What is the use and dosage of Fetroja (cefiderocol) in treating complicated infections?

Fetroja (Cefiderocol) Use and Dosage for Complicated Infections

Fetroja (cefiderocol) is indicated for treating complicated urinary tract infections (cUTI) including pyelonephritis, and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible Gram-negative microorganisms in patients 18 years or older, with the standard dosage being 2 g administered intravenously every 8 hours as a 3-hour infusion. 1

Indications and Clinical Applications

Cefiderocol is specifically indicated for:

• Complicated urinary tract infections (cUTI), including pyelonephritis
• Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)

Cefiderocol is particularly valuable for treating infections caused by:

• Carbapenem-resistant Enterobacterales (CRE)
• Difficult-to-treat or carbapenem-resistant Pseudomonas aeruginosa (DTR-PA/CRPA)
• Other multidrug-resistant Gram-negative bacteria

Dosage Recommendations

Standard Dosing:

• Dose: 2 g intravenously
• Frequency: Every 8 hours
• Administration: 3-hour infusion
• Duration:
  • 5-10 days for complicated UTI
  • 10-14 days for HABP/VABP and bloodstream infections 2

Renal Dose Adjustments:

Dosage must be adjusted based on creatinine clearance:

• CrCl 60-119 ml/min: Standard dosing (2 g q8h)
• CrCl <60 ml/min: Dose reduction required
• CrCl ≥120 ml/min: Dose adjustment required 3, 4

Mechanism of Action and Advantages

Cefiderocol is a novel siderophore cephalosporin with unique properties:

1. Uses a "Trojan horse" strategy - binds to extracellular free iron and enters bacteria through active iron transport channels 5
2. Has enhanced stability against various β-lactamases, including:
   • Extended-spectrum β-lactamases (ESBLs)
   • AmpC β-lactamases
   • Carbapenemases (including metallo-β-lactamases) 6

Clinical Evidence and Efficacy

In the APEKS-cUTI phase 2 trial comparing cefiderocol to imipenem-cilastatin for complicated UTI:

• Composite clinical and microbiological success: 73% for cefiderocol vs 55% for imipenem-cilastatin
• Clinical response rates: 89.7% for cefiderocol vs 87.4% for imipenem-cilastatin
• Microbiological eradication rates: 73% for cefiderocol vs 56.3% for imipenem-cilastatin 7

Place in Therapy

According to guidelines, cefiderocol should be positioned as:

1. For carbapenem-resistant Enterobacterales (CRE):

   • Conditionally recommended for patients with severe infections due to CRE carrying metallo-β-lactamases and/or resistant to other antibiotics, including ceftazidime-avibactam and meropenem-vaborbactam 2

2. For difficult-to-treat Pseudomonas aeruginosa (DTR-PA):

   • Considered as one of the treatment options (along with colistin, ceftolozane/tazobactam, and ceftazidime/avibactam) 2

Safety and Adverse Effects

Common adverse events include:

• Gastrointestinal symptoms (diarrhea, constipation)
• Phlebitis at infusion site 6, 4

Important Considerations and Caveats

1. Antimicrobial Stewardship: Cefiderocol should be reserved for infections with limited treatment options due to resistance patterns 1

2. Mortality Concern: In the CREDIBLE-CR trial, higher all-cause mortality was observed in patients receiving cefiderocol, particularly those with severe Acinetobacter infections 5

3. Pharmacodynamics: The efficacy of cefiderocol correlates with the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (%fT > MIC) 3, 6

4. Culture and Susceptibility: Always obtain cultures before initiating therapy and adjust treatment based on susceptibility results

5. Monitoring: Regular clinical assessment for treatment response within 48-72 hours is essential

Cefiderocol represents an important addition to the antimicrobial armamentarium for treating complicated infections caused by multidrug-resistant Gram-negative bacteria, particularly when other options are limited.