Intracellular pharmacokinetics and localization of antibiotics as predictors of their efficacy against intraphagocytic infections.

To be effective against intracellular bacteria, antibiotics must not only reach and preferably be retained in the infected subcellular compartments, but also be able to express their activity therein. beta-lactams are most often ineffective because they fail to concentrate in phagocytes. Aminoglycosides are taken up at a very slow rate and localize almost exclusively in lysosomes where their activity is largely defeated by the acid pH. Lincosamides and macrolides accumulate rapidly by phagocytes, and distribute both in lysosomes and in cytosol. Yet, most surprisingly, macrolides are active, whereas lincosamides are not, or only weakly active against sensitive organisms. Fluoroquinolones are also accumulated by phagocytes, but are not associated with a specific organelle. They show good activity against most sensitive organisms. A model of Staphylococcus aureus-infected macrophages is presented to determine the intrinsic intracellular activity of antibiotics, i.e. to distinguish the influence of drug uptake from the other factors that modulate drug activity such as drug disposition and inactivation. This approach confirms the superiority of the fluoroquinolones as compared to presently available macrolides or to lincosamides. Thus, analysis of the pharmacokinetic and pharmacodynamic behavior of antibiotics in appropriate models of infected cells may help in directing future research towards improved derivatives, and may rationalize their use in vivo.