Polymyxin Dosing in Adults with Normal Renal Function
Polymyxin B: Preferred Agent
For adults with normal renal function, administer polymyxin B at 2.5-3.0 mg/kg/day divided into 2 daily intravenous doses, preceded by a mandatory loading dose of 2-2.5 mg/kg. 1
Standard Dosing Protocol
- Loading dose: 2-2.5 mg/kg administered as the first dose to rapidly achieve therapeutic plasma concentrations 2, 1
- Maintenance dose: 1.5-3 mg/kg/day (typically 2.5-3.0 mg/kg/day) divided into 2 daily doses 2, 1
- Critical advantage: No dose adjustment required for renal impairment, as polymyxin B clearance is not influenced by renal function 3, 4
Key Pharmacokinetic Considerations
- Polymyxin B is administered as the active drug (not a prodrug), allowing immediate therapeutic effect 2
- Total body clearance shows remarkably low interindividual variability (32.4% coefficient of variation) when scaled by total body weight 4
- Dosing should be based on actual body weight, not ideal body weight 5, 4
- The drug is predominantly non-renally cleared with median urinary recovery of only 4.04% 4
Colistin (Colistimethate Sodium): Alternative Agent
If polymyxin B is unavailable, administer colistin with a loading dose of 6-9 million IU regardless of renal function, followed by maintenance doses of 4.5 million IU every 12 hours in patients with normal renal function. 2, 6
Standard Dosing Protocol
- Loading dose: 6-9 million IU (critical for all patients regardless of renal function) 2, 6
- Maintenance dose: 4.5 million IU every 12 hours for critically ill patients with creatinine clearance >50 mL/min 2, 6
- Alternative maintenance: 2.5-5 mg/kg/day divided into 2-4 doses, or 9 million IU/day in 2-3 divided doses 6, 7
Important Pharmacokinetic Differences
- Colistin is administered as colistimethate sodium (CMS), an inactive prodrug that requires conversion to active colistin 6
- One million IU of colistin equals 80 mg of colistimethate sodium 3, 6
- Plasma colistin concentrations remain sub-optimal for 2-3 days before reaching steady state without a loading dose 2
- The loading dose is critical because colistin displays a relatively long half-life in relation to dosing intervals 2, 6
Critical Clinical Pitfalls to Avoid
Never Omit the Loading Dose
- Failure to administer a loading dose results in subtherapeutic levels for the first 24-48 hours, regardless of which polymyxin is used 2, 1
- This delay in achieving therapeutic concentrations can lead to clinical failure and increased mortality 3
Do Not Confuse Polymyxin B with Colistin Dosing
- These agents have completely different unit conversions and dosing requirements 1
- Polymyxin B is dosed in mg/kg, while colistin is dosed in million IU 2, 1
Avoid Monotherapy When Possible
- Polymyxin B should be used in combination therapy rather than monotherapy for carbapenem-resistant infections 1
- For ventilator-associated pneumonia with suspected multidrug-resistant gram-negative pathogens, combine with an antipseudomonal β-lactam agent 1
Minimize Concurrent Nephrotoxic Agents
- Avoid concurrent use of aminoglycosides, NSAIDs, diuretics, and ACE inhibitors/ARBs to minimize nephrotoxicity risk 1
- Concurrent vancomycin use increases nephrotoxicity risk (HR 1.89) 8
- Contrast media administration increases nephrotoxicity risk (HR 1.79) 8
Nephrotoxicity Considerations
Polymyxin B Has Lower Nephrotoxicity
- Polymyxin B causes nephrotoxicity in 11.8% of patients versus 39.3% with colistin 3, 1
- The incidence of renal failure is significantly lower with polymyxin B than colistin 2, 3
Risk Factors for Nephrotoxicity
- Higher daily doses by actual body weight increase nephrotoxicity risk (HR 1.73 per mg/kg increase) 8
- Median onset of nephrotoxicity occurs at 9 days of therapy 8
- Most nephrotoxicity is reversible within one week after discontinuation 3
Monitoring Requirements
- Monitor renal function closely at baseline and 2-3 times per week during treatment 6
- Acute kidney injury during treatment is a major factor related to clinical failure and mortality 3, 6
Special Administration Considerations
Infusion Method for Colistin
- A 4-hour infusion is suggested to optimize pharmacokinetic/pharmacodynamic properties 6
- For intravenous administration, slowly inject one-half of the total daily dose over 3-5 minutes every 12 hours 7