General principles of antibiotic tissue penetration

Abstract

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.

Pulmonary Administration of Gentamicin During Liquid Ventilation in a Newborn Lamb Lung Injury Model

“…In addition, an antibiotic that reaches bronchial secretions can be inhibited by local conditions of inflammation. [23][24][25] These circumstances can demand high serum levels that carry associated renal toxicity and ototoxicity. The fact that it is difficult to permeate the respiratory system with IV gentamicin is of particular concern in the presence of consolidated pulmonary infection with associated V/Q abnormalities and decreased pulmonary perfusion to affected parenchyma.…”

Drug delivery to equine digital lamellar tissue

“…As discussed in Chapter 2, one of the caveats of performing pharmacokinetic studies in normal animals is that tissue drug concentrations may be altered by inflammation and changes in vascular permeability occurring during the diseased state (Barza and Cuchural 1985). In this study, LUF marimastat concentrations did not appear to vary from one perfusion to the next ( Figure 5.5) in spite of the development of laminitis and accompanying inflammation and changes in vascular permeability, suggesting these had minimal effect on lamellar marimastat distribution.…”

“…The vasodilation and increased vascular permeability that accompany inflammation can cause an increase in drug delivery to the tissue, but viscosity is also increased, slowing diffusion (Barza and Cuchural 1985). Generally the low level of inflammation compared to infected tissue is a concern in antimicrobial pharmacokinetic studies using ultrafiltration (Frazier et al 2000;Bidgood and Papich 2003), as it is preferable to measure drug concentrations in tissue conditions similar to the diseased state.…”

“…Techniques available to determine tissue drug concentrations include implanted tissue cages, biopsies, microdialysis and ultrafiltration Davis et al 2006;Voermans et al 2006; (Barza and Cuchural 1985). The combination of blood, interstitial fluid (IF) and intracellular fluid in homogenised the biopsy samples may under-or over-estimate drug concentrations, and complicated homogenisation and extraction procedures reduces the accuracy of the technique (Cars and Ogren 1985;Nix et al 1991).…”

“…Serial lamellar biopsies potentially allow measurement of lamellar drug concentrations. However, only a limited number of samples can be obtained and the technique is invasive resulting in inflammation (Visser 2009), which may affect drug distribution (Barza and Cuchural 1985).…”