higher AUC achievement correlates with increased AKI risk, making monitoring valuable for safety 2
• International consensus recommends TDM for all polymyxin use to optimize dosing and reduce adverse reactions 1

Combination Therapy Approach

Polymyxin B should be used in combination with another active agent for severe carbapenem-resistant infections rather than as monotherapy. 1, 6, 7

• Combination therapy reduces mortality (35.7% vs 55.5% for monotherapy; OR 0.46,95% CI 0.30-0.69) 5
• Preferred combinations include polymyxin B plus carbapenem (when MIC ≤8 mg/L for CRE or ≤32 mg/L for CRAB), tigecycline, fosfomycin, or aminoglycosides 1, 5
• Use high-dose extended-infusion meropenem (2g over 3 hours every 8 hours) when combining with carbapenems 1

Adjunctive Aerosolized Administration

For respiratory tract infections, add aerosolized polymyxin B to intravenous therapy. 1, 6

• Aerosolized polymyxin reduces clinical treatment failure (RR 0.82,95% CI 0.70-0.96) and pathogen eradication failure (RR 0.84,95% CI 0.69-1.03) 6
• This combination approach is particularly valuable for ventilator-associated pneumonia caused by carbapenem-resistant organisms 8

Critical Safety Monitoring

Monitor renal function closely throughout treatment, as nephrotoxicity occurs in 10-14% of patients. 9, 10

• Nephrotoxicity typically develops 4-10 days after initiation 10
• Risk increases with older age (76 vs 59 years, p=0.02) but is independent of daily or cumulative dose 9
• Avoid concurrent nephrotoxic or ototoxic drugs 1
• Mortality increases to 50-57% in patients who develop renal failure 9, 10

Common Pitfalls to Avoid

• Do not reduce polymyxin B dose for renal impairment - this is a critical difference from colistin and will lead to subtherapeutic levels 1
• Do not confuse dosing units - polymyxin B sulfate: 1 mg = 10,000 units; ensure proper conversion 1
• Do not skip the loading dose - failure to load results in delayed achievement of therapeutic concentrations 1
• Do not use as monotherapy for severe infections - combination therapy significantly improves outcomes 1, 6, 5