Colistin Combination Therapy for Multidrug-Resistant Gram-Negative Infections
For carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA), colistin should be used in combination with at least one additional agent to which the pathogen is susceptible, while for carbapenem-resistant Acinetobacter baumannii (CRAB), colistin-carbapenem combinations are NOT recommended despite older observational data suggesting benefit. 1
Pathogen-Specific Recommendations
Carbapenem-Resistant Enterobacterales (CRE)
Preferred regimens for CRE bloodstream infections:
- Colistin 5 mg CBA/kg IV loading dose, then 2.5 mg CBA × (1.5 × CrCl + 30) IV q12h PLUS tigecycline 100 mg IV loading dose, then 50 mg IV q12h 1
- Alternative: Colistin (same dosing) PLUS meropenem 1 g IV q8h by extended infusion (3 hours) 1
- Duration: 7-14 days for bloodstream infections 1
For CRE complicated intra-abdominal infections:
- Colistin (same dosing as above) PLUS tigecycline OR meropenem by extended infusion 1
- Duration: 5-7 days 1
The combination approach is based on weak evidence (2D recommendation), but expert consensus supports it over monotherapy to prevent resistance emergence 1
Difficult-to-Treat Resistant Pseudomonas aeruginosa (DTR-PA)
For severe DTR-PA infections, combination therapy with two in vitro active drugs (including colistin) is recommended 2, 3
Dosing for critically ill patients:
- Loading dose: 9 MU (5 mg/kg) of colistin methanesulfonate 1
- Maintenance: 4.5 MU (2.5 mg × [1.5 × CrCl + 30]) IV q12h 1
- This dosing is a strong recommendation (1C) despite low-quality evidence 1
Combination partners should be selected based on susceptibility testing:
- Aminoglycosides (amikacin 15 mg/kg/day IV QD or gentamicin 5-7 mg/kg/day IV QD) 1
- Novel β-lactam/β-lactamase inhibitors if susceptible (ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam) 1
- Meropenem by extended infusion if MIC ≤8 mg/L 1
The evidence for combination therapy in DTR-PA is controversial - one RCT showed no mortality benefit of colistin-meropenem over monotherapy (25% vs 31% mortality, p=1.0), while observational data suggested benefit even when the second agent lacked in vitro activity 1. However, combination therapy is still recommended to prevent resistance emergence 2
Carbapenem-Resistant Acinetobacter baumannii (CRAB)
DO NOT use colistin-meropenem combination therapy for CRAB - this is a strong recommendation against this combination based on high-certainty evidence 1, 3, 4
The OVERCOME trial and AIDA RCT definitively showed no mortality benefit of colistin-meropenem combination over colistin monotherapy for CRAB infections 3, 4. The 2022 ESCMID guidelines provide high-certainty evidence against carbapenem-polymyxin combinations when A. baumannii is highly resistant (MIC >16 mg/L) 1
Specific combination recommendations for CRAB:
- Colistin-rifampin combination showed NO advantage over monotherapy in a powered RCT of 209 patients (no difference in 30-day mortality) 1
- Colistin-fosfomycin showed NO mortality benefit in an RCT of 94 patients 1
- Colistin-vancomycin showed NO mortality benefit and significantly higher nephrotoxicity 1
The only combination with potential benefit for CRAB:
- Colistin PLUS ampicillin-sulbactam IF the isolate is susceptible to ampicillin-sulbactam - one small RCT (49 patients) showed advantage for clinical failure but no mortality benefit 1
Exception: If CRAB has lower carbapenem MICs (≤32 mg/L), high-dose extended-infusion carbapenem combinations may be considered 2, 4
Critical Dosing Considerations
Unit conversion is essential to avoid errors:
- 1 million IU colistin methanesulfonate = 33 mg colistin base activity (CBA) 1, 2
- 1 million IU = 80 mg colistin methanesulfonate 2
Loading dose is critical - pharmacokinetic studies show that without a loading dose, plasma colistin concentrations are insufficient before steady state (which takes ~14.4 hours to reach given colistin's long half-life) 5. The predicted maximum concentration after first dose is only 0.60 mg/L versus 2.3 mg/L at steady state 5
Higher doses correlate with microbiological success - a retrospective study of 76 patients with gram-negative bacteremia found median colistin dose was significantly higher in those achieving microbiological success (2.9 vs 1.5 mg/kg/day, p=0.011), with adjusted OR of 1.74 per 1 mg/kg/day increase 6
Toxicity Monitoring and Management
Nephrotoxicity is the primary concern:
- Occurs in 10.9-53.7% of patients 2
- Polymyxin B appears less nephrotoxic than colistin (adjusted HR 2.27,95% CI 1.35-3.82) 2, 4
- Monitor renal function closely during therapy - this is a strong recommendation (1C) 1
- Higher colistin doses precipitate worsening renal function (3.8 vs 1.6 mg/kg/day in those developing AKI, p<0.001) 6
Risk factors for nephrotoxicity include:
Treatment Duration
Duration varies by infection site:
- Complicated UTI: 5-7 days 1
- Complicated intra-abdominal infection: 5-7 days 1
- Hospital-acquired/ventilator-associated pneumonia: 10-14 days 1
- Bloodstream infection: 7-14 days 1
Special Considerations
For respiratory tract infections:
- Adding aerosolized polymyxin to intravenous therapy may improve clinical outcomes 2
Source control is mandatory:
Follow-up cultures are essential:
Therapeutic drug monitoring:
- Use when available to optimize dosing and minimize toxicity 2
Common Pitfalls to Avoid
Using colistin-meropenem for CRAB - this is explicitly contraindicated by high-quality evidence 1, 3, 4
Omitting the loading dose - leads to subtherapeutic levels for the first 14+ hours 5
Confusing dosing units - always verify whether dose is in MIU, mg CMS, or mg CBA 1, 2
Using monotherapy for severe infections - rapidly selects resistant subpopulations 7
Failing to adjust for renal function - the maintenance dose formula explicitly incorporates creatinine clearance 1