Comparison of the efficacy and pharmacology of formulations of amphotericin B used in treatment of leishmaniasis

PURPOSE OF REVIEW: Several lipid-based formulations of the antifungal and antiparasitic drug amphotericin B are now available on the market. The purpose of this review is to assess their efficacy against leishmaniasis in both experimental and clinical settings, and to point out new developments in the formulation of this antibiotic. RECENT FINDINGS: The development of resistance to pentavalent antimony compounds has shifted the emphasis to amphotericin B for the treatment of visceral leishmaniasis in India. Lipid formulations show good efficacy but are expensive. The treatment period with lipid formulations is shorter, however, which reduces hospitalization costs. As a result, in developed countries where these costs are an important proportion of the treatment, lipid formulations are preferred, whereas they remain largely inaccessible in developing countries. Lipid-associated amphotericin B has been found to be effective for secondary prophylaxis in HIV-positive patients, in studies carried out in European countries bordering the Mediterranean. SUMMARY: The reduced toxicity of lipid-based formulations of amphotericin B is no longer in doubt. In India, their efficacy against visceral leishmaniasis and shorter treatment periods compared with the conventional formulation with deoxycholate has to be counter-balanced against the very high cost. By contrast, in developed countries around the Mediterranean, where leishmaniasis occurs mainly in immunocompromised individuals, lipid formulations have become the treatment of choice for visceral disease. The efficacy against cutaneous lesions is variable, however, and in some reports oral miltefosine was active after failure of treatment with amphotericin B.     

Recent strategies for the chemotherapy of visceral leishmaniasis

Visceral leishmaniasis is a widespread and deadly disease. First-line drugs are antimonials, but amphotericin B and its lipid formulations B is used for treating visceral leishmaniasis that is unresponsive to antimony. New therapeutic approaches are being actively developed, including the following: use of drug carriers targeted specifically to the parasite location, thus reduce adverse effects of drug; use of immunomodulating drugs; evaluation of natural products; pharmacokinetic studies; and drug combinations. Recent clinical trials with paromomycin and miltefosine were successful and these drugs appear to be promising for the future therapy of visceral leishmaniasis. Furthermore, identification and therapeutic evaluation of specific targets in the Leishmania organism could lead to new compounds, such as antileishmanial drugs and reversal agents of drug resistance.     

Leishmaniasis: current status of available drugs and new potential drug targets

The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.     

New world cutaneous leishmaniasis in travellers

As travel to Latin America has become increasingly common, cutaneous leishmaniasis is increasingly seen among returning travellers--eg, the number of observed cases has doubled in the Netherlands and tripled in the UK in the past decade. A surprisingly high proportion of cases were acquired in rural or jungle areas of the Amazon basin in Bolivia. The clinical manifestations range from ulcerative skin lesions (cutaneous leishmaniasis) to a destructive mucosal inflammation (mucocutaneous leishmaniasis), the latter usually being a complication of infection with Leishmania (Viannia) braziliensis. PCR is now the diagnostic method of choice, since it has a high sensitivity and gives a species-specific diagnosis, allowing species-specific treatment. Treatment of cutaneous leishmaniasis aims to prevent mucosal invasion, to accelerate the healing of the skin lesion(s), and to avoid disfiguring scars. Pentavalent antimonials drugs are still the drug of choice for many patients. However, a high rate of adverse events, length of treatment, and relapses in up to 25% of cases highlight the limitations of these drugs. Although only used in a small number of patients thus far, liposomal amphotericin B shows promising results. Further studies are needed to find efficacious and better-tolerated drugs for new world leishmaniasis.     

Successful treatment of cutaneous leishmaniasis with lipid formulations of amphotericin B in two immunocompromised patients

Pentavalent antimonial drugs are habitually the first choice for treating leishmaniasis, although they possess well-known toxicity and may present some therapeutic failure. Lipid formulations of amphotericin B (LFAB) have been increasingly used for treating several types of leishmaniasis. However, the administration of such lipid formulations specifically to patients with cutaneous leishmaniasis (CL) is still rare, including immunocompromised patients to whom standard treatments are more frequently contraindicated. We describe here two cases of immunocompromised patients with CL, one of them with AIDS, representing the first case of AIDS and CL co-infection treated with LFAB described in the literature. The patient achieved therapeutic success with a total 1.500 mg dose of amphotericin B colloidal dispersion. The other had diabetes mellitus as well as kidney failure and was under dialysis, having obtained the healing of lesion with a total dose of 600 mg of liposomal amphotericin B. Thus, the authors suggest that LFAB can represent a safe, efficient and less toxic therapeutic alternative to pentavalent antimonials, as well as to the so-called second line drugs, pentamidine and amphotericin B deoxycholate.     

Oral miltefosine treatment in children with visceral leishmaniasis: a brief review.

Visceral leishmaniasis (VL) or kala-azar is an infection disease caused by hemiflagellate protozoan parasites (Leishmania donovani) and transmitted to humans by the phlebotomine sandfly. Leishmaniasis is distributed worldwide and 13 million people are estimated to be infected, with about 1.8 million new cases each year. All antileishmanial drugs are toxic and most have to be used parenterally for prolonged period. The therapy has been further complicated by large number of infected children and declining effectiveness of pentavalent antimonial compounds. Although the lipid formulations of amphotericin B are an important advance in therapy, their high cost precludes their use. Miltefosine, a phosphocholine analogue originally developed as antimalignant drug, has been found to be highly active against Leishmania in vitro and in animal model. Based on these experiences this drug was tried against human visceral leishmaniasis and found to be highly effective in children. The aim of this review is to evidence the pharmacodymamic and pharmacokinetic characteristics and the safety, tolerance and efficacy of this drug for treatment of visceral leishmaniasis in children.     

Imported mucocutaneous leishmaniasis in New York City. Report of a patient treated with amphotericin B.

A case of mococutaneous leishmaniasis in a patient referred to Memorial Sloan-Kettering Cancer Center, New York, with a presumptive diagnosis of lethal mid-line granuloma is described. The patient had lived in Bolivia and had been treated with antimony during and after which his mucosal lesions progressed. These lesions completely healed with 971 mg of amphotericin B. Mucocutaneous leishmaniasis is endemic in many areas of Central and South America and may occur in patients in the United States who have lived in or traveled to these areas. Organisms may be difficult to identify, and multiple biopsies and cultures may be necessary. The use of amphotericin B for the treatment of leishmaniasis is reviewed. It is an effective alternative to antimony therapy, and in some cases resistant to antimony, it may be the drug of choice.     

Recent developments in Leishmaniasis: Epidemiology,diagnosis, and treatment

The outbreaks of cutaneous disease caused by Leishmania tropica in Afghan refugees, visceral disease in Sudanese refugees, and cutaneous disease caused by Leishmania major in American forces in Iraq are examples of the large number of cases of leishmaniasis that can result when naive human populations intrude into regions where transmission is endemic. Injections of pentavalent antimony for 20 to 30 days have been the standard treatment for all forms of leishmaniasis, but resistance is growing and antimonials have moderate toxicity. Two major advances in the treatment of visceral leishmaniasis have been made in the past few years. Liposomal amphotericin B cures virtually all patients, with little side effects. Miltefosine is the first oral agent that is effective. For cutaneous disease, alternatives to antimony have been effective in certain regions but have not yet been generally evaluated.     

Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World

Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and pentamidine. Although these drugs have been used for decades, there are no systematic reviews about their safety. The objective of this review was to identify and classify the main adverse effects associated with these drugs and to estimate the frequency of these effects, whenever possible. Intervention studies, case series and case reports containing information regarding clinical, laboratory or electrocardiographic adverse effects of drugs used for the treatment of cutaneous leishmaniasis were systematically retrieved from 10 databases searched between August 13, 2008 and March 31, 2009. The 65 studies included in this review had treated a total of 4359 patients from 12 countries infected with eight different Leishmania species. Despite the small number of drugs used in these studies, a wide variability in the therapeutic regimens was observed. As a consequence, the adverse effects of pentavalent antimonials and pentamidine needed to be classified jointly according to system, irrespective of formulation, daily dose, duration of treatment, and route of administration. The frequencies of adverse effects were calculated based on the data of 32 articles involving 1866 patients. The most frequently reported clinical adverse effects of pentavalent antimonials and pentamidine were musculoskeletal pain, gastrointestinal disturbances, and mild to moderate headache. Electrocardiographic QTc interval prolongation and a mild to moderate increase in liver and pancreatic enzymes were additional adverse effects of pentavalent antimonials. Patients treated with liposomal amphotericin B had mild dyspnea and erythema. The adverse effects associated with miltefosine were vomiting, nausea, kinetosis, headache, diarrhea, and a mild to moderate increase in aminotransferases and creatinine. Although closer surveillance is needed for the treatment of cutaneous leishmaniasis, antileishmanial drugs are basically safe and severe side effects requiring the discontinuation of treatment are relatively uncommon.     

Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980-2004

The state of Bihar in India carries the largest share of the world's burden of antimony-resistant visceral leishmaniasis. We analysed clinical studies done in Bihar with different treatments between 1980 and 2004. Overall, 53 studies were included (all but one published), of which 15 were comparative (randomised, quasi-randomised, or non-randomised), 23 dose-finding, and 15 non-comparative. Data from comparative studies were pooled when appropriate for meta-analysis. Overall, these studies enrolled 7263 patients in 123 treatment arms. Adequacy of methods used to do the studies and report on them varied. Unresponsiveness to antimony has developed steadily in the past to such an extent that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy. The classic second-line treatments are unsuited: pentamidine is toxic and its efficacy has also declined, and amphotericin B deoxycholate is effective but requires hospitalisation for long periods and toxicity is common. Liposomal amphotericin B is very effective and safe but currently unaffordable because of its high price. Miltefosine-the first oral drug for visceral leishmaniasis-is now registered and marketed in India and is effective, but should be used under supervision to prevent misuse. Paromomycin (or aminosidine) is effective and safe, and although not yet available, a regulatory submission is due soon. To preserve the limited armamentarium of drugs to treat visceral leishmaniasis, drugs should not be deployed unprotected; combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems. India, Bangladesh, and Nepal agreed recently to undertake measures towards the elimination of visceral leishmaniasis. The lessons learnt in Bihar could help inform policy decisions both regionally and elsewhere.     

Post-Kala-Azar dermal leishmaniasis in an HIV-1-infected woman: recovery after amphotericin B following failure of oral miltefosine

We describe a case of post-kala-azar dermal leishmaniasis occurring after diagnosis of visceral leishmaniasis in an HIV-1-infected woman. The skin lesions did not recover after treatment with oral miltefosine at 100 mg/day for five cycles of 28 days but responded to treatment with liposomal amphotericin B.     

Visceral leishmaniasis: elimination with existing interventions

The world's burden of infectious diseases can be substantially reduced by more-effective use of existing interventions. Advances in case detection, diagnosis, and treatment strategies have made it possible to consider the elimination of visceral leishmaniasis in the Indian subcontinent. The priority must now be to effectively implement existing interventions at the community level by actively finding cases in endemic villages and treating them with single-dose liposomal amphotericin B at primary-health-care centres. Once the elimination target of one case per 10,000 population has been reached, combination therapies involving miltefosine and paromomycin can be introduced to ensure long-term availability of several drugs for visceral leishmaniasis and to protect against resistance.     

Visceral leishmaniasis: An immunological viewpoint on asymptomatic infections and post kala azar dermal leishmaniasis

Elimination of visceral leishmaniasis is a priority programme in Indian subcontinent.The World Health Organization has set a new target to eliminate kala-azar by the year 2020 as previous target elimination year(2015) has passed.The elimination programme has successfully curbed the rate of infection in endemic regions; however, there are still few challenges in its route.The current drug control regime is extremely limited and comprises only two(amphotericin B and miltefosine) drugs, which are also susceptible for parasites resistance.Moreover, these drugs do not produce sterile cure, and cured patients may develop post kala-azar dermal leishmaniasis even after a decade of cure leaving behind a potent source of parasitic reservoirs for further disease transmission.A significant proportion of endemic population remain seropositive but aymptomatic for many years without any clinical symptom that serve as latent parasitic reservoirs.The lack of tools to identify live parasites in asymptomatic infections and there association in disease transmission, parameters of sterile cure along with post kala-azar dermal leishmaniasis progression remain a major threat in its elimination.In this review, we discuss the potential of host immune inhibitory mechanisms to identify immune correlates of protective immunity to understand the mystery of asymptomatic infections, sterile cure and post kala azar dermal leishmaniasis.     

Atypical multifocal cutaneous leishmaniasis in an immunocompetent patient treated by liposomal amphotericin B

Multifocal cutaneous leishmaniasis (MCL) is an extremely rare disease in South Europe, and it mainly affects immunosuppressed patients.We report a case of MCL in an immunocompetent patient affected by type II diabetes mellitus that clinically presented with three large ulcers on the legs with a non-linear distribution and several months later with an erythematous-crusty lesion on the left cheek. Diagnosis of leishmaniasis due to Leishmania infantum was formulated by PCR analysis. Given the diffuse and wide lesions, the unresponsiveness to previous local and systemic treatments, a parenteral i.v. therapy with liposomal amphotericin B at a dosage of 3 mg/kg/day for 5 days was started and then repeated on the 14th and 21st days, leading to a clear improvement in the clinical picture.The different clinical expression and the evolution of leishmaniasis depend on both the parasite subtype and the host's immunity status. L. infantum manifests with an atypical clinical feature more frequently than other species. The differential diagnosis for multiple ulcers must include several skin diseases, such as cutaneous TBC, bacterial ulcers, traumatic ulcers, deep mycoses, and sarcoidosis. However, an MCL should always be considered in subjects coming from endemic areas. In our case, the multifocality, the size of the lesions and the unresponsiveness to other treatment indicate a short course treatment with liposomal B amphotericin that proved to be a suitable alternative to traditional drugs used in MCL.     

Treatment of leishmaniasis in HIV-positive patients

Although, in southern Europe, there has been considerable experience in the treatment of visceral leishmaniasis (VL) in HIV-positive patients, the optimal therapy has yet to be established. Pentavalent antimony salts, free amphotericin B deoxycholate (ABD) and lipidic formulations of amphotericin B are the drugs most commonly used. Treatment with pentavalent antimonials requires daily injections for 28 days, is not well tolerated and leads to initial clinical cure in only 66% of the co-infected cases. Free ABD has to be given, intravenously, for just as long, has significant toxicity and leads to initial clinical cure in even fewer cases (62%). In a prospective, comparative trial, treatment of co-infected cases with a pentavalent antimonial was found to have similar efficacy and toxicity to treatment with free ABD. The duration of treatment and the associated toxicity may both be reduced by the use of lipidic formulations of amphotericin B. Anecdotal evidence and the results of non-randomized trials indicate that treatment with liposomal amphotericin B is highly effective. In a comparative trial, amphotericin B lipid complex was found to be not only as effective as a pentavalent antimonial but also better tolerated. At the moment, however, such lipidic formulations have only been tested against VL/HIV cases in Europe, not elsewhere in the world, and they remain very expensive. However successful the treatment in terms of initial clinical cure, almost all VL/HIV cases develop VL relapses. Although the data available on secondary prophylaxis are limited and often inconclusive, it appears that regular treatment with a pentavalent antimonial drug, liposomal amphothericin B or amphotericin B lipid complex can reduce the incidence of leishmanial relapses in HIV-positive patients with VL. The development of new regimens, use of new oral drugs (such as miltefosine) and the development of new antileishmanial drugs could all improve the treatment of HIV-related VL in the future.     

Advances in the treatment of leishmaniasis

PURPOSE OF REVIEW: Treatment of leishmaniasis is far from satisfactory: all antileishmanial drugs are toxic and most have to be used parenterally for prolonged periods, especially for visceral leishmaniasis. In recent years, there has been a steady erosion in the efficacy of pentavalent antimony to cure visceral leishmaniasis in Bihar, India. In addition, several new antileishmanial formulations have become available. RECENT FINDINGS: Through the publication of three studies from Africa, generic sodium stibogluconate, which is a fraction of the price of the branded drug Pentostam, has proven to be equivalent to Pentostam both in terms of safety and efficacy. The first oral drug, miltefosine, has been approved for treating visceral leishmaniasis in India, and preliminary reports of its efficacy against cutaneous leishmaniasis have been published. Interesting studies on successful low/single dose treatment of Indian visceral leishmaniasis with liposomal amphotericin B have been published. Several trials using different approaches towards treating cutaneous leishmaniasis are also reviewed. The results of clinical trials of two oral compounds are reported - fluconazole in treating cutaneous leishmaniasis was found to be safe and effective, whereas sitamaquine (WR6026) for visceral leishmaniasis was found to be toxic with poor efficacy. SUMMARY: Generic stibogluconate enables the cost effective treatment of all forms of leishmaniasis as it remains the most important antileishmanial drug in most parts of the world. In India, successful single dose AmBisome for visceral leishmaniasis makes therapy simple and enables mass treatment, provided the drug cost is brought down. For cutaneous leishmaniasis, two new oral drugs, fluconazole and miltefosine, provide wider options to the clinician.     

First report on Ambisome-associated allergic reaction in two Sudanese leishmaniasis patients

Post kala-azar dermal leishmaniasis (PKDL) and mucosal leishmaniasis (ML) are serious clinical forms of leishmaniasis caused by Leishmania donovani parasites in Sudan. Although pentavalent antimonys are used as the first line of treatment of all clinical forms of leishmaniasis, persistent PKDL and ML patients are treated with liposomal amphotericin B (Ambisome) as a second-line drug. In this work, we report the development of allergic reactions by a PKDL and a ML Sudanese patient to Ambisome. The findings warrant future close supervision of patients to be treated with the drug.     

HISTORICAL SERIES OF PATIENTS WITH VISCERAL LEISHMANIASIS TREATED WITH MEGLUMINE ANTIMONIATE IN A HOSPITAL FOR TROPICAL DISEASES,MACEIó-AL, BRAZIL

Introduction: Visceral leishmaniasis is an endemic protozoan found in Brazil. It is characterized by fever, pallor, hepatosplenomegaly, lymphadenopathy, and progressive weakness in the patient. It may lead to death if untreated. The drug of choice for treatment is meglumine antimoniate (Glucantime^®). The aim of this study was to evaluate patients with visceral leishmaniasis according to criteria used for diagnosis, possible reactions to Glucantime^® and blood pressure measured before and after treatment. Methods: 89 patients admitted to the Teaching Hospital Dr. Hélvio Auto (HEHA) in Maceió-AL, in the period from May 2006 to December 2009 were evaluated. Data were collected on age, sex, origin, method of diagnosis, adverse effects of drugs, duration of hospitalization, duration of treatment and dosage up to the onset of adverse effects. Results: There was a predominance of child male patients, aged between one and five years old, from the interior of the State of Alagoas. Parasitological diagnosis was made by bone marrow aspirate; three (3.37%) patients died, 12 (13.48%) had adverse reactions and treatment was changed to amphotericin B, and 74 (83.14%) were cured. Changes that led to replacing Glucantime^® were persistent fever, jaundice, rash, bleeding and cyanosis. Conclusion: During the study, 89 patients hospitalized for VL were analyzed: 74 were healed, 12 were replaced by amphotericin B treatment and three died. Most of them were under five years old, male and came from the interior. The dosage and duration of treatment with Glucantime^® were consistent with that advocated by the Ministry of Health. Persistence of fever, jaundice, rash, cyanosis and bleeding were the reactions that led the physician to modify treatment. No change was observed in blood pressure before and after treatment. This study demonstrated the work of a hospital, a reference in the treatment of leishmaniasis, which has many patients demanding its services in this area. It demonstrates that this disease is still important today, and needs to be addressed properly to prevent injury and death due to the disease.     

Actualités sur les leishmanioses viscérales

During the last decade, visceral leishmaniasis has been reconsidered in its epidemiology and strategies for diagnosis, treatment and prevention. This vectorial disease, responsible for more than 50,000 deaths each year across India, East Africa, South America, the Mediterranean area, Central Asia and China, is currently spreading over new territories. This formerly rural disease has even reached cities in South America. This spreading is caused by environmental changes due to global warming or human activity, and by the movement of workers and refugees. As a consequence, the burden of HIV/Leishmania coinfection is increasing in many developing countries even though effective antiretroviral therapy has led to a marked decrease in its incidence in Europe. The disease is now handled differently than it was 10 years ago: PCR has become the most accurate tool for diagnosis and follow-up in developed countries, and field diagnostic tools have been developed (antigenuria, rK39 dipstick). While resistance to antimoniate has appeared in India and Europe, new therapies have been evaluated such as miltefosine, the first oral therapy, or short treatment with liposomal amphotericin B. In France, liposomal amphotericin B has supplanted antimoniate meglumine because of better tolerance and shorter hospitalization duration. Protecting dogs through immunization or collars impregnated with deltamethrin proved effective to prevent zoonotic leishmaniasis due to Leishmania infantum.     

Drug resistance in Indian visceral leishmaniasis

Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.