Influence of protein binding under controlled conditions on the bactericidal activity of daptomycin in an in vitro pharmacodynamic model.
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.
Cha
Raymond
R
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Rybak
Michael J
MJ
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003470:Culture Media; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D016984:Enterococcus faecium / Q000187:drug effects; D016908:Gram-Positive Bacterial Infections / Q000382:microbiology; D006801:Humans; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D015610:Serum Bactericidal Test; D013211:Staphylococcus aureus / Q000187:drug effects; D020713:Vancomycin Resistance
D000900:Anti-Bacterial Agents; D003470:Culture Media; D012709:Serum Albumin; D017576:Daptomycin