What is the recommended dosage and treatment duration for Cefiderocol (Cefiderocol) in patients with complicated urinary tract infections or hospital-acquired pneumonia caused by multidrug-resistant Gram-negative bacteria?

Cefiderocol Dosing and Treatment Duration for Multidrug-Resistant Gram-Negative Infections

For complicated urinary tract infections (cUTI), administer cefiderocol 2 g IV every 8 hours over 3 hours for 5-7 days; for hospital-acquired/ventilator-associated pneumonia (HAP/VABP), use the same dose for 10-14 days, with dose adjustments required for renal impairment. 1

FDA-Approved Dosing Regimen

Standard Dosing:

• 2 g IV every 8 hours infused over 3 hours for patients with creatinine clearance (CrCL) 60-119 mL/min 1, 2
• Dose adjustments are mandatory for CrCL <60 mL/min (including hemodialysis and CRRT) and CrCL ≥120 mL/min 1, 2

Treatment Duration by Indication

Complicated Urinary Tract Infections:

• 5-7 days is the recommended duration 3
• In the pivotal APEKS-cUTI trial, treatment ranged from 7-14 days, with cefiderocol demonstrating 73% composite clinical and microbiological cure versus 55% with imipenem-cilastatin 4

Hospital-Acquired/Ventilator-Associated Pneumonia:

• 10-14 days is the recommended duration 3
• Duration should be based on clinical response, source control, and underlying comorbidities 3

Critical Clinical Context: When to Use Cefiderocol

Appropriate Use - Metallo-β-Lactamase (MBL) Producing CRE:

• Cefiderocol is conditionally recommended for severe infections caused by MBL-producing carbapenem-resistant Enterobacterales when ceftazidime-avibactam plus aztreonam is unavailable 3, 5
• Clinical cure rates of 75% were achieved versus 29% with best available therapy in MBL-producing organisms 5
• Recent pooled data showed 70.8% clinical cure and 12.5% 28-day mortality in MBL-producing isolates 5

Appropriate Use - Pan-Resistant Organisms:

• Use when organisms are resistant to both ceftazidime-avibactam and meropenem-vaborbactam 3, 5
• Reserve as a last-line agent per antibiotic stewardship principles 5

Critical Contraindication

DO NOT USE for Carbapenem-Resistant Acinetobacter baumannii (CRAB):

• Guidelines conditionally recommend AGAINST cefiderocol for CRAB infections 3, 5
• Mortality with cefiderocol was 49% versus 18% with best available therapy in CRAB infections 5
• In the CREDIBLE-CR trial, 28-day mortality was 24.8% with cefiderocol versus 18.4% with best available therapy 5

Combination Therapy Guidance

Monotherapy is Preferred:

• Do NOT use combination therapy for CRE infections susceptible to cefiderocol - this is a strong recommendation 3, 5
• No evidence supports combinations with new β-lactam/β-lactamase inhibitors for carbapenem-resistant Pseudomonas aeruginosa 5

Renal Dosing Adjustments

Critical Pharmacokinetic Consideration:

• CrCL is the most significant covariate affecting cefiderocol exposure 2
• Probability of target attainment (100% fT>MIC) was >90% against MICs ≤4 μg/mL for all infection sites except BSI/sepsis with normal renal function (85%) 2
• Dose adjustments are required for both decreased AND augmented renal clearance 1, 2

Antibiotic Stewardship Pitfalls

Avoid These Common Errors:

• Do not use cefiderocol for third-generation cephalosporin-resistant Enterobacterales when other options exist (ceftazidime-avibactam, meropenem-vaborbactam preferred) 5
• Do not use for CRAB under any circumstances due to excess mortality 3, 5
• Monitor for treatment-emergent resistance, particularly with MBL-producing organisms 5
• High MIC values in some MBL-producers may predict treatment failure 5

Pharmacodynamic Target

The pharmacodynamic target is 100% fT>MIC:

• This target was achieved in most enrolled patients across clinical trials 2
• No clear PK/PD relationship was found for outcomes because exposure targets were consistently met 2
• Infection site and mechanical ventilation did not significantly affect pharmacokinetics 2