High frequency of skin reactions in patients with leishmaniasis treated with meglumine antimoniate contaminated with heavy metals: a comparative approach using historical controls

We analyzed data from historical controls treated with meglumine antimoniate to compare the frequency of adverse events observed in patients with cutaneous leishmaniasis treated with the same dose of meglumine antimoniate contaminated with heavy metals in an endemic area of the State of Bahia, Brazil. Group A patients were treated in 2000 with the drug produced by Eurofarma Laborat rios Ltda., S o Paulo, Brazil (lot A) and group B patients were treated in 1996 with the reference drug produced by Rhodia Farma Ltda., S o Paulo, Brazil (lot B). We observed an unusual higher frequency of skin reactions in group A patients. However, all type of adverse events observed in group A were also observed in group B. The physico-chemical analysis of these lots revealed that lot A had lower pH and higher concentration of total and trivalent antimony, lead, cadmium, and arsenic. Our findings suggest that the skin reactions could be attributed to heavy metal contamination of lot A.     

Sensitivity of Leishmania braziliensis promastigotes to meglumine antimoniate (glucantime) is higher than that of other Leishmania species and correlates with response to therapy in American tegumentary leishmaniasis

The first line drugs for the treatment of leishmaniasis are antimonial derivatives. Poor clinical response may be credited to factors linked to the host, the drug, or the parasite. We determined the sensitivity of Leishmania sp. promastigotes and amastigotes by counting parasites exposed to increasing concentrations of meglumine antimoniate (Glucantime). Leishmania braziliensis promastigotes were significantly more sensitive than those belonging to other species. The sensitivity of L. braziliensis isolates from patients with unfavorable clinical outcome, such as therapeutic failure or relapse, was significantly lower than those from patients who had clinical cure. Poor clinical response to therapy (therapeutic failure or relapse) was also associated with inadequate antimonial therapy. We also found a significant and positive correlation between promastigotes and intracellular amastigotes with regard to their in vitro susceptibilities to meglumine antimoniate. Our data provide evidence for an association between the sensitivity of promastigotes to antimonials in vitro and clinical response to therapy in American tegumentary leishmaniasis. The high sensitivity of the local L. braziliensis to meglumine antimoniate in vitro provides an explanation for the good clinical response of cutaneous leishmaniasis in the municipality of Rio de Janeiro, Brazil, even when low-dose regimens are employed.     

Chemotherapeutic Potential of 17-AAG against Cutaneous Leishmaniasis Caused by Leishmania (Viannia) braziliensis

Background

Leishmaniasis remains a worldwide public health problem. The limited therapeutic options, drug toxicity and reports of resistance, reinforce the need for the development of new treatment options. Previously, we showed that 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a Heat Shock Protein 90 (HSP90)-specific inhibitor, reduces L. (L.) amazonensis infection in vitro. Herein, we expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with L. (V.) braziliensis.

Methodology/Principal findings

Exposure of axenic L. (V.) braziliensis promastigotes to 17-AAG resulted in direct dose-dependent parasite killing. These results were extended to L. (V.) braziliensis-infected macrophages, an effect that was dissociated from the production of nitric oxide (NO), superoxide (O⁻²) or inflammatory mediators such as TNF-α, IL-6 and MCP-1. The leishmanicidal effect was then demonstrated in vivo, employing BALB/c mice infected with L. braziliensis. In this model, 17-AAG treatment resulted in smaller skin lesions and parasite counts were also significantly reduced. Lastly, 17-AAG showed a similar effect to amphotericin B regarding the ability to reduce parasite viability.

Conclusion/Significance

17-AAG effectively inhibited the growth of L. braziliensis, both in vitro and in vivo. Given the chronicity of L. (V.) braziliensis infection and its association with mucocutaneous leishmaniasis, 17-AAG can be envisaged as a new chemotherapeutic alternative for cutaneous Leishmaniasis.     

Ex Vivo Host and Parasite Response to Antileishmanial Drugs and Immunomodulators

Background

Therapeutic response in infectious disease involves host as well as microbial determinants. Because the immune and inflammatory response to Leishmania (Viannia) species defines the outcome of infection and efficacy of treatment, immunomodulation is considered a promising therapeutic strategy. However, since Leishmania infection and antileishmanial drugs can themselves modulate drug transport, metabolism and/or immune responses, immunotherapeutic approaches require integrated assessment of host and parasite responses.

Methodology

To achieve an integrated assessment of current and innovative therapeutic strategies, we determined host and parasite responses to miltefosine and meglumine antimoniate alone and in combination with pentoxifylline or CpG 2006 in peripheral blood mononuclear cells (PBMCs) of cutaneous leishmaniasis patients. Parasite survival and secretion of TNF-α, IFN-γ, IL-10 and IL-13 were evaluated concomitantly in PBMCs infected with Luc-L. (V.) panamensis exposed to meglumine antimoniate (4, 8, 16, 32 and 64 μg Sb^V/mL) or miltefosine (2, 4, 8, 16 and 32 μM HePC). Concentrations of 4 μM of miltefosine and 8 μg Sb^V/mL were selected for evaluation in combination with immunomodulators based on the high but partial reduction of parasite burden by these antileishmanial concentrations without affecting cytokine secretion of infected PBMCs. Intracellular parasite survival was determined by luminometry and cytokine secretion measured by ELISA and multiplex assays.

Principal Findings

Anti- and pro-inflammatory cytokines characteristic of L. (V.) panamensis infection were evaluable concomitantly with viability of Leishmania within monocyte-derived macrophages present in PBMC cultures. Both antileishmanial drugs reduced the parasite load of macrophages; miltefosine also suppressed IL-10 and IL-13 secretion in a dose dependent manner. Pentoxifylline did not affect parasite survival or alter antileishmanial effects of miltefosine or meglumine antimoniate. However, pentoxifylline diminished secretion of TNF-α, IFN-γ and IL-13, cytokines associated with the outcome of infection by species of the Viannia subgenus. Exposure to CpG diminished the leishmanicidal effect of meglumine antimoniate, but not miltefosine, and significantly reduced secretion of IL -10, alone and in combination with either antileishmanial drug. IL-13 increased in response to CpG plus miltefosine.

Conclusions and Significance

Human PBMCs allow integrated ex vivo assessment of antileishmanial treatments, providing information on host and parasite determinants of therapeutic response that may be used to tailor therapeutic strategies to optimize clinical resolution.     

Potential of Artesunate in the treatment of visceral leishmaniasis in dogs naturally infected by Leishmania infantum: Efficacy evidence from a randomized field trial

Leishmaniasis is among the world’s most neglected diseases. Dogs are the main reservoirs/hosts of Leishmania infantum, causative agent of both canine and human visceral leishmaniosis. Canine leishmaniasis (CanL) represents a public health problem as one of the most prevalent zoonotic diseases worldwide. Current therapeutics present drawbacks; thus, there is a need for more effective, safer, and cheaper drugs. The aim of this study was to evaluate and to compare the efficacy of oral administration of artesunate or meglumine antimoniate/allopurinol in dogs with clinical leishmaniasis. Forty-two dogs with naturally occurring clinical leishmaniasis were included in this open-label, simple randomized positive-control clinical field trial with 6 months of follow-up. Dogs received meglumine antimoniate 100 mg/kg/day and allopurinol 30 mg/kg/day for 28 days (control group, n = 26) or artesunate 25 mg/kg/day for 6 days (test group, n = 16). The animals were evaluated for their clinical evolution, parasite load (by qPCR) and humoral response at different time points: 0, 30, 90, and 180 days after treatment. Data analyses showed a significant improvement in both groups in clinical scores, parasitemia and antibody titers after treatment. Compared to the control group, the artesunate group showed significantly lower clinical score (P = 0.0001), lower parasitemia (P = 0.0001) and antibody titers after 6 months of follow-up. Compared to baseline values, a rapid, significant reduction (P < 0.012) in antibody levels, 2.28- versus 3.04-fold for the control versus artesunate groups, respectively, was observed 30 days after treatment. Antibody levels continued to decrease further in the artesunate group, where 58% of cases became seronegative at the 6-month follow-up. All qPCR-positive dogs were negative after treatment with artesunate, while 14.3% remained positive with the appearance of two new cases in the control group. Artesunate was well tolerated, and no side effects were recorded. Treatment failures were similar in both groups with 27.27% (6/22), including 18.18% (4/22) mortality in the control group, versus 26.66% (4/15), including 13.33% (2/15) mortality in the artesunate group. This is the first report showing the potential of artesunate in the treatment of dogs with clinical leishmaniasis. Artesunate showed higher efficacy than the current first-line treatment for CanL without any adverse effects. It could be a good alternative chemotherapy for CanL, and may be considered for further studies in human leishmaniases. Further clinical trials are needed to confirm these findings, to determine if there are relapses after treatment and if dogs remain infective to sandflies, to define the ideal therapeutic dosage and duration of treatment with artesunate.     

Pediatric Visceral Leishmaniasis in Albania: A Retrospective Analysis of 1,210 Consecutive Hospitalized Patients (1995–2009)

Background

Little information is available about infantile visceral leishmaniasis (VL) in Albania as regards incidence, diagnosis and management of the disease.

Methodology/Principal Findings

Demographic data, clinical and laboratory features and therapeutic findings were considered in children admitted to University Hospital of Tirana from 1995 to 2009, and diagnosed as having VL. The diagnosis was based on bone-marrow microscopy/culture in 77.5% of patients, serology in 16.1%, and ex juvantibus in 6.4%. A total of 1,210 children were considered, of whom 74% came from urbanized areas. All patients were in the age range 0–14 years, with a median of 4 years. Hepatosplenomegaly was recorded in 100%, fever in 95.4% and moderate to severe anemia in 88% of cases. Concomitant conditions were frequent: 84% had bronchopneumonia; diarrhea was present in 27%, with acute manifestations in 5%; 3% had salmonellosis. First-line therapy was meglumine antimoniate for all patients, given at the standard Sb^v dosage of 20 mg/kg/day for 21 to 28 days. Two children died under treatment, one of sepsis, the other of acute renal impairment. There were no cases of primary unresponsiveness to treatment, and only 8 (0.67%) relapsed within 6–12 months after therapy. These patients have been re-treated with liposomal amphotericin B, with successful cure.

Conclusions

Visceral leishmaniasis in pediatric age is relatively frequent in Albania; therefore an improvement is warranted of a disease-specific surveillance system in this country, especially as regards diagnosis. Despite recent reports on decreased responses to antimonial drugs of patients with Mediterranean VL, meglumine antimoniate treatment appears to be still highly effective in Albania.     

Species-Directed Therapy for Leishmaniasis in Returning Travellers: A Comprehensive Guide

Background

Leishmaniasis is increasingly reported among travellers. Leishmania species vary in sensitivity to available therapies. Fast and reliable molecular techniques have made species-directed treatment feasible. Many treatment trials have been designed poorly, thus developing evidence-based guidelines for species-directed treatment is difficult. Published guidelines on leishmaniasis in travellers do not aim to be comprehensive or do not quantify overall treatment success for available therapies. We aimed at providing comprehensive species-directed treatment guidelines.

Methodology/Principal Findings

English literature was searched using PubMed. Trials and observational studies were included if all cases were parasitologically confirmed, the Leishmania species was known, clear clinical end-points and time points for evaluation of treatment success were defined, duration of follow-up was adequate and loss to follow-up was acceptable. The proportion of successful treatment responses was pooled using mixed effects methods to estimate the efficacy of specific therapies. Final ranking of treatment options was done by an expert panel based on pooled efficacy estimates and practical considerations. 168 studies were included, with 287 treatment arms. Based on Leishmania species, symptoms and geography, 25 clinical categories were defined and therapy options ranked. In 12/25 categories, proposed treatment agreed with highest efficacy data from literature. For 5/25 categories no literature was found, and in 8/25 categories treatment advise differed from literature evidence. For uncomplicated cutaneous leishmaniasis, combination of intralesional antimony with cryotherapy is advised, except for L. guyanensis and L. braziliensis infections, for which systemic treatment is preferred. Treatment of complicated (muco)cutaneous leishmaniasis differs per species. For visceral leishmaniasis, liposomal amphotericin B is treatment of choice.

Conclusions/Significance

Our study highlights current knowledge about species-directed therapy of leishmaniasis in returning travellers and also demonstrates lack of evidence for treatment of several clinical categories. New data can easily be incorporated in the presented overview. Updates will be of use for clinical decision making and for defining further research.     

Identification of Leishmania species causing cutaneous leishmaniasis using Random Amplified Polymorphic DNA (RAPD-PCR) in Kharve,Iran

Background:

Leishmaniasis, especially cutaneous leishmaniasis, is considered an important health problem in many parts of Iran including Kharve, Khorasan Razavi province. Cutaneous leishmaniasis is caused by various species of Leishmania, each having a different secondary host. Thus, identifying the parasites’ specie is of paramount importance for containment strategy planning. The morphological differentiation of Leishmania species is not possible, rendering the molecular methods as the sole means to this purpose. Therefore, to identify the causative agent of cutaneous leishmaniasis in Kharve, Random Amplified Polymorphic DNA-PCR (RAPD-PCR) was used.

Methods:

The disease was first confirmed by direct smears. Samples were gathered from 22 patients with established cutaneous leishmaniasis. The samples were immediately cultured in NNN medium, followed by sub-culture in RPMI-1640. Afterwards, DNA was extracted and amplified using RAPD-PCR. Electrophoresis patterns from each isolate were compared with reference strains of Leishmania major (L. major) and Leishmania tropica (L. tropica).

Results:

The results of this study indicated that the parasite causing cutaneous leishmaniasis in Kharve is L. tropica.

Conclusion:

It seems that L. tropica is the only causative agent of cutaneous leishmaniasis in Kharve, and RAPD-PCR is a suitable tool for Leishmania characterization in epidemiological studies.Key Words: Leishmania major, Leishmania tropica, RAPD-PCR, Khorasan, Kharve     

Amphotericin B deoxycholate for relapse visceral leishmaniasis in Bangladesh: a cross-sectional study

Objective

Based on studies in India (as there was no studies from outside India) amphotericin B deoxycholate has been considered as a backup drug for treatment of visceral leishmaniasis. However, treatment response and adverse effect to anti-leishmanial drugs may vary across different populations and in Bangladesh the effect to amphotericin B deoxycholate for treatment of visceral leishmaniasis is still unknown. Therefore, there is a need to explore cure rate and adverse effects to amphotericin B deoxycholate to justify its use on visceral leishmaniasis patients in Bangladesh.

Result

Here we report 34 visceral leishmaniasis patients who received treatment with amphotericin B deoxycholate in the Surya Kanta Kala-azar Research Centre from December 2011 to June 2015. The dose of the treatment was 1 mg/kg body weight for 15 days followed up until 12 months after treatment. Response to amphotericin B deoxycholate treatment was excellent as all 34 patients achieved a final cure. Hypokalaemia (47%), shivering (47%), vomiting (35%) and acidity (15%) were most common adverse events. However, we did not observe any serious adverse events. Amphotericin B deoxycholate for relapse visceral leishmaniasis was found to be highly effective and safe. Our study justified to include amphotericin B deoxycholate as a second line drug for visceral leishmaniasis in Bangladesh.

     

Miltefosine and Antimonial Drug Susceptibility of Leishmania Viannia Species and Populations in Regions of High Transmission in Colombia

Background

Pentavalent antimonials have been the first line treatment for dermal leishmaniasis in Colombia for over 30 years. Miltefosine is administered as second line treatment since 2005. The susceptibility of circulating populations of Leishmania to these drugs is unknown despite clinical evidence supporting the emergence of resistance.

Methodology/Principal Findings

In vitro susceptibility was determined for intracellular amastigotes of 245 clinical strains of the most prevalent Leishmania Viannia species in Colombia to miltefosine (HePC) and/or meglumine antimoniate (Sb^V); 163, (80%) were evaluated for both drugs. Additionally, susceptibility to Sb^V was examined in two cohorts of 85 L. V. panamensis strains isolated between 1980–1989 and 2000–2009 in the municipality of Tumaco. Susceptibility to each drug differed among strains of the same species and between species. Whereas 68% of L. V. braziliensis strains presented in vitro resistance to HePC, 69% were sensitive to Sb^V. Resistance to HePC and Sb^V occurred respectively, in 20% y 21% of L. panamensis strains. Only 3% of L. V. guyanensis were resistant to HePC, and none to Sb^V. Drug susceptibility differed between geographic regions and time periods. Subpopulations having disparate susceptibility to Sb^V were discerned among L. V. panamensis strains isolated during 1980–1990 in Tumaco where resistant strains belonged to zymodeme 2.3, and sensitive strains to zymodeme 2.2.

Conclusions/Significance

Large scale evaluation of clinical strains of Leishmania Viannia species demonstrated species, population, geographic, and epidemiologic differences in susceptibility to meglumine antimoniate and miltefosine, and provided baseline information for monitoring susceptibility to these drugs. Sensitive and resistant clinical strains within each species, and zymodeme as a proxy marker of antimony susceptibility for L. V. panamensis, will be useful in deciphering factors involved in susceptibility and the distribution of sensitive and resistant populations.     

Leishmania infantum infection rates in Phlebotomus perniciosus fed on naturally infected dogs under antimonial treatment

Dogs naturally infected with Leishmania infantum Nicolle were treated with three courses of meglumine antimoniate. Changes were observed in the dogs' clinical signs, antibody titres and in infection rates of Phlebotomus perniciosus Newstead fed on the dogs. A large reduction in the sandfly infection rate was observed for 4-5 months after the first treatment. The use of antimonial drugs is advocated for the control of canine leishmaniasis and to reduce risks of L.infantum transmission.     

Visceral Leishmaniasis without Fever in an 11-Month-Old Infant: a Rare Clinical Feature of Kala-azar

Visceral leishmaniasis or kala-azar is an endemic parasitic disease in some parts of the world which is characterized by fever, splenomegaly, and pancytopenia in most of the cases. Herein we report an 11 month-old male infant with diagnosis of kala-azar who presented with pallor, hepatosplenomegaly, failure to gain weight, and no history of fever. Surprisingly, fever started after beginning of meglumine antimoniate treatment in this patient. As far as we are aware of, this is a rare presentation of visceral leishmaniasis. Therefore, clinicians especially in endemic areas are highly recommended to include kala-azar among differential diagnosis of unexplained anemia without fever to prevent misdiagnosis of this potentially fatal, but treatable condition.     

Leishmania infantum: stage-specific activity of pentavalent antimony related with the assay conditions

The determination of the intrinsic sensitivity of Leishmania strains to pentavalent antimonials in clinical trials, before treatment is begun, is essential in order to avoid failures and to allow alternative drugs to be chosen. A comparative study of SbV activity on promastigotes, axenic amastigote-like cells, and intracellular amastigotes of Leishmania infantum, when administered in the form of meglumine antimoniate and free, in hydrochloric solution, was performed. Results indicate that the conditions under which the promastigotes were cultured affect the IC(50) obtained, although results were homogeneous when the products were assayed on axenic-like and intracellular amastigotes. The IC(50) obtained for SbV in the form of meglumine antimoniate or in hydrochloric solution on promastigotes cultured in Schneider's medium depends on the growth rate of the culture and therefore could be regulated by modifying the fetal calf serum concentration in the medium. The pH of the culture medium strongly affected the activity of meglumine antimoniate but not that of the SbV hydrochloric solution on promastigotes cultured in Schneider's medium. This influence of pH was observed to a much lesser extent when promastigotes were cultured on M199 or RPMI media. In homogeneous culture conditions, which included the regulation of the promastigote growth rate through the heat-inactivated fetal calf serum concentration in the medium and the dilution of the meglumine antimoniate with Schneider's medium at pH 6.5, the activity of SbV, free or in the form of meglumine antimoniate, was the same in promastigotes, intracellular amastigotes, and axenic amastigote-like cells.     

Speciation of antimony (III) and antimony (V) using hydride generation for meglumine antimoniate pharmaceutical formulations quality control

The pentavalent antimonies, mainly the meglumine antimoniate, are recommends as first-choice medicines for leishmaniasis therapy. In this work we described the development of formulations of meglumine antimoniate injectable medication, as well as the analytical methodology used in the selective determination of Sb(III) and Sb(Total) by hydride generation - inductively coupled plasma atomic emission spectrometry (HG-ICP-AES) and ICP-AES, respectively. On that purpose the analytical methodology was developed focusing on the HG-ICP-AES technique. The formulations using propylene glycol/water as vehicles in a 20:80 proportion were more appropriate for subsequent use in industrial scale. These formulations also showed a lower variation on Sb(III) percentage, no need of buffer solution to stabilize the formulation and no influence of the autoclaving in the quality of the product. The results of the development of the analytical methodology point out the proposed method as an efficient alternative for the determination of Sb(III) in the presence of large quantities of Sb(V) in injectable solutions of meglumine antimoniate, in a selective, linear, accurate and precise manner. In addition, the method showed a low limit of quantification, less interference of the matrix, and more resilience than batch techniques proposed in the Brazilian Pharmacopeia.     

An old drug and different ways to treat cutaneous leishmaniasis: Intralesional and intramuscular meglumine antimoniate in a reference center,Rio de Janeiro,Brazil

BackgroundTreatment of cutaneous leishmaniasis (CL) remains challenging since the drugs currently used are quite toxic, thus contributing to lethality unrelated to the disease itself but to adverse events (AE). The main objective was to evaluate different treatment regimens with meglumine antimoniate (MA), in a reference center in Rio de Janeiro, Brazil.MethodologyA historical cohort of 592 patients that underwent physical and laboratory examination were enrolled between 2000 and 2017. The outcome measures of effectiveness were epithelialization and complete healing of cutaneous lesions. AE were graded using a standardized scale. Three groups were evaluated: Standard regimen (SR): intramuscular (IM) MA 10–20 mg Sb⁵⁺/kg/day during 20 days (n = 46); Alternative regimen (AR): IM MA 5 mg Sb⁵⁺/kg/day during 30 days (n = 456); Intralesional route (IL): MA infiltration in the lesion(s) through subcutaneous injections (n = 90). Statistical analysis was performed through Fisher exact and Pearson Chi-square tests, Kruskal-Wallis, Kaplan-Meier and log-rank tests.ResultsSR, AR and IL showed efficacy of 95.3%, 84.3% and 75.9%, with abandonment rate of 6.5%, 2.4% and 3.4%, respectively. IL patients had more comorbidities (58.9%; p = 0.001), were mostly over 50 years of age (55.6%), and had an evolution time longer than 2 months (65.6%; p = 0.02). Time for epithelialization and complete healing were similar in IL and IM MA groups (p = 0.9 and p = 0.5; respectively). Total AE and moderate to severe AE that frequently led to treatment interruption were more common in SR group, while AR and IL showed less toxicity.Conclusions/SignificanceAR and IL showed less toxicity and may be good options especially in CL cases with comorbidities, although SR treatment was more effective. IL treatment was an effective and safe strategy, and it may be used as first therapy option as well as a rescue scheme in patients initially treated with other drugs.     

Canine visceral leishmaniasis in Rio de Janeiro, Brazil. Clinical, parasitological, therapeutical and epidemiological findings (1977-1983)

Forty dogs from the periphery of the city of Rio de Janeiro were studied. All dogs where diagnosed as positive for leishmaniasis either parasitologically and/or serologically. Among them, 19 came from areas where only Visceral Leishmaniasis (VL) occurs (Realengo, Bangu, Senador Camará). Clinical signs of the disease were seen in 36.8% of the cases, including emaciation - 100%, lymphadenopathy and depilation - 85.7%. The other 21 dogs came from an area (Campo Grande) where both diseases (VL, and American Cutaneous Leishmaniasis - ACL) occur. Clinical signs of the disease, mainly cutaneous or mucocutaneous ulcers were seen in 76.2% of the cases. Leishmania parasites were found in 39 cases: 22% in viscera, 42.5% in viscera and normal skin and 35% in cutaneous or mucocutaneous ulcers. All the Leishmania stocks isolated from dogs which came from Realengo, Bangu, Senador Camará (VL area), and from Campo Grande (VL + ACL area) were characterized as L. donovani (except in one case) according to their schizodeme, zymodeme and serodeme. The only stock characterized as L. b. braziliensis, was isolated from the lymph node of a dog from Campo Grande with visceral disease and without skin lesions. Antimony therapy attempted in eight Leishmania donovani positive dogs was unsuccessful.     

The effect of oral miltefosine in treatment of antimoniate resistant anthroponotic cutaneous leishmaniasis: An uncontrolled clinical trial

BackgroundRecent circumstantial evidence suggests increasing number of Iranian patients with cutaneous leishmaniasis (CL) who are unresponsive to meglumine antimoniate (MA), the first line of treatment in Iran. Oral meltifosine was previously reported to be effective in visceral leishmaniasis as well CL. The current study is designed to determine efficacy and safety of oral miltefosine for the treatment of anthroponotic cutaneous leishmaniasis (ACL) cases who were refractory to MA in Iran.Methodology/Principal findingsMiltefosine was orally administered for 27 patients with MA resistant ACL with approved L.tropica infection, at a dosage of ∼2.5 mg/kg daily for 28 days. Patients were evaluated on day 14 and 28, as well as 3, 6 and 12 month post treatment follow up sessions. Laboratory data were performed and repeated at each visit. Data were analyzed using SPSS version 17. Twenty-seven patients including 16 men (59.25%) and 11 women (40.74%) with mean age of 28.56 ± 4.8 (range 3–54 years old) were enrolled. Total number of lesions were 42 (1–4 in each patient). Most of lesions were on face (76.19%). Mean lesions’ induration size was 2.38 ± 0.73 cm at the base-line which significantly decreased to1.31 ± 0.58 cm and 0.61 ±0.49 cm after 14 and 28 days of therapy, respectively (p value <0.05). At 12-months follow-up post treatment, 22 patients had definite/partial cure (81.48%) including 17 definitely cured patients, corresponding to a cure rate of 68% on per protocol analysis, and 62.96% according to intention to treat analysis. Recurrence of lesion was only occurred in one patient (3.70%). Nausea was the most subjective complication during the therapy (33.33%).ConclusionOral miltefosine could be an effective alternative for the treatment of MA-resistant ACL.