Running Title: Enterococcal Infective Endocarditis 1 2 Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin 3 against Biofilm-forming Enterococcus faecalis or E. faecium in an In Vitro 4 Pharmacodynamic Model using Simulated Endo

Abstract Enterococci are the third most frequent cause of infective endocarditis. A high-24 inoculum stationary phase in vitro pharmacodynamic model with simulated endocardial 25 vegetations was used to simulate human pharmacokinetics of daptomycin 6 or 10mg/kg/day, 26 or linezolid 600mg q12h alone and in combination with gentamicin 1.3mg/kg q12h, rifampin 27 300mg q8h or 900mg q24h. Biofilm-forming vancomycin-susceptible Enterococcus faecalis 28 and vancomycin-resistant E. faecium (VRE) were tested. At 24, 48 and 72h, all daptomycin-29 containing regimens demonstrated significantly more activity (decline in CFU/g) than any 30 linezolid-containing regimen against biofilm-forming E. faecalis. The addition of gentamicin 31 to daptomycin (6 and 10mg/kg) in the first 24 hours significantly improved the bactericidal 32 activity. In contrast, addition of rifampin delayed the bactericidal activity of daptomycin 33 against E. faecalis; and against VRE, antagonized all regimens at 24h. Also, against VRE, 3