Treatment options outlined for cutaneous leishmaniasis

December 2005

Leishmaniasis is a parasitic infection caused by more than 30 different species, all belonging to the genus Leishmania. There are various forms of the disease, and they range from cutaneous disease to the more lethal visceral infection.

Recently, there has been an increasing incidence of cutaneous leishmaniasis reported in the United States. This is due not only to foreign travel but also the deployment of military personnel to endemic areas. More than 90% of cutaneous disease occurs in Afghanistan, Peru, Brazil, Iran, Saudi Arabia and Syria. According to the American Society of Tropical Medicine and Hygiene, more than 600 soldiers have contracted cutaneous disease since spring 2003. Although the cutaneous form of the disease is often self-limiting, it does result in significant scarring and can spread to more invasive, mucocutaneous disease. Therefore, treatment may be considered to prevent these complications.

Although the decision of whether or not to treat requires a careful assessment of any given patient, Peter J. Weina, MD, PhD, et al has suggested the following criteria to determine the patients in which systemic therapy may have benefit.

• Lesions present on the face, ear or other cosmetically evident areas
• Lesions have not healed for many months
• Lesions are present over areas with joints where scaring could impede range of motion
• Lesions are present on the hands and feet
• Lesions suggest local evidence of dissemination
• Sores are occurring on immunocompromised hosts
• Multiple lesions (more than 5)
• Large lesions (>4 cm)

Once the decision to treat has been made, the selection of agent requires more careful consideration. Unfortunately, there are relatively few available drugs for leishmaniasis in the United States. Systemic medications that are approved by the FDA that have been used to treat leishmaniasis come from a variety of different therapeutic classes. None would be considered antiparasitic as their primary mode of activity. Factors that need to be considered for determining which treatment is best include the activity of the agent against disease from the likely location of infection (ie, South America vs. southern Europe). Also, the route of administration and toxicity profile of each agent are important.

Gold standard

The pentavalent antimonials are considered the gold standard for treatment of leishmaniasis. Two preparations are currently available abroad: sodium stibogluconate (Pentostam, GlaxoSmithKline) and meglumine antimoniate (Glucantime, Specia Rhone Poulenc). Neither of these agents is approved for use in the United States, but sodium stibogluconate can be obtained under an investigational New Drug Application held by the CDC. (For further information, contact the CDC drug service at 404-639-3670.) In addition, military personnel can obtain this agent through specific military protocols run at Army Medical Centers in Washington and San Antonio.

This therapy has been shown effective for treating cutaneous disease; however, several issues surrounding its administration can complicate therapy. These include the requirement to administer this agent parenterally. Both IV and intramuscular (IM) routes are acceptable. However, the requirement for IV access or the pain associated with repeated IM injections of more than 10 mL daily, respectively, can each be associated with administration-related complications.

The adverse effects of the drug can also be significant and include pancreatitis, hepatitis, marrow suppression and changes to the electrocardiograph (QT prolongation). Other common adverse effects include myalgias, fatigue, headache, rash and nausea. In most instances, these events resolve when therapy is discontinued, and, therefore, weekly monitoring is recommended to rapidly detect toxicities and address them as they occur.

A new treatment option has recently been approved for use in Columbia, Germany and India for treatment of visceral leishmaniasis. This phospholipid agent was originally developed as a therapeutic agent for breast cancer, but its activity against this parasite was recognized early in development. Miltefosine (Impavido, Zentaris) offers an oral treatment option for leishmaniasis. It is not, however, without adverse effects., which should be considered when initiating therapy. Elevated transaminases and reproductive health risks do occur.

Other available alternatives for systemic therapy include agents commonly employed for treatment and prophylaxis of fungal infections and Pneumocystis jiroveci. Amphotericin B deoxycholate, ketoconazole, itraconazole (Sporanox, Janssen Pharmaceutica), dapsone, pentamidine, allopurinol and liposomal amphotericin B have all been used.

Historically, amphotericin B and pentamidine were considered second line to the antimony compounds. This was primarily based on the toxicity associated with systemic administration of these drugs. These therapies have come back into favor because of newer, less toxic formulations (lipid preparations of amphotericin B), which provide treatment options for refractory disease. In fact, liposomal amphotericin B is the first agent approved for treatment of visceral leishmaniasis in the United States, but amphotericin B preparation is not currently recommended to treat cutaneous disease. The role of these agents in management of cutaneous disease remains controversial, as adverse effects are still common. Therefore, the risks may not be warranted for this form of disease.

Two azole antifungal agents, itraconazole and ketoconazole, have been used to treat cutaneous disease. Ketoconazole has the broadest spectrum, but it is, unfortunately, very poorly tolerated. Therapy-limiting adverse events include gastrointestinal symptoms (nausea, vomiting) as well as hepatotoxicity. Itraconazole, although better tolerated than ketoconazole, is associated with more treatment failures than the other azole compound. Use of both of these agents is limited by the fact that they demonstrate a slower activity against a limited number of strains.

Topical therapies

Localized therapy may be used. Although both the antimony compounds and paromomycin may be given intra-lesionally as a treatment modality, topical therapy is often considered adjunctive to systemic drugs.

Topical therapies to treat cutaneous leishmaniasis include both pharmacologic and non-drug modalities. The simplest of these treatments is the local application of heat. As Leishmania species are heat labile, this topical therapy has been proven effective in placebo-controlled studies. There is an FDA-approved device (ThermoMed, Thermosurgery Technologies) that treats cutaneous disease. This radio-frequency heat generator can be used either as a single treatment or as part of a multiple treatment course.

Localized immune modulation has also been considered as adjunctive therapy to systemic treatments. A recent report of topical imiquimod (Aldara, 3M) administered with a systemic antimonial compound was able to reduce scar formation in patients with cutaneous disease. The activity of this immune modulator in leishmaniasis appears to be derived from its ability to stimulate nitric oxide production by macrophages. It is important to note that trials of imiquimod without systemic antimony therapy were unsuccessful.

Other topical creams that produce nitric oxide may also be beneficial for cutaneous leishmaniasis. These include SNAP (S-nitroso-N-acetylpenicillamine), ascorbic acid, salicylic acid and nitrite creams. Studies with each of these agents have had variable results. It does appear that the vehicle plays an important role in the effectiveness of topical treatments. Further studies are needed to determine their exact role in therapy.

Given the limited treatment options for cutaneous leishmaniasis, it is important for clinicians to understand the available agents to treat this disease. The selection of therapeutic agent depends on the potential benefit of treatment vs. the significant toxicities of many of these therapies.

For more information:

• Miranda-Verastegui C, Llanos-Cuentas A, Arevalo I, et al. Randomized, double-blind clinical trial of topical imiquimod 5% with parenteral meglumine antimoniate in the treatment of cutaneous leishmaniasis in Peru. Clin Infect Dis. 2005;40:1395-1403.
• Weina PJ, Neafie RC, Wortmann G, et al. Old world leishmaniasis: an emerging infection among deployed US military and civilian workers. Clin Infect Dis. 2004;39:1674-1680.
• Herwaldt BL. Leishmaniasis. Lancet. 1999;354:1191-1199.