Abstract
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 < 0.0001). A Lineweaver-Burk plot of the reciprocal transformation of these data yielded a poor fit (r = -0.38; P > 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 < 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2334-2337 |
| Number of pages | 4 |
| Journal | Antimicrobial Agents and Chemotherapy |
| Volume | 36 |
| Issue number | 10 |
| DOIs | |
| State | Published - Jan 1 1992 |
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Investigation of the early killing of Staphylococcus aureus by daptomycin by using an in vitro pharmacodynamic model. / Vance-Bryan, K.; Larson, Tom A; Rotschafer, John C; Toscano, J. P.
In: Antimicrobial Agents and Chemotherapy, Vol. 36, No. 10, 01.01.1992, p. 2334-2337.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Investigation of the early killing of Staphylococcus aureus by daptomycin by using an in vitro pharmacodynamic model
AU - Vance-Bryan, K.
AU - Larson, Tom A
AU - Rotschafer, John C
AU - Toscano, J. P.
PY - 1992/1/1
Y1 - 1992/1/1
N2 - 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 < 0.0001). A Lineweaver-Burk plot of the reciprocal transformation of these data yielded a poor fit (r = -0.38; P > 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 < 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.
AB - 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 < 0.0001). A Lineweaver-Burk plot of the reciprocal transformation of these data yielded a poor fit (r = -0.38; P > 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 < 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0026660936&partnerID=8YFLogxK
U2 - 10.1128/AAC.36.10.2334
DO - 10.1128/AAC.36.10.2334
M3 - Article
C2 - 1332596
AN - SCOPUS:0026660936
VL - 36
SP - 2334
EP - 2337
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 10
ER -