Activity of aztreonam-avibactam, cefiderocol, and cefepime-taniborbactam against a global collection of genetically characterized metallo-β-lactamase-producing Enterobacterales

We evaluated the activity of aztreonam-avibactam and comparators tested against 490 MBL-producing Enterobacterales isolates collected in 27 countries during 2019-2022. The most common MBL was NDM-1, which was detected among 307 isolates. The genes encoding NDM-5 and VIM-1 were detected among 68 and 53 isolates, respectively. Other 14 MBL-encoding genes or combinations were detected among 62 isolates. Mexico, Turkey, and Greece had the highest number of isolates (60, 59, and 57, respectively). All isolates were susceptible to aztreonam-avibactam (MIC_50/90, 0.12/0.5 mg/L) when applying the EUCAST or FDA recently approved breakpoints (≤4 mg/L susceptible). Cefiderocol inhibited 66.7%/90.8% of the isolates when using EUCAST/FDA breakpoints. Cefepime-taniborbactam was active against 36.7%/55.5% of the isolates using the cefepime breakpoint for comparison purposes. Tigecycline and colistin inhibited 94.1% and 76.6% of the isolates (FDA and EUCAST breakpoints, respectively). The analysis of resistance mechanisms and genetic background of the MBL-producing isolates demonstrated genetic diversity among main species and presence of multiple resistance mechanisms including Other β-lactamases, porin changes, and disruptions of efflux pump repressors. Aztreonam-avibactam was active despite the presence of these additional resistance mechanisms, but cefiderocol and cefepime-taniborbactam displayed variable activity. PBP3 YRIN and YRIK insertions were observed among 30 MBL-producing E. coli isolates. Aztreonam-avibactam MIC values ranged from 0.03 to 4 mg/L for these isolates, including an isolate carrying bla_NDM-7, bla_CMY-42, and porin changes. MBL-producing organisms are still considered an unmet medical need. Aztreonam-avibactam was active against this large collection of MBL-producing isolates that had elevated MIC values for many comparator agents.

Enterobacterales; metallo-β-lactamases; new antimicrobial agents; resistance mechanisms; susceptibility.