Polymyxin with High-Dose Sulbactam for CRKP Infections: Rationale and Evidence
Polymyxin (colistin) combined with high-dose sulbactam is recommended for treating Carbapenem-Resistant Klebsiella pneumoniae (CRKP) infections because this combination therapy significantly reduces treatment failure rates compared to polymyxin monotherapy, with approximately 119 fewer treatment failures per 1000 patients. 1
Rationale for This Combination
Synergistic Activity
- Polymyxin disrupts bacterial outer membrane, allowing better penetration of sulbactam
- Sulbactam has intrinsic antimicrobial activity against many gram-negative bacteria, including some carbapenem-resistant strains
- The combination provides synergistic killing effect against CRKP
Clinical Outcomes
- Polymyxin-based combination therapy shows:
- 119 fewer treatment failures per 1000 patients (RR = 0.82,95% CI 0.72-0.93) 1
- 74 fewer cases of pathogen eradication failure per 1000 patients (RR = 0.81,95% CI 0.67-0.98) 1
- Shorter time to microbiological clearance 1
- Reduced mortality compared to polymyxin monotherapy (35.7% vs 55.5%; OR: 0.46,95% CI, 0.30-0.69) 1
Specific Recommendations for CRKP
First-line recommendation: Polymyxin-based combination therapy is strongly recommended over monotherapy for CRKP infections 1
Selection of combination agent:
- Should be based on susceptibility testing results 1
- Sulbactam is particularly effective when combined with polymyxin for CRKP
Dosing considerations:
- Polymyxin (colistin): Loading dose of 300 mg CMS (9 MU) infused for 0.5-1 h, followed by maintenance dose of 300-360 mg CMS (9 MU-10.9 MU) divided in two doses 1
- High-dose sulbactam: Typically 4 g/day divided in multiple doses (higher doses may be used based on infection severity and patient factors)
Alternative Combinations
While polymyxin-sulbactam is effective, guidelines also mention other potential combinations:
- For bloodstream infections: Polymyxin + tigecycline (OR 1.88,95% CI 1.05-3.37) or polymyxin + carbapenem (OR 3.11,95% CI 1.25-7.74) 1, 2
- For severe infections: Three-drug combinations including polymyxin show significant survival benefit (OR 3.86,95% CI 1.60-9.32) 2
- For newer options: Ceftazidime-avibactam (2.5 g IV q8h) is recommended for CRE-BSI when available 1
Monitoring and Precautions
- Renal function: Monitor closely during polymyxin treatment; consider therapeutic drug monitoring 1
- Drug interactions: Avoid other nephrotoxic or ototoxic drugs in combination with polymyxin 1
- Dose conversion: Pay careful attention to correct dose conversion (1 million U = 80 mg mass CMS = 33 mg colistin base activity) 1
- Acute kidney injury: Occurs in approximately 27-52% of patients receiving polymyxin therapy 3, 4
Special Considerations
- For respiratory infections: Consider adding aerosolized polymyxin to intravenous therapy 5
- For critically ill patients: Higher doses of polymyxin may be necessary but must be balanced against nephrotoxicity risk 6
- For patients with renal impairment: Dose adjustment is required to minimize toxicity while maintaining efficacy
The combination of polymyxin with high-dose sulbactam represents an important therapeutic strategy for managing CRKP infections in an era of increasing antimicrobial resistance, with evidence supporting improved clinical outcomes compared to monotherapy approaches.