Aztreonam-avibactam (ATM-AVI) is one of the few remaining therapeutic options for infections caused by metallo-β-lactamase (MBL)-producing Enterobacterales, yet resistance is increasingly reported. Alternative strategies are therefore critically needed. We investigated the in vitro activity of aztreonam in combination with three marketed β-lactamase inhibitors (avibactam, vaborbactam, relebactam) against 48 well-characterized ATM-resistant MBL-producing Escherichia coli, including 34 ATM-AVI-resistant isolates. Among ATM-AVI-susceptible isolates, ATM-relebactam and ATM-vaborbactam showed reduced activity compared with ATM-AVI (MIC_50/90 1/4 mg/L), with MIC_50/90 values of 8/64 mg/L and 64/256 mg/L, respectively. Among ATM-AVI-resistant isolates, none of the combinations restored aztreonam susceptibility. CMY-type enzymes seem to play a pivotal role in the failure of both relebactam and vaborbactam to restore aztreonam susceptibility in our collection of isolates.