Contribution of mutational resistance mechanisms and acquired β-lactamases to cefiderocol/xeruborbactam susceptibility in Pseudomonas aeruginosa
Cefiderocol/xeruborbactam is a novel β-lactam/β-lactamase inhibitor combination in which the siderophore-cephalosporin cefiderocol is paired with xeruborbactam, a broad-spectrum inhibitor that targets class A to D β-lactamases. We evaluated the contribution of resistance mechanisms to cefiderocol/xe...
| Autores: | , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Conselleria de Salut i Consum del Govern de les Illes Balears |
| Repositorio: | Docusalut |
| Idioma: | inglés |
| OAI Identifier: | oai:docusalut.com:20.500.13003/26193 |
| Acceso en línea: | https://hdl.handle.net/20.500.13003/26193 |
| Access Level: | acceso abierto |
| Palabra clave: | Pseudomonas aeruginosa Cefiderocol beta-Lactams beta-Lactam Resistance beta-Lactamase Inhibitors beta-Lactamas Resistencia betalactámica Inhibidores de beta-Lactamasas cefiderocol mutational mechanisms taniborbactam xeruborbactam β-lactam β-lactam resistance β-lactamase β-lactamase inhibitor |
| Sumario: | Cefiderocol/xeruborbactam is a novel β-lactam/β-lactamase inhibitor combination in which the siderophore-cephalosporin cefiderocol is paired with xeruborbactam, a broad-spectrum inhibitor that targets class A to D β-lactamases. We evaluated the contribution of resistance mechanisms to cefiderocol/xeruborbactam susceptibility. A panel of 61 . PAO1 derivatives was tested, including 20 knockout mutants representing key chromosomal resistance mechanisms (e.g., overexpression, efflux upregulation, porin loss, iron uptake deficiency) and 41 transformants producing major circulating β-lactamases. Xeruborbactam was assessed in combination with cefiderocol and cefepime at 4 and 8 mg/L and compared with taniborbactam. Additionally, 99 cefiderocol-resistant clinical isolates were evaluated. Cefiderocol/xeruborbactam retained activity against most mutants with chromosomally encoded resistance mechanisms. However, the defective mutant yielded increased cefiderocol minimum inhibitory concentrations (MIC = 2 mg/L), which could not be restored by xeruborbactam. Xeruborbactam significantly increased the activity of cefiderocol against the majority of PAO1 transformants, including those producing PER-1, SHV-12, KPC Ω-loop mutants, or NDM variants. Cefiderocol/xeruborbactam was active against IMP-type MBLs (which only weakly hydrolyze cefiderocol), including xeruborbactam-resistant enzymes. Relative to taniborbactam, xeruborbactam-based combinations showed similar activity against PAO1 transformants, but with slightly higher MIC values when tested against metallo-β-lactamase producers. This MIC increase in xeruborbactam-based combinations was partly because of the constitutive MexAB-OprM efflux in the background, as confirmed with PAO1 efflux mutants. Importantly, xeruborbactam restored susceptibility in 78% of 99 cefiderocol-resistant strains, reducing the MIC from 64 to 4 mg/L. Cefiderocol/xeruborbactam shows promising activity against . |
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