Carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections present significant therapeutic challenges and high mortality rates. Outer membrane vesicles (OMVs), secreted by Gram-negative bacteria, play a pivotal role in modulating host-pathogen interactions. This study investigates the contribution of CRKP OMVs to invasive infections and the impact of antibiotic misuse on OMV dynamics. CRKP OMVs significantly promote bacterial invasion into the bloodstream by inducing excessive pyroptosis via Gasdermin D (GSDMD) cleavage, compromising local immune defenses, and amplifying pro-inflammatory responses. Antibiotic treatments, including carbapenems and aztreonam, exacerbated infections by enhancing OMV production, leading to increased mortality in murine models. The inhibition of GSDMD-mediated pyroptosis using disulfiram markedly improved survival rates, highlighting a potential therapeutic target. These findings underscore the dual role of CRKP OMVs as infection accelerators and inflammatory mediators, offering critical insights into optimizing antimicrobial strategies against multidrug-resistant infections.