In vitro and animal PK/PD models

Abstract

A large variety of in vitro and animal models have been used to characterize the pharmacodynamics of antimicrobials. In vitro kill curves report two different patterns of antimicrobial killing (concentration dependent and time dependent) that can be followed by persistent effects that delay bacterial regrowth. In vitro kinetic models using dilution or dialysis have the ability to simulate the changing drug concentrations observed in humans and study their effect on different bacteria. New hollow-fiber dialysis models have reduced the chance of contamination and have allowed longer studies of the emergence and suppression of resistant mutants. Animal models have the advantage of determining antimicrobial efficacy at specific body sites such as the thigh in mice, the peritoneum in mice and rats, the lung in mice, rats, and guinea pigs, endocarditis in rabbits and rats, and meningitis in rabbits. However, clearance of antimicrobials is more rapid in animals than in humans. Many factors, such as inoculum, media, growth-phase of the organism, site of infection, drug concentrations to measure correct drug exposure, presence of neutropenia, and measurement of outcome by colony-forming units (CFUs), survival/mortality, or another form of assessment, need to be considered to develop meaningful conclusions.