Development of an integrated semi-automated system for in vitro pharmacodynamic modelling.
OBJECTIVE
The aim of this study was to develop an integrated system for in vitro pharmacodynamic modelling of antimicrobials with greater flexibility, easier control and better accuracy than existing in vitro models.


METHODS
Custom-made bottle caps, fittings, valve controllers and a modified bench-top shaking incubator were used. A temperature-controlled automated sample collector was built. Computer software was developed to manage experiments and to control the entire system including solenoid pinch valves, peristaltic pumps and the sample collector. The system was validated by pharmacokinetic simulations of linezolid 600 mg infusion. The antibacterial effect of linezolid against multiple Staphylococcus aureus strains was also studied in this system.


RESULTS
An integrated semi-automated bench-top system was built and validated. The temperature-controlled automated sample collector allowed unattended collection and temporary storage of samples. The system software reduced the labour necessary for many tasks and also improved the timing accuracy for performing simultaneous actions in multiple parallel experiments. The system was able to simulate human pharmacokinetics of linezolid 600 mg intravenous infusion accurately. A pharmacodynamic study of linezolid against multiple S. aureus strains with a range of MICs showed that the required 24 h free drug AUC/MIC ratio was approximately 30 in order to keep the organism counts at the same level as their initial inoculum and was about > or = 68 in order to achieve > 2 log(10) cfu/mL reduction in the in vitro model.


CONCLUSIONS
The integrated semi-automated bench-top system provided the ability to overcome many of the drawbacks of existing in vitro models. It can be used for various simple or complicated pharmacokinetic/pharmacodynamic studies efficiently and conveniently.
Wang
Liangsu
L
Department of Infectious Disease Research, Merck Research Laboratories, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA. liangsu_wang@merck.com
Wismer
Michael K
MK
Racine
Fred
F
Conway
Donald
D
Giacobbe
Robert A
RA
Berejnaia
Olga
O
Kath
Gary S
GS
D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001331:Automation; D015169:Colony Count, Microbial; D006801:Humans; D066298:In Vitro Techniques; D000069349:Linezolid; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid