General principles of antibiotic tissue penetration.

It is well established that, at equilibrium, the concentrations of free drug on either side of a porous capillary are equal. However, the dynamic factors which operate on the way to achieving this equilibrium, while drug levels fluctuate in serum and extravascular sites, have been less well studied. This paper reviews some of the physical principles relating to diffusion through capillary pores and permeation through capillary membranes. Emphasis has been placed on the importance of the surface area-to-volume ratio in determining the time required to reach various stages of equilibrium. The effects of infection have been considered. At equilibrium, the AUC of free drug in serum and non-specialized extravascular compartments must be equal. Therefore, although the mode of administration (e.g. continuous infusion versus intermittent bolus) will affect the profile of the concentration-time curve in extravascular loci, it will not affect the overall AUC of drug in these sites. We have derived an equation to estimate the levels of drug within an abscess when bacteria are destroying the drug. Brief consideration has been given to transport in specialized sites with non-porous capillaries and with active transport systems. Throughout the analysis, we have focused on the application of these principles to in-vitro models and the potential use of in-vitro models to substantiate these principles.