Time-kill and synergism studies of ceftobiprole against Enterococcus faecalis, including β-lactamase-producing and vancomycin-resistant isolates

Ceftobiprole (BAL9141) is an investigational cephalosporin with broad in vitro activity against grampositive cocci, including enterococci. Ceftobiprole MICs were determined for 93 isolates of Enterococcus faecalis (including 16 beta-lactamase [Bla] producers and 17 vancomycin-resistant isolates) by an agar dilution method following the Clinical and Laboratory Standards Institute recommendations. Ceftobiprole MICs were also determined with a high inoculum concentration (10(7) CFU/ml) for a subset of five Bla producers belonging to different previously characterized clones by a broth dilution method. Time-kill and synergism studies (with either streptomycin or gentamicin) were performed with two beta-lactamase-producing isolates (TX0630 and TX5070) and two vancomycin-resistant isolates (TX2484 [VanB] and TX2784 [VanA]). The MICs of ceftobiprole for 50 and 90% of the isolates tested were 0.25 and 1 mu g/ml, respectively. All Bla producers and vancomycin-resistant isolates were inhibited by concentrations of <= 1 and <= 4 mu g/ml, respectively, at the standard inoculum concentration. Ceftobiprole MICs at a high inoculum concentration for a subset of five Bla(+) E. faecalis isolates were <= 1 mu g/ml. Bactericidal activity was observed against four isolates tested at concentrations as low as 1 mu g/ml regardless of the production of beta-lactamase or vancomycin resistance. A combination of ceftobiprole (0.5 mu g/ml) and streptomycin (25 mu g/ml) was synergistic against Bla(+) TX0630 and TX5070. Ceftobiprole (0.5 mu g/ml) plus gentamicin (10 mu g/ml) was synergistic against VanB isolate TX2484 and showed enhanced killing, but not synergism, against TX2784 (VanA), despite the absence of high-level resistance to gentamicin. In conclusion, ceftobiprole exhibited good in vitro activity against E.faecalis, including Bla(+) and vancomycin-resistant strains, and exhibited synergism with aminoglycosides against selected isolates.