What are the indications for Cefiderocol (Cefiderocol)?

Cefiderocol (Fetroja) Indications

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

Approved Indications

1. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

   • Recommended dosage: 2 grams IV every 8 hours administered over 3 hours 1
   • Dose adjustments required for patients with:
     • CrCl less than 60 mL/min
     • Patients receiving hemodialysis or continuous renal replacement therapy
     • CrCl 120 mL/min or greater

2. Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

   • Same dosing regimen as for cUTI 1

Role in Treatment of Multidrug-Resistant Infections

Cefiderocol is particularly valuable for treating infections caused by multidrug-resistant Gram-negative bacteria due to its unique mechanism of action:

• Mechanism: Siderophore cephalosporin that forms a complex with extracellular free ferric iron, facilitating transport across the outer cell membrane of bacteria 2

• Spectrum of activity: Active against difficult-to-treat Gram-negative pathogens, including:

  • Carbapenem-resistant Enterobacterales (CRE)
  • Carbapenem-resistant Pseudomonas aeruginosa (CRPA)
  • Multidrug-resistant Acinetobacter species
  • Stenotrophomonas maltophilia 3

• European Association of Urology guidelines: Cefiderocol (2g t.i.d.) is listed as a treatment option for uncomplicated pyelonephritis requiring hospitalization, particularly when early culture results indicate the presence of multidrug-resistant organisms 4

Important Clinical Considerations

1. Mortality warning: An increase in all-cause mortality was observed in cefiderocol-treated patients compared to those treated with best available therapy, particularly in patients with Acinetobacter infections. Close monitoring of clinical response is essential 1, 2

2. Carbapenem-resistant infections:

   • For CRE infections, European Society of Clinical Microbiology and Infectious Diseases (ESCMID) conditionally recommends cefiderocol for severe infections due to CRE carrying metallo-β-lactamases and/or resistant to all other antibiotics 4
   • For complicated UTIs caused by CRE, cefiderocol is recommended as an option 4
   • ESCMID conditionally recommends against cefiderocol for treatment of infections caused by carbapenem-resistant Acinetobacter baumannii 4

3. Combination therapy:

   • For CRE infections susceptible to and treated with cefiderocol, combination therapy is not recommended 4
   • For CRPA infections, there is insufficient evidence to recommend for or against combination therapy with cefiderocol 4

4. Antibiotic stewardship considerations:

   • Cefiderocol should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria 1
   • Should be reserved for patients with limited treatment options due to resistance patterns 4, 3

Antimicrobial Activity

Cefiderocol demonstrates excellent in vitro activity against:

• 99.8% of Enterobacterales (98.2% of CRE)
• 99.6% of P. aeruginosa (97.3% of XDR P. aeruginosa)
• 97.7% of Acinetobacter species
• 100% of S. maltophilia 3

Adverse Effects

The most common adverse reactions include:

• For cUTI: diarrhea, infusion site reactions, constipation, rash, candidiasis, cough, liver enzyme elevations, headache, hypokalemia, nausea, and vomiting 1
• For HABP/VABP: liver enzyme elevations, hypokalemia, diarrhea, hypomagnesemia, and atrial fibrillation 1

Contraindications

Cefiderocol is contraindicated in patients with known history of severe hypersensitivity to cefiderocol, other beta-lactam antibiotics, or other components of the formulation 1.