| Summary: | Objectives: The ceragenins, or CSAs, were designed to mimic the activities of antimicrobial peptides and represent a new class of antimicrobial agent. The aim of this study was to comparatively investigate the antimicrobial activities of first/second generation ceragenins and various antibiotics against multidrug-resistant (MDR) <i>Klebsiella pneumoniae</i>, including colistin-resistant bacteria. Also, the synergistic effects of two ceragenins with colistin or meropenem were investigated with six <i>K. pneumoniae</i> strains presenting different resistant patterns. Methods: Minimal inhibition concentrations (MICs) were determined by the microdilution method according to the CLSI. Antibiotic combination studies were evaluated by the time−kill curve method. Results: MIC<sub>50</sub> and MIC<sub>90</sub> values of tested ceragenins ranged from 8 to 32 mg/L and 16 to 128 mg/L. Overall, among the ceragenins tested, CSA-131 showed the lowest MIC<sub>50</sub> and MIC<sub>90</sub> values against all microorganisms. The MICs of the ceragenins were similar or better than tested antibiotics, except for colistin. Synergistic activities of CSA-131 in combination with colistin was found for strains both at 1× MIC and 4× MIC. No antagonism was observed with any combination. Conclusions: First-generation ceragenins CSA-13 and CSA-44 and second-generation ceragenins CSA-131, CSA-138 and CSA-142 have significant antimicrobial effects on MDR <i>K. pneumoniae</i>. Mechanisms allowing resistance to clinical comparator antibiotics like colistin did not impact the activity of ceragenins. These results suggest that ceragenins may play a role in treating infections that are resistant to known antibiotics.
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