Carbapenemase-producing Enterobacteriaceae (CPE) has spread worldwide becoming a threat to public health. However, no randomized clinical trials about the efficacy of optimizing antibiotic treatment have been published. Experimental studies have been designed to find combinations of antibiotics with synergistic activity. Their main aim has been increasing the speed of bacterial destruction and decreasing resistance. The latest guidelines recommend combination therapy. The carbapenems has been chosen as the basis of such therapy. We face limited therapeutic options. Polymyxins, fosfomycin and gentamicin have reemerged in this context, becoming the basis of multiple combination regimens, with beneficial effects both in vitro and in murine models of infection.