American cutaneous leishmaniasis: a comparison of three sodium stibogluconate treatment schedules

Thirty-six patients with American cutaneous leishmaniasis were randomized to receive intravenous sodium stibogluconate for 10 days at a dose of 600 mg antimony (Sb) per day by one of three schedules: once daily by rapid infusion (A), by continuous 24 hr infusion (B), or in divided doses every eight hours by rapid infusion (C). Patients not cured after initial treatment were rerandomized to one of the other treatment schedules. An additional 19 patients who were not part of the randomized study received standard (STD) sodium stibogluconate treatment (600 mg Sb once daily by rapid infusion for 10 days, identical with schedule A). In the randomized study, the overall cure rate after the first course of treatment was 64%, but was higher for schedule A (100%) than for B (50%) or C (42%) (P less than 0.01). Considering all courses of treatment, schedule A was more effective (94%) than B (53%) or C (43%) (P less than 0.01). Paradoxically, patients in group A had a higher cure rate than patients in group STD (42% after the first course of treatment and 51% when all courses of treatment were considered). Side effects were mild and well tolerated. Total side effects were more frequent in groups B + C (52%) than A + STD (23%) due to an increased incidence of subjective complaints (26% vs. 10%, P less than 0.05) in patients receiving other than once daily rapid infusion. We conclude that giving the same total amount of sodium stibogluconate in three divided doses or by continuous infusion offers no advantage over standard, once daily treatment of American cutaneous leishmaniasis.     

Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala.

To determine the relative efficacy and toxicity of stibogluconate and ketoconazole for the treatment of cutaneous leishmaniasis, a comparative trial was conducted in which 120 Guatemalan men with parasitologically proven cutaneous leishmaniasis were randomly divided into three treatment groups: sodium stibogluconate (20 mg of antimony per kilogram per day intravenously for 20 days), ketoconazole (600 mg per day orally for 28 days), and placebo. Treatment outcome was influenced by species. Among patients infected with Leishmania braziliensis, 24 (96%) of 25 in the stibogluconate group but only 7 (30%) of 23 in the ketoconazole group responded. Among Leishmania mexicana-infected patients, only 4 (57%) of 7 in the stibogluconate group but 8 (89%) of 9 in the ketoconazole group responded. These differences emphasize the importance of speciation in the treatment of leishmaniasis.     

Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies.

Pentavalent antimonial compounds have been the mainstay of the treatment of visceral, cutaneous, and mucosal leishmaniasis for approximately half a century. Pentostam (sodium stibogluconate) is the pentavalent antimonial compound available in the United States (through the Centers for Disease Control). As dosage regimens for treating leishmaniasis have evolved, the daily dose of antimony and the duration of therapy have been progressively increased to combat unresponsiveness to therapy. In the 1980s, the use of 20 mg/kg/day (instead of 10 mg/kg/day) of antimony was recommended, but only to a maximum daily dose of 850 mg. The authors have concluded on the basis of recent efficacy and toxicity data that this 850-mg restriction should be removed; the evidence to date, which is summarized here, suggests that a regimen of 20 mg/kg/day of pentavalent antimony, without an upper limit on the daily dose, is more efficacious and is not substantially more toxic than regimens with lower daily doses. We recommend treating all forms of leishmaniasis with a full 20 mg/kg/day of pentavalent antimony. We treat cutaneous leishmaniasis for 20 days and visceral and mucosal leishmaniasis for 28 days. Our judgment of cure is based on clinical criteria.     

Pharmacokinetics of pentavalent antimony (Pentostam) in hamsters

Pentavalent antimony (Sb) is the classical treatment for visceral and cutaneous leishmaniasis. We investigated Sb levels in serum, liver, spleen, and skin of hamsters administered therapeutic dosages of Sb (600 and 300 mg Sb/kg). Single administration of Sb was more effective against hepatic parasites than dividing the same total dose into multiple administrations, which suggests that for elimination of hepatic parasites in vivo, peak Sb concentration is more important than total area-under-the-curve levels. Serum Sb declined with an initial half-life of 1 hr. Skin Sb levels (352 micrograms Sb/g 1 hr after 600 mg Sb/kg) were initially higher than liver levels (77 micrograms Sb/g) or splenic levels (156 micrograms Sb/g), but levels were comparable (7-24 micrograms Sb/g) in the three organs by 8 hr after dosing. The generally comparable levels of Sb in the skin and in the visceral organs support the present clinical practice of administering the same dosage of Sb for cutaneous and visceral leishmaniasis.     

Manifestations of paediatric Leishmania infantum infections in Malta

Leishmania infantum is endemic in the Maltese archipelago, a group of islands in the Mediterranean which are visited frequently by tourists from Northern European countries. The burden of leishmaniasis is highest in children who may present with cutaneous or visceral manifestations. We describe systematically the manifestations, diagnosis and management of leishmaniasis in children <14 years of age, who had a histopathological diagnosis of leishmaniasis in Malta, from 2004 to 2008. Eleven children were diagnosed with leishmaniasis; 8 children (15-44 months of age) had visceral disease and three (aged 9-13 years) suffered cutaneous infections. Prolonged high grade fever, pallor, hepatosplenomegaly, and pancytopenia were common presenting features of visceralisation. Diagnosis was based on the visualisation of amastigotes from bone marrow aspirates. Pentavalent antimonials were associated with treatment failure in two children, whilst liposomal amphotericin B was curative in all. Children with cutaneous leishmaniasis had dry crusted ulcero-nodular lesions on exposed areas which responded to intra-lesional instillation of sodium stibogluconate or to cryotherapy. Leishmaniasis should be included in the differential diagnosis of fever and hepatosplenomegaly or chronic cutaneous lesions in children who travel to Malta.     

Antisecretory effects of three omeprazole regimens for maintenance treatment in duodenal ulcer

This study was carried out to assess the antisecretory effects and their possible changes over time of three different dose regimens of omeprazole that could be proposed for maintenance treatment in duodenal ulcer. Forty-five patients with endoscopically proven duodenal ulcer were studied by means of 24-hr gastric pH-metry both in basal conditions and on the fifth day of acute treatment with omeprazole 20 mg in the morning. Ulcers healed after four weeks (in three cases after eight weeks) and afterwards, 15 patients were randomized to receive orally at 0800 hr in single-blind fashion omeprazole 10 mg daily (group A), 15 to receive omeprazole 40 mg on Saturday and Sunday followed by a five-day period without medication (group B), and 15 to receive omeprazole 20 mg every other day (group C) for up to three months. On the 20th and 80th days of these maintenance treatments 24-hr gastric pH-metry was repeated to assess the antisecretory effectiveness of each regimen over a two-month period. In patients of group B these tests began at 1700 hr on Friday, the last of five days off treatment, and in those of group C at 1700 hr of the day off medication. All three dose regimens of omeprazole were able to raise pH values significantly (P<0.01–0.001) compared to basal levels. Omeprazole 20 mg every other day was more effective (P<0.01) than omeprazole 40 mg weekend, but did not differ significantly from omeprazole 10 mg daily. The durations of acid inhibition (pH>3.0 units/24 hr) were 12.44, 10.00, and 17.38 hr with groups A, B, and C, respectively. There was no significant difference between the pH profiles of the 20th and 80th days with every dose regimen. It is concluded that all three dose regimens of omeprazole are effective in reducing gastric acidity and their pharmacodynamic action does not change with time. Therefore they are suitable to be assessed in large clinical trials aimed at verifying the prevention of duodenal ulcer recurrence for longer periods.     

Randomized, double-blind study of stibogluconate plus human granulocyte macrophage colony-stimulating factor versus stibogluconate alone in the treatment of cutaneous Leishmaniasis.

The response to recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) in the treatment of cutaneous leishmaniasis was evaluated. Twenty patients with cutaneous leishmaniasis who had lesions for 60 days were enrolled in a double-blind placebo trial of GM-CSF with standard parenteral sodium stibogluconate (20 mg/kg-1/day-1) for 20 days. Ten patients were randomized to receive intralesionally injected GM-CSF (200 microgram) at enrollment and 1 week after, and 10 patients received saline as placebo. GM-CSF- and antimony-treated patients healed faster than patients who received antimony alone (49+/-32.8 vs. 110+/-61.6 days, P<.05). Seven of 10 patients were healed of their lesions before 40 days after therapy in the GM-CSF group, compared with only 1 of 10 patients in the placebo group (relative risk, 7; 95% confidence interval, 1.04-47.00). Thus, GM-CSF plus antimony significantly increased the chance of lesion healing in 40 days.     

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.     

Leishmaniasis in the United States: treatment in 2012

Although civilian physicians in the United States seldom encounter patients with leishmaniasis, therapeutic advances in endemic regions have opened the door to approaches that can be applied in this country. Advances revolve around the use of oral miltefosine in all forms of leishmaniasis and the use of short-course intravenous liposomal amphotericin B in visceral and possibly cutaneous infection. Lengthy, traditional intravenous treatment with pentavalent antimony (sodium stibogluconate) still has a role in the United States; however, although expensive, miltefosine and liposomal amphotericin B are considerably more appealing selections for initial therapy.     

Case report: Acute renal injury as a result of liposomal amphotericin B treatment in sodium stibogluconate unresponsive visceral leishmaniasis

We report an unusual case of visceral leishmaniasis occurring in a patient from Sichuan China. The patient presented with a remitting fever, anemia, and pancytopenia. The case was confirmed as visceral leishmaniasis by microscopical detection of the Leishmania species amastigote in bone marrow aspirate. The patient was treated with 10 mg/kg/day of sodium stibogluconate for 5 days, with no therapeutic response. As a result, the patient was treated with liposomal amphotericin B (LAB) at 10 mg/day as an initial dosage. After treatment with an increasing drug dosage for 7 days, acute renal injury was evident as indicated by increased serum creatinine and urea nitrogen. LAB administration was discontinued until serum creatinine and serum urea nitrogen regressed on Day 15. Two maintenance treatments of 100 mg/day LAB were given on Days 19 and 26 (total 870 mg, 14.5 mg/kg). Bone marrow aspirate and clinical examination suggested total remission.     

Pharmacokinetics of oral sitamaquine taken with or without food and safety and efficacy for treatment of visceral leishmaniais: a randomized study in Bihar, India

This randomized, open-label study of patients in India with visceral leishmaniasis (VL) investigated the effect of food on sitamaquine and desethyl-sitamaquine pharmacokinetics. Patients were randomized to receive oral sitamaquine, 2 mg/kg/day, once a day for 21 days across four cohorts (n = 41) (fasted/fed, fed/fasted, fed/fed, and fasted/fasted) over two periods (days 1-10 and 11-21), or intravenous amphotericin B (AmB), 1 mg/kg every other day for 30 days (n = 20). Mean day 21 pharmacokinetics across the four cohorts were sitamaquine, area under curve (AUC)((0-τ)) = 6,627-8,903 ng.hr/mL, AUC((0-16)) = 4,859-6,633 ng.hr/mL, maximum plasma concentration (C(max)) = 401-570 ng/mL, apparent terminal half-life (t(1/2)) = 18.3-22.8 hr, time to reach C(max) (t(max)) = 3.5-6 hr; and desethyl-sitamaquine, AUC((0-τ)) = 2,307-3,163 ng.hr/mL, C(max) = 109-154 ng/mL, t(1/2) = 23.0-27.9 hr, t(max) = 2-10 hr, with no significant food effect. On-therapy adverse events were observed for sitamaquine in 4 (10%) of 41 patients and for AmB in 17 (85%) of 20 patients. The final clinical cure (day 180) was 85% (95% confidence interval = 70.8-94.4%) for sitamaquine and 95% (95% confidence interval = 75.1-99.9) for AmB. Sitamaquine can be taken regardless of food intake, was generally well tolerated, and showed potential efficacy in patients with visceral leishmaniasis.     

Visceral leishmaniasis unresponsive to pentostam caused by Leishmania tropica in Kenya

We report the characterization of 6 Leishmania tropica isolates from 2 patients with visceral leishmaniasis who were unresponsive to treatment with sodium stibogluconate. The Leishmania isolates, MHOM/KE/81/NLB-029A, -029XIB, and -029XIC and MHOM/KE/81/NLB-030I, -030B, and -030XXA, all from splenic aspirates, were characterized by cellulose acetate electrophoresis using 11 enzymes: malate dehydrogenase, malic enzyme, phosphogluconate dehydrogenase, glucose-6-phosphate dehydrogenase, superoxide dismutase, glutamate-oxaloacetate transaminase, adenylate kinase, nucleoside hydrolase, mannose phosphate isomerase, glucose phosphate isomerase, and phosphoglucomutase. Isozyme migration patterns were indistinguishable from those of 2 WHO reference strains of Leishmania tropica (MHOM/SU/60/LRC-L39, NLB-305 and MHOM/IQ/OO/LRC-L36, NLB-067). These are the first reported cases of visceral leishmaniasis (kala-azar) caused by L. tropica in Africa; these cases were refractory to sodium stibogluconate.     

Treatment of visceral leishmaniasis (kala-azar): a decade of progress and future approaches.

In 1990, there was essentially one treatment regimen in use for visceral leishmaniasis (kala-azar) around the world: 20 to 28 days of daily injections of pentavalent antimony (Sb). During the past 10 years, however, new agents have been tested alone or in combination, in more than 50 studies carried out worldwide. This renewed clinical effort was spurred by a variety of factors, including the emergence of large-scale Sb unresponsiveness in India, where up to one-half of the world's cases of kala-azar now are found. As this new decade opens, the success of this clinical research effort is tangible: three additional, highly effective parenteral regimens now are available (amphotericin B, lipid formulations of amphotericin B, aminosidine), and an active oral agent, a long sought after objective in kala-azar, has been identified (miltefosine). This report reviews the evolution of treatment of visceral leishmaniasis, considers the interaction of the immune response and chemotherapy, highlights therapeutic successes and failures, examines advantages and disadvantages of current treatments, and looks at future therapeutic approaches to the management of this disseminated intracellular protozoal infection.     

Successful treatment of post-kala-azar dermal leishmaniasis (PKDL) in a HIV infected patient with multiple relapsing leishmaniasis from Western Europe

We present a 42-year-old man who was admitted with worsening of his general condition and facial skin lesions. He had previously been diagnosed with HIV infection and visceral leishmaniasis (VL). Diagnostic work-up revealed a new relapse of VL paralleled by the diagnosis of post-kala-azar dermal leishmaniasis (PKDL). The patient was treated with IV liposomal amphotericin B as well as sodium stibogluconate followed by oral hexadecylphosphocholine (miltefosine) over a period of 9 months. PKDL lesions began to disappear after 8 months of treatment. In addition, severe and relapsing VL so far remains in remission. This case demonstrates successful treatment of PKDL and relapsing VL in a Western European patient with HIV infection.     

Immunochemotherapy for intracellular Leishmania donovani infection: gamma interferon plus pentavalent antimony

To determine if the macrophage-activating T cell lymphokine gamma interferon (IFN-gamma) can enhance the effect of conventional chemotherapy against intracellular Leishmania donovani, we treated human macrophages in vitro with both recombinant (r) IFN-gamma and sodium stibogluconate (Pentostam). After pretreatment with a nonactivating dose of rIFN-gamma (10 U/mL), ineffective concentrations of Pentostam (1 and 5 micrograms/mL) were converted to leishmanistatic concentrations, and a leishmanistatic dose (10 micrograms/mL) was converted to uptake of Pentostam. In a model of visceral leishmaniasis, infected mice were treated with ineffective concentrations of rIFN-gamma (10(4) U) plus suboptimal doses of Pentostam (10 or 50 mg/kg). With combination therapy, the doses of Pentostam required to achieve 50% inhibition or killing of visceral L. donovani were reduced by 10-fold and fourfold, respectively. These results suggest that IFN-gamma therapy may be a useful adjunct in visceral leishmaniasis and illustrate one potential role for IFN-gamma in the treatment of systemic intracellular infections.     

Interleukin 10 receptor blockade--pentavalent antimony treatment in experimental visceral leishmaniasis

Interleukin 10 (IL-10), a suppressive Th2 cell-type cytokine, promotes disease progression in experimental visceral leishmaniasis. To extend testing the therapeutic effects of applying IL-10 receptor (IL-10R) blockade with antileishmanial chemotherapy, BALB/c mice with established intracellular Leishmania donovani infection were injected once with anti-IL-10R mAb at the time low-dose, daily pentavalent antimony (Sb) therapy was initiated. In this treatment model, simultaneous administration of anti-IL-10R enhanced overall antileishmanial activity in the liver in an interferon-gamma-dependent fashion, and accelerated the kinetics of Sb-associated killing, induced a >10-fold Sb dose-sparing effect and shortened the required duration of Sb treatment. These results suggest the possibility of using mAb-induced IL-10R blockade to develop low-dose and/or short-course immunochemotherapeutic regimens in visceral leishmaniasis.     

Death from an Adult-onset Still’s disease triggered by visceral leishmaniasis

A 24-year-old patient presented with a 4-month-long high-spiking fever, characteristic rash, sore throat and arthralgias. Bone marrow biopsy examination demonstrated visceral leishmaniasis with the presence of typical Leishman-Donovan bodies. During the treatment for visceral leishmaniasis with the sodium stibogluconate, he died suddenly. According to the symptoms, we infer that the patient catch the adult-onset Still's disease due to the visceral leishmaniasis.     

非疫源地黑热病2例资料分析

分析2例非疫源地黑热病病历资料。2例患者均有黑热病疫区生活史,且长期不规则发热,脾脏呈进行性肿大,肝脏肿大,白细胞计数降低,贫血,血小板减少等症状;骨髓检查显示网状吞噬型细胞多见,吞噬细胞内外可见利杜体,因此确诊为黑热病。予以对症治疗和葡萄糖酸锑杀虫治疗,患者发热症状消失,血细胞数回升,脾脏回缩,肝功能恢复,2例患者痊愈出院。     

A new focus of visceral leishmaniasis in sub-Himalayan (Kumaon) region of northern India

A localised focus of visceral leishmaniasis is reported for the first time from Kumaon region of North India. During a period of 18 months from July 1997 to December 1998 several cases of pyrexia of unknown origin with unresponsiveness to antibiotics and anti-tubercular treatments were referred to the All India Institute of Medical Sciences, New Delhi. Five of these were diagnosed to have visceral leishmaniasis. One of these was also co-infected with HIV-1. All the five cases came from an adjoining area falling under Almora (4) and Nainital(1) districts. Of these four were males and one female. One patient died within 48 hours of hospitalization at AIIMS while rest of four responded completely to sodium stibogluconate therapy.     

Efficacy of liposomal amphotericin B (AmBisome) in the treatment of persistent post-kala-azar dermal leishmaniasis (PKDL)

A dermatosis commonly known as post-kala-azar dermal leishmaniasis (PKDL) may develop following the treatment of human visceral leishmaniasis (VL). In about 15% of PKDL cases the disfiguring lesions persist, sometimes for many years. Such persistent lesions currently require daily injections of sodium stibogluconate (SSG) for 2-4 months and even then treatment may not be successful. Alternative, quicker and cheaper treatment options that cause less toxicity are being explored. Immuno-chemotherapeutic regimens (based on leishmaniasis candidate vaccines/BCG with SSG) are still experimental but treatment with liposomal amphotericin B (AmBisome) has already been found effective, albeit in a small number of patients. AmBisome is considered less nephrotoxic than non-liposomal amphotericin B because it specifically targets the macrophages in which the Leishmania parasites develop. The aim of the present study was to evaluate further the usefulness of AmBisome in the treatment of persistent PKDL, in Sudan. The 12 subjects, all of whom gave their informed consent, had each had PKDL lesions for >6 months and shown no improvement after repeated injections of SSG. During the study period, they were hospitalized and regularly screened, haematologically and biochemically, for adverse effects. The AmBisome, given intravenously at 2.5 mg/kg.day for 20 days, completely cleared the skin rash of 10 (83%) of the patients and caused no detectable adverse effects. In the 10 patients who responded well to the treatment, the papular lesions regressed and became flat while the hypopigmented lesions darkened (continuing to do so even after the last AmBisome injections). Treatment outcome appeared to be unaffected by the age or gender of the patient (P = 0.7 for each) but the time taken for the PKDL lesions to heal was correlated with the age of the lesions (P = 0.009). The macular lesions healed more slowly than the papular (P = 0.02). In conclusion, Ambisome appears suitable for the treatment of persistent PKDL lesions in Sudan. Once certain favourable clinical signs (the regression and/or darkening of the PKDL lesions) have been noted, the lesions will probably continue to clear without the need for more injections.