In Vitro Synergistic Effect of Lefamulin with Doxycycline, Rifampin, and Quinupristin/Dalfopristin Against Enterococci

The widespread resistance of enterococci to many commonly used antimicrobial agents is a growing concern. Given that the current treatment options for enterococcal infections are limited, the discovery of new therapies, including combination therapies, is necessary. We evaluated double-drug combinations of lefamulin with doxycycline, rifampin, and quinupristin/dalfopristin for in vitro synergy against strains of <i>Enterococcus faecium</i> (<i>E. faecium</i>) and <i>Enterococcus faecalis</i> (<i>E. faecalis</i>) by using checkerboard and time-kill assays. In the checkerboard assay, the synergistic effect of lefamulin with doxycycline and rifampin was observed in 29 (85.3%) and 33 (97.1%) of the 34 different <i>E. faecium</i> strains tested, respectively. These combinations also showed synergistic effects against 17 (94.4%) of the 18 different vancomycin-resistant <i>E. faecium</i> strains. Among the 33 different <i>E. faecalis</i> strains, the combination of lefamulin with doxycycline, quinupristin/dalfopristin, and rifampin displayed synergistic effects in 31 (93.9%), 26 (78.8%), and 20 (60.6%) strains, respectively. No antagonism was observed in any of the combinations. The time-kill assay confirmed the synergistic effects of all these combinations. These synergistic combinations exhibited bacteriostatic activity. Although lefamulin is not currently used to treat enterococcal infections, we suggest that these combinations may serve as alternative drug regimens.