What is the recommended use and dosage of Cefiderocol (Cefiderocol) for treating infections caused by multidrug-resistant Gram-negative bacteria?

Cefiderocol for Multidrug-Resistant Gram-Negative Infections

Cefiderocol is FDA-approved at 2 grams IV every 8 hours (infused over 3 hours) for complicated urinary tract infections caused by susceptible Gram-negative organisms, but should be reserved as a last-line agent for metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) when ceftazidime-avibactam plus aztreonam is unavailable, and should NOT be used for carbapenem-resistant Acinetobacter baumannii (CRAB) infections due to significantly higher mortality. 1, 2, 3

FDA-Approved Indications and Dosing

• Standard dose: 2 grams IV every 8 hours, infused over 3 hours 3
• Approved for: Complicated urinary tract infections (cUTI) including pyelonephritis in adults and pediatric patients ≥3 months with limited treatment options 3
• Renal dose adjustments required: Cefiderocol is primarily renally excreted (90.6% unchanged in urine), necessitating dose modifications based on creatinine clearance 3

Renal Dosing Adjustments

• CrCl 60-89 mL/min: Dose adjustment needed as AUC increases 1.37-fold 3
• CrCl 30-59 mL/min: AUC increases 2.35-fold, requiring significant dose reduction 3
• CrCl 15-29 mL/min: AUC increases 3.21-fold 3
• CrCl <15 mL/min: AUC increases 4.69-fold 3
• Augmented renal clearance (CrCl >120 mL/min): Increase frequency to 2 grams every 6 hours to maintain target exposures 3, 4
• CRRT patients: Effluent flow rate-based dosing required to achieve comparable exposures 3

Primary Clinical Role: MBL-Producing CRE

Cefiderocol should be reserved for MBL-producing carbapenem-resistant Enterobacterales when first-line therapy (ceftazidime-avibactam plus aztreonam) is unavailable or not feasible. 1, 2

• Clinical cure rates of 75% were achieved with cefiderocol versus 29% with best available therapy in MBL-producing organisms 2
• Pooled data from CREDIBLE-CR and APEKS-NP trials showed 70.8% clinical cure, 58.3% microbiological eradication, and 12.5% 28-day mortality in MBL-producing isolates 2
• The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) conditionally recommends cefiderocol for severe CRE infections carrying metallo-β-lactamases when resistant to ceftazidime-avibactam and meropenem-vaborbactam 1

Why MBL-Producers Specifically?

• New Delhi Metallo-β-lactamase (NDM)-positive isolates show higher MICs than other carbapenemase-producing Enterobacterales, with 83.4% susceptibility to cefiderocol 5
• Cefiderocol's siderophore mechanism allows active transport across bacterial membranes, achieving high periplasmic concentrations even against MBL-producers 4, 6

Critical Contraindication: CRAB Infections

Do NOT use cefiderocol for carbapenem-resistant Acinetobacter baumannii (CRAB) infections. 2

• Mortality with cefiderocol was 49% versus 18% with best available therapy in CRAB infections 2
• The American College of Clinical Pharmacy conditionally recommends against cefiderocol for CRAB due to this mortality signal 2
• ESCMID guidelines conclude there is low-certainty evidence against cefiderocol for CRAB 2

Combination Therapy Guidance

Do NOT use combination therapy when treating CRE infections susceptible to cefiderocol—monotherapy is strongly recommended. 1, 2

• The Infectious Diseases Society of America (IDSA) strongly recommends against combination therapy for CRE infections susceptible to cefiderocol 2
• ESCMID does not recommend combination therapy for CRE susceptible to ceftazidime-avibactam, meropenem-vaborbactam, or cefiderocol 1
• For carbapenem-resistant Pseudomonas aeruginosa (CRPA), there is insufficient evidence to recommend for or against combinations with new β-lactam/β-lactamase inhibitors 2

Pharmacokinetic/Pharmacodynamic Considerations

• Time-dependent killing: Target is ≥75% fT>MIC (free drug concentration above MIC for ≥75% of dosing interval) 4
• Protein binding: 40-60% (primarily albumin) 3
• Half-life: 2-3 hours 3, 4
• Volume of distribution: 18.0 L 3
• Lung penetration: Achieves therapeutic concentrations in epithelial lining fluid (3.1-20.7 mg/L at end of infusion) 3

Antibiotic Stewardship Principles

Reserve cefiderocol as a last-line agent and avoid use for third-generation cephalosporin-resistant Enterobacterales when other options exist. 2

• The Society for Healthcare Epidemiology of America recommends strict stewardship to preserve cefiderocol activity 2
• Cefiderocol should NOT be used for routine CRE infections when ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam are active and available 1
• Treatment-emergent resistance has been reported, particularly in MBL-producing organisms with high MICs 2

Clinical Efficacy Data

Complicated UTI (APEKS-cUTI Trial)

• 73% (183/252) of cefiderocol patients achieved composite clinical and microbiological cure versus 55% (65/119) with imipenem-cilastatin 7, 8
• Treatment difference of 18.58% (95% CI 8.23-28.92, p=0.0004), establishing non-inferiority 8
• Active against E. coli, K. pneumoniae, P. aeruginosa, Proteus mirabilis, Enterobacter cloacae, Morganella morganii, and Citrobacter freundii 7

Mortality Concerns (CREDIBLE-CR Trial)

• 28-day mortality was 24.8% with cefiderocol versus 18.4% with best available therapy 2
• End-of-follow-up mortality was 33.7% with cefiderocol versus 18.4% with best available therapy 2
• This mortality signal led to FDA and EMA warnings in prescribing information 6

Common Pitfalls and How to Avoid Them

• Susceptibility testing issues: Commercial tests may have accuracy and reliability problems—interpret results carefully and consider sending to reference laboratories 6
• Ignoring renal function: Failure to adjust doses in renal impairment leads to excessive drug accumulation and potential toxicity 3
• Missing augmented renal clearance: Critically ill patients with CrCl >120 mL/min require more frequent dosing (every 6 hours instead of every 8 hours) 3, 4
• Using for CRAB: This is associated with significantly higher mortality and should be avoided 2
• Overuse for non-MBL CRE: When other newer agents (ceftazidime-avibactam, meropenem-vaborbactam) are active, use those first to preserve cefiderocol 1, 2

Safety Profile

• Most common adverse events: Gastrointestinal symptoms including diarrhea, constipation, nausea, vomiting, and abdominal pain (12% with cefiderocol vs 18% with imipenem-cilastatin) 8
• Well-tolerated overall: No QT interval prolongation or clinically significant drug-drug interactions via organic anion transporters 4
• No CYP interactions: Not an inhibitor or inducer of major CYP enzymes 3
• Hemodialysis: Approximately 60% removed during a 3-4 hour session 3

Spectrum of Activity

• Active against: Extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, carbapenem-resistant Enterobacterales (including KPC and MBL producers), P. aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, and some colistin-resistant E. coli with mcr-1 3, 6, 5
• Limited activity: Gram-positive bacteria and anaerobes like Bacteroides fragilis 7