A two-year, 14-hospital Italian investigation of multi-carbapenemase-producing Klebsiella pneumoniae found extensive resistance and genomic diversity across isolates. Despite that variability, aztreonam/avibactam and cefepime/zidebactam retained full in vitro activity, while aztreonam-based combinations showed consistent synergy against metallo-beta-lactamase producers. The data helps clinicians and antimicrobial stewardship teams prioritize combination regimens in high-resistance, high-diversity settings where empirical choices often fail against emergent resistance mechanisms.