What is the preferred treatment between Fetroja (cefiderocol) and high dose Unasyn (ampicillin/sulbactam) for carbapenem-resistant Acinetobacter baumannii (CRAB) infections?

Treatment of CRAB: Fetroja (Cefiderocol) vs High-Dose Ampicillin-Sulbactam

High-dose ampicillin-sulbactam is preferred over cefiderocol (Fetroja) for CRAB infections, particularly for hospital-acquired/ventilator-associated pneumonia when the isolate is susceptible to sulbactam. 1

Primary Recommendation Against Cefiderocol

The ESCMID guidelines conditionally recommend against cefiderocol for CRAB treatment based on concerning mortality data. 1 In the CREDIBLE-CR trial, 28-day mortality was 49% (19/39 patients) in the cefiderocol group versus only 18% (3/17 patients) in the best available therapy group for CRAB infections. 1 This represents a nearly three-fold increase in mortality with cefiderocol. 2

The guideline panel concluded there is "low-certainty evidence against cefiderocol treatment of CRAB infections" based on these findings. 1

Sulbactam-Based Therapy as Preferred Option

For CRAB susceptible to sulbactam with HAP/VAP, the ESCMID guidelines suggest ampicillin-sulbactam as the preferred agent. 1 This recommendation is supported by multiple retrospective studies showing superior outcomes:

• A Taiwanese ICU study demonstrated significantly lower ICU mortality (adjusted OR 0.12,95% CI 0.01-1.02) and treatment failure (adjusted OR 0.14,95% CI 0.04-0.55) with sulbactam-based therapy compared to tigecycline. 1

• A Chinese study of 210 CRAB-BSI patients showed significantly lower 28-day mortality with sulbactam-based treatment (adjusted HR 0.57,95% CI 0.34-0.94), even though 80% of isolates were resistant to sulbactam by standard testing. 1

• Another Taiwanese study of 84 CRAB pneumonia patients found no significant difference in 30-day mortality but demonstrated significant advantage in microbiological cure with sulbactam-based therapy. 1

Critical Caveat: Sulbactam Susceptibility Testing

The key limitation is that sulbactam susceptibility must be confirmed. 1 For CRAB resistant to sulbactam, the guidelines state that polymyxins or high-dose tigecycline can be used if active in vitro, but no preferred antibiotic can be recommended. 1

Combination Therapy Considerations

For severe and high-risk CRAB infections, combination therapy with two in vitro active antibiotics is suggested, which may include polymyxin, aminoglycoside, tigecycline, or sulbactam combinations. 1 This approach is based on very low certainty evidence but reflects the severity of these infections. 1

Avoid polymyxin-meropenem combination (strong recommendation against) and polymyxin-rifampin combination (strong recommendation against). 1

Emerging Real-World Data on Cefiderocol

Despite guideline recommendations against cefiderocol, a 2024 prospective observational study showed that cefiderocol-based regimens achieved 100% early clinical success when used as monotherapy versus 70.6% for combination regimens, with fewer adverse drug reactions compared to colistin-based treatment. 3 However, this contradicts the higher-quality randomized trial data and should be interpreted cautiously. 3

Clinical Algorithm

1. Obtain susceptibility testing immediately - particularly for sulbactam susceptibility 1
2. If sulbactam-susceptible with HAP/VAP: Use high-dose ampicillin-sulbactam 1
3. If sulbactam-resistant: Consider polymyxins or high-dose tigecycline if active in vitro 1
4. For severe/high-risk infections: Add a second in vitro active agent (avoid polymyxin-meropenem and polymyxin-rifampin combinations) 1
5. Avoid cefiderocol as first-line therapy given mortality concerns in randomized trials 1

Important Pitfall

The most critical error would be selecting cefiderocol over sulbactam-based therapy when sulbactam susceptibility exists, given the substantial mortality difference observed in the CREDIBLE-CR trial. 1, 2 The 49% versus 18% mortality difference represents a clinically meaningful harm signal that outweighs theoretical advantages of newer agents. 1