Cutaneous leishmaniasis is often self-healing, particularly in infection with
L. major and L. mexicana; therefore, treatment is not always recommended.
However, if lesions do not spontaneously heal within six months or if the lesions
are especially disfiguring and in a cosmetically sensitive area, treatment is
indicated. Even though lesions may heal eventually in absence of treatment,
the process is often long and produces significant scarring, thereby justifying
the use of chemotherapy. Cutaneous cases should also be treated if they are
relatively more likely to develop into mucocutaneous leishmaniasis, for example
if the cutaneous case is suspected to be part of the Viannia subgenus
of the New World. The goal of treating cutaneous leishmaniasis is twofold, eradication
of amastigotes as well as reducing the size of the lesions so that healing will
take place with minimal scarring.
Pentavalent antimony compounds like meglumine antimonate and stibogluconate
have been used as first line drugs to treat cutaneous leishmaniasis for the
past 50 years. Although these drugs do have excellent cure rates in endemic
areas without resistance (between 90 and 100%), their high levels of toxicity
makes them a poor clinical agent. Other difficulties with their provision (for
example, parental route administration, duration of treatment, and excessive
cost) are great obstacles preventing true effectiveness in endemic areas.
Mucocutaneous leishmaniasis begins just like the cutaneous form with dermal
lesions. Certain species of Leishmania are more likely than others to progress
to this form; for example, it is estimated that 3 % of patients with L. braziliensis
develop mucosal disease. 90% of all cases of mucocutaneous leishmaniasis occur
in Bolivia, Brazil and Peru. The time delay between first signs of the cutaneous
ulcer to the noticeable involvement of mucosal membranes of nose and mouth can
be anywhere from one month to 24 years. This variance significantly impacts
when treatment is first indicated. The same pentavalent antimony compounds are
recommended as the standard treatment option at the same dose, though treatment
must be maintained for a much longer duration to be as effective for the mucosal
Visceral leishmaniasis, the most fatal form is also the form of leishmaniasis
least likely to be clinically apparent. The visceral form is endemic in 60 countries
but the heaviest burden of disease falls to just 5: India, Nepal, Bangladesh,
Brazil, and Sudan. Once infected, treatment is essential to ensure recovery.
Visceral Leishmania, or kala-azar, is primarily cause by L. donovani
on the Indian subcontinent and in Africa, L. infantum in the Mediterranean
region, and L. chagasi in Latin America. Visceral Leishmaniasis has been
treated successfully with pentavalent antimony compounds but widespread resistance
in India has rendered them ineffective. Other compounds are being used now but
the same problems of toxicity, difficulty in route of administration, and cost
are great obstacles in their effective delivery. Co-infection with HIV, now
quite common in many of the endemic areas, accounts for new challenges to the
effective treatment of visceral leishmaniasis. Immunocompromised patients need
to be given a suppressive regimen in order to minimize the chance of recurrence.
lllllllllllllllllllllllllllllllMeglumine antimonate lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllStibogluconate
|Treatment||Recommended Dose||Clinical Efficacy||Side Effects|
|Meglumine antimonate (Glucantime),
|20 mg/kg/day for 10 days, IM or IV||Standard pentavalent antimony compounds show cure rates as high as 90 100% in areas not plagued by resistance||Sb compounds exhibit a high level of toxicity: frequent fatigue, nausea, muscle and joint pain, increased transaminase, changes in ECG, cardiotoxicity, occasionally hepatic and renal dysfunction, shock and (rarely) sudden death|
|20 mg/kg/day in 2 divided doses for 10 days, IM or IV||same as Meglumine antimonate||same as Meglumine antimonate|
|Pentamidine (aromatic diamidine)||2-4 mg/kg every other day for up to 15 doses, IM||A study from Surinam found pentamidine to have a 90 % cure rate||frequent hypotension, hypoglycemia often followed by diabetes mellitus, renal damage, pain at injection site, GI disturbance, vomiting|
|Treatment||Recommended Dose||Side Effects|
|20 mg/kg/day in 2 divided doses for 30 days, IV or IM||Sb compounds exhibit a high level of toxicity: frequent fatigue, nausea, muscle and joint pain, increased transaminase, changes in ECG, cardiotoxicity, occasionally hepatic and renal dysfunction, shock and (rarely) sudden death|
|Treatment||Recommended Dose||Side Effects|
|20 mg/kg/day in 2 divided doses for 30 days, IM or IV||Sb compounds exhibit a high level of toxicity: frequent fatigue, nausea, muscle and joint pain, increased transaminase, changes in ECG, cardiotoxicity, occasionally hepatic and renal dysfunction, shock and (rarely) sudden death|
If resistance to Pentavalent Antimonials:
Pentamidine (aromatic diamidine)
|4 mg/kg 3 times per week for 5 weeks||frequent hypotension, hypoglycemia often followed by diabetes mellitus, renal damage, pain at injection site, GI disturbance, vomiting|
If resistence to Pentavalent Antimonials:
Amphotericin B (polyene macrolide antibiotics)
|1 mg/kg every other day for up to 20 days IV||extreme toxicity: generalized pain, convulsions, anaphylaxis, flushing chills, fever, phlebitis, anemia, thrombocytopenia, nephrotoxicity|
llllllllllllllFormula for Amphotericin B
Other Common Therapies
Lipid-encapsulation amphotericin B:
15-20 mg/kg total dose over 5 or more days. Less side effects. AmBisome
is very expensive, a patients ability to pay determines use. There was
a recent study on pediatric Mediterranean visceral leishmaniasis that showed
short-course lipid formulation amphotericin B (2 doses) to be a cost effective
Paromomycin, an aminoglycoside antibiotic, is an alternative drug for the treatment
of cutaneous leishmaniasis. Ointment contains 15% paromomycin and transdermal
enhancing 12% methyl benzethonium chloride. Paromomycin is to be used topically
twice daily for 15 days. Trials indicate considerable potential for treatment:
74% cure rates in Europe, Asia, and Africa and 85% cure rates in North and South
Why is Leishmaniasis difficult to treat?
Although its not known whether antimonials work directly
by acting against the parasite in the amastigote stage or indirectly by activating
macrophages and other components of the immune system, one recent study done
on cutaneous leishmaniasis suggests that they work by inducing high levels of
certain cytokines to positively affect macrophage populations. However, Leishmania
parasites are also trying their best negatively affect the function of macrophages.
Metacyclic promastigotes, the infective stage transmitted by the sand fly, manipulates
the complement system to get silently taken up by macrophages (no oxidative
burst takes place as a result of crosslinking). While in the macrophages, the
parasites down-regulate the expression of MHC class II molecules on the surface
of the macrophage; thus, hiding from the immune system and free to replicate.
Leishmania parasites weaken components of the immune system, making immuno-competent
communication difficult, and attempts to counter the immuno-boostering effects
of the standard treatments.
What are the obstacles to delivering effective treatments?
The standard treatments, as outlined above, make effective treatment
delivery exceedingly difficult. First of all, treatment is difficult to administer.
The standard antimonials must be administered by intravenous, intramuscular,
or by intralesion injections depending on disease progression; more systemic
disease calls for IV or IM while localized disease may be treated with intralesion
injections. In addition to requiring parenteral administration, antimonial therapy
is toxic, possible side effects are listed above. Because antimony is rapidly
excreted from the body, treatment with these agents must be repeated daily,
especially for individuals suffering from visceral disease. These therapies
are expensive and cost often becomes a barrier to treatment.
Perhaps the biggest challenge now with standard therapy is the
increasing resistance to antimonials. Although pentavalent antimonial therapy
can have a cure rate of 90 100% in cutaneous disease, a recent Brazilian
study found that cure rates were only 51 and 26% for patients with L.
braziliensis and L. guyanensis, respectively, thereby suggesting
resistance in Latin America. Resistance has long plagued effective treatment
of visceral leishmaniasis in India, making second round treatements and extended
hospitalization more common.
Leishmaniasis is a generally neglected disease, particularly in
terms of new drug development for which there is little potential for financial
return. Although there have been significant advances in treatment for leishmaniasis
in the past decade, these developments cannot match the scale of more profitable
drugs. The real challenge now will be proper translation, distribution and expansion
of the advances made; it is essential that the new treatment options become
truly accessible, not simply available, in endemic areas so that they may promote
healing and save lives.
(hexadecylphosphocholine) is the first oral drug to treat leishmaniasis. Miltefosine
works by inhibiting choline transport to promastigotes; its a phosphocholine
analog, a new class of inhibitors that may be used in the treatment of leishmania.
The drug seems quite promising against visceral leishmaniasis, giving a 97%
cure rate (100 mg/day for 28 days) in largest of four studies that took place
in the past five years. Miltefosine is a result of collaboration between the
government of India, the German biopharmaceutical company Zentaris and Tropical
Disease Research (TDR), a program sponsored by the WHO,UNDP, and World Bank.
The drug has been approved for use in India to treat visceral leishmaniasis.
Although half of all cases of visceral leishmaniasis occur in India, with this
new treatment the Indian government has set goal of elimination by 2010.
Side effects for Miltefosine do not seem to be as harsh as those
of the standard treatments. 38% of people being treated reported vomiting and
20% reported diarrhea. These gastrointestinal side lasted 1-2 days in _ of patients.
Side effects for liposomal amphotericin B were also minimal but its high cost
does not make it a good candidate for treatment in endemic areas. Miltefosine
is likely to cost less than current therapies and, as an oral drug, it is much
easier to administer.
recent study in Brazil has demonstrated that Azithromycin, a macrolide derivative
structurally similar to erythromycin, may be a good treatment option for cutaneous
leishmaniasis caused by L. braziliensis. Azithromycin is an oral medication
that can concentrate itself in various organs and tissues; its found in especially
high concentrations in phagocytes (leishmania promastigotes taken up by macrophages).
Treatments were administered orally according to schedules of 500 mg per day
for 3,5, and 10 days and of 1000 mg for 2 days. The study concluded with an
85% cure rate.
is a triazole antifungal agent that can be administered orally or parenterally.
Oral Fluconazole given at a dose of 200 mg per day for six weeks was evaluated
as a treatment for cutaneous leishmaniasis caused by L. major. A study
that took place in Saudi Arabia found that Fluconazole was useful and well tolerated.
It significantly improved chances that lesions would heal more rapidly. Rate
of complete healing was 1.76 times higher in Fluconazole group as in placebo
and 2.33 times as high at 6 weeks and 3 months, respectively. Fluconazole appears
to be a safe and effective treatment for cutaneous leishmaniasis caused by L.
Photodynamic therapy involves irradiating lesions in order to
induce healing. A photosensitizing compound must be applied and selectively
accumulate in the lesion and then the lesion is irradiated with visible light.
A recent study suggests Photodynamic therapy could be a promising treatment
for L. major. Aminolevulinic acid (ALA) was used as the photosensitizing
compound. This is the first time that photodynamic techniques have been applied
to a cutaneous parasitic infection. Photodynamic therapy as a treatment for
leishmaniasis is exciting because resistance seems quite unlikely and amastigotes
are eradicated from local site rapidly. There was a significant reduction in
lesion size just one week after treatment. Further randomized, controlled studies
will need to be done before photodynamic therapy could take a place among other
natural compound, PX 6518, extracted from leaves of the Maesa balansae plant
shows promise as an anti-leishmanial agent. The leaves are picked by villagers
by hand and sent to the Chemical Institute at the National Center for Natural
Science and Technology (NCNST) in Hanoi, Vietnam where the leaves are dried,
crushed to extract partially purified PX 6518. The partially purified powder
is sent to a company in Belgium, Tibotec. Tibotec is working in collaboration
with the NCNST and TDR (Tropical Disease Research) on this potential treatment.
PX 6518 has shown good anti-leishmanial activity after a single injection in
animal models. The compound is being analyzed in further studies and may be
an important treatment in the near future. PX 6518, if successful, would significantly
shorten the duration of treatment.
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