Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 752

common syndrome is cervical lymphadenitis ( Centers for Disease Control and
Prevention ). Unlike tuberculosis, a MAC infection cannot be passed from one
person to another.
MAC can invade and translocate across the mucosal epithelium. The bacteria
subsequently infect the resting macrophages in the lamina propria and spread in the
submucosal tissue; they are then carried to the local lymph nodes by lymphatics. In
immunocompromised hosts, they are subsequently spread hematogenously to the
liver, spleen, bone marrow, and other sites.
Mycobacterium spp replicates within alveolar macrophages (Cosma et al. 2003 ).
The Mycobacteria pathogen vacuole (MPV) arrests at the early endosomal (EEA1,
Rab5-positive) stage (Philips 2008 ). The MPV retains the ability to interact with
early and recycling endosomes, presumably to acquire nutrients delivered by endo-
somal recycling pathways. Despite the arrest in MPV maturation, Mycobacterium
spp can be delivered to phagolysosomes in macrophages after induction of
autophagy with rapamycin treatment or in response to IFNg treatment (Gutierrez
et al. 2004 ; Hope et al. 2004 ). As with the salmonella containing vacuola (SCV),
ubiquitination of bacterial products and autophagy are potent host defenses against
establishment of the MPV. Not surprisingly, Mycobacterium spp have acquired
mechanisms to minimize the induction of autophagy (Kumar and Valdivia 2009 ).

2.1 Conventional Treatments

If well there are drugs that successfully act against tuberculosis, the complexity of
treatment (de Cock and Wilkinson 1995 ; Gelband 2000 ), the adverse side effects
(Myers 2005 ) and acquisition of drug resistance (Mitchison 2005 ; Toit et al. 2006 )
are impediments to eradicate this infection.
Long treatment (6-8 months of daily intake) stems from the presence of non-
metabolizing bacteria that are not killed by the antibiotics and of pathogens in
stationary phase or proliferating at extremely low rates in old lesions or within
fibrotic or calcified sites (Rook and Hernandez-Pando 1996 ). The prolonged phar-
macotherapy and the pill burden can hamper patient lifestyle and thus low compli-
ance and adherence to administration schedules remain the main reasons for
therapeutic failure and contribute to the development of multi-drug resistant strains
(Dye 2006 ). In developing countries and rural areas, additional difficulties to com-
plete the treatment are the difficult supervision of the regimens and the prohibitive
costs of the drugs involved (Gupta et al. 2001 ).
The most effective pharmacotherapy against tuberculosis is comprised of a
multi-drug combination of isoniazid (INH), pyrazinamide (PYZ) and rifampicin
(RIF). INH is a synthetic prodrug that inhibits the synthesis of mycolic acid,
required for the mycobacterial cell wall. It eliminates only active (growing)
bacteria. Since the bacteria may exist in a resting (nongrowing) state for long peri-
ods, therapy with INH must be continued for a long time (usually 6-12 months)
(National Institutes of Health). PYZ is a bacteriostatic/bacteriocide prodrug that