In vitro sensitivity of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis Brazilian isolates to meglumine antimoniate and amphotericin B

Resistance of Leishmania parasites to specific chemotherapy has become a well-documented problem in the Indian subcontinent in recent years but only a few studies have focused on the susceptibility of American Leishmania isolates. Our susceptibility assays to meglumine antimoniate were performed against intracellular amastigotes after standardizing an in vitro model of macrophage infection appropriate for Leishmania (Viannia) braziliensis isolates. For the determination of promastigote susceptibility to amphotericin B, we developed a simplified MTT-test. The sensitivity in vitro to meglumine antimoniate and amphotericin B of 13 isolates obtained from Brazilian patients was determined. L. (V.) braziliensis isolates were more susceptible to meglumine antimoniate than Leishmania (Leishmania) amazonensis . EC₅₀, EC₉₀ and activity indexes (calculated over the sensitivity of reference strains), suggested that all isolates tested were susceptible in vitro to meglumine antimoniate, and did not show association with the clinical outcomes. Isolates were also uniformly susceptible in vitro to amphotericin B.     

A randomized clinical trial comparing oral azithromycin and meglumine antimoniate for the treatment of American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis

Azithromycin was compared with meglumine antimoniate for treatment of patients with cutaneous leishmaniasis. Patients were randomized to receive oral azithromycin, 500 mg/day (22 patients) or intramuscular meglumine antimoniate, 10 mg Sb/kg/day (23 patients), both for 28 days, with a second cycle of 15 days if necessary, and followed-up for one year after completion of treatment. Efficacy, defined as complete re-epithelization without relapse for 12 months after completing therapy, was 82.6% (95% confidence interval [CI] = 67-98%) for meglumine antimoniate and 45.5% (95% CI = 25-66%) for azithromycin. All patients who failed treatment with azithromycin were treated with meglumine antimoniate and clinically cured. Azithromycin was well tolerated; meglumine antimoniate caused arthralgias and local symptoms in 78% of the patients. In 17 cases, species identification was obtained; Leishmania (Viannia) braziliensis was identified in all of them. For the treatment of American cutaneous leishmaniasis caused by L. (V.) braziliensis, meglumine antimoniate is significatively more efficacious than azithromycin, which was clinically curative in almost half of the patients and well-tolerated.     

Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran

This study was a randomized, open label comparison that was designed to determine efficacy and safety of miltefosine as the first oral drug for the treatment of zoonotic cutaneous leishmaniasis caused by Leishmania major in comparison with meglumine antimoniate. Complete clinical response was defined as 100% re-epithelialization of the lesion. Definitions of lesion cure and failure were based on both clinical and parasitological criteria two weeks after the end of treatment and clinical recovery three months after this period. Of 32 patients enrolled for miltefosine treatment 28 patients completed treatment, of which 26 were cured at three months, corresponding to a cure rate of 92.9% on a per protocol analysis, and 81.3% according to intention to treat analysis. There was one failure (3.1%), one relapse (3.1%) and four dropouts due to lack of tolerability (12.5%) during the first week of treatment. Of 31 patients who received intramuscular meglumine antimoniate (20mgSb(5)/kg body weight daily for 14 days) 25 were cured (83.3% on a per protocol basis, 80.6% on intention to treat basis), five failed (16.1%) and one was lost (3.2%) at 3-month follow-up. At 6-month follow-up after the end of treatment, no relapse was observed. Both regimens were tolerated but averages of nausea (32.2%) and vomiting (21.5%) were observed in patients during two weeks after initiation of miltefosine treatment. Other gastrointestinal, musculoskeletal, and total adverse events were not statistically different in the two groups during one to four weeks after therapy initiation. No relevant changes were observed in levels of liver enzymes, creatinine and hematological tests before and after end of treatment in both groups. In conclusion, miltefosine is apparently at least as good as meglumine antimoniate for the treatment of cutaneous leishmaniasis caused by L. major in Iran, based on parasitological as well as clinical criteria two weeks, three months, and six months after end of treatment.     

Intralesional Meglumine Antimoniate for Treatment of Cutaneous Leishmaniasis Patients with Contraindication to Systemic Therapy from Rio de Janeiro (2000 to 2006)

Abstract. We evaluated the effectiveness and safety of intralesional meglumine antimoniate (MA) in 24 not submitted to previous treatment patients with cutaneous leishmaniasis (CL) and with contraindication to systemic therapy. Each treatment consisted of one to four intralesional applications of MA at 15-day intervals. Patients' age ranged from 3 to 90 years; fourteen were females. Intralesional treatment in the absence of any relevant toxicity was successful in 20 (83.3%) patients. Three patients required additional treatment with amphotericin B and one required systemic MA. None of the patients developed mucosal lesions when followed up to 60 months. Intralesional MA is an effective and less toxic alternative treatment of patients with CL and contraindication to systemic therapy.     

High frequency of serious side effects from meglumine antimoniate given without an upper limit dose for the treatment of visceral leishmaniasis in human immunodeficiency virus type-1-infected patients

Organic pentavalent antimonials are one of the mainstays of treatment for visceral leishmaniasis (VL). Few data are available on the toxicity and efficacy of these drugs at the dosing schedule recommended by the Centers for Disease Control and Prevention (CDC) (Atlanta, GA). We analyzed 25 VL episodes in human immunodeficiency virus (HIV)-infected patients who were treated with meglumine antimoniate (MA) at the CDC-recommended dose in southern Spain. Adverse effects were observed in 14 (56%) VL episodes. In 7 (28%), treatment with MA was permanently discontinued due to serious adverse effects that included acute pancreatitis, acute renal failure, and leukopenia. Three (12%) patients died during therapy due to severe acute pancreatitis attributable to MA. The dosing regimen of MA currently recommended for treating VL is associated with a high rate of serious side effects in HIV-1-infected patients.     

Safety and effectiveness of amphotericin B deoxycholate for the treatment of visceral leishmaniasis in Uganda

Between September 2003 and April 2004, the supply of antimonial drugs to Amudat Hospital, in north-eastern Uganda, was interrupted and all cases of visceral leishmaniasis presenting at the hospital could only be treated with amphotericin B deoxycholate (AmB). This allowed the safety and effectiveness of the AmB to be evaluated, in comparison with an historical cohort of patients treated, at the same hospital, with meglumine antimoniate (Sb(V)). Demographic and clinical data were collected before and after treatment. Adverse effects were recorded passively in all the subjects, and actively, using a standardized questionnaire, in a sub-group of the patients given AmB. The in hospital case-fatality 'rates' were 4.8% [95% confidence interval (CI) = 2.4%-8.8%] among the 210 patients treated with AmB and 3.7% (CI = 1.4%-7.9%) among the 161 patients treated with Sb(V) (P>0.20). Adverse effects requiring treatment interruption were rare in both cohorts. Treatment failures (i.e. non-responses or relapses) were observed in 2.9% (CI = 1.2%-6.4%) of the patients treated with AmB and 1.2% (CI = 0.1%-4.4%) of the patients treated with Sb(V) (P>0.20). For the treatment of visceral leishmaniasis in Uganda, AmB therefore had a similar effectiveness and safety profile to that of meglumine antimoniate.     

The efficacy of treatment with intralesional meglumine antimoniate alone,compared with that of cryotherapy combined with the meglumine antimoniate or intralesional sodium stibogluconate,in the treatment of cutaneous leishmaniasis

It would be very useful to have a more effective and more rapid method available for the treatment of cutaneous leishmaniasis (CL). The main aim of the present, Iranian study, was to see if the combination of cryotherapy and intralesional injections with meglumine antimoniate (C + MA) would be more effective than the injections given alone (MA) or the combination of cryotherapy plus intralesional sodium stibogluconate (C + SS). Forty patients (with 67 lesions) were treated with C + MA, another 40 (with 65 lesions) were treated with C + SS and 100 patients (with 180 lesions) were treated with MA. Follow-up for 6 months after the final treatment indicated that 89.5% of the lesions treated with C + MA, 92.3% of those treated with C + SS but only 50% of the lesions treated with MA only were completely cured. The frequencies of cure in the two cryotherapy groups were similar, both being significantly higher than that in the MA group (P < 0.05). The combination of cryotherapy with intralesional injections of meglumine antimoniate or sodium stibogluconate, which is much more effective than the use of intralesional meglumine antimoniate alone, should be promoted.     

Short-Course Treatment Regimen of Indian Visceral Leishmaniasis with an Indian Liposomal Amphotericin B Preparation (Fungisome?)

India bears the burden of about half of global visceral leishmaniasis (VL) cases with emerging problems of stibanate resistance. Liposomal preparations have improved treatment outcome through shorter duration of therapy and lower toxicity compared with conventional amphotericin B. We report the efficacy of two short-course regimens of an Indian preparation of liposomal amphotericin B (Fungisome™) for VL caused by Leishmania donovani in India. An open-label, randomized, single-center comparative study was undertaken from 2008 to 2011, involving 120 treatment naive non–human immunodeficiency virus VL patients randomly allocated to two groups. Fungisome™ was given, in groups A (N = 60), 5 mg/kg daily for 2 days and B (N = 60), 7.5 mg/kg daily for 2 days, as intravenous infusion. Initial cure rate was 100% in both the groups after 1 month posttreatment. At 6 months after completion of treatment, definitive cure rate was group A 90% (54/60, 95% confidence interval (CI): 80.55–95.72%); group B: 100% (95% CI: 95.92–100%); (P = 0.027). No serious adverse events occurred in either group. The short-course, 2-day regimen of 15 mg/kg Fungisome™ infusion is easy to administer, effective, and safe for treatment of VL caused by L. donovani in India.     

Assessment of allopurinol plus meglumine antimoniate in the treatment of visceral leishmaniasis in patients infected with HIV

We report on 11 patients with HIV infection and visceral leishmaniasis and who were treated with meglumine antimoniate plus allopurinol for 3 weeks (six patients) or 4 weeks (five patients). Clinical and parasitological cures were achieved in four of the five patients treated for 4 weeks and in one of the six patients treated for 3 weeks. Only one patient developed a severe maculopapular rash. Allopurinol plus meglumine antimoniate was found to be a safe combination of drugs for the treatment of visceral leishmaniasis in patients infected with HIV. The optimal length of this treatment is unknown but a course of at least 4 weeks' duration would appear to be necessary for obtaining parasitological cure in most cases.     

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.     

FIRST REPORT ON OTOTOXICITY OF MEGLUMINE ANTIMONIATE

Introduction: Pentavalent antimonials are the first drug of choice in the treatment of tegumentary leishmaniasis. Data on ototoxicity related with such drugs is scarcely available in literature, leading us to develop a study on cochleovestibular functions. Case Report: A case of a tegumentary leishmaniasis patient, a 78-year-old man who presented a substantial increase in auditory threshold with tinnitus and severe rotatory dizziness during the treatment with meglumine antimoniate, is reported. These symptoms worsened in two weeks after treatment was interrupted. Conclusion: Dizziness and tinnitus had already been related to meglumine antimoniate. However, this is the first well documented case of cochlear-vestibular toxicity related to meglumine antimoniate.     

Decreased sensitivity to meglumine antimoniate (Glucantime) of Leishmania infantum isolated from dogs after several courses of drug treatment.

Although unresponsiveness to antimonial drugs in human leishmaniasis appears to be increasing, resistance to antimony in Leishmania is not well documented. Treatment of leishmaniasis in dogs, the domestic reservoir of L. infantum, with meglumine antimoniate (Glucantime) is a common practice in many Mediterranean countries. The dogs, however, remain highly infective to the phlebotomine vectors, even after several courses of treatment. A study was therefore carried out to test the comparative susceptibility to meglumine antimoniate of L. infantum stocks isolated from four naturally-infected dogs, before (BT) and after treatment (AT) with three to six courses of the drug, and used to infect Balb/c mice. Significant differences in suppression between the BT and AT stocks were observed in the infected mice when they were given the drug at a rate of 0.01-10 mg kg-1 day-1 for five days. Each AT stock was between eight and 41 times more resistant to meglumine antimoniate than the BT stock from the same dog, in terms of the ratios of the AT ED50 values to the corresponding BT values, which were calculated as indices of resistance. This result underlines the futility and danger of repeated antimonial treatments of dogs with signs of leishmaniasis, as these may produce a permanent reservoir of parasites unsusceptible to the drugs in human clinical use.     

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.     

Comparison of generic to branded pentavalent antimony for treatment of new world cutaneous leishmaniasis

The cost of generic pentavalent antimony (generic stibogluconate) is approximately one-sixth that of branded pentavalent antimony (stibogluconate in the form of Pentostam or meglumine antimoniate in the form of Glucantime. We compared generic stibogluconate to Pentostam and Glucantime for the treatment of cutaneous leishmaniasis patients in Bolivia and Colombia. For all 114 patients, the per-protocol cure rates were 83-91% and the intent-to-treat cure rates were 75-83%. The highest values were in the generic stibogluconate group. The incidence of pancreatic enzyme abnormalities was 48-88% and the incidence of liver enzyme abnormalities was 48-87%. The lowest incidences were in the generic stibogluconate group. The efficacy and tolerance of inexpensive generic stibogluconate appears comparable to branded formulations for the treatment of cutaneous leishmaniasis in these endemic regions.     

Efficacy of Miltefosine for the Treatment of American Cutaneous Leishmaniasis

Miltefosine is an oral agent used for cutaneous leishmaniasis treatment. An open-label, randomized, phase III clinical trial was carried out in the Colombian army population. Miltefosine, 50 mg capsule was taken orally three times per day for 28 days (N = 145) or meglumine antimoniate, 20 mg/kg body weight per day for 20 days by intramuscular injection (N = 143). The efficacy of miltefosine by protocol was 69.8% (85/122 patients) and 58.6% (85/145 patients) by intention to treat. For meglumine antimoniate, the efficacy by protocol was 85.1% (103/121 patients) and 72% (103/143 patients) by intention to treat. No association was found between drug efficacy and L. (V.) braziliensis or L. (V.) panamensis species of Leishmania responsible for infection. Adverse gastrointestinal events were associated with the use of miltefosine, the meglumine antimoniate treatment was associated with adverse effects on the skeletal musculature, fever, cephalea, and higher toxicity in kidney, liver, pancreas, and hematological system.     

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.     

Combined effect of the essential oil from Chenopodium ambrosioides and antileishmanial drugs on promastigotes of Leishmania amazonensis

To date, there are no vaccines against Leishmania, and chemotherapy remains the mainstay for the control of leishmaniasis. The drugs of choice used for leishmaniasis therapy are significantly toxic, expensive and with a growing frequency of refractory infections. Because of these limitations, a combination therapy is the better hope. This work demonstrates that the essential oil from Chenopodium ambrosioides shows a synergic activity after incubation in conjunction with pentamidine against promastigotes of Leishmania amazonensis. However, an indifferent effect has been found for combinations of meglumine antimoniate or amphotericin B and the essential oil.     

Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. A comparative study

Visceral leishmaniasis is an endemic infection in Mediterranean countries, where it has become a frequent complication of acquired immunodeficiency syndrome (AIDS). The incidence of visceral leishmaniasis is increasing in Spain due to human immunodeficiency virus (HIV)-related cases, but some aspects of its epidemiology, clinical features, and management remain unknown. In addition, no comparative clinical studies about the disease in HIV-infected and non-HIV-infected patients have been reported. During a 24-year period, 120 cases of visceral leishmaniasis were diagnosed at our institution and 80 (66%) were associated with HIV infection. The mean age at diagnosis was higher in HIV-infected that in non-HIV-infected patients (33.2 versus 23.2 yr; p = 0.002), but the male/female ratio was similar in both groups. The main risk factor for HIV infection was intravenous drug abuse (78.7%). The clinical presentation of leishmaniasis was similar in both groups, but HIV-infected patients had a lower frequency of splenomegaly than HIV-negative individuals (80.8% versus 97.4%; p = 0.02). HIV-infected patients had a greater frequency and degree of leukopenia, lymphocytopenia, and thrombocytopenia. Most of them were profoundly immunosuppressed (mean CD4+ lymphocyte count, 90 cells/mm3) at the time of diagnosis of leishmaniasis, and 53.7% had AIDS. The sensitivity of serologic studies for Leishmania was significantly lower in HIV-infected than in non-HIV-infected patients (50% versus 80%; p < 0.001), but the diagnostic yield of bone marrow aspirate (67.1% versus 79.4%) and bone marrow culture (62.9% versus 66.6%) was similar in both groups. After initial treatment, the response rate was significantly lower in HIV-infected than in non-HIV-infected individuals (54.8% versus 89.7%; p = 0.001). The relapse rate was 46.2% and 7.5%, respectively (p < 0.001). Secondary prophylaxis with antimonial compounds or amphotericin B seems to be useful in preventing relapses in HIV-infected patients. The mortality rate was higher (53.7% versus 7.5%; p < 0.001) and the median survival time shorter (25 versus > 160 mo; p < 0.001) in AIDS patients than in HIV-negative individuals. Although leishmaniasis could contribute to death in a significant number of HIV-infected patients, it was the main cause of death in only a few of them. The CD4+ lymphocyte count and the use of highly active antiretroviral therapy and secondary prophylaxis for leishmaniasis were the most significant prognostic factors for survival in AIDS patients. Visceral leishmaniasis behaves as an opportunistic infection in HIV-infected individuals and should be considered as an AIDS-defining disease.     

A Controlled,Randomized-Blinded Clinical Trial to Assess the Efficacy of a Nitric Oxide Releasing Patch in the Treatment of Cutaneous Leishmaniasis by Leishmania (V.) panamensis

A topical nanofiber nitric oxide (NO) releasing patch (≈3.5 μmol NO/cm²/day for 20 days, NOP) was compared with intramuscular meglumine antimoniate (Glucantime, 20 mg/kg/day for 20 days) for the treatment of cutaneous leishmaniasis (CL) caused by Leishmania (V.) panamensis in Santander and Tolima, Colombia. A double-blind, randomized, placebo-controlled, clinical trial was conducted to determine whether the NOP is as effective as Glucantime for the treatment of CL. Patients were randomly assigned to Glucantime and placebo patches or NOP and placebo of Glucantime. The cure rates after a 3-month follow-up were 94.8% for the group that received Glucantime compared with 37.1% in the NOP group. Despite the lower efficacy of the NOP versus Glucantime, a significantly lower frequency of non-serious adverse events and a reduced variation in serum markers were observed in patients treated with NOP. Treatment of CL with NOP resulted in a lower effectiveness compared with Glucantime; however, the low frequency of adverse events and the facility of topic administration justify the development of new generations of NOP systems for the treatment of CL.     

RESOLUTION OF CUTANEOUS LEISHMANIASIS AFTER ACUTE ECZEMA DUE TO INTRALESIONAL MEGLUMINE ANTIMONIATE

We report a case of a 42 year-old female, who came to a leishmaniasis reference center in Rio de Janeiro, Brazil, presenting a cutaneous leishmaniasis lesion in the right forearm. Treatment with low-dose intramuscular meglumine antimoniate (MA) (5 mg Sb⁵⁺/kg/day) was initiated, with improvement after 28 days, although with the development of generalized eczema. After 87 days, the lesion worsened. Patient refused treatment with amphotericin B. MA was then infiltrated in the lesion, in two sessions, resulting in local eczema, with bullae formation; however, twenty days after, both the ulcer and eczema receded. Intralesional administration of MA should be used carefully when previous cutaneous hypersensitivity is detected.