What is the recommended colistin combination regimen for treating sepsis due to multidrug-resistant gram-negative bacteria?

Colistin Combination Regimen for Sepsis Due to Multidrug-Resistant Gram-Negative Bacteria

For sepsis caused by carbapenem-resistant Enterobacterales (CRE), use colistin in combination with at least one additional in vitro active agent, with the preferred regimen being colistin 5 mg/kg loading dose followed by 2.5 mg × (1.5 × CrCl + 30) IV every 12 hours PLUS tigecycline 100 mg loading dose then 50 mg IV every 12 hours for 7-14 days. 1

Pathogen-Specific Combination Strategies

Carbapenem-Resistant Enterobacterales (CRE)

• Combination therapy with two in vitro active antibiotics is strongly recommended over monotherapy for severe infections and high-risk patients (INCREMENT score 8-15). 2 This approach reduces 30-day mortality (adjusted HR 0.56,95% CI 0.34-0.91) in critically ill patients. 2

• The preferred companion agent to colistin is tigecycline, particularly for bloodstream infections. 1 This combination addresses the suboptimal pharmacokinetics of either agent alone. 2

• Aminoglycosides (gentamicin or amikacin) represent an alternative combination partner, especially for urinary tract infections where they demonstrate superiority over tigecycline-based regimens. 2 For fully susceptible isolates (MIC ≤4 mg/L), gentamicin combined with colistin showed significantly higher 30-day survival (adjusted HR 0.30,95% CI 0.11-0.84). 2

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

• Use combination therapy with two in vitro active drugs including colistin for severe infections. 1, 3 This is a strong recommendation despite low-quality evidence, reflecting the severity of these infections and risk of treatment failure with monotherapy. 1

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• Polymyxin-based combination therapy is recommended over monotherapy for severe CRAB infections. 1, 3

• If meropenem MIC is ≤32 mg/L, use colistin-meropenem combination with extended 3-hour infusion of meropenem. 3 This combination achieves high clinical cure rates (SUCRA 91.7%). 3

• Do NOT use colistin-meropenem combination if meropenem MIC is >16 mg/L, as high-quality RCT evidence (AIDA and OVERCOME trials) shows no mortality benefit. 2, 4, 3 In these trials, 28-day mortality was similar between colistin monotherapy and colistin-carbapenem combination: 35% vs 21% (p=0.24) in AIDA and 31% vs 19% (p=0.25) in OVERCOME. 2

• Avoid colistin-rifampin combinations as powered RCTs show no mortality advantage. 3

• Avoid colistin-vancomycin combinations due to significantly higher nephrotoxicity without mortality benefit. 3

Critical Dosing Parameters

Loading Dose (Essential for Adequate Plasma Concentrations)

• Administer 9 million units (MU) or 5 mg/kg of colistin methanesulfonate as a loading dose. 1, 3 Without a loading dose, plasma concentrations remain insufficient before steady state is achieved. 1

Maintenance Dosing

• For critically ill patients with normal renal function: 4.5 MU (2.5 mg × [1.5 × CrCl + 30]) IV every 12 hours. 1, 3

• Higher doses independently predict microbiological success: median dose of 2.9 mg/kg/day in patients achieving 7-day microbiological success versus 1.5 mg/kg/day in failures (adjusted OR per 1 mg/kg/day = 1.74,95% CI 1.11-2.71). 5

Unit Conversion (Critical to Avoid Errors)

• 1 million IU colistin methanesulfonate = 80 mg colistin methanesulfonate = 33 mg colistin base activity (CBA). 1

Treatment Duration by Infection Site

• Bloodstream infection: 7-14 days 1
• Hospital-acquired/ventilator-associated pneumonia: 10-14 days 1
• Complicated urinary tract infection: 5-7 days 1
• Complicated intra-abdominal infection: 5-7 days 1

Special Considerations for Respiratory Infections

• For ventilator-associated pneumonia, add aerosolized polymyxin (1 MU every 12 hours) to intravenous therapy to improve clinical outcomes. 1, 6 This dual approach addresses the poor lung penetration of systemic polymyxins. 1

Nephrotoxicity Monitoring and Risk Mitigation

• Nephrotoxicity occurs in 10.9-53.7% of patients receiving polymyxins. 1, 3 Regular monitoring of renal function is mandatory throughout treatment. 1, 3

• Risk factors include: pre-existing renal impairment, older age, concomitant nephrotoxic medications, and higher colistin doses (median 3.8 mg/kg/day in patients developing acute kidney injury versus 1.6 mg/kg/day in those who did not, p<0.001). 1, 5

• Polymyxin B may have lower nephrotoxicity than colistin (adjusted HR 2.27,95% CI 1.35-3.82 for colistin versus polymyxin B). 1

• Avoid combining polymyxins with other nephrotoxic agents when possible. 3

Mandatory Adjunctive Measures

• Source control is mandatory to optimize outcomes and shorten treatment duration. 1, 4 This includes drainage of abscesses, removal of infected catheters, and debridement of infected tissue. 1

• Obtain follow-up cultures in case of treatment failure to detect resistance development. 1, 4

• Therapeutic drug monitoring is recommended when available to optimize dosing and minimize toxicity. 1

Common Pitfalls to Avoid

• Do not use monotherapy for severe infections or high-risk patients (INCREMENT score ≥8), as combination therapy significantly reduces mortality in this population. 2

• Do not add carbapenems to colistin for CRE infections if meropenem MIC is >8 mg/L, as this provides no benefit and increases toxicity risk. 2

• Do not omit the loading dose, as this delays achievement of therapeutic concentrations and may contribute to treatment failure. 1

• Do not use colistin-glycopeptide combinations routinely, though this may be protective if administered for ≥5 days (HR 0.42,95% CI 0.19-0.93) in select cases with documented Gram-positive coinfection. 7