Blanco Martín, TaniaLópez-Hernández, InmaculadaAracil, BelénGonzález-Pinto, LucíaAja-Macaya, PabloAlonso-García, IsaacRodríguez-Pallares, SaludSánchez-Peña, LucíaOuteda-García, MichellePérez-Vázquez, MaríaVázquez-Ucha, Juan CarlosBeceiro Casas, AlejandroPascual, ÁlvaroBou, GermánLópez-Cerero, LorenaOteo, JesúsArca-Suárez, Jorge2025-04-212025-04-212024-10-09Blanco-Martín T, López-Hernández I, Aracil B, González-Pinto L, Aja-Macaya P, Alonso-García I, Rodríguez-Pallares S, Sánchez-Peña L, Outeda-García M, Pérez-Vázquez M, Vázquez-Ucha JC, Beceiro A, Pascual Á, Bou G, López-Cerero L, Oteo-Iglesias J, Arca-Suárez J; GEMARA-SEIMC/CIBERINFEC Study Group on the activity and resistance mechanisms to new β-lactams and β-lactamase inhibitors (PROTECT). Assessment of the activity and mechanisms of resistance to cefiderocol and combinations of β-lactams and the novel β-lactamase inhibitors avibactam, taniborbactam, zidebactam, nacubactam, xeruborbactam, and ANT3310 in emerging double-carbapenemase-producing Enterobacterales. Antimicrob Agents Chemother. 2024 Nov 6;68(11):e0092424.0066-4804http://hdl.handle.net/2183/41794[Abstract] We aimed to investigate the activity of and mechanisms of resistance to cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations in a nationwide collection of double-carbapenemase-producing Enterobacterales. In all, 57 clinical isolates co-producing two carbapenemases collected from Spanish hospitals during the period 2017-2022 were analyzed. Minimum inhibitory concentration (MIC) values for ceftazidime, ceftazidime/avibactam, aztreonam, aztreonam/avibactam, aztreonam/nacubactam, cefiderocol, cefepime, cefepime/taniborbactam, cefepime/zidebactam, cefepime/nacubactam, imipenem, imipenem/relebactam, meropenem, meropenem/vaborbactam, meropenem/xeruborbactam, and meropenem/ANT3310 were determined by reference broth microdilution. Genetic drivers of resistance were analyzed by whole-genome sequencing (WGS). The collection covered nine carbapenemase associations: VIM + OXA-48 (21/57), NDM + OXA-48 (11/57), KPC + VIM (10/57), KPC + OXA-48 (6/57), IMP + OXA-48 (3/57), NDM + KPC (2/57), NDM + VIM (2/57), NDM + GES (1/57), and KPC + IMP (1/57). Ceftazidime/avibactam, imipenem/relebactam, and meropenem/vaborbactam were the least active options. Aztreonam/avibactam and aztreonam/nacubactam were active against the whole collection and yielded MIC50/MIC90 values of ≤0.25/0.5 mg/L and 1/2 mg/L, respectively. Cefepime/zidebactam (56/57 susceptible), meropenem/xeruborbactam (56/57 susceptible), cefepime/nacubactam (55/57 susceptible), and cefiderocol (53/57 susceptible) were also highly active, with MIC50/MIC90 values ranging from ≤0.25-2 mg/L to 2-4 mg/L, respectively. Meropenem/ANT3310 (MIC50/MIC90 = 0.5/≥64 mg/L; 47/57 susceptible) and cefepime/taniborbactam (MIC50/MIC90 = 0.5/16 mg/L; 44/57 susceptible) also retained high levels of activity, although they were affected by NDM-type enzymes in combination with porin deficiency. Our findings highlight that cefiderocol and combinations of β-lactams and the novel β-lactamase inhibitors avibactam, nacubactam, taniborbactam, zidebactam, xeruborbactam, and ANT3310 show promising activity against double-carbapenemase-producing Enterobacterales.engCreative Commons Attribution 4.0 International License (CC-BY 4.0)http://creativecommons.org/licenses/by/3.0/es/EnterobacteralesAntimicrobial resistanceCarbapenemaseCefiderocolDouble carbapenemaseβ-lactamaseβ-lactamase inhibitorjournal articleopen access10.1128/aac.00924-24