Treatment

Introduction

CUTANEOUS LEISHMANIASIS

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

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 form.

VISCERAL LEISHMANIASIS

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.

Standard Therapy

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lllllllllllllllllllllllllllllllMeglumine antimonate lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllStibogluconate

Cutaneous Leishmaniasis

Mucocutaneous Leishmaniasis

Visceral Leishmaniasis

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Other Common Therapies

Lipid-encapsulation amphotericin B:

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15-20 mg/kg total dose over 5 or more days. Less side effects. “AmBisome” is very expensive, a patient’s 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 therapy.

Paromomycin:

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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 America.

Why is Leishmaniasis difficult to treat?

Although it’s 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.

Promising New Therapies

Miltefosine

Miltefosine (hexadecylphosphocholine) is the first oral drug to treat leishmaniasis. Miltefosine works by inhibiting choline transport to promastigotes; it’s 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.

Azithromycin

A 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.

Fluconazole

Fluconazole 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. major.

Photodynamic Therapy

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 leishmaniasis treatments.

PX 6518

A 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.

References

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Bogitch, Burton J. and Thomas C. Cheng. Human Parasitology. Second Edition. Academic Press, San Diego. 1998. 107-112

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Kocyigit, Abdurrahim et al. Antimonial Therapy induces Circulating proinflammatory Cytokines in Patients with Cutaneous Leishmaniasis. Infection and Immunity, Vol 70, No. 12, Dec 2002. pp 6589-6591

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Murray, Henry, M.D. Kala-Azar - Progress Against a Neglected Disease. New England Journal of Medicine, Vol 347, No. 22. Nov 28, 2002

Prata, Aluizo et al. Efficacy of Azithromycin in the Treatment of Cutaneous Lishmaniasis. revista da Sociendade Brasileira de medicina Tropical. Jan-Fev, 2003. Vol 36 (1): 65-69

Sundar, Shyam, M.D. et al. Oral Miltefosine for Indian Visceral Leishmaniasis. New England Journal of Medicine, Vol 347, No. 22. Nov 28, 2002. pp 1739-1746

Syriopoulou, Vassiliki, et al. Two Doses of a Lipid Formulation of Amphotericin B for the Treatment of Mediterranean Visceral Leishmaniasis. CID vol 36, 1 March, 2003. pp 560-566

Tropical Disease Research. Fifteenth Programme Report, 1999-2000. Special Programme for Research and Training in Tropical Disease. www.whqlibdoc.who/hq/2001/TDR_GEN_01.5.pdf

World Health Organization. New Treatment for Leishmaniasis is 95% Effective. Bulletin of the World Health Organization. Vol 80 (8), 2002. pp 688