A novel in vitro pharmacokinetic/pharmacodynamic model based on two-compartment open model used to simulate serum drug concentration-time profiles.
An in vitro pharmacokinetic/pharmacodynamic perfusion model that simulates a two-compartment open model of serum drug concentration-time profiles following intravenous bolus injection and infusion was developed and mathematically described. In the present apparatus model, flow was kept in a one-way mode to avoid liquid traffic, and the washout effect seen in dilution models was overcome by embedding the tested bacteria in low melting point agarose gel. The validity of the equations and the reproducibility of the apparatus model were ascertained by simulating the concentration-time profiles of cefazolin and fosfomycin by substitution of their pharmacokinetic parameters obtained from humans for the equations. An empirical regimen 1X(q24h) of 1 g with cefazolin administered by intravenous infusion effectively killed a Staphylococcus aureus strain. The same regimen with fosfomycin produced a marked kill-curve with a fosfomycin-susceptible enterohaemorrhagic Escherichia coli O157:H7, whereas considerable regrowth was observed with a resistant strain. These results indicated that the present model was able to provide a convenient and reliable method for evaluating the efficacy of antimicrobial agents administered by intravenous infusion.
Tomita
Tsutomu
T
Cine-Science Laboratory, Itabashi-ku, Tokyo 174-0071, Japan.
Ohara-Nemoto
Yuko
Y
Moriyama
Hitomi
H
Ozawa
Ayako
A
Takeda
Yoshifumi
Y
Kikuchi
Ken
K
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001825:Body Fluid Compartments; D002437:Cefazolin / Q000493:pharmacokinetics / Q000494:pharmacology; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism; D019453:Escherichia coli O157; D005578:Fosfomycin / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000097:blood*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism; D013211:Staphylococcus aureus
D000900:Anti-Bacterial Agents; D004364:Pharmaceutical Preparations; D005578:Fosfomycin; D002437:Cefazolin