Challenges to antibiotic activity in tissue.

The most important determinants of antibiotic efficacy in infectious sites are the pharmacokinetic profile of the drug, the biochemical characteristics of the local environment, and the susceptibility of the infecting microorganisms under local growth conditions. The role of these variables is fairly clear for extracellular infections but not for intracellular infections or tissues as a whole. Many agents, including the macrolides, azalides, lincosamides, and quinolones, are concentrated within cells--notably, phagocytic cells. The mechanisms and pharmacokinetics of accumulation as well as the subcellular localization of accumulated drug are poorly understood in most instances. High intracellular drug concentrations do not necessarily translate into potent anti-infective activity. Many drugs with high intracellular concentrations are weak bases that accumulate within acidic lysosomes, where their activity may be reduced; the site at which drug accumulation is greatest may differ from that at which the microbe is found; and slow rates of intracellular growth may lessen the susceptibility of microbes to a variety of agents. Nevertheless, some drugs display good antimicrobial activity within cells. Future studies must better identify the determinants of this activity and clarify the clinical utility of drugs that reach high intracellular levels.