Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 749

Labro 1996 ; Maurin and Raoult 1997 ; Tulkens 1991 ). Poor penetration into the cells
and decreased activity intracellularly are the major reasons for the limited activity of
most antibiotics (penicillins, cephalosporins and aminoglycosides) in intracellular
infections. An equivalent classification for antiprotozoan agents is not available.
Macrolides such as erythromycin and tilmicosin have been shown to be 75-fold more
concentrated in lung macrophages compared with parenchymal cells (Blais and
Chamberland 1994 ). This differential accumulation of macrolides within phagocytes
and other cells involved in immunity explains in part the excellent clinical effect of
these antibiotics against organisms for which they possess a moderate minimum
inhibitory concentration (MIC) value (Smith 1988 ) as well as high activity against
phagocytosed intracellular gram-negative bacteria, compared with their weaker activ-
ity against extracellular bacteria (Rakita et al. 1994 ). While macrolides generally
distribute evenly in the cell cytosol and phagosomes/lysosomes, azolides concentrate
in phagosomes. The accumulation of these antibiotics within host cells is partly
owing to protonation of the weak base macrolides intracellularly, which enhances
their retention (Labro 1996 ). Such localized concentrations are likely to increase the
activity of these antibiotics against bacteria located in the same compartment. The
enhanced concentration of macrolides and azolides in phagosomes could therefore
retard the development of resistant strains of intraphagosomal bacteria, such as
Chlamydia spp. The intracellular location of tetracyclines, however, remains poorly
defined. The various members of the macrolide and azolide group have a relatively
wide range of MIC values for any particular intracellular organism, possibly reflect-
ing subtle variations in the intracellular location of the antibiotic (McOrist 2000 ).
Most antibiotics are more effective at neutral or basic pHs, although rifampin,
pyrazinamide, and to a lesser extent the tetracyclines, which more active at acidic pH,
are exceptions (Maurin and Raoult 1997 ). Weak base antibiotics such as the amino-
glycosides and the macrolides are concentrated within lysosomes by a pH-dependent
mechanism. Although these antibiotics may be concentrated several folds within cells,
their localization within the lysosomal compartment and partial inactivation of their
activity by acidic pH represent major disadvantages (Rakita et al. 1994 ). Intracellular
location and activity as a function of pH of antibiotics are shown in Table 2 .

Table 2 Mode of entry within eukaryotic cells, subcellular localization and pH activity of
antibiotics (Maurin and Raoult 1997 )

Localization Antibiotic activity at pH

Antibiotics Mode of entry Cytoplasm Lysosomes Basic Neutral Acidic

Betalactams Diffusion + +++ ++ +

Aminoglicosides Pinocytosis +++ +++ + -

Tetracyclines Diffusion ++ ? ++ +++ +

Chloramphenicol Diffusion ++ ? +++ + -

Rifampin Diffusion ++ ++ ++ ++ +++

Erythromycin Transport + +++ +++ + -

Clindamycin Transport + +++ +++ + -

Fluoroquinolones Unknown ++ ++ +++ + -