What is Cefiderocol used for?

Cefiderocol Use in Multidrug-Resistant Gram-Negative Infections

Cefiderocol is conditionally recommended for severe infections caused by carbapenem-resistant Enterobacterales (CRE) carrying metallo-β-lactamases (MBLs) or organisms resistant to all other antibiotics including ceftazidime-avibactam and meropenem-vaborbactam, but should be avoided for carbapenem-resistant Acinetobacter baumannii (CRAB) infections due to higher mortality. 1

Primary Indications

Carbapenem-Resistant Enterobacterales (CRE)

For MBL-producing CRE specifically:

• Cefiderocol is conditionally recommended as an alternative option when ceftazidime-avibactam plus aztreonam (the preferred first-line) 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 1, 2
• Recent 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 1

For severe CRE infections resistant to newer agents:

• Use cefiderocol when organisms are resistant to ceftazidime-avibactam and meropenem-vaborbactam 1
• This represents a last-line option with low certainty evidence 1, 2

Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)

Limited role with very low certainty evidence:

• Cefiderocol showed non-inferiority to best available therapy in small numbers (2/11 mortality with cefiderocol vs 2/11 with comparator) 1
• Insufficient evidence exists to recommend for or against combination therapy with cefiderocol for CRPA 1
• Guidelines cannot recommend for or against its use due to paucity of data 1, 2

Complicated Urinary Tract Infections (cUTI)

FDA-approved indication with demonstrated efficacy:

• Cefiderocol achieved 73% composite clinical and microbiological cure versus 55% with imipenem-cilastatin in the APEKS-cUTI trial (treatment difference 18.58%, p=0.0004) 3, 4
• Active against E. coli, K. pneumoniae, P. aeruginosa, Proteus mirabilis, Enterobacter cloacae complex, Morganella morganii, and Citrobacter freundii 3, 4
• Recommended dose: 2 grams IV every 8 hours infused over 3 hours 5, 4

Critical Contraindication

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

Conditionally recommended AGAINST cefiderocol for CRAB infections:

• Mortality with cefiderocol was 49% versus 18% with best available therapy 1, 2
• In CREDIBLE-CR trial, 28-day mortality was 24.8% with cefiderocol versus 18.4% with comparator 2
• End-of-follow-up mortality reached 33.7% with cefiderocol versus 18.4% with best available therapy 2
• Use ampicillin-sulbactam for sulbactam-susceptible CRAB or polymyxins/high-dose tigecycline for resistant strains instead 1

Dosing Considerations

Renal Function Adjustments

Cefiderocol requires careful dose adjustment based on creatinine clearance:

• Standard dose (2g IV q8h over 3 hours) for CrCl 60-119 mL/min 5
• CrCl 30-59 mL/min: Reduced dosing required (AUC increases 2.35-fold) 5
• CrCl 15-29 mL/min: Further reduction needed (AUC increases 3.21-fold) 5
• CrCl <15 mL/min: Significant reduction required (AUC increases 4.69-fold) 5
• Augmented renal clearance (CrCl ≥120 mL/min): Increase to 2g IV every 6 hours over 3 hours 5, 6

Continuous Renal Replacement Therapy (CRRT)

• Approximately 60% removed by 3-4 hour hemodialysis session 5
• Effluent flow rate is the major determinant of clearance during CRRT 5
• Dose adjustments based on effluent flow rate to maintain therapeutic exposures 5, 6

Microbiological Spectrum

Active against multiple resistance mechanisms:

• Stable against all four Ambler classes of β-lactamases including metallo-β-lactamases (NDM, VIM, IMP) 5, 7
• Active against serine carbapenemases (KPC, OXA-48) 5
• Maintains activity despite porin deletions (OmpK35/36 in K. pneumoniae, OprD in P. aeruginosa) and efflux pump upregulation 5
• Active against some colistin-resistant E. coli with mcr-1 5
• Also covers Stenotrophomonas maltophilia, Burkholderia cepacia, and Achromobacter species 6

Limited activity:

• No clinically relevant activity against Gram-positive bacteria 5, 3
• No activity against anaerobes including Bacteroides fragilis 3

Combination Therapy Recommendations

Monotherapy is preferred when cefiderocol is susceptible:

• Strong recommendation against combination therapy for CRE infections susceptible to cefiderocol 1
• No recommendation for or against combinations with new β-lactam/β-lactamase inhibitors for CRPA 1

Consider combinations only for:

• Pan-resistant organisms where cefiderocol MIC is elevated 1
• Severe infections with limited alternatives 1

Safety Profile and Adverse Events

Generally well-tolerated with gastrointestinal predominance:

• Most common: diarrhea, constipation, nausea, vomiting, upper abdominal pain 3, 4
• Lower nephrotoxicity compared to polymyxins 1
• Minimal metabolism (<10% of dose) 5
• No clinically significant drug-drug interactions with furosemide, metformin, or rosuvastatin 5

Critical Pitfalls and Caveats

Mortality signal in certain infections:

• Higher all-cause mortality observed in CREDIBLE-CR and APEKS-NP trials for pneumonia and bloodstream infections 3, 8
• FDA and European prescribing information include warnings about this mortality difference 6
• Reserve cefiderocol for patients with limited or no alternative treatment options 3

Susceptibility testing challenges:

• Commercial susceptibility tests have accuracy and reliability issues 6
• Results should be carefully evaluated and confirmed 6
• Iron-depleted media required for accurate MIC determination 5

Resistance development:

• Frequency of resistance at 10× MIC ranges from 10⁻⁶ to <10⁻⁸ 5
• Risk of treatment-emergent resistance with MBL-producing organisms requires monitoring 1
• High MIC values in some MBL-producers may predict treatment failure 1

Antibiotic Stewardship Considerations

Reserve cefiderocol as a last-line agent:

• Avoid use for third-generation cephalosporin-resistant Enterobacterales (3GCephRE) when other options exist 1
• For non-severe CRE infections, consider older antibiotics active in vitro first 1
• New β-lactam/β-lactamase inhibitors are reserved antibiotics; use judiciously 1