Activity of cefiderocol against <i>Pseudomonas aeruginosa</i> from the USA and Europe (2020–2023) with difficult-to-treat resistance phenotype, including those nonsusceptible to recently developed β-lactam/β-lactamase inhibitor combinations: results

Cefiderocol and the β-lactam/β-lactamase inhibitor (BL-BLI) combinations ceftazidime-avibactam (CAZ-AVI), imipenem-relebactam (IMI-REL), and ceftolozane-tazobactam (TOL-TAZ) are recommended for the treatment of difficult-to-treat resistance (DTR) <i>Pseudomonas aeruginosa</i> by IDSA guidelines. The activity of cefiderocol and the three BL-BLI combinations described above was examined against DTR <i>P. aeruginosa</i> and molecularly characterized subsets collected from the USA and Europe (2020-2023). Approximately 4% of isolates showed a DTR phenotype, and cefiderocol remained active against 98.1% (CLSI breakpoint) of these isolates, whereas the three BL-BLI combinations had susceptibilities of 52.3%-56.0%. A total of 63% of DTR isolates were nonsusceptible to ≥1 of these BL-BLI combinations, and cefiderocol was active against ≥95.5% (CLSI) of these isolates, regardless of the nonsusceptible phenotype(s) to these combinations. In contrast, susceptibilities of the BL-BLI combinations varied from 0.0% to 30.3%. Almost 20% of DTR isolates carried carbapenemases, mostly metallo-β-lactamases, represented by 14 different STs from 15 countries. Cefiderocol had MIC_50/90 of 0.25/2 mg/L against these carbapenemase-carrying DTR isolates and 97.3% (CLSI) of the isolates were susceptible to cefiderocol, whereas <6% of these isolates were susceptible to any of the BL-BLI combinations. MIC_50/90 of cefiderocol against the non-carbapenemase DTR subset was 0.12/1 mg/L, and 98.3% (CLSI) of the isolates were susceptible to cefiderocol, vs 63.7%-69.6% for the BL-BLI combinations. Cefiderocol demonstrated high activity against a large and contemporary collection of DTR <i>P. aeruginosa</i>, regardless of carbapenemase status. The three currently recommended BL-BLI combinations for treating certain <i>P. aeruginosa</i> infections demonstrated limited activity and high degree of cross-resistance.IMPORTANCECefiderocol and the β-lactam/β-lactamase inhibitor (BL-BLI) combinations ceftazidime-avibactam (CAZ-AVI), imipenem-relebactam (IMI-REL), and ceftolozane-tazobactam (TOL-TAZ) are recommended for the treatment of difficult-to-treat resistance (DTR) <i>Pseudomonas aeruginosa</i> by IDSA guidelines. However, this study shows that cefiderocol demonstrated high activity against a large collection of <i>P. aeruginosa</i>, including DTR isolates. In contrast, the three currently recommended BL-BLI combinations had limited activity, especially against isolates carrying carbapenemase genes, and high degree of cross-resistance. Cefiderocol also sustained activity against a diverse array of isolates with various BL-BLI nonsusceptible phenotypes, and regardless of carbapenemase status. These findings support the use of cefiderocol as a first treatment option for infections caused by DTR <i>P. aeruginosa</i>.