Klebsiella pneumoniae, a Gram-negative bacterium, poses a significant threat as a nosocomial pathogen due to its ability to rapidly develop resistance to various antibiotics. Gastrointestinal colonization by antibiotic-resistant strains among hospitalized patients not only increases the risk of nosocomial Klebsiella infections but also contributes to the dissemination of this pathogen within healthcare facilities. In this study, we investigate the efficacy of the bacteriocin KvarM in two different animal models to address K. pneumoniae sepsis and gut colonization. In our previous research, we characterized klebicin KvarM, a wide spectrum bacteriocin with activity against K. pneumoniae, K. quasipneumoniae, K. variicola, K. oxytoca, and K. aerogenes. Notably, KvarM exhibited significant activity against 85% of antibiotic-resistant clinical K. pneumoniae isolates. To assess the potential of KvarM in treating K. pneumoniae infections, we conducted experiments using murine models of sepsis and gastrointestinal colonization. In the sepsis model, mice were intraperitoneally infected with K. pneumoniae ATCC BAA 1705, and KvarM was administered intravenously either alone or in combination with meropenem. KvarM treatment resulted in a dose-dependent reduction in bacterial burden compared to the control group receiving the vehicle. Combination therapy with KvarM and meropenem exhibited superior efficacy compared to monotherapy with meropenem alone. For the gastrointestinal colonization model, we orally administered Eudragit®-coated KvarM to C57BL/6J mice after establishing colonization with K. pneumoniae strain ATCC 43816. The Eudragit coating protected KvarM from gastroduodenal proteases and enabled controlled release based on pH. Quantification of Klebsiella in fecal samples using the Klebsiella haemolysin gene (khe) as a marker revealed significant reductions in khe levels following treatment with Eudragit-coated KvarM, indicating a substantial decrease in K. pneumoniae gut colonization. In conclusion, our findings highlight the potential of bacteriocin KvarM as an intravenous treatment for K. pneumoniae sepsis. Moreover, orally administered KvarM, delivered using an Eudragit coating, shows promise as a preventive measure to target multidrug-resistant K. pneumoniae colonization in the gastrointestinal tract, potentially reducing the risk of infection and spread among hospitalized patients.