Much
confusion exists over the pharmacodynamics of
macrolides, azalides, and
ketolides, as the concentration-time profile for these agents is low relative to the minimum inhibitory concentration (MIC) of the pathogens for which they are used. Studies of
respiratory tract infection have highlighted the importance of
drug concentrations at the site of
infection and have demonstrated a role for white blood cells in the delivery of
drug to the
infection site. Population mathematical modeling and Monte Carlo simulation have shown that the ability of
macrolides, azalides, and
ketolides to concentrate at the
infection site has a considerable effect on microbial activity. Studies of the pharmacodynamics of these agents in animal models have centered on the mouse thigh model; however, the suitability of this model for investigation of
respiratory tract infections for
macrolides and
macrolide-like drugs is questionable. Comparison of the mouse thigh model with the mouse lung model shows immediate discrepancies, such as a need for higher area under the concentration-time curve (AUC):MIC ratios in the mouse thigh. There are obvious failings in the use of a thigh model, as it does not take into account the accumulation of white blood cells in the epithelial lining fluid and therefore ignores the impact of white blood cell delivery to the site of
infection and release of significant amounts of
drug during phagocytosis. Ultimately, whereas the mouse
pneumonia model is useful in identifying pharmacodynamically linked variables and the magnitude of variable required for a successful microbiologic outcome, extrapolation to human dosing must involve the use of human epithelial lining fluid penetration data.