JAC Advance Access originally published online on May 18, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(1):259-262; doi:10.1093/jac/dkh259
JAC vol.54 no.1 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
Influence of protein binding under controlled conditions on the bactericidal activity of daptomycin in an in vitro pharmacodynamic model
1 Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences; 2 School of Medicine, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA
* Corresponding author. Tel: +1-313-577-4376; Fax: +1-313-577-8915; Email: m.rybak{at}wayne.edu
Objective: Daptomycin exhibits bactericidal activity against clinically significant Gram-positive bacteria despite being highly bound to human proteins. Evaluations characterizing the effect of protein on daptomycin pharmacodynamics are warranted.
Methods: We utilized an in vitro pharmacodynamic model to simulate daptomycin regimens of 6 mg/kg/day under controlled conditions of pH, calcium and/or protein. Free concentrations were simulated in broth, whereas total concentrations were simulated in broth supplemented with human albumin. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA) and two vancomycin-resistant Enterococcus faecium (VREF) clinical isolates.
Results: Daptomycin exhibited bactericidal activity against both MRSA isolates, with time to 99.9% killing occurring at 0.5 h and 8 h in broth and in albumin-supplemented broth, respectively. Initial kill was observed against both VREF isolates followed by regrowth. There was no statistical difference (P>0.05) in extent of bacterial kill at 24 or 48 h between the different media.
Conclusions: Although delayed, the extent of kill for daptomycin was unaltered against all isolates in albumin-supplemented broth. Further antimicrobial studies that incorporate protein are warranted to assess the influence of protein in the pharmacodynamic evaluation of antimicrobials.
Keywords: bacteria , resistance , cyclic lipopeptides , antimicrobials , albumin
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