Investigation of the early killing of Staphylococcus aureus by daptomycin by using an in vitro pharmacodynamic model.
The purpose of this study was to develop a pharmacodynamic model to describe the dependency of the rate of Staphylococcus aureus killing upon the concentration of daptomycin. A range of free (unbound) daptomycin concentrations ranging from 0.12 to 27 times the MIC were simulated in the peripheral compartment of a two-compartment pharmacokinetic model. Log-linear regression of free daptomycin concentrations versus growth or kill rate constants showed a significant correlation (r = -0.90; P less than 0.001). A Lineweaver-Burk plot of the reciprocal transformation of these data yielded a poor fit (r = -0.38; P greater than 0.05). When a Lineweaver-Burk-type regression analysis was performed on the reciprocal of the change in the rate constant rather than the rate constant itself, the result demonstrated good correlation (r = 0.90; P less than 0.0001). The observations were also well described by a sigmoidal maximum plateau pharmacologic effect model, in which the pharmacologic effect of daptomycin is a reduction in the bacterial exponential growth rate constant from the baseline in the absence of antibiotic to a lower (positive) growth or (negative) death rate constant observed in the presence of antibiotic. These data confirm that daptomycin exhibits concentration-dependent killing over a wide range of free daptomycin concentrations relative to the MIC and suggest that this is a saturable process similar to the Michaelis-Menten pharmacokinetic elimination of certain drugs.
Vance-Bryan
K
K
College of Pharmacy, University of Minnesota, Minneapolis 55455.
Larson
T A
TA
Rotschafer
J C
JC
Toscano
J P
JP
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017576:Daptomycin; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D010455:Peptides / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
D000900:Anti-Bacterial Agents; D010455:Peptides; D017576:Daptomycin