Synergistic but clinically unattainable: amoxicillin/ceftriaxone combination against ampicillin-susceptible Enterococcus faecium

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BACKGROUND: Infective endocarditis (IE) is a severe infection requiring efficient, sometimes combined, antibiotic therapy. For β-lactam-susceptible Enteroccus spp., particularly Enterococcus faecalis (EFS), the combination of amoxicillin and ceftriaxone is currently recommended. However, limited data are available for ampicillin-susceptible E. faecium strains (EFM-S). OBJECTIVES: To characterize the in vitro synergy of amoxicillin/ceftriaxone combination against clinical isolates of EFM-S and evaluate its clinical relevance. METHODS: Twenty-six EFM-S and 10 EFS clinical isolates from the Henri Mondor Hospital (Créteil, France) were tested. EFM-S clades were previously determined by whole-genome sequencing. Checkerboard assays were performed to assess the MICs and synergy across a range of amoxicillin and ceftriaxone concentrations. The fractional inhibitory concentration (FIC) index was computed for each combination, with synergy defined as ΣFIC ≤ 0.5. RESULTS: Amoxicillin and ceftriaxone MIC distributions were comparable between EFM-S (amoxicillin, 0.06-2 mg/L; ceftriaxone, 1 to ≥1024 mg/L) and EFS (amoxicillin, 0.5-2 mg/L; ceftriaxone, 64 to ≥1024 mg/L). Synergy was observed in 21/26 EFM-S and all EFS strains. The five non-synergistic EFM-S strains had low ceftriaxone MICs (1-16 mg/L), probably limiting synergy detection. No difference was observed according to EFM clades. The minimal synergistic concentrations were consistently higher for EFM-S (median amoxicillin, 0.125 mg/L; ceftriaxone, 32 mg/L) compared to EFS (amoxicillin, 0.03 mg/L; ceftriaxone, 2 mg/L). CONCLUSIONS: Despite in vitro synergy, the amoxicillin/ceftriaxone combination is clinically irrelevant for EFM-S IE due to unachievable drug concentrations in vivo. These findings support clearer guidelines explicitly excluding this regimen for E. faecium, regardless of β-lactam susceptibility.

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