Background/Objectives: Carbapenem-resistant Klebsiella pneumoniae (CRKp) remains a critical driver of antimicrobial resistance (AMR) in hospital settings worldwide. Methods: This study examined trends in CRKp bloodstream infections over a seven-year period (2019–2025) in a tertiary care hospital in Greece, with particular attention given to resistance patterns and patient outcomes, including the impact of the COVID-19 pandemic. Results: A total of 671 non-duplicate CRKp isolates were analyzed and classified into three groups: KPC producers (67.4%), dual carbapenemase producers (dual CP) (17.4%), and single metallo-β-lactamase (MBL) producers (15.2%). Overall incidence showed a slight but non-significant increase over time. KPC-producing strains rose significantly until 2022 (p < 0.001), followed by a marked decline (p < 0.001). In contrast, dual CPs—mainly KPC combined with VIM or NDM—and single-MBL producers, particularly NDM, increased steadily, indicating a notable epidemiological shift. Resistance to aminoglycosides and tigecycline increased around 2021, followed by partial declines, whereas colistin resistance demonstrated a continuous upward trend throughout the study period. Despite phenotypic differences, overall mortality remained high, with no statistically significant differences between groups (p = 0.37), likely reflecting either the severity of patients’ clinical condition or inadequate empirical antibiotic therapy. Conclusions: This study highlights a dynamic evolution in CRKp epidemiology with decreasing KPC dominance and increasing prevalence of MBL- and dual CP strains. This transition, which became evident during and after the COVID-19 pandemic, underscores ongoing epidemiological adaptation and the urgent need for improved antimicrobial stewardship, rapid diagnostics, and broader access to effective therapies.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKp) remains a critical driver of antimicrobial resistance (AMR) in hospital settings worldwide. Methods: This study examined trends in CRKp bloodstream infections over a seven-year period (2019–2025) in a tertiary care hospital in Greece, with particular attention to resistance patterns and patient outcomes, including the impact of the COVID-19 pandemic. Results: A total of 671 non-duplicate CRKp isolates were analyzed and classified into three groups: KPC producers (67.4%), dual carbapenemase producers (17.4%), and single metallo-β-lactamase (MBL) producers (15.2%). Overall incidence showed a slight but non-significant increase over time. KPC-producing strains rose significantly until 2022 (p<0.001), followed by a marked decline (p<0.001). In contrast, dual carbapenemase producers—mainly KPC combined with VIM or NDM—and single-MBL producers, particularly NDM, increased steadily, indicating a notable epidemiological shift. Resistance to aminoglycosides and tigecycline increased around 2021, followed by partial declines, whereas colistin resistance demonstrated a continuous upward trend throughout the study period. Despite phenotypic differences, overall mortality remained high, with no statistically significant differences between groups (p = 0.37), likely reflecting either the severity of patients’ clinical condition or inadequate empirical antibiotic therapy. Conclusions: This study highlights a dynamic evolution in CRKp epidemiology with decreasing KPC dominance and increasing prevalence of MBL- and dual carbapenemase- producing strains. This transition, which became evident during and after the COVID-19 pandemic, underscores ongoing epidemiological adaptation and the urgent need for improved antimicrobial stewardship, rapid diagnostics, and broader access to effective therapies.