When to Add Polymyxin to Ampicillin-Sulbactam in CRAB Ventilator-Associated Pneumonia
Add polymyxin (colistin or polymyxin B) to ampicillin-sulbactam when the sulbactam MIC is >4 mg/L, when the isolate is sulbactam-resistant, or when treating severe infections with septic shock regardless of sulbactam susceptibility. 1
Treatment Algorithm Based on Sulbactam Susceptibility
When Sulbactam MIC ≤4 mg/L
- Use high-dose ampicillin-sulbactam monotherapy (3g sulbactam every 8 hours as a 4-hour infusion) without adding polymyxin 1
- Ampicillin-sulbactam demonstrates superior outcomes compared to polymyxins with significantly lower nephrotoxicity (15.3% vs 33%) and comparable or better clinical cure rates 1
- Multiple studies show ampicillin-sulbactam achieves higher clinical response rates and lower mortality than colistin monotherapy in CRAB VAP 1
When Sulbactam MIC >4 mg/L or Sulbactam-Resistant
- Polymyxin (colistin or polymyxin B) becomes the primary agent and should be used instead of ampicillin-sulbactam 1
- Intravenous polymyxin is strongly recommended when the isolate is sensitive only to polymyxins 1
- Consider adding adjunctive inhaled colistin (2-6 million IU daily) to improve pulmonary penetration 1, 2
Combination Therapy Indications
Add Polymyxin to Ampicillin-Sulbactam When:
- The patient remains in septic shock or has high mortality risk (>25%) even after susceptibility results are known 1, 2
- Severe infections requiring combination therapy with two in-vitro active agents 1, 2
- Clinical failure on ampicillin-sulbactam monotherapy or infections with MIC at the upper limit of susceptibility (MIC = 4 mg/L) 1, 2
Recommended Combination Regimen for Severe CRAB VAP:
- High-dose ampicillin-sulbactam (3g sulbactam every 8 hours as 4-hour infusion) PLUS
- Intravenous colistin (loading dose 9 million IU, then 4.5 million IU every 12 hours) PLUS
- Consider a third agent (tigecycline, rifampicin, or fosfomycin) for pan-resistant or critically ill patients 2, 3
Critical Dosing Details
Ampicillin-Sulbactam Dosing:
- 9-12g/day of sulbactam (18-24g/day of ampicillin-sulbactam 2:1) divided into 3 doses 1, 2
- Administer as 4-hour infusions to optimize pharmacokinetics 1, 2
- This extended infusion allows treatment of isolates with MIC up to 8 mg/L 1
Colistin Dosing:
- Loading dose: 9 million IU, followed by maintenance 4.5 million IU every 12 hours 2
- Adjust for renal function to minimize nephrotoxicity 2, 4
- Add inhaled colistin 2-6 million IU daily for respiratory infections 1, 5
Combinations to Avoid
- Never combine colistin with rifampicin as a two-drug regimen - lacks proven clinical benefit and increases hepatotoxicity 1, 2
- Never combine colistin with glycopeptides (vancomycin) - increases nephrotoxicity without added antimicrobial effect 1, 2
- Avoid polymyxin-meropenem combination when carbapenem MIC >16 mg/L - no synergy at high-level resistance 1, 6
Monitoring Requirements
- Monitor renal function closely in all patients receiving colistin - nephrotoxicity occurs in 20-57% depending on dose and duration 1, 7
- Baseline and peak creatinine should be tracked; colistin causes significantly more nephrotoxicity than ampicillin-sulbactam 1, 7
- Weekly liver function tests when rifampicin is part of the regimen 2
Key Clinical Pitfalls
- Do not use sulbactam as empiric monotherapy - only use for directed therapy after susceptibility confirmation 1, 2
- Verify MIC by E-test or broth microdilution - automated methods are unreliable for sulbactam susceptibility testing 1
- Never use tigecycline as monotherapy for CRAB bacteremia - suboptimal serum concentrations lead to treatment failure 1, 2
- Resistance to tigecycline can emerge rapidly during therapy (4 of 6 isolates in one study) 7