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.

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.