Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 753

transforms in pyrazinoic acid. RIF is a bactericidal semisynthetic drug of the
rifamycin group, that inhibits DNA-dependent RNA polymerase by binding its
b-subunit, thus preventing transcription to RNA and subsequent translation to pro-
teins. RIF is active against microorganisms of the genus Mycobacterium, including
M. tuberculosis , M. kansasii , M. marinum , MAC and M. leprae . The limited bio-
availability of RIF is a main clinical issue (Gohel and Sarvaiya 2007 ).
During the initial intensive stage (2 months), these three agents are administered
together with ethambutol (ETB), a bacteriostatic drug against actively growing
tuberculosis bacilli that works by obstructing the formation of cell wall and is
responsible for permanent visual loss (Lim 2006 ; WHO 2003 ). The second phase
(4 months) comprises exclusively RIF and INH. These four drugs together with the
aminoglycoside streptomycin constitute the first-line therapy. INH, PYZ, RIF and
streptomycin have been shown to induce hepatotoxicity when used alone or in
combination (Davidson and Quec 1992 ).
RIF is the first line drug currently used for treatment of latent M. tuberculosis
infection in adults. But a number of side effects like lack of appetite, nausea, hepa-
totoxicity, fever, chill, allergic rashes, itching and immunological disturbances,
patient non-compliance in long term therapy limit its use (Laura et al. 2000 ).
MAC is intrinsically resistant to many antibiotics and antituberculosis drugs
(Bermudez 1994 ; Leitzke et al. 1998 ) but is fairly susceptible to macrolides
(clarithromycin, azithromycin), rifamycins (RIF, rifabutin), ETB, clofazimine, flu-
oroquinolones, amikacin and streptomycin (Koirala 2010 ).

2.2 Preclinical Delivery Systems

Delivery systems against Mycobacteria spp were by far the most varied, outnum-
bering those used against other bacterial infections. In first place, the performance
of oral polymeric nanoparticles, which are not absorbed but that increased drug
bioavailability was extensively explored. Their use led to a reduced number of
administrations and increased accumulation of drug in tissues. On the other hand,
i.v. nanoparticles which are captured by fixed accessible or circulating mac-
rophages, allowed a targeted delivery of drugs to infected macrophages. Once
phagocitosed, drugs within nanoparticles probably followed the same intracellular
pathway and unless being carried by pH-sensitive nanoparticles, drugs were deliv-
ered inside phagosomes. Alveolar macrophages were refractary to the uptake of i.v.
nanoparticles and so the disease burden was less diminished than in liver and
spleen. Only pulmonary administration allowed an effective targeting to alveolar
macrophages and therefore the frequency of administrations could be pronouncedly
reduced as compared to the other vias.
In the recent review of Sosnik et al. ( 2010 ) the strategies based in the use of
nanoparticles for sustained or targeted delivery of antibiotics against tuberculosis are
extensively discussed. In this chapter will only be included works showing biodistribu-
tion of nanoparticles and or preclinical therapeutic efficacy against disease models.