Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 748

Table 1 (continued)
Bacteria Cell type infected Subcellular localization

Rickettsia rickettsii, R. prowazekii,
R. shigella

Endotelial cell cytoplasm/nucleus

Salmonella enterica Intestinal epithelial

cell/macrophage

Vacuole

S. typhimurium Macrophages Vacuole

Shigella flexneri Epithelial cell Cytoplasm

Staphylococus aureus Human endothelial cells,

bovine epithelial cells
and murine fibroblasts

Phagolysosome without
alkalinization

Yersinia enterocolitica Intestinal epithelial cell Vacuole

Y. pestis Macrophage Phagolysosome without

alkalinization

Protozoa
Plasmodium spp.

Erythrocyte/hepatocyte Parasitophorous vacuole

Leishmania spp. Macrophage Phagolysosome

Trypanosoma cruzi Macrophage, smooth and

striated muscle cells
and fibroblast

Cytoplasm

Toxoplasma gondii All nucleated cells Parasitophorous vacuole

live inside a parasitophorous vacuola (PV) like Plasmodium spp and Toxoplasma
gondii. Besides tissue accessibility, the host cell/PV/parasite and food vacuola or
endoplasmic reticulum membranes are the barrieres interposed to the access of
antiparasitic agents against Plasmodium spp and T. gondii . Host cell, phagolyso-
some and parasite membranes are the barriers interposed by Leishmania spp,
whereas host cell and parasite membranes are interposed by T. cruzi .
Clearly, the intracellular location of potozoaria and bacteria is a true challenge
for the delivery of antimicrobial agents. As seen, a series of structural/phenomeno-
logical barriers impairs the antimicrobials to achieve therapeutic intracellular con-
centrations during the required time period. Besides, a potential drug may be too
toxic, leading to a maximum tolerated dose well below what is necessary for effi-
cient eradication of the infection (Mehta 1996 ). Pharmacokinetic and pharmacody-
namic parameters of antimicrobials are dependent of their chemical structure
(Tulkens 1991 ; van den Broek 1989 ).
To be used against intracellular target, a given antimicrobial has to satisfy many
selection criteria for optimal activity including entry, retention, subcellular distribu-
tion, expression of activity in the infected compartments, and susceptibility of
microorganism at the infection site with regard to the growth phase.
The ratio of the intracellular concentration to the extracellular concentration
( C i: C e) is the parameter used to classify the ability for intraphagocytic accumulation
of antibiotics. According to this, antibiotics can be poor cell penetrating ( Ci:Ce <1,
penicyllin G), antibiotics that penetrate but do not concentrate ( Ci:Ce ~1 such as
aminoglycosides, rifampin, sulfonamides, chloramphenicol, tetracyclines) and antibiotics
that concentrate within cells ( Ci:Ce > 1, macrolides and azoles) (Asanuma et al. 1983 ;