Treatment of high-level gentamicin-resistant Enterococcus faecalis endocarditis with daptomycin plus ceftaroline

Abstract

A recurrent case of left-sided endocarditis caused by high-level aminoglycoside-resistant Enterococcus faecalis was successfully treated with ceftaroline and daptomycin. This combination demonstrated excellent synergy in vitro. Mechanistically, ceftaroline enhanced binding of daptomycin to the cell membrane and sensitized E. faecalis to killing by human cathelicidin LL-37, a cationic innate host defense peptide. Daptomycin plus ceftaroline may be considered in salvage therapy in E. faecalis endovascular infections and requires further study.

Figures

Fig 1

(A and B) Time-kill assays (24 h) in Mueller-Hinton broth supplemented to 50 mg/liter Ca2+, evaluating the activity of daptomycin (DAP) alone or with ceftaroline (CPT) (A) or ampicillin (AMP) (B) against E. faecalis. (C and D) Results of similar experiments, showing an effect of AMP with either ceftriaxone (CRO) or CPT (C) and vancomycin (VAN) with CPT (D) against E. faecalis. Data are means of three experiments, with duplicate plating in each experiment. The limit of detection was 3.0 log10 CFU/ml.

Fig 2

E. faecalis labeled with bodipy-daptomycin (16 mg/liter; 4× MIC; baseline MIC, 4 mg/liter) in LB broth for 15 min after a 45-min treatment with either ampicillin (AMP) at 10 mg/liter or ceftaroline (CPT) at 1 mg/liter or 5 mg/liter, compared to control untreated cells. The normalized total intensity of signal per cell (bottom left) and number of binding spots per cell (bottom right) are shown. Microscopy method details have been described elsewhere (2, 8).

Fig 3

Percent survival of E. faecalis after 2 h of exposure to 64 μM (A) or 128 μM (B) cathelicidin LL37 in untreated controls compared to cells grown overnight in either ampicillin (AMP) at 4 mg/liter or ceftaroline (CPT) at 0.1 mg/liter. Method details have been described previously (2).