Leprosy is a chronic
infectious disease caused by Myco-bacterium
leprae. Host defenses are crucial in determin-ing the patient’s response to
the disease, the clinical pres-entation, and the bacillary load. These factors
also influence the length of therapy and the risk of adverse re-actions to
medication. M. leprae cannot be grown
on rou-tine laboratory culture media, so drug sensitivity testing in vitro is
not possible. Growth and drug susceptibility testing are done by injecting into
One description of a clinical
picture that results from tuberculoid
leprosy is characterized by intact cell-mediated immunity, a positive
lepromin skin reaction, granuloma formation, and a relative paucity of bacilli.
At the other extreme, lepromatous leprosy
is character-ized by depressed cell-mediated immunity, numerous bacilli within
the tissues, no granulomas, and a negative skin test for lepromin. Within these
two extremes are the patients with an intermediate or borderline form of
leprosy who show a variable lepromin reaction and few bacilli; they may
progress to either tuberculoid or lep-romatous leprosy.
Current recommendations for
the treatment of leprosy suggest multidrug regimens rather than monotherapy
because such a regimen has proven to be more effective, delays the emergence of
resistance, pre-vents relapse, and shortens the duration of therapy.
Established agents used in the treatment of leprosy are dapsone, clofazimine,
and rifampin. Treatment of tuber-culoid leprosy is continued for at least 1 to
2 years, while patients with lepromatous leprosy are generally treated for 5
years. In addition to chemotherapy, patients with leprosy need psychosocial
support, rehabilitation, and surgical repair of any disfiguration.
The sulfones are structural
analogues of PABA and are competitive inhibitors of folic acid synthesis.
Sulfones are bacteriostatic and are used only in the treatment ofleprosy.
Dapsone (Avlosulfon) is the most
widely used sulfone for the long-term therapy of leprosy. Although the sulfones
are highly effective against most strains of M. leprae, a small number of organisms, especially those found in lepromatous leprosy patients,
are less suscepti-ble and can persist for many years, resulting in relapse.
Before the introduction of current multidrug regimens, resistance rates were as
high as 20% with dapsone monotherapy.
Sulfones, such as dapsone and
sulfoxone (Diasone), are well
absorbed orally and are widely distributed throughout body fluids and tissues.
Peak concentrations of dapsone are reached within 1 to 3 hours of oral
ad-ministration and have a half-life of 21 to 44 hours; about 50% of
administered dapsone is bound to serum pro-teins. The sulfones tend to remain
in the skin, muscle, kidney, and liver up to 3 weeks after therapy is stopped.
The concentration in inflamed skin is 10 to 15 times higher than that found in
normal skin. The sulfones are retained in the circulation for a long time
(12–35 days) because of hepatobiliary drug recirculation. The sul-fones are
acetylated in the liver, and 70 to 80% of drug is excreted in the urine as
Dapsone, combined with other
antileprosy agents like rifampin and clofazimine, is used in the treatment of
both multibacillary and paucibacillary M.
leprae in-fections. Dapsone is also used in the treatment and prevention of
Pneumocystis carinii pneumonia in
AIDS patients who are allergic to or intolerant of
Acedapsone is a derivative of
dapsone that has little activity against M.
leprae but is converted to an active dapsone metabolite. It is a
long-acting intramuscular repository form of dapsone with a half-life of 46
days. It may prove useful in leprosy patients who cannot toler-ate long-term
oral dapsone therapy.
The sulfones can produce
nonhemolytic anemia, methemoglobinemia, and sometimes acute hemolytic anemia in
persons with a glucose-6-phosphate dehydro-genase deficiency. Within a few
weeks of therapy some patients may develop acute skin lesions described as
sulfone syndrome or dapsone dermatitis. Some rare side effects include fever,
pruritus, paresthesia, reversible neuropathy, and hepatotoxicity.
Clofazimine is a weakly
bactericidal dye that has some activity against M. leprae. Its precise mechanism of ac-tion is unknown but may
involve mycobacterial DNA binding. Its oral absorption is quite variable, with
9 to 70% of the drug eliminated in the feces. Clofazimine achieves significant
concentrations in tissues, including the phagocytic cells; it has a plasma
half-life of 70 days. It is primarily excreted in bile, with less than 1%
excre-tion in urine.
Clofazimine is given to treat
sulfone-resistant lep-rosy or to patients who are intolerant to sulfones. It
also exerts an antiinflammatory effect and prevents ery-thema nodosum leprosum,
which can interrupt treat-ment with dapsone. This is a major advantage of
clofaz-imine over other antileprosy drugs. Ulcerative lesions caused by Mycobacterium ulcerans respond well to
clo-fazimine. It also has some activity against M. tuberculo-sis and can be used as last resort therapy for the
treat-ment of MDR tuberculosis.
The most disturbing adverse
reaction to clofazimine is a red-brown discoloration of the skin, especially in
light-skinned persons. A rare but serious adverse reac-tion is acute abdominal
pain significant enough to war-rant exploratory laparotomy or laparoscopy.
Other in-frequent side effects include splenic infarction, bowel obstruction,
paralytic ileus, and upper GI bleeding.
Ethionamide and prothionamide
are weakly bacterioci-dal against M.
leprae and can be used as alternatives to clofazimine in the treatment of
MDR leprosy. Both cause GI intolerance and are expensive.