DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

disease, which has early hypopigmented lesions without features
of the lepromatous and tuberculoid leprosy.
Mycobacterium leprae was discovered by Armauer Hansen
in 1873. The M. leprae genome has undergone reductive evolution
and has radically downsized its genome (Cole et al., 2001). As a
result, M. leprae cannot produce ATP from NADH or utilize
acetate or galactose as carbon sources; moreover, it has lost the
anaerobic electron transfer system and cannot survive under
hypoxic conditions. It has a long doubling time (14 days) and is
an obligate intracellular pathogen. As a result, M. leprae is difficult
to culture on synthetic media, an impediment to basic research on
the disease.
Types of Anti-Leprosy Therapy
Therapy for leprosy is based on multi-drug regimens
using rifampin, clofazimine, and dapsone. The reasons
for using combinations of agents include reduction in
the development of resistance, the need for adequate
therapy when primary resistance already exists, and
reduction in the duration of therapy. The most bactericidal
drug in current regimens is rifampin. Because of
high kill rates and massive release of bacterial antigens,
rifampin is not often given during a “reversal”
reaction (see below) or in patients with erythema
nodosum leprosum. Clofazimine is only bacteriostatic
against M. leprae. However, it also has anti-inflammatory
effects and can treat reversal reactions and erythema
nodosum leprosum. The third major agent in the regimen
is dapsone. The objective of administering these drugs
is total cure.
Definitive Therapy; Standard Therapy
Pauci-Bacillary Leprosy. The WHO regimen consists of a single dose
of oral rifampin, 600 mg, combined with dapsone, 100 mg, administered
under direct supervision once every month for 6 months, and
dapsone, 100 mg a day, in between for 6 months. In the U.S., the regimen
consists of dapsone, 100 mg, and rifampin, 600 mg, daily for
6 months, followed by dapsone monotherapy for 3-5 years.
Multibacillary Therapy. The WHO recommends the same regimen
as for paucibacillary leprosy, with two major changes. First, clofazimine,
300 mg a day, is added for the entirety of therapy. Second,
the regimen lasts 1 year instead of 6 months. In the U.S., the regimen
is also the same as for paucibacillary, but dual therapy continues for
3 years, followed by dapsone monotherapy for 10 years. Clofazimine
(an orphan drug) is added when there is dapsone resistance or chronically
reactional patients.
The duration of therapy for multi-bacillary leprosy is a drawback.
Studies in murine leprosy, and in patients, have demonstrated
that viable bacilli are killed within 3 months of therapy (Ji et al.,
1996) suggesting that the length of current therapy for multibacillary
leprosy may be unnecessarily long. Recently, the WHO proposed
that all forms of leprosy be treated with the same dose as for paucibacillary
leprosy; a clinical trial was promising (Kroger et al.,
2008). This new shorter regimen promises to reduce duration of therapy
radically.
Treatment of Reactions in Leprosy. Patients with tuberculoid leprosy
may develop “reversal reactions,” manifestations of delayed
Table 56–5
Drugs Used in the Treatment of Mycobacteria Other Than for Tuberculosis, Leprosy, or MAC
MYCOBACTERIAL SPECIES FIRST-LINE THERAPY ALTERNATIVE AGENTS
M. kansasii Isoniazid + rifampin a + Trimethoprim-sulfamethoxazole; ethionamide;
ethambutol
cycloserine; clarithromycin; amikacin; streptomycin;
moxifloxacin or gatifloxacin
M. fortuitum complex Amikacin + doxycycline Cefoxitin; rifampin; a sulfonamide; moxifloxacin
or gatifloxacin; clarithromycin; trimethoprimsulfamethoxazole;
imipenem
M. marinum Rifampin + ethambutol Trimethoprim-sulfamethoxazole; clarithromycin;
minocycline; doxycycline
Mycobacterium ulcerans Rifampin + streptomycin c Clarithromycin b ; rifapentine b
M. malmoense Rifampin + ethambutol Fluoroquinolone
± clarithromycin
M. haemophilum Clarithromycin + -
rifampin + quinolone
a
In HIV-infected patients, the substitution of rifabutin for rifampin minimizes drug interactions with the HIV protease inhibitors and non-nucleoside
reverse transcriptase inhibitors. b Based on animal models. c For Mycobacterium ulcerans, surgery is the primary therapy.