Objective: Israeli hospitals were confronted with a major national outbreak of carbapenemase-producing Enterobacterales (CPE) starting in 2006, caused predominantly by monoclonal Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae. Our hospital, Rambam Health Care Campus (RHCC), was one of the medical centers affected by this outbreak. We aimed to investigate the changing epidemiology of CPE at RHCC since 2006. Methods: This was a retrospective observational cohort study performed in Northern Israel (Haifa) at RHCC, which is a primary tertiary acute care academic hospital. The study included all patients who had acquired CPE at RHCC between January 2005 and December 2020. Results: The proportion of patients infected with K. pneumoniae dropped from 100% of all CPE in the first years to 28% (37/134) in 2020. In 2014, the carbapenemase in 94% of all CPE patients (89/95) was KPC. This decreased to 56% in 2020, while New Delhi metallo-β-lactamase (NDM) and OXA-48 carbapenemases increased from 4% and 2% to 29% (39/134) and 12.7% (17/134) of CPE, respectively. Conclusions: The CPE epidemic evolved from KPC-producing K. pneumoniae to involve different Enterobacterales and carbapenemases. Our results are a microcosm of the current global epidemiology attesting to globalization in bacteriology. The results have implications for infection control and antibiotic treatment of CPE infections.