Ampicillin-Sulbactam Combined with Polymyxin B for Carbapenem-Resistant Acinetobacter baumannii
Highest Quality Evidence Supporting the Combination
The 2022 European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines provide the most comprehensive evidence comparing ampicillin-sulbactam with polymyxins for CRAB infections, demonstrating that ampicillin-sulbactam shows superior outcomes over polymyxins when used as monotherapy. 1
However, when addressing the specific combination of ampicillin-sulbactam plus polymyxin B, the evidence shifts toward triple-drug regimens for the most resistant organisms.
Evidence for the Combination Regimen
When to Use Ampicillin-Sulbactam Plus Polymyxin B
For pan-resistant CRAB (resistant to carbapenems, polymyxins, and sulbactam), a triple combination of high-dose ampicillin-sulbactam (8/4 g every 8 hours) plus meropenem (2 g every 8 hours) plus polymyxin B (1.43 mg/kg every 12 hours with loading dose) achieved complete eradication by 96 hours in hollow-fiber infection models. 2, 3
This triple combination was effective even when each individual agent lacked activity against the isolate, demonstrating synergistic killing that monotherapies and two-drug combinations could not achieve. 3
For extremely drug-resistant isolates, the combination of sulbactam/meropenem/polymyxin B showed important synergistic activity (FICI ≤0.281) in five of six tested isolates, with recommended dosing of 2/4 g meropenem/sulbactam every 8 hours plus 0.5 mg/kg polymyxin B every 12 hours. 4
Clinical Outcomes Data
A retrospective study of 167 patients with CRAB infections found that ampicillin-sulbactam was associated with significantly lower mortality at end of treatment compared to polymyxins (adjusted OR 2.07 for polymyxin group, 95% CI 1.03-4.16). 1
When ampicillin-sulbactam was compared directly with polymyxins in multiple studies, ampicillin-sulbactam demonstrated lower nephrotoxicity (15.3% versus 33%) while maintaining comparable or superior clinical cure rates. 5, 6
Independent predictors of mortality during treatment included polymyxin use, higher APACHE II scores, septic shock, delayed treatment initiation, and renal failure, making ampicillin-sulbactam the preferred agent when susceptible. 6
Specific Dosing Recommendations for the Combination
High-Dose Ampicillin-Sulbactam Component
Administer 3 g sulbactam every 8 hours (9-12 g/day total) as a 4-hour infusion for isolates with sulbactam MIC ≤4 mg/L. 5, 7
For isolates with MIC of 8 mg/L or in critically ill patients with augmented renal clearance, doses up to 12 g/day of sulbactam may be necessary. 5
The 4-hour extended infusion optimizes pharmacokinetic/pharmacodynamic properties and allows treatment of isolates with higher MICs. 5, 7
Polymyxin B Component
Administer a loading dose of 5 mg CBA/kg IV followed by maintenance dosing using the formula: 2.5 mg CBA × (1.5 × CrCl + 30) IV every 12 hours. 8
Alternative dosing is a loading dose of 6-9 million IU followed by 9 million IU/day divided into 2-3 doses. 8
For the triple combination regimen, lower polymyxin B doses (0.5-1.43 mg/kg every 12 hours) may be sufficient when combined with high-dose sulbactam and a carbapenem. 4, 2
When This Combination Is Indicated
Primary Indications
Severe CRAB infections with septic shock or high mortality risk where combination therapy with two in vitro active agents is recommended. 1, 5
Pan-resistant CRAB isolates that show resistance to both sulbactam (MIC >4 mg/L) and polymyxins when used individually, requiring a triple-drug regimen including a carbapenem. 2, 3
Clinical failures on monotherapy or infections with MIC values at the upper limit of susceptibility. 5
Preferred Alternatives When Applicable
If the isolate has sulbactam MIC ≤4 mg/L, high-dose ampicillin-sulbactam monotherapy or in combination with tigecycline is preferred over polymyxin-based regimens due to superior safety profile. 1, 5
Ampicillin-sulbactam should be chosen over polymyxins for susceptible strains because it demonstrates lower nephrotoxicity and comparable or better efficacy. 1, 5, 6
Critical Combinations to AVOID
Never combine colistin with rifampin alone—this lacks proven clinical benefit despite microbiological eradication and increases hepatotoxicity risk. 5, 8
Never combine polymyxins with glycopeptides (vancomycin)—this dramatically increases nephrotoxicity up to 33% without added antimicrobial benefit. 5, 8
Avoid polymyxin-meropenem combinations for CRAB with high-level carbapenem resistance (MIC >16 mg/L) unless part of a triple regimen with sulbactam. 5
Mandatory Monitoring Requirements
Monitor renal function every 2-3 days during therapy, as nephrotoxicity occurs in up to 33% of polymyxin-treated patients compared to 15.3% with ampicillin-sulbactam. 1, 5, 8
Check serum creatinine and adjust polymyxin dosing based on creatinine clearance using the weight-based formula. 8
Monitor for clinical response at 48-72 hours and consider repeat cultures to document microbiological clearance. 5
Treatment Duration
Maintain therapy for a minimum of 2 weeks (14 days) for severe CRAB infections including pneumonia, bacteremia, or septic shock. 5, 8
Shorter durations of 7-14 days may be acceptable for less severe infections with adequate source control and good clinical response. 5, 8
Key Journal Publications
The most important peer-reviewed evidence documenting this combination includes:
The 2022 ESCMID guidelines in Clinical Microbiology and Infection provide the highest-quality systematic review comparing ampicillin-sulbactam with polymyxins, showing ampicillin-sulbactam superiority in multiple studies. 1
The 2017 Antimicrobial Agents and Chemotherapy study by Lenhard et al. demonstrated that high-dose ampicillin-sulbactam (8/4 g every 8 hours) combined with meropenem and polymyxin B achieved rapid eradication of polymyxin-resistant CRAB in hollow-fiber models. 2
The 2017 Journal of Antimicrobial Chemotherapy study showed that the triple combination of polymyxin B, meropenem, and ampicillin-sulbactam eradicated pan-resistant A. baumannii by 96 hours when monotherapies and double combinations failed. 3
The 2008 Journal of Antimicrobial Chemotherapy retrospective study of 167 patients found ampicillin-sulbactam was more efficacious than polymyxins, with polymyxin use being an independent predictor of mortality. 6
Common Pitfalls to Avoid
Do not use standard ampicillin-sulbactam doses (6 g/day)—this is inadequate for severe CRAB infections; high-dose regimens (9-12 g/day sulbactam) are required. 5, 7
Do not use polymyxins as monotherapy for severe infections or septic shock—combination therapy with two active agents significantly improves outcomes. 8
Do not assume susceptibility without MIC testing—automated methods are unreliable for sulbactam; use E-test or broth microdilution for accurate MIC determination. 5
Do not delay appropriate therapy while awaiting susceptibility results in critically ill patients with known CRAB colonization or during outbreaks. 5