Introduction

Leishmaniasis is one of the top 10 neglected tropical diseases, and it is older than most civilisations. The disease records date back 3500 years before the common era (BCE). However, more than 12 million people currently have leishmaniasis worldwide.

Leishmaniasis is widespread in 99 countries, with cutaneous leishmaniasis present in 90 countries, visceral leishmaniasis (VL) in 80 countries, and both forms are present in 71 countries.¹

The treatment approach for leishmaniasis has evolved over time. It began with early vaccination attempts in the Middle East and Central Asia. As time went on, pentavalent antimonials became the standard treatment. Now, lipid formulations of amphotericin B advancements offer safer and more effective treatment options.²

This article will explain the different treatment options used to manage leishmaniasis over time.

Understanding Leishmaniasis

Leishmaniasis is a disease caused by Leishmania parasites, which belong to the Trypanosomatidae family. These parasites are spread to humans through bites from infected female sandflies, usually of the Phlebotomus or Lutzomyia species.

The disease is commonly found in tropical and subtropical regions including Asia, Africa, the Middle East, and Latin America.

Once the parasite enters the body, it moves into compartments in the immune cells known as phagolysosomes, which are responsible for destroying pathogens. Depending on the subtype of phagocytic cells affected, the disease presents as either cutaneous leishmaniasis or visceral leishmaniasis.

In cutaneous leishmaniasis, the Leishmania protozoa affects special cells of the immune system, called macrophages, found in the skin. The parasite fills up these cells, causing them to burst and release the parasite into nearby macrophages, spreading the infection.

In visceral leishmaniasis, the parasite affects cells in the liver, spleen, bone marrow, and lymph nodes, especially around the intestines.²

Clinical forms and symptoms of Leishmaniasis 

Leishmaniasis can appear in three main forms: cutaneous, mucocutaneous, and visceral.

Cutaneous leishmaniasis is the most common form. It can be further divided into localised cutaneous and diffuse cutaneous types.

In the localised type, the first signs usually appear 2 to 4 weeks after infection. During this time, a small raised bump could develop at the site of the sandfly bite; this bump could be asymptomatic (painless and not itchy), symptomatic (painful or itchy), or it could form as a nodule, which is a firm lump under or on the skin. Over time, the bump becomes larger and turns into a clear round sore with raised purple edges. The surface layer of the skin begins to break down, forming an open ulcer. These ulcers usually heal on their own within 2 to 5 years, depending on the type of Leishmania species involved, and often leave a sunken scar.

Mucocutaneous leishmaniasis occurs when the infection spreads to the mucous membranes of the nose, mouth, or throat, and typically develops after the skin ulcers have healed. The symptoms could appear within 2 years, however in some cases, they are delayed for multiple years. This form is usually caused by Leishmania braziliensis.

Visceral leishmaniasis, also called kala-azar, affects the internal organs. It commonly leads to fever, enlarged spleen (splenomegaly), high levels of antibodies in the blood (hypergammaglobulinemia), which indicates an immune response, and low blood cell counts (pancytopenia), which leads to anaemia and increases the risk of infections.²

Diagnosis of Leishmaniasis

Diagnosis relies on examining tissue samples under a microscope, which is the gold standard for identifying the parasite directly.

Clinicians could perform parasitic cultures, however, this method often requires more time and could give inconsistent results.

Molecular techniques, such as polymerase chain reaction (PCR), detect parasite DNA with greater sensitivity, allowing identification even when traditional methods fail.

In visceral leishmaniasis, serological tests, such as the rK39 rapid test, detect antibodies in the patient’s blood; this provides a faster and less invasive diagnostic option and could be particularly useful where resources are limited.²

Therapeutic approaches to Leishmaniasis

Historical treatment: antimonial therapy

Different treatment strategies have been used to manage leishmaniasis. In cases of cutaneous leishmaniasis, early methods included scraping or removing lesions, along with the use of heat, copper sulfate, plant extracts, and honey. Trivalent antimonials were used as treatment, however, they were soon abandoned due to their instability and high toxicity.

In the early 20th century, the discovery of pentavalent antimonials marked a turning point in the treatment of leishmaniasis. To that extent, antimony potassium tartrate represented a significant advancement in anti-leishmanial therapy.

Despite this progress, treatment with antimony potassium faced major setbacks, including high toxicity, prolonged treatment duration, and the emergence of drug resistance. In 1947, researchers introduced the less toxic sodium stibogluconate, which achieved recovery rates as high as 90%, making it the preferred treatment for many years.

 However, resistance to sodium stibogluconate increased over time, and the treatment itself was demanding. It required twenty daily infusions that raised pancreatic enzymes in over 90% of patients, raised liver enzymes, and resulted in joint or muscle pain. In rare cases, patients developed shingles or experienced heart rhythm changes. These concerns pushed researchers to look for safer and more effective options, leading to the treatment we have today.^3,4

Current treatment landscape

Amphotericin B emerged as an alternative in the 1960s, when antimonial therapies proved ineffective, particularly for cases of mucosal and cutaneous leishmaniasis. Even though it showed strong efficacy, amphotericin B use was limited since it caused serious kidney and systemic toxicity and required intravenous administration. Ultimately, these issues made it difficult to administer treatment in regions where the disease was common. To overcome these challenges, researchers developed lipid-based formulations, which were safer and made treatment more accessible.

The breakthrough: liposomal amphotericin B

Liposomal amphotericin B marked a turning point in leishmaniasis treatment because it encapsulates the drug in a lipid form to enhance its delivery to infected tissues while reducing adverse events.

A study in the Indian Subcontinent found that a single 10 mg/kg dose of liposomal amphotericin B cured 95.7% of patients with visceral leishmaniasis. Since then, the World Health Organization has recommended liposomal amphotericin B for treating visceral leishmaniasis in South Asia. In addition to the high efficacy of liposomal amphotericin B, the ability to administer a single dose improves patient compliance, cuts down hospital stays, and reduces overall costs.⁵

How does it work?

Liposomal amphotericin B is formulated by incorporating cholesterol and phospholipids into a small, single-layered unilamellar liposome (spherical capsule); this minimises interactions with other cell membranes in the body, reduces toxicity, and reduces drug accumulation in non-target tissues, such as the liver and spleen.

Liposomal amphotericin B binds to compounds on the parasite called ergosterol, which help the parasite build its cell membrane. By binding to ergosterol, the drug disrupts the membrane’s integrity, which ultimately kills the parasite.

This targeted design helps the drug concentrate in the organs most affected by visceral leishmaniasis, such as the spleen, liver, and bone marrow—where the parasite tends to hide. The liposomal form enables the drug to stay in the bloodstream longer, improves the efficacy, and lowers the need for repeated dosing. Therefore, the treatment is simpler and more practical in regions with limited access to healthcare.

FAQs

What is the most effective treatment for visceral leishmaniasis?

Currently, liposomal amphotericin B (AmBisome) is the most effective treatment, especially in South Asia. A single dose has high recovery rates and fewer side effects.

Why are antimonials still in use despite their side effects?

In some regions, antimonials are still used because they are affordable and locally available. However, resistance and toxicity remain major concerns.

Is leishmaniasis curable?

Yes, most forms of leishmaniasis can be cured if diagnosed early and treated adequately. However, delayed treatment can lead to complications, especially in visceral cases.

Is there a vaccine for leishmaniasis?

No licensed vaccine exists, however, research is ongoing. Several vaccine candidates are currently in development and testing.

Can someone get leishmaniasis more than once?

Yes, especially if they live in or return to an area where the disease is common. Immunity can 

develop after some infections, however, it is not always long-lasting or complete.

Summary

The treatment of leishmaniasis has come a long way from traditional remedies and toxic antimonial drugs to safer and more effective options, such as liposomal amphotericin B. The change in treatment highlights major progress: Treatments are now better tolerated, easier to administer, and more accessible in areas where the disease is common. As research continues, there is hope for newer therapies that are even safer, simpler, and more affordable, thus making it easier to manage and eventually eliminate leishmaniasis.