Scand J Infect Dis Suppl 1990;74:209-17

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

Tulkens PM

Laboratory of Physiological Chemistry, Catholic University of Louvain, Belgium.

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.

PMID: 2097709, UI: 91271866