Abstract
Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis. Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis. Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm2 reduction. Results: Daptomycin bMICs were 2–8-fold higher than BMD. In the presence of other antimicrobials, daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981. Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response.
Highlights
E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis)
In the presence of ampicillin, ceftriaxone, fosfomycin, or rifampin, daptomycin biofilm Minimum inhibitory concentrations (MIC) decreased 16-fold, 4–8-fold, 8–32-fold, and 4–16-fold, respectively, often reducing the daptomycin bMIC to values that would be susceptible in Broth microdilution (BMD) testing (Table 1)
Against the daptomycin non-susceptible mutant E. faecium strain (E. faecium 5938), synergistic activity with daptomycin plus either ampicillin or ceftriaxone combinations occurred, but the effect was less pronounced than the killing observed against the daptomycin susceptible parent strain
Summary
E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms These combinations warrant further evaluation to determine the optimal dose and response. The resistance rates in enterococci, especially to vancomycin, are increasing, leaving few alternative therapeutic options Complicating matters further, both Enterococcus faecium and E. faecalis are capable of producing bacterial biofilm [2]. Biofilm formation encapsulates the organism, leading to an increased adherence to prosthetic material and the prevention of antimicrobial and host immune system penetration [3,4] These cells often display a decreased susceptibility to antimicrobials due to resistance mutations. Treatment failures are frequently observed with biofilm-associated medical device infections [5]
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