Polymyxin-Based Therapy for CRAB and CRPA in the ICU
For Carbapenem-Resistant Acinetobacter baumannii (CRAB)
Combination therapy with polymyxins is recommended over monotherapy for CRAB infections in the ICU, though the specific combination partner depends on susceptibility patterns and carbapenem MICs. 1, 2
First-Line Approach: Sulbactam-Susceptible CRAB
- Ampicillin-sulbactam is the preferred treatment for CRAB susceptible to sulbactam, particularly for hospital-acquired/ventilator-associated pneumonia (HAP/VAP) 1, 2
- Dosing: 6-9g sulbactam per day (e.g., ampicillin 18g/sulbactam 9g per day or cefoperazone 1.5g/sulbactam 1.5g every 6 hours) 2
Polymyxin-Based Regimens for Sulbactam-Resistant CRAB
Colistin-Carbapenem Combinations
- Colistin-meropenem combination is recommended when meropenem MIC is ≤32 mg/L, using extended infusion of meropenem over 3 hours 2, 3
- This combination ranked highest for clinical cure (SUCRA 91.7%) and second for microbiological cure (SUCRA 68.7%) in network meta-analyses 2, 3
- High-certainty evidence exists AGAINST carbapenem-polymyxin combinations when carbapenem MICs are >16 mg/L based on large RCTs showing no mortality benefit 1, 2
Colistin-Rifampin: NOT Recommended
- Colistin-rifampin combination showed no advantage over colistin monotherapy in a powered RCT of 209 patients with CRAB infections (mostly pneumonia), with no difference in 30-day mortality 1, 2
Colistin-Tigecycline Combinations
- Colistin-tigecycline showed the lowest mortality rates (SUCRA 93.4%) in some analyses 2
- However, tigecycline monotherapy is not recommended for CRAB pneumonia due to higher treatment failure rates 2
Other Combinations: Limited Evidence
- Colistin-vancomycin showed significantly higher nephrotoxicity with no mortality benefit in a retrospective study of 57 ICU patients 1
- Colistin-fosfomycin showed no difference in 30-day mortality but lower microbiological failure in an RCT of 94 patients 1
Dosing for Colistin in ICU Patients
- Loading dose: 9 million units (MU) of colistin methanesulfonate (CMS) 1, 4, 5
- Maintenance dose: 4.5 MU twice daily for critically ill patients with normal renal function 1, 4, 5
- Critical conversion: 1 million U = 80 mg CMS = 33 mg colistin base activity 4, 2
- Therapeutic drug monitoring is recommended when available 4
Polymyxin B Dosing (Alternative to Colistin)
- 15,000-25,000 units/kg/day for adults and children with normal renal function, not exceeding 25,000 units/kg/day 6
- Infusions given every 12 hours 6
- Polymyxin B appears to have less nephrotoxicity than colistin (adjusted HR 2.27,95% CI 1.35-3.82 for colistin) 4, 3
Adjunctive Aerosolized Therapy for Respiratory Infections
- Adding aerosolized polymyxin to intravenous therapy is suggested for CRAB respiratory tract infections 4, 2, 3
- This may reduce clinical treatment failure (RR=0.82,95% CI 0.70-0.96) 3
For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)
For severe CRPA infections, combination therapy with two in vitro active drugs (including a polymyxin) is suggested over monotherapy, though evidence quality is very low. 1, 3
Monotherapy vs. Combination Therapy
- Very low-certainty evidence suggests an advantage of polymyxin combined with another active antibiotic over polymyxin alone or combined with inactive antibiotics 1, 3
- For non-severe or low-risk CRPA infections, monotherapy with a polymyxin may be appropriate 3
- Low-certainty evidence shows no advantage of carbapenem-polymyxin combination over polymyxin monotherapy for CRPA 1
Alternative Agents When Available
- Newer agents like ceftolozane-tazobactam are preferred over polymyxins when active in vitro due to lower nephrotoxicity 3
- A cohort study showed no difference in cure rates between ceftolozane-tazobactam monotherapy (66.7%) and combination with colistin or aminoglycoside (60%) 1
Dosing for CRPA
- Same colistin dosing as for CRAB: loading dose 9 MU, maintenance 4.5 MU twice daily 1, 4
- For polymyxin B: 15,000-25,000 units/kg/day, not exceeding 25,000 units/kg/day 6
Aerosolized Therapy for Respiratory Infections
- Adding aerosolized polymyxin to intravenous therapy may improve clinical outcomes for CRPA respiratory infections 4, 3
Critical Monitoring and Safety Considerations
Nephrotoxicity Surveillance
- Nephrotoxicity occurs in 10.9-53.7% of patients receiving polymyxins 4
- Regular monitoring of renal function is strongly recommended during treatment 4, 2, 3
- Risk factors include pre-existing renal impairment, older age, and concomitant nephrotoxic medications 4
- Colistin trough concentrations ≥3.3 μg/mL indicate increased nephrotoxicity risk based on RIFLE criteria 7
- Avoid combining polymyxins with other nephrotoxic or ototoxic drugs 2
Dose Adjustments in Renal Impairment
- Reduce polymyxin B dosage from 15,000 units/kg downward in patients with kidney impairment 6
- Colistin dosing should be adjusted based on creatinine clearance 1
Resistance Prevention
- Follow-up cultures are recommended in case of treatment failure to detect resistance development 4
- Combination therapy may help prevent emergence of resistant sub-populations 4, 3
Key Clinical Pitfalls to Avoid
Do NOT use polymyxin-meropenem combinations for CRAB with high-level carbapenem resistance (MICs >16 mg/L) - high-quality RCT evidence shows no benefit 1, 2
Do NOT use colistin-rifampin combinations - powered RCTs show no mortality advantage 1, 2
Do NOT use colistin-vancomycin combinations - significantly higher nephrotoxicity without mortality benefit 1
Ensure proper colistin unit conversion - dosing errors are common due to confusion between CMS mass, colistin base activity, and international units 4, 2
Source control should always be a priority to optimize outcomes and shorten antibiotic treatment durations 1, 4
For pan-resistant organisms, select antibiotics with the lowest MICs relative to breakpoints 2