Paradoxical interaction between dalbavancin and β-lactams against endocarditis-associated Enterococcus faecalis clinical isolates.

Abstract

Background: There are limited in vitro synergistic studies on dalbavancin against enterococci. We aimed to assess the in vitro activity of dalbavancin against Enterococcus faecalis strains, and to explore the interaction between dalbavancin and β-lactams.

Methods: MIC and MBC values were determined against a panel of 10 clinical isolates and two reference strains of E. faecalis. Checkerboard assays were conducted for the initial screening for additive, synergistic or antagonistic effect between dalbavancin and different classes of antibiotics. Thereafter, time-kill (TK) assays with β-lactams were performed to confirm the results.

Results: All strains were tolerant to dalbavancin (MBC/MIC ratios >32). For 11 of the 12 strains tested, a synergy was found in TK assays between dalbavancin (0.5 × MIC) and each β-lactam (0.25 × MIC), namely amoxicillin, cefazolin, ceftriaxone, cefepime, ceftobiprole, ertapenem and meropenem. Paradoxically, we systematically found reduced efficacy of β-lactams in combination with dalbavancin at concentrations greater than or equal to MIC. At these concentrations, TK assays demonstrated that a combination with dalbavancin resulted in an antagonism of amoxicillin (8/12 strains), ceftobiprole (10/12 strains) and ertapenem (5/12 strains) activities. Dalbavancin alone at 32 mg/L or in combination with amoxicillin at 2 mg/L induced a slow bacterial reduction (median decrease of 0.4 log10 at 24 h for both regimens), whereas amoxicillin alone at 2 mg/L reduced the E. faecalis inoculum by 3.2 log10 (IQR, 3.1-3.4).

Conclusions: Dalbavancin exhibits poor activity against E. faecalis, and impairs the activity of β-lactams, especially amoxicillin. Dalbavancin should be used with caution in the treatment of E. faecalis infective endocarditis.