What is the recommended dosing regimen for intravenous colistimethate sodium (colistin) in an adult with a serious multidrug‑resistant gram‑negative infection, including loading dose, maintenance dose, adjustments for reduced creatinine clearance, monitoring parameters, and alternative or combination therapy options?

Colistin Dosing for Serious Multidrug-Resistant Gram-Negative Infections

All adult patients with serious MDR gram-negative infections should receive an intravenous loading dose of 9 million IU (≈5 mg/kg colistin base activity) regardless of renal function, followed by a maintenance dose calculated as 2.5 mg CBA × (1.5 × creatinine clearance + 30) mg every 12 hours, with mandatory combination therapy using at least one additional active agent (preferably a carbapenem when feasible) to reduce mortality and prevent resistance. 1

Loading Dose (Universal for All Patients)

• Administer 9 million IU (≈5 mg/kg CBA) intravenously to every patient, regardless of renal function, including those on dialysis or CRRT 1
• The loading dose is critical because omitting it results in subtherapeutic plasma concentrations for 48-72 hours, significantly increasing treatment failure risk 1
• This dose achieves therapeutic levels rapidly; colistin's long half-life means waiting 2-3 days to reach steady state without a loading dose 1

Maintenance Dosing for Normal Renal Function

• For patients with creatinine clearance >50 mL/min and severe sepsis/septic shock: 4.5 million IU (≈150 mg CBA) every 12 hours intravenously 1
• Formula-based dosing (preferred method): Calculate as 2.5 mg CBA × (1.5 × creatinine clearance + 30) mg administered every 12 hours 1
• This formula automatically adjusts for renal function and represents the most current guideline recommendation 1

Renal Impairment Adjustments

Mild to Moderate Renal Impairment

• Use the formula-based maintenance dose which inherently adjusts for creatinine clearance: 2.5 mg CBA × (1.5 × CrCl + 30) mg every 12 hours 1
• Never reduce the loading dose for renal impairment 1

Continuous Renal Replacement Therapy (CRRT)

• Loading dose: Standard 9 million IU 1, 2
• Maintenance dose: 3 million IU (≈100 mg CBA) every 8 hours 1, 2
• Critical error to avoid: Do NOT reduce the maintenance dose for CRRT patients; they require at least 9 million IU per day total to maintain therapeutic levels 1
• CRRT clearance accounts for approximately 41% of total CMS clearance and 28% of colistin clearance 2

Intermittent Hemodialysis (IHD)

• Loading dose: Standard 9 million IU 1
• Maintenance dose: 2 million IU every 12 hours 1
• Timing strategy: Schedule dialysis toward the end of the colistin dosing interval to minimize drug removal 1

Critical Dosing Conversions

• 1 million IU colistimethate sodium = 80 mg CMS = 33 mg colistin base activity (CBA) 1
• This conversion is essential to prevent 2-3 fold dosing errors that commonly occur in clinical practice 1

Monitoring Parameters

Renal Function Monitoring

• Baseline renal function before initiating therapy 1
• Monitor creatinine 2-3 times per week during treatment 1
• Acute kidney injury during colistin therapy is a major determinant of clinical failure and mortality 1
• Most colistin-associated nephrotoxicity is reversible within one week of discontinuation 3
• Nephrotoxicity rates: approximately 17-18% in recent studies using optimized dosing 4

Therapeutic Drug Monitoring

• Consider therapeutic drug monitoring when available to optimize dosing and minimize toxicity 5
• Target steady-state average colistin concentration of approximately 2.5 mg/L or higher 6, 2

Combination Therapy (Mandatory for Serious Infections)

General Principles

• Never use colistin monotherapy for serious infections; combination therapy with at least one additional antimicrobial improves clinical outcomes and reduces resistance selection 1
• Select companion agents based on in vitro susceptibility, prioritizing those with the lowest MIC even when formal susceptibility is not established 1

Carbapenem-Resistant Enterobacterales (CRE)

• High-dose extended-infusion meropenem (6 g/day over 3 hours) plus colistin shows survival benefit when meropenem MIC ≤16 mg/L, particularly for KPC-producing organisms 5
• Combination therapy is most beneficial in patients with INCREMENT score 8-15 (high risk for death), showing adjusted HR 0.56 (95% CI 0.34-0.91) for 30-day mortality 5
• Two or more in vitro active antibiotics (including colistin, tigecycline, gentamicin, carbapenems, rifampin) independently associated with 30-day survival in critically ill patients with septic shock 5

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• Very low-certainty evidence for combination therapy benefit over monotherapy 5
• If CRAB is susceptible to more than one antibiotic, consider double-covering therapy (e.g., colistin plus ampicillin-sulbactam) which showed advantage for clinical failure but not mortality 5
• Avoid colistin-vancomycin combination: significantly higher nephrotoxicity without mortality benefit 5
• Colistin-rifampin: No mortality benefit demonstrated in RCTs 5

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• Prefer ceftolozane-tazobactam over polymyxin-based regimens when organism is susceptible in vitro (adjusted OR 2.63 for clinical cure, 95% CI 1.31-5.30) 7
• If polymyxins must be used, combine with at least one additional in vitro active agent 7

Administration Method

• 4-hour infusion is suggested to optimize pharmacokinetic/pharmacodynamic properties 1

Adjunctive Inhaled Therapy

• For ventilator-associated pneumonia (VAP) caused by carbapenem-resistant organisms susceptible only to polymyxins: add inhaled colistin to the intravenous regimen 1
• Inhaled colistin is preferred over inhaled polymyxin B based on clinical evidence 7

Alternative: Polymyxin B Considerations

When to Consider Polymyxin B Instead of Colistin

• Patients with pre-existing renal dysfunction: Polymyxin B has lower nephrotoxicity (11.8% vs 39.3% with colistin) 7
• Patients on CRRT: Polymyxin B requires no dose adjustment for renal replacement therapy 7
• Polymyxin B is administered as the active drug (not a prodrug), with plasma concentrations not influenced by renal function 7

Polymyxin B Dosing

• Loading dose: 2-2.5 mg/kg regardless of renal function 7, 8
• Maintenance dose: 1.5-3 mg/kg/day divided into 2 doses 7, 8
• No dose adjustment needed for renal impairment or CRRT 7, 8

Critical Pitfalls to Avoid

1. Never omit the loading dose – this is the single most common error leading to treatment failure 1
2. Never reduce maintenance doses in CRRT patients – full dosing (at least 9 million IU/day total) is required 1
3. Never use colistin monotherapy for serious infections – combination therapy is mandatory 1
4. Never combine colistin with vancomycin – significantly increases nephrotoxicity without benefit 5
5. Never fail to adjust maintenance doses for creatinine clearance in non-CRRT patients – markedly increases nephrotoxicity risk 1

Source Control and Stewardship

• Source control is always a priority to optimize outcomes and shorten antibiotic treatment duration 5
• Follow-up cultures are recommended in case of treatment failure to detect resistance development 5
• Avoid concomitant nephrotoxic agents (aminoglycosides, NSAIDs, diuretics, ACE inhibitors/ARBs) when possible 8