- Author: Craig G Stark, MD; Chief Editor: Pranatharthi Haran Chandrasekar, MBBS, MD more...
The goals of pharmacotherapy are to eradicate the leishmaniasis infection, to reduce morbidity, and to prevent complications, recurrence, and the development of mucocutaneous forms of the disease.
Antiparasitic pentavalent antimonial agents
Antiparasitic pentavalent antimonials, such as sodium stibogluconate (Pentostam) or meglumine antimonate, have been the mainstays of therapy for all forms of the disease. Until recently, sodium stibogluconate was the drug of choice in most areas and the only recommended treatment in the United States, but resistance is rising.
Pentavalent antimony is not marketed in the United States, but it can be obtained through the Centers for Disease Control and Prevention (CDC) Drug Service (404-639-3670), under an Investigational New Drug (IND) approved by the Food and Drug Administration (FDA), and by the CDC’S Institutional Review Board (IRB).
Cure rates for pentavalent antimony are 90-97% with 1-3 full intravenous treatment courses; however, the drawbacks are considerable. These drugs are expensive and difficult to obtain. They must be delivered parenterally, they have numerous adverse effects, they may have lot-to-lot variability, and they are becoming increasingly less effective because of the emergence of drug-resistant parasites (especially in certain countries such as India). Interferon-gamma plus antimony may be an alternative option with an acceptable cure rate.
In other parts of the world, intralesional injections have shown promise with less toxicity (although with much lower patient tolerability owing to the pain associated with the intralesional injections).
Alternative treatment regimens with acceptable cure rates but that are not FDA approved for treating selected cases of leishmaniasis are parenteral agents pentamidine and amphotericin B deoxycholate, as well as oral agents ketoconazole, itraconazole, and fluconazole.
However, although much has been made of the use of azoles for the Iraqi L major cutaneous disease, few practitioners in the field believe this is a prudent consideration for routine treatment of this disease. Liposomal amphotericin B has been used with good success in the treatment of cutaneous disease from many parts of the world and is gaining increased acceptance with many practitioners.
Although paromomycin also has acceptable cure rates, it is not available in the US or potentially available only through specific channels.
Liposomal amphotericin B
Amphotericin B in its liposomal form (as opposed to amphotericin B deoxycholate) is now considered to be the drug of choice for visceral leishmaniasis because of its shorter course and lower toxicity. This agent is not approved for the cutaneous or mucosal forms of the disease.
Cost issues prevent the use of liposomal drugs in most countries, where the mainstay of treatment is still prolonged intravenous treatment with antimonial agents, despite ever-increasing patterns of resistance and an increasing incidence of treatment failures. Alternative treatments, such as amphotericin B, should be used when resistance is endemic or when other reasons for using an alternative parenteral exist (eg, lower toxicity profile).
Miltefosine is the sole oral agent that has been shown to be effective against leishmaniasis. This medication was developed first as an antineoplastic agent and later found to have considerable antiproliferative activity against leishmaniasis as well as against other trypanosome parasites. It is an attractive agent in areas, such as India, that have drug resistance against traditional chemotherapy.
In August 2013, the CDC made available an expanded access investigational new drug (IND) protocol for miltefosine for treatment of free-living amebae (FLA) in the United States. In March 2014, the CDC approved miltefosine for the treatment of specific species that cutaneous, mucosal, and visceral leishmaniasis, in adults and adolescents who aged at least 12 years, weigh at least 66 lb, and are not pregnant or breastfeeding.
This medication is approved in India for visceral leishmaniasis.
Antifungal and antiparasitic medications are used in resistant leishmaniasis in combination with other agents. The mechanisms of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell. The major sterol in Leishmania organisms and fungi is ergosterol. Antiergosterol agents are marketed as antifungals.
When systemic agents are administered, monitor patients for adverse effects and complications common to the drug.
Traditionally, amphotericin B, produced by a strain of Streptomyces nodosus, is a fungistatic or fungicidal agent that attacks the ergosterol wall of the Leishmania parasite, causing intracellular components to leak with subsequent fungal cell death. Its use has been limited because of its high adverse effect profile, but newer lipophilic formulations that reduce toxicity have shown promise in treating resistant visceral and mucocutaneous disease. These formulations are taken up well by the reticuloendothelial system and poorly by the kidney, decreasing the risk of nephrotoxicity.
Liposomal amphotericin B has become the drug of choice in antimony-resistant infections (especially if contracted in India).
In addition to miltefosine, AmBisome is the only FDA-approved drug for the treatment of visceral leishmaniasis in the United States. This agent is available as a 100 mg/20 mL preparation.
Cure rates of 90% and higher have been observed in various studies, except possibly in patients with HIV infection. A short-course regimen consisting of a single dose of liposomal amphotericin followed by 7-14 days of miltefosine has resulted in cure rates greater than 90% in north India.
The high cost of liposomal amphotericin B is a disadvantage to its use in areas where visceral leishmaniasis is prevalent.
Ketoconazole is an imidazole broad-spectrum antifungal agent that inhibits synthesis of ergosterol, causing cellular components to leak and resulting in fungal cell death.
Itraconazole is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.
Xanthine Oxidase Inhibitors
Xanthine oxidase inhibitors may be added to first-line drugs for treatment against protozoal infections.
Allopurinol inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. This reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines.
Allopurinol is not effective as monotherapy for leishmaniasis.
Antiprotozoan compounds are the drugs of choice in patients with visceral leishmaniasis. Parasite biochemical pathways are sufficiently different from the human host to allow selective interference by chemotherapeutic agents in relatively small doses.
Protozoal infections are typically more severe in immunocompromised patients than in immunocompetent patients. These infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Primary immune deficiency is rare, whereas secondary deficiency is more common.
Immunosuppressive therapy, cancer and its treatment, infection with human immunodeficiency virus (HIV), and splenectomy all may increase vulnerability to infection. The infectious risk is proportional to neutropenia duration and severity.
Pentamidine is a first-line medication in cutaneous leishmaniasis except for L mexicana (ketoconazole 600 mg PO qd for 28 d). It is a treatment alternative in visceral leishmaniasis.
This agent inhibits growth of protozoa by (1) interacting with trypanosomal kinetoplast DNA, (2) interfering with polyamine synthesis by a decrease in the activity of ornithine decarboxylase, and (3) and inhibiting incorporation of nucleic acids into RNA and DNA, causing inhibition of protein and phospholipid synthesis.
Pentamidine is well absorbed and highly tissue bound. This medication is formulated as a sterile powder and must be reconstituted and administered as slow IV infusion or via the IM route. Because patients receiving daily injections do not reach a steady-state plasma concentration and elimination half-life is 12 days, a great deal of accumulation of pentamidine can occur in tissues such as the liver, kidney, and spleen.
Resistance to pentamidine is common in India, with high relapse rates reported.
Paromomycin is an oral orphan drug consisting of an amebicidal and antibacterial aminoglycoside obtained from a strain of Streptomyces rimosus that is active in intestinal amebiasis.
Paromomycin has a relatively favorable adverse effect profile, but it is not as effective as antimony or amphotericin B for visceral disease when used as monotherapy. Paromomycin can be used in combination with sodium antimony gluconate to reduce the total time of therapy, and it has better cure rates.
Intravenous and topical paromomycin products are not available in the United States.
Interferons are naturally occurring cytokines that possess various biologic functions, which include immunosuppressive action. They are produced by cells in response to viruses, double-stranded RNA, antigens, or mitogens, and are classified in relation to biochemical properties and cell of origin. Interferons are commercially produced with recombinant DNA technology.
Interferon gamma-1b is a naturally occurring cytokine that possesses antiviral, immunomodulatory, and antiproliferative activity. This agent is commercially available as a protein product manufactured by recombinant DNA technology.
Interferon gamma-1b is administered with sodium antimony gluconate (probably ineffective alone).
Miltefosine is a new oral drug that is now approved in the United States to treat cutaneous, mucocutaneous, and visceral disease from specific Leishmania species. The antiprotozoal effect is poorly understood.
Sodium stibogluconate is a compound available in English-speaking countries, and meglumine antimonate is a compound available in Latin American countries.
Sodium stibogluconate has been the drug of choice for the treatment of cutaneous and mucocutaneous leishmaniasis in the United States. This agent is also effective against visceral leishmaniasis and is often the first-line treatment outside the United States. Patients with long-standing disease may require long-term therapy. Although not FDA approved, sodium stibogluconate is currently available from the Centers for Disease Control and Prevention (CDC) as an investigational new drug (404-639-3670).
Sodium stibogluconate acts by interfering with the metabolism of the parasite. This agent may be administered intravenously (IV) or intramuscularly (IM), with similar pharmacokinetic parameters. IV use is preferred, because large volumes are required. Sodium stibogluconate is available only from the CDC at 100 mg/mL. Dilute each mL in 10 mL of 5% dextrose water, and administer it over 15 minutes to prevent thrombophlebitis.
This agent can be administered at recommended dose for 30 days without toxicity. Children often tolerate adverse effects better than adults and may not require electrocardiographic (ECG) monitoring.
Primary unresponsiveness ranges from 2-8%. The relapse rate is usually below 10%, but it has been reported to be as high as 30% in Kenya. An increasing incidence of resistance is reported in India.
Miltefosine is an alkylphosphocholine that was originally developed as an antineoplastic agent. The specific mode of action against Leishmania species is unknown but is likely to involve interaction with lipids (phospholipids and sterols), including membrane lipids, inhibition of cytochrome C oxidase (mitochondrial function), and apoptosis-like cell death.
In March 2014, the FDA approved miltefosine for visceral leishmaniasis caused by L donovani; cutaneous leishmaniasis due to L braziliensis, L guyanensis, and L panamensis; and mucosal leishmaniasis due to L braziliensis. FDA approval was for patients aged 12 years or older, those who weigh at least 66 lb, and those who aren't pregnant or breastfeeding.
Since 2002, this agent has rapidly become the drug of choice for visceral leishmaniasis in India. A short-course regimen consisting of a single dose of liposomal amphotericin followed by 7-14 days of miltefosine has resulted in cure rates greater than 90% in north India. Miltefosine is registered in India and Europe for the treatment of visceral leishmaniasis.
Its mechanism of action is likely due to inhibition of phospholipid and sterol biosynthesis via interference with cell signal transduction pathways. Resistance against miltefosine has been found.
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