How well does cefiderocol cover Pseudomonas aeruginosa?

Cefiderocol Coverage of Pseudomonas aeruginosa

Cefiderocol demonstrates excellent in vitro activity against Pseudomonas aeruginosa, including multidrug-resistant and carbapenem-resistant strains, with 97-98% susceptibility rates, making it a valuable treatment option for difficult-to-treat resistant infections. 1, 2

In Vitro Activity Against P. aeruginosa

Cefiderocol shows robust microbiological activity against P. aeruginosa across resistance phenotypes:

• 97.9% of multidrug-resistant (MDR) P. aeruginosa isolates remain susceptible to cefiderocol (MIC ≤4 μg/mL) 1
• 97.4% of extensively drug-resistant (XDR) P. aeruginosa isolates remain susceptible to cefiderocol 1
• 98.3% overall susceptibility was demonstrated in a large surveillance study of 1,050 highly antimicrobial-resistant P. aeruginosa isolates 1
• Cefiderocol maintains activity against isolates resistant to ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-relebactam 1
• Among carbapenem-resistant P. aeruginosa (CR-Pa) isolates in Germany, only 8.3% (9/108) showed cefiderocol resistance 2

Mechanism Explaining Broad Coverage

Cefiderocol's unique properties enable it to overcome common P. aeruginosa resistance mechanisms:

• Active transport via iron uptake systems allows cefiderocol to bypass porin channel loss (OprD deletions), which typically confers carbapenem resistance 3, 4
• Stability against multiple β-lactamases including AmpC, extended-spectrum β-lactamases (ESBLs), and both serine- and metallo-carbapenemases (VIM, IMP, GES) 3, 4
• Resistance to efflux pump upregulation (MexAB-OprM, MexCD-OprJ, MexEF-OprN, MexXY) maintains periplasmic drug concentrations 3, 4
• The siderophore-like catechol moiety enables iron-mediated active transport across the bacterial outer membrane 5

Clinical Guideline Recommendations

For difficult-to-treat resistant P. aeruginosa (DTR-PA), cefiderocol is recommended as a potential alternative when first-line agents are not suitable:

• Ceftolozane-tazobactam and ceftazidime-avibactam remain first-line options for DTR-PA based on stronger clinical evidence 6
• Cefiderocol is positioned as an alternative option alongside imipenem-relebactam and colistin-based therapy 6
• This recommendation carries STRONG strength but MODERATE certainty of evidence 6
• European guidelines note very-low-certainty evidence for non-inferiority of cefiderocol compared with best available therapy for carbapenem-resistant P. aeruginosa 7

Clinical Outcomes Data

Real-world clinical experience supports cefiderocol's effectiveness:

• In the compassionate use program, clinical response rates were 69% for isolates with MIC ≤1 μg/mL and 69% for isolates with MIC 2-4 μg/mL 8
• 28-day mortality was 23% for MIC ≤1 μg/mL and 33% for MIC 2-4 μg/mL, with no statistically significant difference 8
• Patients with cefiderocol MICs of 2-4 μg/mL did not have significantly worse outcomes than those with MICs ≤1 μg/mL 8
• 80% of P. aeruginosa isolates in the compassionate use program were not susceptible to ceftolozane-tazobactam, highlighting cefiderocol's role for salvage therapy 8

Breakpoint Considerations

Two different susceptibility breakpoints exist, affecting interpretation:

• FDA breakpoint: susceptible ≤1 μg/mL results in 63% susceptibility classification 8
• CLSI breakpoint: susceptible ≤4 μg/mL results in 91% susceptibility classification 8
• Clinical outcomes data suggest the CLSI breakpoint may be more clinically relevant, as isolates with MICs 2-4 μg/mL showed similar response rates to those ≤1 μg/mL 8

Resistance Development Risk

The risk of treatment-emergent resistance appears low but requires monitoring:

• Frequency of resistance development in P. aeruginosa exposed to 10× MIC ranged from 10⁻⁶ to <10⁻⁸ 3
• Among CR-Pa isolates without prior cefiderocol exposure, resistance prevalence was only 8.3% 2
• Resistance mechanisms when present involve mutations in iron uptake systems (fptA, fpvB, chtA), efflux pumps, AmpC β-lactamase, and penicillin-binding proteins 2
• Notably, the presence of carbapenemases does not correlate with cefiderocol resistance 2

Combination Therapy Considerations

Monotherapy is generally preferred when P. aeruginosa is susceptible to cefiderocol:

• Guidelines do not recommend for or against combinations with new β-lactam/β-lactamase inhibitors for carbapenem-resistant P. aeruginosa 7
• In vitro studies show no antagonism between cefiderocol and other antipseudomonal agents (amikacin, meropenem, colistin, ciprofloxacin) 3
• The role of combination therapy remains undefined and should be considered case-by-case with infectious diseases consultation 6

Critical Caveats

• Cefiderocol should be reserved as a last-line agent and avoided for third-generation cephalosporin-resistant Enterobacterales when other options exist 7
• Testing must be performed in iron-depleted cation-adjusted Mueller-Hinton broth to obtain accurate MIC values 2
• Cross-resistance with other antibacterial classes has not been identified, so isolates resistant to other agents may remain susceptible to cefiderocol 3
• Cefiderocol has no clinically relevant activity against Gram-positive bacteria or anaerobes 3