Maximum Dose of Polymyxin B
The maximum daily dose of polymyxin B is 25,000 units/kg/day (equivalent to 2.5 mg/kg/day), as specified by the FDA-approved prescribing information, though recent guidelines support higher maintenance dosing up to 3.0 mg/kg/day divided into two doses when treating multidrug-resistant infections. 1, 2
FDA-Approved Maximum Dosing
The FDA label establishes clear upper limits for polymyxin B administration:
- Adults and children: Maximum of 25,000 units/kg/day (2.5 mg/kg/day) in individuals with normal kidney function 1
- Infants: May receive up to 40,000 units/kg/day without adverse effects 1
- Premature and newborn infants: Doses as high as 45,000 units/kg/day have been used in limited studies for Pseudomonas aeruginosa sepsis 1
Note: 1 mg of polymyxin B = 10,000 units 2
Contemporary Guideline Recommendations
Recent infectious disease guidelines recommend slightly higher maintenance dosing than the FDA maximum:
- Loading dose: 2-2.5 mg/kg administered once, regardless of renal function 2, 3, 4
- Maintenance dose: 1.5-3.0 mg/kg/day divided into two doses (every 12 hours) 2, 3
The upper end of this range (3.0 mg/kg/day) exceeds the FDA maximum by 0.5 mg/kg/day (5,000 units/kg/day). This reflects evolving understanding of polymyxin B pharmacokinetics in critically ill patients with multidrug-resistant infections 3, 4.
Dose-Limiting Toxicity Considerations
Acute toxicity, particularly neurotoxicity, is the primary dose-limiting factor for intravenous polymyxin B, not nephrotoxicity. 5
Key toxicity findings:
- At 1.5 mg/kg single doses in healthy subjects, all participants experienced neurotoxicity (perioral paresthesia, dizziness, numbness of extremities) 5
- Female subjects at 1.5 mg/kg experienced additional adverse effects including abdominal pain (60%), vulvar pruritus (40%), and abnormal uterine bleeding 5
- In cystic fibrosis adults receiving 50-100 mg every 12 hours, neurotoxicities occurred in 100% of patients, with acute kidney injury in 22% 6
- All toxicity events resolved within 2-4 days after discontinuation 5, 6
Critical Renal Function Caveat
Despite FDA labeling recommending dose reduction for renal impairment, current pharmacokinetic evidence demonstrates that polymyxin B clearance does not correlate with creatinine clearance and dose adjustment for renal function is not necessary. 7, 8
Supporting evidence:
- Polymyxin B exposures were comparable between patients with normal renal function (AUC 63.5 ± 16.6 mg·h/L) versus renal insufficiency (AUC 56.0 ± 17.5 mg·h/L, P=0.42) 7
- Total body clearance showed no relationship with creatinine clearance (r²=0.008) 8
- Polymyxin B is predominantly non-renally cleared with median urinary recovery of only 4.04% 8
- No dose adjustment is required for patients on continuous renal replacement therapy 2, 3
Practical Dosing Algorithm
For a 70 kg adult with multidrug-resistant gram-negative infection:
Day 1: Administer loading dose of 175 mg (2.5 mg/kg × 70 kg) as single intravenous infusion 3, 4
Day 2 onward: Administer maintenance dose of 105-210 mg/day (1.5-3.0 mg/kg/day) divided into two doses every 12 hours 2, 3
- For MIC ≤1 mg/L: Use lower end (105-140 mg/day)
- For MIC ≥2 mg/L: Consider higher end (175-210 mg/day), but monitor closely for neurotoxicity 9
Do not reduce dose for renal impairment, including dialysis patients 3, 10, 7
Always use combination therapy with another active agent (carbapenem, tigecycline, or β-lactam) rather than monotherapy 2, 4
Common Pitfalls to Avoid
- Do not omit the loading dose: Failure to administer a loading dose results in subtherapeutic levels for 24-48 hours 3, 4
- Do not confuse with colistin dosing: Polymyxin B and colistin have different unit conversions and dosing requirements 2, 4
- Do not reduce doses in renal failure: This contradicts older FDA labeling but is supported by current pharmacokinetic evidence 3, 10, 7
- Do not exceed 3.0 mg/kg/day maintenance dosing: Higher doses significantly increase risk of dose-limiting neurotoxicity without proven additional benefit 5, 6