Penetration accumulation and efficacy of intracellular antibacterial agents

In order to be active against an intracellular pathogen, an antibiotic must be able to penetrate the cell, to be retained by the cell, and to express its activity in the environment where the bacteria are located. Uptake and release of antimicrobials

Marked intracellular accumulation of macrolide antibiotics has been observed in several types of culture cells. Thus the concentration of erythromycin in the macrophage may be twice to 10 times the extracellular concentration. Uptake of macrolides is non-saturable and usually rapid, but so is efflux. A marked recent exception is azithromycin, which, in contrast with other macrolides, has a slow penetration and a very high intracellular level (the ratio of intra- to extracellular level is greater than 400), contrasting with a low extracellular level and a slow release. Macrolides accumulate and distribute themselves in both lysosomes and the cytosol. Fluoroquinolones accumulate in phagocytic cells and are not associated with a specific organelle. The uptake is rapid, and the accumulated drugs are also quickly released. Accumulation of fluoroquinolones is similar to that of erythromycin (two- to eightfold) and is not influenced by the activation of macrophages. Very few data have been reported for other antibiotic families used in the treatment of intracellular infection. Rifampin (rifampicin) accumulates moderately in phagocytes (two- to threefold). Therefore it is possible that a high intracellular concentration does not reflect the effectiveness of an antimicrobial.

Antibiotic uptake may be influenced by other factors. For example, macrophages infected with Legionella pneumophila retain more pefloxacin than uninfected macrophages. It has been reported that interferon-g and tumor necrosis factor enhance the uptake of azithromycin by macrophages.

Intracellular activity

Intracellular pH, oxygen content, and enzymatic activity within cell cytoplasm and phagocytic lysosome are different from those in serum. Any of these variables may render the antibacterial agent inactive, even if the agent and the bacteria are in the same intracellular location. However, the intracellular environment does not have too detrimental an effect on the antibacterial properties of macrolides and fluoroquinolones. Despite a relatively low intracellular concentration, rifampin is very active against intracellular bacteria. The most widely accepted hypothesis is that the activity of rifampin is somehow enhanced by the intracellular physicochemical (low pH)

conditions at the site of infection.

Antibiotic-phagocyte interaction

Several antimicrobials can interfere directly with phagocyte function at different levels. However, available data gave conflicting results. An exception is the possible inhibition of neutrophil function by tetracycline which acts as a calcium chelator.

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