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J Antimicrob Chemother. 2014 Aug;69(8):2148-54. doi: 10.1093/jac/dku113. Epub 2014 Apr 28.

Evaluation of the novel combination of daptomycin plus ceftriaxone against vancomycin-resistant enterococci in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation model.

Author information

1
Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA.
2
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.
3
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.
4
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.

Abstract

OBJECTIVES:

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.

KEYWORDS:

Enterococcus faecalis; Enterococcus faecium; combination therapy; endocarditis

PMID:
24777900
DOI:
10.1093/jac/dku113
[Indexed for MEDLINE]

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