P2804 Alternative dual beta-lactam combinations for Enterococcus faecalis infective endocarditis Jaclyn Cusumano*1,2, Kathryn Daffinee1, Emily Bodo1,2, Kerry Laplante3,2,1,4

1 Providence VA Medical Center, Providence, United States, 2 College of Pharmacy , Kingston, United States, 3 Center of Innovation in Long-Term Support Services, Providence, United States, 4 Warren Alpert Medical School , Providence, United States Background: Dual beta-lactam therapy has emerged as a novel treatment strategy for Enterococcus faecalis infective endocarditis due to favorable side effect profiles and tolerability during long-term use compared to traditional beta-lactam plus aminoglycoside combinations. Ampicillin-ceftriaxone is the only guideline recommended dual beta-lactam for E. faecalis, but mortality rates still exceed 40%. Alternative dual beta-lactam combinations must be assessed and we sought to describe in vitro synergistic beta-lactam combinations against E. faecalis. Materials/methods: E. faecalis strain JH2-2 was utilized in a 24-hour time kill assay to detect dual beta-lactam synergy. Subinhibitory concentrations of a penicillin (ampicillin, penicillin, piperacillin, or nafcillin) or a carbapenem (ertapenem, imipenem, or meropenem) were combined with a cephalosporin (ceftriaxone, cefepime, or ceftaroline), as previously described, in order to detect synergy. Synergy was defined as a ≥2-log10 decrease in colony-forming units (CFU)/mL at 24 hours from the most active single agent. Antagonism was defined as a ≥2- log10 increase in CFU/mL at 24 hours from the most active single agent, and indifference was defined as any CFU/mL in between.

Table 1. JH2-2 24-hour time kill log10 CFU/mL decrease Ceftriaxone Cefepime Ceftaroline MIC 0.12x 0.25x 0.5x 0.12x 0.25x 0.5x 0.12x 0.25x 0.5x concentrations Ampicillin 3.48 3.94 2.98 2.03 4.31 3.54 2.17 4.42 3.32 Penicillin 0.47 0.41 -0.15 0.22 0.46 0.7 2.27 3.4 2.26 Piperacillin 0.72 1.31 2.14 0.1 0.24 1.31 0.42 0.39 0.78 Nafcillin 0.32 0.91 1.25 -0.08 0.11 0.33 0.25 0.4 0.04 Ertapenem 3.12 3.88 3.25 0.53 1.27 2.91 0.63 1.96 3.25 Imipenem 0.58 1.24 1.83 0.01 0.02 0.08 0.25 0.15 0.42 Meropenem 4.8 4.29 3.62 1.02 3.38 4.14 0.92 4.49 4.2 Results: In vitro synergy was detected for the standard of care ampicillin-ceftriaxone, which served as a control. Several other combinations described in Table 1, including ampicillin-cephalosporin combinations, penicillin- ceftaroline, piperacillin-ceftriaxone, ertapenem-cephalosporin, and meropenem-cephalosporin combinations, demonstrated in vitro synergy. All other combinations exhibited indifference. Conclusions: Demonstrated synergy between penicillin-ceftaroline, ertapenem-cephalosporin, and meropenem- cephalosporin combinations warrant further exploration to determine optimal dosing. Commonly described E. faecalis susceptible beta-lactams, penicillin and imipenem, did not consistently demonstrate in vitro synergy when combined with a cephalosporin and may not be safe regimens for patients.

29TH ECCMID 13-16 APRIL 2019 AMSTERDAM, NETHERLANDS POWERED BY M-ANAGE.COM