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00925njm 22002777a 4500 dc Blanco-Martín, Tania author Alonso-García, Isaac author González-Pinto, Lucía author Outeda-García, Michelle author Guijarro-Sánchez, Paula author López-Hernández, Inmaculada author Perez-Vazquez, Maria author Aracil, Belen author López-Cerero, Lorena author Fraile-Ribot, Pablo author Oliver, Antonio author Vázquez-Ucha, Juan Carlos author Beceiro, Alejandro author Bou, Germán author Arca-Suárez, Jorge author GEMARA/SEIMC-CIBERINFEC Study Group on the activity and resistance mechanisms to new β-lactams and β-lactamase inhibitors (PROTECT) author 2024-05 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. Blanco-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. 10.1016/j.ijantimicag.2024.107150 1872-7913 International journal of antimicrobial agents 38513748 http://hdl.handle.net/20.500.12105/19906 β-lactamases Cefiderocol β-lactam/β-lactamase inhibitor Combinations Permeability Double-carbapenemase Escherichia coli 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