Polymyxin B Sulfate Dosing for Severe MDR Gram-Negative Infections with Renal Impairment
Administer a loading dose of 2-2.5 mg/kg polymyxin B sulfate followed by maintenance dosing of 1.5-3 mg/kg/day divided into two daily doses, with no dose adjustment required for renal dysfunction. 1, 2
Loading Dose: Critical First Step
Always administer the loading dose regardless of renal function. 1, 2 The loading dose of 2-2.5 mg/kg is essential to rapidly achieve therapeutic plasma concentrations on day one, as omitting this can delay therapeutic levels by several days and compromise clinical outcomes. 2
Maintenance Dosing Strategy
Standard maintenance dose: 1.5-3 mg/kg/day divided into two daily IV doses (equivalent to 15,000-30,000 units/kg/day, using the conversion 1 mg = 10,000 units). 1, 3, 4
No renal dose adjustment required: Unlike colistin, polymyxin B clearance is predominantly non-renal (median urinary recovery only 4.04%), and total body clearance shows no relationship with creatinine clearance. 5 This makes polymyxin B the superior polymyxin choice when renal function is compromised. 2
Dosing based on total body weight: Scale all doses by total body weight rather than adjusted body weight or renal function, as polymyxin B clearance when scaled by total body weight shows remarkably low interindividual variability (32.4% coefficient of variation). 5
Combination Therapy: Strongly Recommended
Do not use polymyxin B as monotherapy for severe MDR infections. 1, 2 Combination therapy reduces treatment failure by 119 per 1000 patients (RR 0.82) and pathogen eradication failure by 74 per 1000 patients (RR 0.81) compared to monotherapy. 2
Combination Partners Based on Pathogen:
For carbapenem-resistant Acinetobacter baumannii (CRAB): If meropenem MIC ≤32 mg/L, combine polymyxin B with extended-infusion meropenem (infused over 3 hours). 1 Alternative combinations include rifampicin or ampicillin-sulbactam. 2
For carbapenem-resistant Enterobacterales (CRE): Combine with tigecycline or meropenem based on susceptibility testing. 6, 1
For carbapenem-resistant Klebsiella pneumoniae (CRKP): Polymyxin B plus fosfomycin shows synergistic activity with treatment efficacy of 54.2% in ICU patients. 1
Administration and Monitoring
Route: Intravenous administration only for systemic infections. 4
Infusion method: Can be administered as intermittent infusion every 12 hours or continuous infusion in select cases. 1, 4
Therapeutic drug monitoring (TDM): Perform TDM whenever available due to high interpatient variability, with target steady-state average concentration (Css,avg) ≥1 mg/L. 1, 2 Only 65-75% of critically ill patients with normal renal function achieve target concentrations without TDM. 1
Nephrotoxicity Management
Polymyxin B has lower nephrotoxicity risk than colistin (adjusted HR 2.27 for colistin vs polymyxin B). 2 However, nephrotoxicity still occurs in approximately 14% of patients with normal baseline renal function. 1, 7
Risk Mitigation Strategies:
Monitor renal function closely throughout treatment, particularly in elderly patients and those with elevated baseline creatinine. 2
Avoid concurrent nephrotoxic agents: Do not combine with NSAIDs, diuretics, and ACE inhibitors/ARBs simultaneously, as this triple combination significantly increases nephrotoxicity risk. 3
Age consideration: Development of renal failure is significantly associated with older age (76 vs 59 years, P=0.02) but is independent of daily dose, cumulative dose, or treatment duration. 7
Critical Pitfalls to Avoid
Never omit the loading dose in any patient, including those with renal dysfunction or on continuous renal replacement therapy (CRRT). 2 CRRT does not require dose adjustment for polymyxin B. 3
Do not reduce doses based on renal function: This is the most common dosing error, as polymyxin B pharmacokinetics are not significantly affected by renal impairment. 2, 5
Avoid monotherapy for severe infections: The evidence strongly supports combination therapy over monotherapy for all carbapenem-resistant infections. 1, 2
Do not exceed maximum daily dose: The FDA label specifies not to exceed 25,000 units/kg/day (2.5 mg/kg/day) in adults and children with normal kidney function. 4