Evaluation of the novel combination of daptomycin plus ceftriaxone against vancomycin-resistant enterococci in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation model.
OBJECTIVE
Daptomycin has demonstrated synergy with β-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to daptomycin. We investigated daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model.


METHODS
Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess β-lactam-induced changes in cell surface charge.


RESULTS
For 8019 and 6981, daptomycin 6 mg/kg with ceftriaxone and daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding.


CONCLUSIONS
The combination of daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of daptomycin and innate immunity killing of VRE by ceftriaxone and other β-lactams.
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA.
Ashley
A
Hall Snyder
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA Department of Pharmacy, University of Washington, Seattle, WA 98195, USA.
Brian J
BJ
Werth
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA.
Katie E
KE
Barber
Department of Pediatrics, University of San Diego School of Medicine, San Diego, CA 92123, USA Infectious Diseases, Sharp Memorial Hospital, San Diego, CA 92123, USA.
George
G
Sakoulas
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA School of Medicine, Wayne State University, Detroit, MI 48201, USA m.rybak@wayne.edu.
Michael J
MJ
Rybak
D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D013293:Enterococcus faecalis / Q000187:drug effects*; D016984:Enterococcus faecium / Q000187:drug effects; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D008826:Microbial Sensitivity Tests; D014640:Vancomycin / Q000494:pharmacology; D020713:Vancomycin Resistance; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D014640:Vancomycin; D002443:Ceftriaxone; D000667:Ampicillin; D017576:Daptomycin
Enterococcus faecalis; Enterococcus faecium; combination therapy; endocarditis