Cefiderocol: A Novel Siderophore Cephalosporin for Multidrug-Resistant Gram-Negative Infections
Cefiderocol should be reserved for treating serious infections caused by multidrug-resistant gram-negative bacteria, particularly those with metallo-β-lactamase production, when other treatment options are limited or unavailable. 1
Mechanism of Action and Unique Properties
Cefiderocol is a novel siderophore cephalosporin with a distinct mechanism for penetrating the bacterial outer membrane:
- Uses a "trojan horse" approach with its catechol moiety to enter bacterial cells via iron transport systems 2
- Maintains stability against various β-lactamases including extended-spectrum β-lactamases (ESBLs), AmpC, and carbapenemases 2
- Active against all Ambler classes of β-lactamases (A, B, C, and D) 3
Clinical Applications
Recommended Uses
- Metallo-β-lactamase (MBL) producing Enterobacterales infections: Cefiderocol is conditionally recommended as an alternative option for infections caused by MBL-producing CRE 4
- Complicated urinary tract infections: FDA-approved for cUTI, including pyelonephritis, in patients with limited or no alternative treatment options 3
- Nosocomial pneumonia: Non-inferior to high-dose, extended-infusion meropenem for treatment of gram-negative nosocomial pneumonia 5
Not Recommended For
- Carbapenem-resistant Acinetobacter baumannii (CRAB) infections: ESCMID guidelines provide low-certainty evidence against cefiderocol treatment of CRAB infections due to higher mortality rates observed in clinical trials 4
Efficacy Data
- APEKS-NP trial: Demonstrated non-inferiority to high-dose meropenem for nosocomial pneumonia with 14-day all-cause mortality of 12.4% for cefiderocol vs. 11.6% for meropenem 5
- CREDIBLE-CR trial: Showed similar clinical and microbiological efficacy to best available therapy for carbapenem-resistant infections, but with numerically higher mortality (34% vs 18%), particularly in patients with Acinetobacter infections 6
Dosing and Administration
- Standard dosing: 2g administered intravenously every 8 hours as a 3-hour infusion 2
- Dosage adjustment required for patients with renal impairment 7
- Pharmacodynamic target: Time above MIC (%fT > MIC) is the main predictor of efficacy 7
Combination Therapy Considerations
- For CRE infections treated with cefiderocol, combination therapy is not recommended based on available evidence 1
- For MBL-producing CRE, ceftazidime-avibactam plus aztreonam is strongly recommended over cefiderocol (which is conditionally recommended) 4
- For CRPA infections, insufficient evidence exists to recommend for or against combination therapy with cefiderocol 1
Antimicrobial Stewardship Considerations
- Reserve cefiderocol for patients with limited treatment options due to resistance patterns 1
- Consider as a targeted therapy based on susceptibility testing rather than empiric treatment
- Use should be guided by antimicrobial stewardship programs to prevent development of resistance
Safety Profile
- Generally well-tolerated with a side effect profile comparable to other cephalosporins 2
- Most common adverse events include gastrointestinal effects and phlebitis 2
- In the APEKS-NP trial, treatment-emergent adverse events occurred in 88% of cefiderocol patients, with urinary tract infection being most common (16%) 5
Clinical Pearls and Pitfalls
- Mortality concern: Higher mortality was observed in the cefiderocol group in the CREDIBLE-CR trial, particularly in patients with Acinetobacter infections 6
- Susceptibility testing: Special testing methods may be required as standard methods may not accurately predict clinical response
- Renal function monitoring: Dosage adjustment is critical in patients with changing renal function 7
- Resistance development: Monitor for emergence of resistance during therapy
Cefiderocol represents an important addition to the antimicrobial armamentarium against multidrug-resistant gram-negative pathogens, but should be used judiciously with careful consideration of both benefits and potential risks, particularly in patients with Acinetobacter infections.