β-Lactams enhance daptomycin activity against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium in in vitro pharmacokinetic/pharmacodynamic models

Abstract

Enterococcus faecalis and Enterococcus faecium are frequently resistant to vancomycin and β-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate β-lactam synergy with daptomycin (DAP) against resistant enterococci. One E. faecalis strain (R6981) and two E. faecium strains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h, in vitro models were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 μg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P < 0.001 and log10 CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (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). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted.

FIG 1

A 96-hour, one-compartment PK/PD model. Solid line with circles, growth control; solid line with upward triangles, DAP at 10 mg/kg/day; solid line with downward triangles, CPT at 600 mg q12h; solid line with squares, ERT at 1 g q24h; solid line with diamonds, AMP at 2 g q4h; dashed line with downward triangles, DAP-CPT; dashed line with squares, DAP-ERT; dashed line with diamonds, DAP-AMP. (A) E. faecalis R6981; (B) E. faecium R6370; (C) E. faecium 8019.

FIG 2

Percent survival of E. faecalis R6981 against 32 μM LL37 (A), E. faecium R6370 against 16 μM LL37 (B), and E. faecium 8019 against 16 μM LL37 (C) compared to the untreated growth control at 2 h. Whiskers indicate standard deviations.