Enterococcus faecium strains are commonly resistant to
vancomycin and β-
lactams. In addition, E. faecium often causes biofilm-associated
infections and these
infections are difficult to treat. In this context, we investigated the activity of dosing regimens using
daptomycin (DAP) (8, 10, 12, and 14 mg/kg of
body weight/day) alone and in combination with
ceftaroline (
CPT),
ampicillin (
AMP),
ertapenem (ERT), and
rifampin (RIF) against 2 clinical strains of biofilm-producing
vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to
CPT,
AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human
antibiotic exposures) were used with
titanium and
polyurethane coupons to evaluate the efficacy of
antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus
CPT improved killing, they did not reach bactericidal reduction against S447. Combination of
AMP,
CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with
AMP, ERT,
CPT, and RIF in
infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.