Blanco Martín, TaniaAlonso-García, IsaacGonzález-Pinto, LucíaOuteda-García, MichelleGuijarro-Sánchez, PaulaLópez-Hernández, InmaculadaPérez-Vázquez, MaríaAracil, BelénLópez-Cerero, LorenaFraile-Ribot, Pablo ArturoOliver, AntonioVázquez-Ucha, Juan CarlosBeceiro Casas, AlejandroBou, GermánArca-Suárez, Jorge2025-01-292025-01-292024-04-16Blanco-Martín T, Alonso-García I, González-Pinto L, Outeda-García M, Guijarro-Sánchez P, López-Hernández I, Pérez-Vázquez M, Aracil B, López-Cerero L, Fraile-Ribot P, Oliver A, Vázquez-Ucha JC, Beceiro A, Bou G, Arca-Suárez J; GEMARA/SEIMC-CIBERINFEC Study Group on the activity and resistance mechanisms to new β-lactams and β-lactamase inhibitors (PROTECT). Activity of cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double β-lactamases under high and low permeability conditions. Int J Antimicrob Agents. 2024 May;63(5):107150.0924-8579http://hdl.handle.net/2183/40944[Abstract] Objectives: To analyse the impact of the most clinically relevant β-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. Methods: We constructed 82 E. coli laboratory transformants expressing the main β-lactamases circulating in Enterobacterales (70 expressing single β-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. Results: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of β-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. Conclusions: Our findings highlight the promising activity that cefiderocol and new β-lactam/β-lactamase inhibitors have against recombinant E. coli strains expressing widespread β-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.engCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC-BY-NC-ND 4.0)http://creativecommons.org/licenses/by-nc-nd/3.0/es/CefiderocolDouble-carbapenemaseEscherichia coliPermeabilityβ-lactam/β-lactamase inhibitor combinationsβ-lactamasesjournal articleopen access10.1016/j.ijantimicag.2024.107150