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An experimental study was performed to evaluate both in vitro and in vivo the kind of interaction between the Laur-CKK-NH2 dimer and daptomycin using two Enterococcus faecalis strains with different patterns of susceptibilities.We evaluated whether selection for daptomycin-resistant E. faecalis could be prevented in vitro by combining daptomycin with the Laur-CKK-NH2 dimer. The strains were serially exposed in broth to 2-fold stepwise increasing concentrations of daptomycin alone or in combination with a fixed concentration (0.25× MIC) of the Laur-CKK-NH2 dimer. We also performed an in vitro synergy study. For in vivo studies, a mouse model of enterococcal sepsis was used.In vitro experiments: exposure to daptomycin alone gradually selected for enterococci with increased MICs; and the Laur-CKK-NH2 dimer showed a positive interaction with daptomycin and was able to prevent the resistance. In vivo experiments: the main outcome measures were lethality and quantitative blood cultures; and the Laur-CKK-NH2 dimer combined with daptomycin exhibited the highest efficacy for all main outcome measurements.These results highlight the potential usefulness of combining daptomycin with the Laur-CKK-NH2 dimer. The combination provides a future therapeutic alternative for the treatment of enterococcal severe infections.