Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 774

F. tularensis bacteria were not significantly acidified (Clemens et al. 2004 ).
F. tularensis bacteria are capable to alter the maturation of the phagosome, as
evidenced by the exclusion of cathepsin D, lysosomal tracers, and the lack of acidi-
fication, and then, by an unknown mechanism, disrupt the phagosomal membrane.

4.1 Conventional Treatments

Tularemia in humans can be treated with antibiotics, including streptomycin, gen-
tamicin and chloramphenicol, but even with prolonged daily therapy, relapse and
failure rates can range from 0% to 33% (Enderlin et al. 1994 ).

4.2 Preclinical Delivery Systems

CIP was encapsulated in 100 nm large unilamellar vesicles (LUV) by remote
loading using an ammonium sulfate gradient (Wong et al. 2003 ). Biodistribution of
liposomal CIP upon i.v. administration or aerosol inhalation in mice were deter-
mined using 14 C-CIP. Intravenous administration of liposomal CIP resulted in
higher serum levels of drug in serum, as well as increased drug retention in lungs,
liver and spleen, compared to that of free drug. Liposomal CIP has been shown to
be stable when aerosolized with no measurable liposome disruption (Finlay and
Wong 1998 ). Aerosol administration of liposomal CIP by jet nebulization resulted
in significantly higher drug levels and prolonged drug retention in the lower respi-
ratory tract compared to the free drug. Aerosol inhalation of liposome-encapsulated
CIP, given either prophylactically or therapeutically, provided complete protection
to BALB/c mice against a pulmonary lethal infection of F. tularensis . In contrast,
CIP given in its free form was ineffective. The aerosol delivery of liposomal CIP
provided very effective prophylaxis and post exposure treatment of pulmonary
F. tularensis infection in mice, while aerosolized free CIP, provided little or no
protection. The enhanced therapeutic efficacy can be partly attributable to increased
lung retention of CIP provided by the sustained release from the liposomes, as well
as to enhanced intracellular delivery of CIP by liposomes. Previous results showed
the total eradication of intracellular bacteria from the lungs, spleen and liver
(Conley et al. 1997 ), which serve as the primary infection sites for these agents.

5 Chlamydia

Chlamydophila pneumoniae, C. psittaci and C. trachomatis are small, gram-
negative, obligate intracellular organisms pathogenic to humans. The three species
can cause pneumonia in humans. C. pneumoniae is responsible for respiratory