What are the indications and usage of Cefiderocol (Cefiderocol) for treating infections caused by Gram-negative bacteria?

Indications and Usage of Cefiderocol for Treating Gram-Negative Bacterial Infections

Cefiderocol is FDA-approved for treating complicated urinary tract infections (cUTI) including pyelonephritis, and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible Gram-negative microorganisms in patients 18 years of age or older. 1

FDA-Approved Indications

Cefiderocol (FETROJA) is specifically indicated for:

1. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
2. Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

Mechanism and Spectrum of Activity

Cefiderocol is a novel siderophore cephalosporin with unique properties:

• Uses a "trojan horse" strategy by binding to iron and utilizing bacterial iron transport systems to enter bacterial cells
• Demonstrates stability against all four Ambler classes of β-lactamases, including metallo-β-lactamases (MBLs) 2
• Shows excellent in vitro activity against multidrug-resistant Gram-negative pathogens 3

Clinical Applications Based on Pathogen Type

1. Metallo-β-lactamase (MBL)-producing Carbapenem-Resistant Enterobacterales (CRE)

• Conditionally recommended for treatment of infections caused by MBL-producing CRE 4
• Clinical cure was achieved in 75% of patients with MBL-producing CRE infections treated with cefiderocol compared to 29% with best available therapy 4

2. KPC-producing Carbapenem-Resistant Enterobacterales

• May be considered as an alternative option for KPC-producing CRE infections when first-line options (ceftazidime/avibactam or meropenem/vaborbactam) are not suitable 4

3. Carbapenem-Resistant Acinetobacter baumannii (CRAB)

• ESCMID conditionally recommends against cefiderocol for treatment of CRAB infections based on low-certainty evidence 4
• Higher mortality was observed in patients with Acinetobacter infections treated with cefiderocol in the CREDIBLE-CR trial 5

4. Pseudomonas aeruginosa

• Highly active against Pseudomonas aeruginosa, including extensively drug-resistant (XDR) strains
• In vitro studies show 99.6% susceptibility of P. aeruginosa isolates to cefiderocol 3

Dosing Considerations

• Standard dosing: 2g administered intravenously every 8 hours as a 3-hour infusion 2
• Dose adjustment required for patients with renal impairment
• Therapeutic drug monitoring may be beneficial when available 4

Combination Therapy Considerations

• For CRE infections susceptible to and treated with cefiderocol, combination therapy is not recommended 6
• For carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections, insufficient evidence exists to recommend for or against combination therapy with cefiderocol 6

Antimicrobial Stewardship Implications

• Cefiderocol should be reserved for patients with limited treatment options due to resistance patterns 6
• Should be used only for infections proven or strongly suspected to be caused by susceptible bacteria 1

Clinical Pearls and Caveats

• Despite excellent in vitro activity, higher mortality was observed with cefiderocol compared to best available therapy in the CREDIBLE-CR trial, particularly in patients with Acinetobacter infections 5
• Susceptibility testing should be performed using iron-depleted media to accurately determine MIC values
• Consider local epidemiology and resistance patterns when selecting cefiderocol for empiric therapy

Cefiderocol represents an important therapeutic option for difficult-to-treat Gram-negative infections, particularly those caused by carbapenem-resistant organisms with limited treatment alternatives. However, its use should be guided by antimicrobial susceptibility testing and reserved for appropriate clinical scenarios.