BACKGROUND:

Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and beta-lactams (BL). In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate BL synergy with daptomycin (DAP) against resistant enterococci.

 

METHODS:

One Efc (R6981) and two Efm strains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37 in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). Ninety-six hour, in vitro models were run simulating DAP 10 mg/kg/day, CPT 600 mg q8h, AMP 2 g q4h, and ERT 1 g q24h both alone and in combination against all strains.

 

RESULTS:

DAP MICs were 2, 4, and 4 μg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP and CPT, AMP, or ERT against strain 8019 (p<0.001 and log10 CFU/ml reduction >2 compared to any single agent). Against strains R6981 and R6370, DAP and AMP demonstrated enhancement against R6370 but not R6981, while the combinations of DAP and CPT or ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 hours (p<0.001) against both strains. CPT, ERT and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (p<0.001).

 

CONCLUSIONS:

Combination regimens provide better kill and prevent resistance compared to DAP alone. Clinical research involving DAP combinations is warranted.