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

  • Caspar J. Hodiamont ,

    c.j.hodiamont@amc.uva.nl

    Affiliation Department of Medical Microbiology, Section of Parasitology, Academic Medical Center, Amsterdam, The Netherlands

  • Piet A. Kager,

    Affiliation Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands

  • Aldert Bart,

    Affiliation Department of Medical Microbiology, Section of Parasitology, Academic Medical Center, Amsterdam, The Netherlands

  • Henry J. C. de Vries,

    Affiliation Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands

  • Pieter P. A. M. van Thiel,

    Affiliations Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands, Ministry of Defence, The Hague, The Netherlands

  • Tjalling Leenstra,

    Affiliations Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands, Ministry of Defence, The Hague, The Netherlands

  • Peter J. de Vries,

    Affiliations Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands, Department of Internal Medicine, Tergooi Hospitals, Hilversum, The Netherlands

  • Michèle van Vugt,

    Affiliation Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands

  • Martin P. Grobusch,

    Affiliation Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands

  • Tom van Gool

    Affiliation Department of Medical Microbiology, Section of Parasitology, Academic Medical Center, Amsterdam, The Netherlands

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

  • Caspar J. Hodiamont, 
  • Piet A. Kager, 
  • Aldert Bart, 
  • Henry J. C. de Vries, 
  • Pieter P. A. M. van Thiel, 
  • Tjalling Leenstra, 
  • Peter J. de Vries, 
  • Michèle van Vugt, 
  • Martin P. Grobusch, 
  • Tom van Gool
PLOS
x

Abstract

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.

Author Summary

Human leishmaniasis is caused by unicellular parasites that are injected into the skin by sand-flies, small, flying insects. Many different Leishmania species cause various manifestations of disease, both of the skin and internal organs. Leishmaniasis is a curable disease but clear guidelines on the best available treatment are lacking. Leishmania species differ in sensitivity to available drugs. Until recently, identification of the infecting Leishmania parasite was laborious, thus therapy could not precisely be targeted to the infecting species, in contrast to many other infectious diseases. Nowadays, Leishmania parasites can be identified relatively easily with new DNA techniques. We studied efficacy of therapies for diseases due to different Leishmania species, limited to the English literature. Efficacy was summarized and presented in an easy to read format. Because of difficulties with identification of parasite species in earlier studies, quality of evidence was often limited. Our findings are a major help for clinicians to easily find optimal treatment for specific patients. Moreover, our results demonstrate where additional research is needed to further improve treatment of leishmaniasis.

Introduction

Leishmaniasis, infection by Leishmania parasites, is increasingly reported among travellers, especially in adventurous and eco-tourists [1][6] and military personnel [7][11]. Three syndromes are distinguished: visceral (VL), cutaneous (CL) and mucocutaneous leishmaniasis (MCL). VL is caused by L. donovani and L. infantum, rarely by other species. If left untreated, it will generally be fatal. CL is caused by L. major and L. tropica in the Old World (OW: Europe, Africa, Asia) and by parasites of the L. mexicana and L. braziliensis complexes in Central and South America (NW, the New World). L. infantum and L. donovani can also cause CL. In Ethiopia and Kenya, L. aethiopica causes CL and diffuse cutaneous leishmaniasis, a difficult-to-treat condition. Most L. major and L. mexicana lesions heal spontaneously within 3 to 6 months [12][14], L. tropica infections within one to two years [14] but L. braziliensis lesions may take much longer to heal [15]. MCL, involving nose, palate and often also pharynx and larynx, is usually caused by L. braziliensis. L. guyanensis, L. panamensis and L. amazonensis rarely cause MCL. Mucosal leishmaniasis of the OW is due to extension of CL to mucosa of mouth or nose, or to local primary infection by the sand-fly; the pathophysiology is different from that of MCL. It is estimated that 500,000 new cases of VL and 1.5 million new cases of CL occur per year, resulting in loss of 2,357,000 disability-adjusted life years [16].

In non-endemic regions, experience with diagnosis and management of leishmaniasis is limited. This may lead to delay in diagnosis and an unfavourable outcome of treatment [17]. In addition to the traditional diagnostic methods of microscopy, culture and serology, molecular techniques are increasingly used. Molecular techniques allow for fast and reliable identification of the aforementioned clinically relevant Leishmania species [6], [18], [19].

Leishmania species vary in sensitivity to available drugs [20]. Current choice of treatment is mainly based on the region where the infection was acquired and on the local experience with treatment. Molecular species identification makes species-directed treatment possible [17].

Development of guidelines for the treatment of leishmaniasis remains difficult. Cochrane Reviews of the treatment of CL and MCL highlight the poverty of current information and emphasize the need for high-standard trials [21], [22]. Absence of parasitological confirmation and species characterization, lack of clearly defined treatment end-points, limited or no follow-up and small sample sizes are amongst the problems encountered, as described in the report of the expert committee of WHO [16], a report wherein the clinical responsibility of the attending health care worker is acknowledged. CL is a self-healing disease which poses particular problems for the evaluation of therapies. These problems are not addressed in many reports.

Published guidelines for the treatment of leishmaniasis in travellers do not aim to be comprehensive or do not provide an easy-to-use tool that quantifies overall success of available treatments [17], [23][27].

Confronted with increasing numbers of patients with leishmaniasis, we aimed at providing comprehensive, yet easily digestible treatment guidelines based on symptoms, knowledge of the Leishmania species involved and the region where leishmaniasis was contracted, whilst taking data quality into account.

Methods

Literature on treatment of the leishmaniases was studied, summarized and subsequently discussed by an expert panel of the staff of the Departments of Tropical Medicine and Travel Medicine, Dermatology and Clinical Parasitology of the Academic Medical Center, Amsterdam who took into consideration patient comfort, duration of treatment, anticipated compliance with treatment, possibility of outpatient treatment, side effects and toxicity and in vitro data of efficacy.

Search strategy

We searched PubMed with keywords “Leishmania AND therapy”, “leishmaniasis AND therapy”, “Leishmania AND treatment” and “leishmaniasis AND treatment” (limited to humans and published in English), from January 1979 to December 2010. Additional searches were performed on August 24th 2012 and December 19th 2012. All treatment studies included in Cochrane reviews on therapy for CL and MCL [21], [22], all references included in the Deutsche Gesellschaft für Tropenmedizin guidelines on therapy for VL and CL/MCL [24] and all references from reviews on treatment of leishmaniasis in travellers [2], [17], [23], [25][28] were considered for inclusion. Only original papers were considered.

Randomized controlled trials (RCTs) and observational studies were included according to the inclusion criteria, summarized in Table 1. If studies comprised several treatment options, separate analyses were performed for each treatment option with a minimum of 5 patients.

Inclusion criteria of literature and considerations

Parasitological proof of infection.

Only studies with parasitological confirmation by microscopy, culture or PCR were included with the exception of African studies of VL, that often lack parasitological confirmation due to resource-limiting circumstances. In Sudan and Ethiopia, Médecins sans Frontières (MSF) uses a diagnostic pathway based on serological diagnosis using the Direct Agglutination Test (DAT) and rK39 rapid test, both of which have been evaluated against parasitological proof [29]. Being the only studies to address VL due to L. donovani outside India, they were included.

Typing to species level.

Aim of the study was to define optimal treatment based on species identification. Studies were included if the reported Leishmania species was typed or had been typed in earlier studies from the same area. Molecular diagnosis, isoenzyme analysis and use of monoclonal antibodies were regarded acceptable typing methods. If species identification was done for part of the isolates and more than one species had been found, the non-typed isolates were excluded, and analysis of treatment efficacy was performed on the typed isolates only. If only one species was known to cause disease in the area, both typed and non-typed isolates were included for analysis. In the Middle East where L. major and L. tropica frequently circulate together, typing was often not performed. Thus a category “L. major/L. tropica” was created.

Evaluation of treatment response.

Studies with clear clinical end-points, clear time points for evaluation of initial treatment success and an adequate duration of follow-up were included. In VL, the end-points were 1) apparent clinical cure at the end of treatment and 2) definite cure without relapse after 6 months follow-up. Studies of VL in Sudan and Ethiopia often have limited follow-up. These were included as a separate category. In CL, lesions had to show initial clinical improvement as defined by the respective authors, usually evaluated after 4 to 6 weeks. Complete healing with or without scar formation had to be achieved within 3 months of treatment initiation in the case of faster-healing species (L. major. L. mexicana) and within 6 months in the case of slower-healing species (L. infantum, L. tropica, L. braziliensis/L.peruviana, L. guyanensis, L. panamensis). In MCL, complete re-epithelialisation or scarring of the lesions without signs of inflammation had to be achieved, without relapse during 12 months of follow-up.

Loss to follow-up.

In many studies, a significant proportion of patients is lost to follow-up, especially in studies of CL in remote areas. We accepted a relatively large percentage of loss to follow-up in CL (50%) and a smaller percentage in VL and MCL (20%).

Calculation of efficacy and pooled efficacy

To guide ranking of treatment options, results from studies were pooled to estimate the efficacy of specific therapies. For each treatment, the number of patients with a successful outcome and the total number treated with that treatment were extracted, irrespective of the dosing regimen, as only few publications report the actual dose per kg body weight [30]. If clinical end-points were related to the number of treated lesions, these were used to calculate the proportion with successful treatment success as separate analyses. Patients lost to follow-up before completing therapy were excluded from analysis. Patients who stopped therapy prematurely because of adverse events or treatment failure were regarded as treatment failures. Patients showing apparent cure that were subsequently lost to follow-up were grouped with patients classified as definite cure (best case scenario). If absolute numbers of treatment successes and failures were not reported, but the proportion of successful treatment responses and the total number of patients per study arm were known, the latter data were used to calculate the absolute numbers. For each combination of diagnosis, species, location and specific treatment, a pooled efficacy and 95% confidence interval was calculated by pooling raw proportions of successfully treated patients from individual studies using the DerSimonian-Laird random effects method after Freeman-Tukey double arcsine transformation of raw proportions using the Meta package (http://CRAN.R-project.org/package=meta). Because substantial heterogeneity between studies was expected, in particular due to differences in patient populations and study procedures, the choice was made to pool estimates using random effects, rather than fixed effects methods. Pooling was done separately for RCTs and for observational studies. Efficacy data from RCTs and observational studies were combined to arrive at the pooled efficacy of all included studies of a particular treatment.

Presentation and ranking of treatment options

Treatments were summarized in relation to Leishmania species, clinical diagnosis and geography and ranked according to efficacy data from literature with type and number of studies, number of patients included and data of pooled efficacy (tables 2 and 3). Final ranking, with therapy of choice (TC) and up to 3 alternative therapies (AT 1–3), was done by the expert panel using the criteria mentioned above. Dosages for treatment options mentioned in tables 2 and 3 are provided in table 4.

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Table 2. Species directed therapy for leishmaniasis from the “Old World.”

https://doi.org/10.1371/journal.pntd.0002832.t002

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Table 3. Species directed therapy for leishmaniasis from the “New World.”

https://doi.org/10.1371/journal.pntd.0002832.t003

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Table 4. Leishmaniasis in travellers: Treatment options and dosages.

https://doi.org/10.1371/journal.pntd.0002832.t004

Combining efficacy data of treatment with different amphotericin B formulations

Because of toxicity of amphotericin B, liposomal vehicles have been developed, notably liposomal amphotericin B (Ambisome), amphotericin B-lipid complex (Abelcet) and amphotericin B colloidal dispersion (Amphocil). All formulations are effective antileishmanial drugs, provided an adequate total dose of amphotericin B is given. Therefore, we pooled the treatment results of all amphotericin B formulations, including non-liposomal amphotericin B (deoxycholate). Liposomal formulations are recommended because higher doses can be given in short courses with limited toxicity. Ambisome is preferred as it is the most widely used and evaluated of the available formulations, it is registered in many countries and is available at reduced price in endemic countries [16] and for free for selected poor countries [16]. Moreover, costs are carried by insurance companies in several industrialized countries.

Treatment options and patient subgroups not included in the study

Azole drugs (ketoconazole, fluconazole and itraconazole) have been applied in the treatment of cutaneous and mucocutaneous leishmaniasis [31][39] although their efficacy is still debated [36]. Recent papers suggest that doses might not have been adequate [40], [41]. More effective, better evaluated alternatives that require shorter treatment duration are available. We consider the azole drugs ‘reserve drugs’; they were not included in the analysis.

Studies on cryotherapy [42][46] and intralesional antimony treatment (ilSbv) [42], [45][47] as monotherapy have shown that these are effective treatments of L. tropica and L. major infections. Recently, ilSbv has been applied in CL from the New World too [48]. Literature on cryotherapy and ilSbv as monotherapy is provided, but these studies have not been included because several trials have shown superior effect of combination therapy [45], [46], [49], which we therefore prefer.

Aminosidine (paromomycin) ointment (15% aminosidine with 12% methylbenzethonium) proved effective for treatment of L. major/tropica and L.mexicana infections [50]. A new formulation of aminosidine with gentamicin, WR 279,396, shows very promising results [51], [52]. Moreover, parenteral aminosidine for VL has recently become available for endemic countries [53]. If proven effective, topical aminosidine would be a welcome treatment especially for children for whom new treatments are eagerly awaited [54]. Registration and availability of these topical formulations are limited; they are not discussed but referred to and mentioned in Table 4.

Combination therapy is advocated for endemic areas in particular, in order to prevent development of resistance. Available data are limited [53], [55]. The contribution of travellers to development of resistance is negligible and combination treatment is not considered here.

Until the introduction and wide application of HAART, HIV-Leishmania co-infection was a frequent problem in southern European countries [56]. More recently, this has become a major problem in eastern Africa [57]. Treatment has been diverse and no universal guideline was developed. Guidelines for secondary prophylaxis (prevention of relapses after apparent cure) were never thoroughly evaluated. Treatment reports focusing exclusively on HIV-Leishmania co-infection and secondary prophylaxis before HAART are not included.

Results

One-hundred-sixty-eight clinical studies were included for final analysis, including 287 separate analyses. Data on recommended therapy and dosages are summarized in Tables 2, 3 and 4. Based on infecting Leishmania species, symptoms and geography, 25 clinical categories were defined: 13 in the Old World and 12 in the New World, comprising 5 and 7 Leishmania species, respectively. For each category, different therapy options (TC, Treatment of choice and AT 1–3, Alternative treatment options 1–3) were proposed with references added for each treatment option. Forest plots comparing proportions cured per study-arm are provided as supplementary information for each therapy option per category that was analysed.

In 12 of 25 categories treatment of choice (TC) is in agreement with highest efficacy data from the literature. In 13/25 categories, TC was not supported by this form of evidence, but depended more on expert opinion. For 5/25 categories (15, 18, 22, 24, 25) no English literature on treatment fulfilling the inclusion criteria could be identified, and for 5/25 (5, 13, 16, 17, 21) categories no literature on TC was available, although literature was available for alternative treatment (AT) in the same category. For 3/25 categories (2, 9, 11) literature evidence for TC was slightly lower than for AT in the same category (tables 2 and 3). Reasons for the preferences of the expert panel in these categories, respectively in VL in East Africa (2) and CL in the Old World (9,11) are mentioned below.

Comments on proposed therapy

VL caused by L. donovani from the Indian subcontinent (cat. 1).

Almost all included studies were from Bihar, India, where antimony (SbV) is no longer advised because of resistance (table 2). Efficacy of amphotericin B is high. Recent studies from India showed 96% and 100% cure rates after a single dose of liposomal amphotericin B of 10 mg/kg and 15 mg/kg, respectively [58], [59]. Current advise of WHO for treatment in India, Bangladesh, Bhutan or Nepal is liposomal amphotericin B, total dose 15 mg/kg in 3–5 days or a single dose of 10 mg/kg [16]. Oral treatment with miltefosine is a proven effective alternative. In India, HIV-rates are still low, thus results reflect efficacy in immunocompetent patients.

VL caused by L. donovani from East Africa (cat. 2).

Antimony resistance is infrequent in Africa; systemic (i.v.) antimony, 20 mg/kg Sbv, once per day (o.d.) for 28 days remains effective but comes with toxicity in HIV infected and severely malnourished patients [60], [61]. These studies include a significant number of HIV-Leishmania spp. co-infected patients and reflect a mixed population of immunocompetent and immunodeficient patients. For liposomal amphotericin B, WHO tends to prefer a total dose of 30 mg/kg in this region, taking into consideration that part of the patient population will be immunodeficient due to HIV infection [16]. For the immunocompetent traveller from this region, we advise liposomal amphotericin B 10 mg/kg o.d. for 2 consecutive days.

VL caused by L. infantum (including L. chagasi; cat. 3, 4, 14).

WHO advises liposomal amphotericin B, total dose 18–21 mg/kg in 3–6 days [16]. For children 2 doses of 10 mg/kg, o.d., on two consecutive days proved very effective [62] and is considered standard of care [25], [63]. This short regimen is likely to be effective in adults as well, but this has not been studied formally. HIV status was known for studies in the Mediterranean region and HIV-positive patients were excluded from analysis.

VL (caused by L. donovani or L. infantum) in the returning traveller.

For the immunocompetent traveller, we propose treatment with liposomal amphotericin B, 20 mg/kg divided over 2–7 days, preferably 10 mg/kg o.d., 2 consecutive days.

CL of the Old World (cat. 5, 6, 7–13).

Separate categories were created for L. tropica and L. major, although recommendations for treatment are identical. Data on healed lesions (instead of healed patients) are between square brackets in Table 2.

In case of few (<5) L. tropica or L. major lesions, local therapy is preferred [16]; systemic treatment can be considered for multiple lesions, disfiguring facial lesions or lesions at sites that make topical treatment less desirable. For CL due to L. tropica and L. major, we propose combination therapy of intralesional antimony and cryotherapy, as this combination proved more effective than antimony or cryotherapy alone, although both also show high cure rates as mono-therapy [45], [46], [49]. This was based on literature and clinical experience of superior efficacy of the combination therapy by the expert panel. Heat therapy has also proven to be effective but requires special equipment [64], [65]. Miltefosine is a promising oral treatment for patients with multiple or complicated L. major lesions [66], [67]; evaluation of treatment of L. tropica infections is limited.

For CL due to L. donovani infection (cat. 5) or L. infantum (cat. 6), combined use of local antimony and cryotherapy is proposed. CL due to L. aethiopica (cat. 13) responds both to monotherapy with systemic antimony treatment and to monotherapy with local cryotherapy [68] suggesting efficacy of the combination of local antimony with cryotherapy.

CL of the New World (cat. 15–17, 19, 21, 23, 25).

The recommendations for CL due to L. infantum in the Old World also apply to L. chagasi ( = L. infantum) CL of the New World. For single or few lesions due to L. mexicana (cat. 16), local therapy (intralesional antimony with cryotherapy or heat therapy [69]) is proposed since there is no risk of MCL.

L. mexicana is relatively resistant to miltefosine in vitro [70] and in vivo [71], thus antimony is preferred if systemic treatment is deemed necessary.

Mucocutaneous spread due to L. panamensis or L. amazonensis is rare, suggesting that there is no need to apply systemic treatment in all cases [16]. Therefore, for single, uncomplicated lesions due to L. panamensis and L. amazonensis (cat. 17 and 21), combination therapy of local antimony and cryotherapy is advised instead of systemic therapy, although literature evidence of efficacy is lacking. Systemic treatment as for MCL due to L. braziliensis can be considered for complicated infections, in the absence of literature data. Systemic pentamidine is the treatment of choice for L. guyanensis lesions (cat. 13) in Surinam and Guyana, but recent evidence from Manaus, Brazil, shows efficacy of only about 50–60% [72]. For single, uncomplicated lesions, local therapy with antimony and cryotherapy can be considered, although MCL due to L. guyanensis is not as rare as formerly thought [73]. Long follow-up is advisable, as for several other leishmaniasis manifestations [74], [75]. Based on the close taxonomic relationship of L. panamensis and L. guyanensis, one would expect pentamidine to be effective for L. panamensis as well, but no data are available.

A case series on CL due to L. naiffi (cat. 25), not fulfilling the inclusion criteria of this study, suggests that local antimony and cryotherapy are effective [76].

Local therapy is not recommended for CL due to L. braziliensis (cat. 19), because of the risk of MCL. However, local therapy has been studied and the dogma that L. braziliensis infection has to be treated systemically has been challenged [16], [22]. Most reports are on systemic antimony, which is considered the gold standard. The few studies on treatment with miltefosine show comparable results, although response varies depending on geography, possibly related to differences in parasite strains [77]. We include amphotericin B formulations as alternative treatment because efficacy with this drug for treatment of MCL was at least equivalent to antimony treatment [78][80].

MCL (cat. 18, 20, 22, 24).

Included MCL treatment studies are limited to infection with L. braziliensis (cat. 20). Traditionally, systemic antimony was used but low success rates prompted research for alternatives. Two small studies on the combination of antimony and pentoxifylline showed high cure rates [81], [82]. We recommend this combination as therapy of choice for MCL while awaiting further information on liposomal amphotericin B and miltefosine, both of which have proven to be alternatives in small studies [78], [80].

MCL due to infection with L. panamensis, L.amazonensis and L. guyanensis (cat. 18, 22 and 24) is rare and literature evidence on efficacy of treatment is not available. Proposed therapy is as for MCL due to L. braziliensis.

Discussion

To optimize efficacy of treatment of leishmaniasis, the clinical diagnosis of the patient, the Leishmania species involved, and geography of infection should be considered. With these aspects as major determinants and with results of literature studies, we created a comprehensive guideline for species-directed treatment of leishmaniasis in the returning traveller. All English literature about treatment of leishmaniasis with a minimum of five persons per treatment was analysed. Efficacy data were pooled, resulting in an overall efficacy figure. Data are presented in easy-to-read overviews (tables 2 and 3). To our knowledge, this form of analysis and presentation has not been used before in overviews for treatment of leishmaniasis. It provides fast insight in current knowledge of treatment choices in clinical practice but also highlights the missing data needed to optimize treatment of leishmaniasis.

It is difficult to define and rank evidence based treatment recommendations for leishmaniasis. Insufficiencies of reported studies include lack of parasitological proof, of species identification, clear definitions and end-points and insufficient follow-up or considerable loss to follow-up. Only few well-designed placebo-controlled trials have been performed and not all specific treatments were compared side-by-side, precluding a comprehensive meta-analysis of RCTs. Cochrane reviews revealed these limitations and called for initiatives to improve studies [21], [22], a plea supported by WHO [16].

In this study, a significant proportion of the included analyses were from observational studies (106/287 = 37%), including case-series of a single treatment regimen. In order to present a comprehensive overview of all available treatment options, we included both randomized controlled trials and observational studies. To allow estimation of pooled efficacy for all treatment modalities and across study designs, we chose a pragmatic approach of calculating the treatment success per treatment arm. As no comparisons between treated and untreated control groups were made, the external validity of the presented (pooled) efficacy estimates depends on the assumption that self-cure was negligible within the study period. However, because of similar timing of outcome assessment across studies, one may assume that when therapies for a specific species and clinical modality are compared, the degree of over-estimation of the treatment effect will have been comparable across studies, thus preserving the relative ranking of treatments which form the basis for our recommendations. A potential risk of not randomising treatment, as in observational studies, is that patients receiving a new treatment may have better or worse prognosis than the average patient. Nevertheless, pooled results from observational studies were comparable with those from RCTs (tables 2 and 3). Diverging results should be viewed with caution.

For several clinical categories as defined in this study, limited literature was available, thus capitalizing on an expert panel was important. Efficacy figures of the literature study were combined with aspects of toxicity, convenience, and possibility of out-patient treatment to develop the guideline (tables 2 and 3).

Combination of intralesional antimony with cryotherapy is advised for all cases of CL with less than 5 lesions. Exceptions are infections with L. guyanensis (pentamidine) and L. braziliensis from Bolivia, Peru and Ecuador (systemic treatment). Treatment of complicated CL and MCL differs per species. For VL in immunocompetent travellers, treatment of choice is liposomal amphotericin B, total dose 20 mg/kg in 2–7 days, preferably 10 mg/kg o.d. on 2 consecutive days. Western European travellers mostly acquire VL in the Mediterranean region, occasionally in Latin America and rarely in the Indian continent or East Africa. For immunodeficient patients a total dose of 40 mg/kg is advised, administered over 4 to 8 days.

In India, cost of treatment is a major consideration and slightly lower cure rates with lower dosages and retreatment of relapsed cases are accepted, if cost-effective. For travellers, highest cure rates and convenience are priorities and cost of drugs is less important; a reason to propose use of higher dosages of liposomal amphotericin B than are currently used in India.

Leishmania species differ in in vitro or in vivo sensitivity to available drugs, in risk of development of complicated disease and in time required for spontaneous healing, thus knowledge of the Leishmania species and/or strain involved is important. Nowadays, PCR is an established diagnostic method, and species identification by molecular methods, e.g. sequence analysis, is available at reasonable cost. With the advent of these techniques, fast, precise and relatively cheap species differentiation has come within reach of many laboratories [6], [18], [19].

There are several limitations to our study. Firstly, we restricted our literature search in PubMed to the English language and may have missed relevant studies, since there is a fairly large body of literature published in other languages, especially in Latin America.

Secondly, using the “best case scenario” for evaluation of treatment success for CL studies with considerable loss to follow-up may have led to overestimation of treatment results. However, this choice seems not unreasonable in view of the spontaneous healing tendency of at least 50% and the assumption that cured patients are less inclined to return for evaluation. Moreover, very few patients with initial cure ultimately fail treatment.

Thirdly, azole drugs and aminosidine ointments are not fully discussed for the aforementioned reasons. New developments regarding aminosidine ointment WR 279,396 are promising, in particular for treatment of children [60].

Fourthly, methods of species identification have not been standardized and the exact status of several species is debated [83]. E.g. it has been argued that L. panamensis is a geographically confined subcluster or subspecies of L. guyanensis rather than a distinct species [84], [85]. L. guyanensis may consist of several (sub)species or of different strains with different behaviour and different sensitivity to drugs [72]. Moreover, in many studies, species identification was not universally performed but based on prior surveys and studies, with inherent uncertainties of older, different ways of typing and possibilities of shifts of endemicity. As molecular techniques are becoming more widely available, we will likely get more and better information in the near future.

Fifthly, due to the relative scarcity of reports of non-L. braziliensis MCL, it is difficult to evaluate the risk of developing MCL due to L. panamensis or L. amazonensis. The decision on local or systemic treatment for CL due to these species requires an individual risk benefit analysis.

Finally, for several drugs a standard dosing schedule was reported in the included studies, but the exact doses in mg/kg for the individual patients (or a mean or median with ranges for the studied population) were hardly ever reported. Since the publication of Herwaldt and Berman [86], antimony treatment of VL is with 20 mg Sbv/kg o.d. during 28–30 days, and this is how antimony treatment of VL has been reported in the literature since then. Dose and duration of antimony have varied in several studies of CL of the New World but WHO [16] advises 20 mg/kg o.d., for 20 days. However, it is impossible to know if in the real world patients actually received 20 mg/kg. Are they actually weighed, and if so, by a calibrated scale? Three antimony preparations are available: meglumine antimoniate (Glucantime) containing 81 mg Sbv per ml according to the WHO [16], although others [30] mention 85 mg/ml, sodium stibogluconate (Pentostam) and generic sodium stibogluconate (SSG, produced in India) both containing 100 mg Sbv per ml. Glucantime is used in Latin America and French speaking countries and comes in ampoules of 5 ml [16]. There will be a tendency to use full ampoules. Pentostam is used in English speaking countries while SSG is mostly used by MSF. The latter two come in bottles of 100 ml; in general full millilitres will be used. Doses will be rounded off, upwards and downwards, regularly leading to under- or overdosing [30]. Actual total doses given per patient are rarely recalculated and reported.

This is relevant for other drugs as well, e.g. for miltefosine that comes in capsules of 50 and 100 mg. An adult with bodyweight ≥50 kg receives 3×50 mg/d. In one study on L. major infections this led to doses of 1.3 to 2.1 mg/kg/d [67].

The difference in individual doses is important for several drugs; too much may lead to toxicity and adverse events, too low doses to treatment failure and development of resistance. We chose a practical approach of extracting all successfully treated patients irrespective of the dosing regimen.

Our study highlights current knowledge of species-directed therapy of leishmaniasis in returning travellers. It also clearly demonstrates the lack of evidence in the literature for treatment of several clinical categories with different Leishmania species. More, well-designed and properly executed trials are needed to optimize advice on treatment [87]. This paucity of knowledge [21], [22] has been recognized and prompted new initiatives to improve study design, diagnosis and evaluation of studies of the leishmaniases [16], [87]. Moreover, in Europe, a study group has been established to integrate research on optimal treatment of VL, CL and MCL among travellers [88].

Updated versions of our overview will be of use both for clinical decision making and for defining further research.

Supporting Information

Figure S1.

Forest plots comparing proportions leishmaniasis patients cured within treatment-arm Study: Study from which a treatment-arm on was included for analysis. Studies are divided in observational studies and randomized controlled trials (RCTs). Events: The number of patients cured in this treatment-arm. Total: The number of patients treated in this treatment-arm. Proportion: The proportion of patients that were cured in this treatment-arm. 95%-CI: 95%-confidence interval of the proportion cured. W(fixed): weight of the study-arm included in the fixed effect model. W(random): weight of the study-arm included in the random effects model.

https://doi.org/10.1371/journal.pntd.0002832.s003

(PDF)

Author Contributions

Conceived and designed the experiments: CJH PAK AB TvG. Analyzed the data: CJH AB TL TvG. Wrote the paper: CJH PAK AB HJCdV PPAMvT TL PJdV MvV MPG TvG. Performed the literature search: CJH PAK. Clinical expert panel on Leishmaniasis treatment: PAK HJCdV PPAMvT TL PJdV MvV MPG.

References

  1. 1. Antinori S, Gianelli E, Calattini S, Longhi E, Gramiccia M, et al. (2005) Cutaneous leishmaniasis: an increasing threat for travellers. Clin Microbiol Infect 11: 343–346 CLM1046 [pii];10.1111/j.1469-0691.2004.01046.x [doi].
  2. 2. Bailey MS, Lockwood DN (2007) Cutaneous leishmaniasis. Clin Dermatol 25: 203–211 S0738-081X(06)00071-X [pii];10.1016/j.clindermatol.2006.05.008 [doi].
  3. 3. Caumes E, Carriere J, Guermonprez G, Bricaire F, Danis M, et al. (1995) Dermatoses associated with travel to tropical countries: a prospective study of the diagnosis and management of 269 patients presenting to a tropical disease unit. Clin Infect Dis 20: 542–548.
  4. 4. El Hajj L, Thellier M, Carriere J, Bricaire F, Danis M, et al. (2004) Localized cutaneous leishmaniasis imported into Paris: a review of 39 cases. Int J Dermatol 43: 120–125.
  5. 5. Lawn SD, Yardley V, Vega-Lopez F, Watson J, Lockwood DN (2003) New World cutaneous leishmaniasis in returned travellers: treatment failures using intravenous sodium stibogluconate. Trans R Soc Trop Med Hyg 97: 443–445.
  6. 6. Bart A, van Thiel PP, de Vries HJ, Hodiamont CJ, van Gool T (2013) Imported leishmaniasis in the Netherlands from 2005 to 2012: epidemiology, diagnostic techniques and sequence-based species typing from 195 patients. Euro Surveill 18: 20544.
  7. 7. Faulde MK, Heyl G, Amirih ML (2006) Zoonotic cutaneous leishmaniasis, Afghanistan. Emerg Infect Dis 12: 1623–1624.
  8. 8. Hepburn NC, Tidman MJ, Hunter JA (1993) Cutaneous leishmaniasis in British troops from Belize. Br J Dermatol 128: 63–68.
  9. 9. Lightburn E, Morand JJ, Meynard JB, Kraemer P, Chaudier B, et al. (2003) [Management of American cutaneous leishmaniasis. Outcome apropos of 326 cases treated with high-dose pentamidine isethionate]. Med Trop (Mars) 63: 35–44.
  10. 10. van Thiel PP, Leenstra T, de Vries HJ, van der Sluis A, van Gool T, et al. (2010) Cutaneous leishmaniasis (Leishmania major infection) in Dutch troops deployed in northern Afghanistan: epidemiology, clinical aspects, and treatment. Am J Trop Med Hyg 83: 1295–1300 83/6/1295 [pii];10.4269/ajtmh.2010.10-0143 [doi].
  11. 11. Weina PJ, Neafie RC, Wortmann G, Polhemus M, Aronson NE (2004) Old world leishmaniasis: an emerging infection among deployed US military and civilian workers. Clin Infect Dis 39: 1674–1680 CID34048 [pii];10.1086/425747 [doi].
  12. 12. Asilian A, Jalayer T, Nilforooshzadeh M, Ghassemi RL, Peto R, et al. (2003) Treatment of cutaneous leishmaniasis with aminosidine (paromomycin) ointment: double-blind, randomized trial in the Islamic Republic of Iran. Bull World Health Organ 81: 353–359 S0042-96862003000500009 [pii].
  13. 13. Ben Salah A, Zakraoui H, Zaatour A, Ftaiti A, Zaafouri B, et al. (1995) A randomized, placebo-controlled trial in Tunisia treating cutaneous leishmaniasis with paromomycin ointment. Am J Trop Med Hyg 53: 162–166.
  14. 14. Dowlati Y (1996) Cutaneous leishmaniasis: clinical aspect. Clin Dermatol 14: 425–431 0738-081X(96)00058-2 [pii].
  15. 15. Herwaldt BL, Arana BA, Navin TR (1992) The natural history of cutaneous leishmaniasis in Guatemala. J Infect Dis 165: 518–527.
  16. 16. WHO (2010) Control of the leishmaniases. Report of a the WHO Expert Committee on the Control of Leishmaniases. World Health Organ Tech Rep Ser 949: 1–186.
  17. 17. Blum JA, Hatz CF (2009) Treatment of cutaneous leishmaniasis in travelers 2009. J Travel Med 16: 123–131 JTM286 [pii];10.1111/j.1708-8305.2008.00286.x [doi].
  18. 18. Marfurt J, Niederwieser I, Makia ND, Beck HP, Felger I (2003) Diagnostic genotyping of Old and New World Leishmania species by PCR-RFLP. Diagn Microbiol Infect Dis 46: 115–124 S0732889303000403 [pii].
  19. 19. Van der Auwera G, Maes I, De Doncker S, Ravel C, Cnops L, et al. (2013) Heat-shock protein 70 gene sequencing for Leishmania species typing in European tropical infectious disease clinics. Euro Surveill 18: 20543.
  20. 20. Croft SL, Sundar S, Fairlamb AH (2006) Drug resistance in leishmaniasis. Clin Microbiol Rev 19: 111–126 19/1/111 [pii];10.1128/CMR.19.1.111-126.2006 [doi].
  21. 21. Gonzalez U, Pinart M, Reveiz L, Alvar J (2008) Interventions for Old World cutaneous leishmaniasis. Cochrane Database Syst Rev CD005067 10.1002/14651858.CD005067.pub3 [doi].
  22. 22. Gonzalez U, Pinart M, Rengifo-Pardo M, Macaya A, Alvar J, et al. (2009) Interventions for American cutaneous and mucocutaneous leishmaniasis. Cochrane Database Syst Rev CD004834 10.1002/14651858.CD004834.pub2 [doi].
  23. 23. Blum J, Desjeux P, Schwartz E, Beck B, Hatz C (2004) Treatment of cutaneous leishmaniasis among travellers. J Antimicrob Chemother 53: 158–166 10.1093/jac/dkh058 [doi];dkh058 [pii].
  24. 24. Boecken G, Sunderkotter C, Bogdan C, Weitzel T, Fischer M, et al. (2011) [Diagnosis and therapy of cutaneous and mucocutaneous Leishmaniasis in Germany]. J Dtsch Dermatol Ges 9 Suppl 8: 1–51 10.1111/j.1610-0379.2011.07820.x [doi].
  25. 25. Buffet PA, Rosenthal E, Gangneux JP, Lightburne E, Couppie P, et al. (2011) [Therapy of leishmaniasis in France: consensus on proposed guidelines]. Presse Med 40: 173–184 S0755-4982(10)00571-3 [pii];10.1016/j.lpm.2010.09.023 [doi].
  26. 26. Goto H, Lindoso JA (2010) Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther 8: 419–433 10.1586/eri.10.19 [doi].
  27. 27. Mitropoulos P, Konidas P, Durkin-Konidas M (2010) New World cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. J Am Acad Dermatol 63: 309–322 S0190-9622(09)01148-7 [pii];10.1016/j.jaad.2009.06.088 [doi].
  28. 28. Schwartz E, Hatz C, Blum J (2006) New world cutaneous leishmaniasis in travellers. Lancet Infect Dis 6: 342–349 S1473-3099(06)70492-3 [pii];10.1016/S1473-3099(06)70492-3 [doi].
  29. 29. Ritmeijer K, Melaku Y, Mueller M, Kipngetich S, O'keeffe C, et al. (2006) Evaluation of a new recombinant K39 rapid diagnostic test for Sudanese visceral leishmaniasis. Am J Trop Med Hyg 74: 76–80 74/1/76 [pii].
  30. 30. Soto J, Toledo J, Vega J, Berman J (2005) Short report: efficacy of pentavalent antimony for treatment of colombian cutaneous leishmaniasis. Am J Trop Med Hyg 72: 421–422 72/4/421 [pii].
  31. 31. al-Fouzan AS, al Saleh QA, Najem NM, Rostom AI (1991) Cutaneous leishmaniasis in Kuwait. Clinical experience with itraconazole. Int J Dermatol 30: 519–521.
  32. 32. Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, Faris RM, et al. (2002) Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 346: 891–895 10.1056/NEJMoa011882 [doi];346/12/891 [pii].
  33. 33. Alsaleh QA, Dvorak R, Nanda A (1995) Ketoconazole in the treatment of cutaneous leishmaniasis in Kuwait. Int J Dermatol 34: 495–497.
  34. 34. Dogra J, Saxena VN (1996) Itraconazole and leishmaniasis: a randomised double-blind trial in cutaneous disease. Int J Parasitol 26: 1413–1415 S0020-7519(96)00128-2 [pii].
  35. 35. Momeni AZ, Jalayer T, Emamjomeh M, Bashardost N, Ghassemi RL, et al. (1996) Treatment of cutaneous leishmaniasis with itraconazole. Randomized double-blind study. Arch Dermatol 132: 784–786.
  36. 36. Morizot G, Delgiudice P, Caumes E, Laffitte E, Marty P, et al. (2007) Healing of Old World cutaneous leishmaniasis in travelers treated with fluconazole: drug effect or spontaneous evolution? Am J Trop Med Hyg 76: 48–52 76/1/48 [pii].
  37. 37. Nassiri-Kashani M, Firooz A, Khamesipour A, Mojtahed F, Nilforoushzadeh M, et al. (2005) A randomized, double-blind, placebo-controlled clinical trial of itraconazole in the treatment of cutaneous leishmaniasis. J Eur Acad Dermatol Venereol 19: 80–83 JDV1133 [pii];10.1111/j.1468-3083.2004.01133.x [doi].
  38. 38. Salmanpour R, Handjani F, Nouhpisheh MK (2001) Comparative study of the efficacy of oral ketoconazole with intra-lesional meglumine antimoniate (Glucantime) for the treatment of cutaneous leishmaniasis. J Dermatolog Treat 12: 159–162 10.1080/09546630152607899 [doi].
  39. 39. Weinrauch L, Livshin R, Even-Paz Z, El-On J (1983) Efficacy of ketoconazole in cutaneous leishmaniasis. Arch Dermatol Res 275: 353–354.
  40. 40. Sousa AQ, Frutuoso MS, Moraes EA, Pearson RD, Pompeu MM (2011) High-dose oral fluconazole therapy effective for cutaneous leishmaniasis due to Leishmania (Vianna) braziliensis. Clin Infect Dis 53: 693–695 cir496 [pii];10.1093/cid/cir496 [doi].
  41. 41. Emad M, Hayati F, Fallahzadeh MK, Namazi MR (2011) Superior efficacy of oral fluconazole 400 mg daily versus oral fluconazole 200 mg daily in the treatment of cutaneous leishmania major infection: a randomized clinical trial. J Am Acad Dermatol 64: 606–608 S0190-9622(10)00486-X [pii];10.1016/j.jaad.2010.04.014 [doi].
  42. 42. Layegh P, Pezeshkpoor F, Soruri AH, Naviafar P, Moghiman T (2009) Efficacy of cryotherapy versus intralesional meglumine antimoniate (glucantime) for treatment of cutaneous leishmaniasis in children. Am J Trop Med Hyg 80: 172–175 80/2/172 [pii].
  43. 43. Leibovici V, Aram H (1986) Cryotherapy in acute cutaneous leishmaniasis. Int J Dermatol 25: 473–475.
  44. 44. Mosleh IM, Geith E, Natsheh L, Schonian G, Abotteen N, et al. (2008) Efficacy of a weekly cryotherapy regimen to treat Leishmania major cutaneous leishmaniasis. J Am Acad Dermatol 58: 617–624 S0190-9622(07)02551-0 [pii];10.1016/j.jaad.2007.12.032 [doi].
  45. 45. Asilian A, Sadeghinia A, Faghihi G, Momeni A (2004) Comparative study of the efficacy of combined cryotherapy and intralesional meglumine antimoniate (Glucantime) vs. cryotherapy and intralesional meglumine antimoniate (Glucantime) alone for the treatment of cutaneous leishmaniasis. Int J Dermatol 43: 281–283 10.1111/j.1365-4632.2004.02002.x [doi];IJD2002 [pii].
  46. 46. Salmanpour R, Razmavar MR, Abtahi N (2006) Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment of cutaneous leishmaniasis. Int J Dermatol 45: 1115–1116 IJD2822 [pii];10.1111/j.1365-4632.2006.02822.x [doi].
  47. 47. Uzun S, Durdu M, Culha G, Allahverdiyev AM, Memisoglu HR (2004) Clinical features, epidemiology, and efficacy and safety of intralesional antimony treatment of cutaneous leishmaniasis: recent experience in Turkey. J Parasitol 90: 853–859 10.1645/GE-185R [doi].
  48. 48. Soto J, Rojas E, Guzman M, Verduguez A, Nena W, et al. (2013) Intralesional antimony for single lesions of bolivian cutaneous leishmaniasis. Clin Infect Dis 56: 1255–1260 cit049 [pii];10.1093/cid/cit049 [doi].
  49. 49. el Darouti MA, al Rubaie SM (1990) Cutaneous leishmaniasis. Treatment with combined cryotherapy and intralesional stibogluconate injection. Int J Dermatol 29: 56–59.
  50. 50. Kim DH, Chung HJ, Bleys J, Ghohestani RF (2009) Is paromomycin an effective and safe treatment against cutaneous leishmaniasis? A meta-analysis of 14 randomized controlled trials. PLoS Negl Trop Dis 3: e381 10.1371/journal.pntd.0000381 [doi].
  51. 51. Ben Salah A, Ben Messaoud N, Guedri E, Zaatour A, Ben Alaya N, et al. (2013) Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med 368: 524–532 10.1056/NEJMoa1202657 [doi].
  52. 52. Sosa N, Capitan Z, Nieto J, Nieto M, Calzada J, et al. (2013) Randomized, double-blinded, phase 2 trial of WR 279,396 (paromomycin and gentamicin) for cutaneous leishmaniasis in Panama. Am J Trop Med Hyg 89: 557–563 ajtmh.12-0736 [pii];10.4269/ajtmh.12-0736 [doi].
  53. 53. Chappuis F, Sundar S, Hailu A, Ghalib H, Rijal S, et al. (2007) Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol 5: 873–882 nrmicro1748 [pii];10.1038/nrmicro1748 [doi].
  54. 54. Blanco VM, Cossio A, Martinez JD, Saravia NG (2013) Clinical and epidemiologic profile of cutaneous leishmaniasis in Colombian children: considerations for local treatment. Am J Trop Med Hyg 89: 359–364 ajtmh.12-0784 [pii];10.4269/ajtmh.12-0784 [doi].
  55. 55. van Griensven J, Boelaert M (2011) Combination therapy for visceral leishmaniasis. Lancet 377: 443–444 S0140-6736(10)62237-4 [pii];10.1016/S0140-6736(10)62237-4 [doi].
  56. 56. Laguna F, Lopez-Velez R, Pulido F, Salas A, Torre-Cisneros J, et al. (1999) Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. Spanish HIV-Leishmania Study Group. AIDS 13: 1063–1069.
  57. 57. Alvar J, Aparicio P, Aseffa A, Den Boer M, Canavate C, et al. (2008) The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 21: 334–59 table. 21/2/334 [pii];10.1128/CMR.00061-07 [doi].
  58. 58. Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW (2010) Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 362: 504–512 362/6/504 [pii];10.1056/NEJMoa0903627 [doi].
  59. 59. Thakur CP (2001) A single high dose treatment of kala-azar with Ambisome (amphotericin B lipid complex): a pilot study. Int J Antimicrob Agents 17: 67–70 S0924-8579(00)00312-5 [pii].
  60. 60. Lyons S, Veeken H, Long J (2003) Visceral leishmaniasis and HIV in Tigray, Ethiopia. Trop Med Int Health 8: 733–739 1088 [pii].
  61. 61. Ritmeijer K, Veeken H, Melaku Y, Leal G, Amsalu R, et al. (2001) Ethiopian visceral leishmaniasis: generic and proprietary sodium stibogluconate are equivalent; HIV co-infected patients have a poor outcome. Trans R Soc Trop Med Hyg 95: 668–672.
  62. 62. Syriopoulou V, Daikos GL, Theodoridou M, Pavlopoulou I, Manolaki AG, et al. (2003) Two doses of a lipid formulation of amphotericin B for the treatment of Mediterranean visceral leishmaniasis. Clin Infect Dis 36: 560–566 CID30154 [pii];10.1086/367843 [doi].
  63. 63. Marty P, Pomares C, Michel G, Delaunay P, Ferrua B, et al. (2011) [Mediterranean visceral leishmaniasis]. Bull Acad Natl Med 195: 181–188.
  64. 64. Aronson NE, Wortmann GW, Byrne WR, Howard RS, Bernstein WB, et al. (2010) A randomized controlled trial of local heat therapy versus intravenous sodium stibogluconate for the treatment of cutaneous Leishmania major infection. PLoS Negl Trop Dis 4: e628 10.1371/journal.pntd.0000628 [doi].
  65. 65. Reithinger R, Mohsen M, Wahid M, Bismullah M, Quinnell RJ, et al. (2005) Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: a randomized, controlled trial. Clin Infect Dis 40: 1148–1155 CID35420 [pii];10.1086/428736 [doi].
  66. 66. Mohebali M, Fotouhi A, Hooshmand B, Zarei Z, Akhoundi B, et al. (2007) Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran. Acta Trop 103: 33–40 S0001-706X(07)00125-8 [pii];10.1016/j.actatropica.2007.05.005 [doi].
  67. 67. van Thiel PP, Leenstra T, Kager PA, de Vries HJ, van Vugt M, et al. (2010) Miltefosine treatment of Leishmania major infection: an observational study involving Dutch military personnel returning from northern Afghanistan. Clin Infect Dis 50: 80–83 10.1086/648726 [doi].
  68. 68. Negera E, Gadisa E, Hussein J, Engers H, Kuru T, et al. (2012) Treatment response of cutaneous leishmaniasis due to Leishmania aethiopica to cryotherapy and generic sodium stibogluconate from patients in Silti, Ethiopia. Trans R Soc Trop Med Hyg 106: 496–503 S0035-9203(12)00042-9 [pii];10.1016/j.trstmh.2012.02.006 [doi].
  69. 69. Velasco-Castrejon O, Walton BC, Rivas-Sanchez B, Garcia MF, Lazaro GJ, et al. (1997) Treatment of cutaneous leishmaniasis with localized current field (radio frequency) in Tabasco, Mexico. Am J Trop Med Hyg 57: 309–312.
  70. 70. Escobar P, Matu S, Marques C, Croft SL (2002) Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B. Acta Trop 81: 151–157 S0001706X01001978 [pii].
  71. 71. Soto J, Arana BA, Toledo J, Rizzo N, Vega JC, et al. (2004) Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis 38: 1266–1272 10.1086/383321 [doi];CID32728 [pii].
  72. 72. Neves LO, Talhari AC, Gadelha EP, Silva Junior RM, Guerra JA, et al. (2011) A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for the treatment of cutaneous leishmaniasis by Leishmania guyanensis. An Bras Dermatol 86: 1092–1101 S0365-05962011000600005 [pii].
  73. 73. Guerra JA, Prestes SR, Silveira H, Coelho LI, Gama P, et al. (2011) Mucosal Leishmaniasis caused by Leishmania (Viannia) braziliensis and Leishmania (Viannia) guyanensis in the Brazilian Amazon. PLoS Negl Trop Dis 5: e980 10.1371/journal.pntd.0000980 [doi].
  74. 74. Gangneux JP, Sauzet S, Donnard S, Meyer N, Cornillet A, et al. (2007) Recurrent American cutaneous leishmaniasis. Emerg Infect Dis 13: 1436–1438 10.3201/eid1309.061446 [doi].
  75. 75. Dedet JP, Pradinaud R, Gay F (1989) Epidemiological aspects of human cutaneous leishmaniasis in French Guiana. Trans R Soc Trop Med Hyg 83: 616–620.
  76. 76. Pratlong F, Deniau M, Darie H, Eichenlaub S, Proll S, et al. (2002) Human cutaneous leishmaniasis caused by Leishmania naiffi is wide-spread in South America. Ann Trop Med Parasitol 96: 781–785 10.1179/000349802125002293 [doi].
  77. 77. Soto J, Rea J, Balderrama M, Toledo J, Soto P, et al. (2008) Efficacy of miltefosine for Bolivian cutaneous leishmaniasis. Am J Trop Med Hyg 78: 210–211 78/2/210 [pii].
  78. 78. Amato VS, Tuon FF, Imamura R, Abegão de Camargo R, Duarte MI, et al. (2009) Mucosal leishmaniasis: description of case management approaches and analysis of risk factors for treatment failure in a cohort of 140 patients in Brazil. J Eur Acad Dermatol Venereol 23: 1026–1034 JDV3238 [pii];10.1111/j.1468-3083.2009.03238.x [doi].
  79. 79. Nonata R, Sampaio R, Marsden PD (1997) Mucosal leishmaniasis unresponsive to glucantime therapy successfully treated with AmBisome. Trans R Soc Trop Med Hyg 91: 77.
  80. 80. Soto J, Toledo J, Valda L, Balderrama M, Rea I, et al. (2007) Treatment of Bolivian mucosal leishmaniasis with miltefosine. Clin Infect Dis 44: 350–356 CID41102 [pii];10.1086/510588 [doi].
  81. 81. Lessa HA, Machado P, Lima F, Cruz AA, Bacellar O, et al. (2001) Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Am J Trop Med Hyg 65: 87–89.
  82. 82. Machado PR, Lessa H, Lessa M, Guimaraes LH, Bang H, et al. (2007) Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis. Clin Infect Dis 44: 788–793 CID40969 [pii];10.1086/511643 [doi].
  83. 83. Schonian G, Mauricio I, Cupolillo E (2010) Is it time to revise the nomenclature of Leishmania? Trends Parasitol 26: 466–469 S1471-4922(10)00134-0 [pii];10.1016/j.pt.2010.06.013 [doi].
  84. 84. Bañuls AL, Jonquieres R, Guerrini F, Le Pont F, Barrera C, et al. (1999) Genetic analysis of leishmania parasites in Ecuador: are Leishmania (Viannia) panamensis and Leishmania (V.) guyanensis distinct taxa? Am J Trop Med Hyg 61: 838–845.
  85. 85. Fraga J, Montalvo AM, De Doncker S, Dujardin JC, Van der Auwera G (2010) Phylogeny of Leishmania species based on the heat-shock protein 70 gene. Infect Genet Evol 10: 238–245 S1567-1348(09)00257-3 [pii];10.1016/j.meegid.2009.11.007 [doi].
  86. 86. Herwaldt BL, Berman JD (1992) Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 46: 296–306.
  87. 87. Olliaro P, Vaillant M, Arana B, Grogl M, Modabber F, et al. (2013) Methodology of clinical trials aimed at assessing interventions for cutaneous leishmaniasis. PLoS Negl Trop Dis 7: e2130 10.1371/journal.pntd.0002130 [doi];PNTD-D-12-01552 [pii].
  88. 88. Blum J (2013) LeishMan: harmonising diagnostic and clinical management of leishmaniasis in Europe. Euro Surveill 18: 20538.
  89. 89. Berman JD, Badaro R, Thakur CP, Wasunna KM, Behbehani K, et al. (1998) Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries. Bull World Health Organ 76: 25–32.
  90. 90. Bodhe PV, Kotwani RN, Kirodian BG, Pathare AV, Pandey AK, et al. (1999) Dose-ranging studies on liposomal amphotericin B (L-AMP-LRC-1) in the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg 93: 314–318.
  91. 91. Das VN, Siddiqui NA, Pandey K, Singh VP, Topno RK, et al. (2009) A controlled, randomized nonblinded clinical trial to assess the efficacy of amphotericin B deoxycholate as compared to pentamidine for the treatment of antimony unresponsive visceral leishmaniasis cases in Bihar, India. Ther Clin Risk Manag 5: 117–124.
  92. 92. Jha TK, Giri YN, Singh TK, Jha S (1995) Use of amphotericin B in drug-resistant cases of visceral leishmaniasis in north Bihar, India. Am J Trop Med Hyg 52: 536–538.
  93. 93. Mishra M, Singh MP, Choudhury D, Singh VP, Khan AB (1991) Amphotericin B for second-line treatment of Indian kala-azar. Lancet 337: 926 0140-6736(91)90268-T [pii].
  94. 94. Mishra M, Biswas UK, Jha DN, Khan AB (1992) Amphotericin versus pentamidine in antimony-unresponsive kala-azar. Lancet 340: 1256–1257 0140-6736(92)92952-C [pii].
  95. 95. Mishra M, Biswas UK, Jha AM, Khan AB (1994) Amphotericin versus sodium stibogluconate in first-line treatment of Indian kala-azar. Lancet 344: 1599–1600 S0140-6736(94)90406-5 [pii].
  96. 96. Singh UK, Prasad R, Jaiswal BP, Singh PK, Thakur CP (2010) Amphotericin B therapy in children with visceral leishmaniasis: daily vs. alternate day, a randomized trial. J Trop Pediatr 56: 321–324 fmp132 [pii];10.1093/tropej/fmp132 [doi].
  97. 97. Sinha PK, Roddy P, Palma PP, Kociejowski A, Lima MA, et al. (2010) Effectiveness and safety of liposomal amphotericin B for visceral leishmaniasis under routine program conditions in Bihar, India. Am J Trop Med Hyg 83: 357–364 83/2/357 [pii];10.4269/ajtmh.2010.10-0156 [doi].
  98. 98. Sundar S, Mehta H, Chhabra A, Singh V, Chauhan V, et al. (2006) Amphotericin B colloidal dispersion for the treatment of Indian visceral leishmaniasis. Clin Infect Dis 42: 608–613 CID37632 [pii];10.1086/500138 [doi].
  99. 99. Sundar S, Mehta H, Suresh AV, Singh SP, Rai M, et al. (2004) Amphotericin B treatment for Indian visceral leishmaniasis: conventional versus lipid formulations. Clin Infect Dis 38: 377–383 CID31917 [pii];10.1086/380971 [doi].
  100. 100. Sundar S, Chakravarty J, Rai VK, Agrawal N, Singh SP, et al. (2007) Amphotericin B treatment for Indian visceral leishmaniasis: response to 15 daily versus alternate-day infusions. Clin Infect Dis 45: 556–561 CID50485 [pii];10.1086/520665 [doi].
  101. 101. Sundar S, Sinha PK, Rai M, Verma DK, Nawin K, et al. (2011) Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 377: 477–486 S0140-6736(10)62050-8 [pii];10.1016/S0140-6736(10)62050-8 [doi].
  102. 102. Sundar S, Murray HW (1996) Cure of antimony-unresponsive Indian visceral leishmaniasis with amphotericin B lipid complex. J Infect Dis 173: 762–765.
  103. 103. Sundar S, Jha TK, Thakur CP, Sinha PK, Bhattacharya SK (2007) Injectable paromomycin for Visceral leishmaniasis in India. N Engl J Med 356: 2571–2581 356/25/2571 [pii];10.1056/NEJMoa066536 [doi].
  104. 104. Sundar S, Jha TK, Thakur CP, Mishra M, Singh VR, et al. (2002) Low-dose liposomal amphotericin B in refractory Indian visceral leishmaniasis: a multicenter study. Am J Trop Med Hyg 66: 143–146.
  105. 105. Sundar S, Rai M, Chakravarty J, Agarwal D, Agrawal N, et al. (2008) New treatment approach in Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed by short-course oral miltefosine. Clin Infect Dis 47: 1000–1006 10.1086/591972 [doi].
  106. 106. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, et al. (2002) Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 347: 1739–1746 10.1056/NEJMoa021556 [doi];347/22/1739 [pii].
  107. 107. Sundar S, Singh A, Agarwal D, Rai M, Agrawal N, et al. (2009) Safety and efficacy of high-dose infusions of a preformed amphotericin B fat emulsion for treatment of Indian visceral leishmaniasis. Am J Trop Med Hyg 80: 700–703 80/5/700 [pii].
  108. 108. Sundar S, Gupta LB, Rastogi V, Agrawal G, Murray HW (2000) Short-course, cost-effective treatment with amphotericin B-fat emulsion cures visceral leishmaniasis. Trans R Soc Trop Med Hyg 94: 200–204.
  109. 109. Sundar S, Agrawal NK, Sinha PR, Horwith GS, Murray HW (1997) Short-course, low-dose amphotericin B lipid complex therapy for visceral leishmaniasis unresponsive to antimony. Ann Intern Med 127: 133–137.
  110. 110. Sundar S, Jha TK, Thakur CP, Mishra M, Singh VP, et al. (2003) Single-dose liposomal amphotericin B in the treatment of visceral leishmaniasis in India: a multicenter study. Clin Infect Dis 37: 800–804 CID31166 [pii];10.1086/377542 [doi].
  111. 111. Sundar S, Goyal AK, More DK, Singh MK, Murray HW (1998) Treatment of antimony-unresponsive Indian visceral leishmaniasis with ultra-short courses of amphotericin-B-lipid complex. Ann Trop Med Parasitol 92: 755–764.
  112. 112. Sundar S, Agrawal G, Rai M, Makharia MK, Murray HW (2001) Treatment of Indian visceral leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: randomised trial. BMJ 323: 419–422.
  113. 113. Thakur CP, Narayan S (2004) A comparative evaluation of amphotericin B and sodium antimony gluconate, as first-line drugs in the treatment of Indian visceral leishmaniasis. Ann Trop Med Parasitol 98: 129–138 10.1179/000349804225003154 [doi].
  114. 114. Thakur CP, Singh RK, Hassan SM, Kumar R, Narain S, et al. (1999) Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of administration and precautions: a study of 938 cases. Trans R Soc Trop Med Hyg 93: 319–323.
  115. 115. Thakur CP, Sinha GP, Barat D, Singh RK (1994) Are incremental doses of amphotericin B required for the treatment of visceral leishmaniasis? Ann Trop Med Parasitol 88: 365–370.
  116. 116. Thakur CP (1994) Comparison of glucose versus fat emulsion in the preparation of amphotericin B for use in kala-azar. Trans R Soc Trop Med Hyg 88: 698–699.
  117. 117. Thakur CP, Sinha GP, Pandey AK (1996) Comparison of regimens of amphotericin B deoxycholate in kala-azar. Indian J Med Res 103: 259–263.
  118. 118. Thakur CP, Pandey AK, Sinha GP, Roy S, Behbehani K, et al. (1996) Comparison of three treatment regimens with liposomal amphotericin B (AmBisome) for visceral leishmaniasis in India: a randomized dose-finding study. Trans R Soc Trop Med Hyg 90: 319–322.
  119. 119. Thakur CP, Thakur S, Narayan S, Sinha A (2008) Comparison of treatment regimens of kala-azar based on culture & sensitivity of amastigotes to sodium antimony gluconate. Indian J Med Res 127: 582–588.
  120. 120. Thakur CP, Sinha GP, Pandey AK, Barat D, Singh RK (1994) Daily versus alternate-day regimen of amphotericin B in the treatment of kala-azar: a randomized comparison. Bull World Health Organ 72: 931–936.
  121. 121. Thakur CP, Sinha GP, Sharma V, Pandey AK, Sinha PK, et al. (1993) Efficacy of amphotericin B in multi-drug resistant kala-azar in children in first decade of life. Indian J Pediatr 60: 29–36.
  122. 122. Thakur CP, Narayan S, Ranjan A (2004) Epidemiological, clinical & pharmacological study of antimony-resistant visceral leishmaniasis in Bihar, India. Indian J Med Res 120: 166–172.
  123. 123. Thakur CP, Sinha GP, Sharma V, Pandey AK, Kumar M, et al. (1993) Evaluation of amphotericin B as a first line drug in comparison to sodium stibogluconate in the treatment of fresh cases of kala-azar. Indian J Med Res 97: 170–175.
  124. 124. Bhattacharya SK, Jha TK, Sundar S, Thakur CP, Engel J, et al. (2004) Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India. Clin Infect Dis 38: 217–221 CID31624 [pii];10.1086/380638 [doi].
  125. 125. Bhattacharya SK, Sinha PK, Sundar S, Thakur CP, Jha TK, et al. (2007) Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 196: 591–598 JID37903 [pii];10.1086/519690 [doi].
  126. 126. Jha TK, Sundar S, Thakur CP, Bachmann P, Karbwang J, et al. (1999) Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med 341: 1795–1800 10.1056/NEJM199912093412403 [doi].
  127. 127. Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, et al. (2003) Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis. Pediatr Infect Dis J 22: 434–438 10.1097/01.inf.0000066877.72624.cb [doi].
  128. 128. Sundar S, Gupta LB, Makharia MK, Singh MK, Voss A, et al. (1999) Oral treatment of visceral leishmaniasis with miltefosine. Ann Trop Med Parasitol 93: 589–597.
  129. 129. Sundar S, Makharia A, More DK, Agrawal G, Voss A, et al. (2000) Short-course of oral miltefosine for treatment of visceral leishmaniasis. Clin Infect Dis 31: 1110–1113 CID000237 [pii];10.1086/318122 [doi].
  130. 130. Sundar S, Rosenkaimer F, Makharia MK, Goyal AK, Mandal AK, et al. (1998) Trial of oral miltefosine for visceral leishmaniasis. Lancet 352: 1821–1823 S0140-6736(98)04367-0 [pii];10.1016/S0140-6736(98)04367-0 [doi].
  131. 131. Jha TK, Olliaro P, Thakur CP, Kanyok TP, Singhania BL, et al. (1998) Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. BMJ 316: 1200–1205.
  132. 132. Rijal S, Chappuis F, Singh R, Bovier PA, Acharya P, et al. (2003) Treatment of visceral leishmaniasis in south-eastern Nepal: decreasing efficacy of sodium stibogluconate and need for a policy to limit further decline. Trans R Soc Trop Med Hyg 97: 350–354.
  133. 133. Sundar S, Rosenkaimer F, Lesser ML, Murray HW (1995) Immunochemotherapy for a systemic intracellular infection: accelerated response using interferon-gamma in visceral leishmaniasis. J Infect Dis 171: 992–996.
  134. 134. Sundar S, Singh VP, Sharma S, Makharia MK, Murray HW (1997) Response to interferon-gamma plus pentavalent antimony in Indian visceral leishmaniasis. J Infect Dis 176: 1117–1119.
  135. 135. Sundar S, More DK, Singh MK, Singh VP, Sharma S, et al. (2000) Failure of pentavalent antimony in visceral leishmaniasis in India: report from the center of the Indian epidemic. Clin Infect Dis 31: 1104–1107 CID000236 [pii];10.1086/318121 [doi].
  136. 136. Thakur CP, Kumar M, Singh SK, Sharma D, Prasad US, et al. (1984) Comparison of regimens of treatment with sodium stibogluconate in kala-azar. Br Med J (Clin Res Ed) 288: 895–897.
  137. 137. Thakur CP, Kumar M, Kumar P, Mishra BN, Pandey AK (1988) Rationalisation of regimens of treatment of kala-azar with sodium stibogluconate in India: a randomised study. Br Med J (Clin Res Ed) 296: 1557–1561.
  138. 138. Thakur CP, Sinha GP, Pandey AK, Kumar N, Kumar P, et al. (1998) Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases. Ann Trop Med Parasitol 92: 561–569.
  139. 139. Thakur CP, Kanyok TP, Pandey AK, Sinha GP, Messick C, et al. (2000) Treatment of visceral leishmaniasis with injectable paromomycin (aminosidine). An open-label randomized phase-II clinical study. Trans R Soc Trop Med Hyg 94: 432–433.
  140. 140. Thakur CP, Kanyok TP, Pandey AK, Sinha GP, Zaniewski AE, et al. (2000) A prospective randomized, comparative, open-label trial of the safety and efficacy of paromomycin (aminosidine) plus sodium stibogluconate versus sodium stibogluconate alone for the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg 94: 429–431.
  141. 141. Mueller Y, Nguimfack A, Cavailler P, Couffignal S, Rwakimari JB, et al. (2008) Safety and effectiveness of amphotericin B deoxycholate for the treatment of visceral leishmaniasis in Uganda. Ann Trop Med Parasitol 102: 11–19 10.1179/136485908X252142 [doi].
  142. 142. Seaman J, Boer C, Wilkinson R, de Jong J, de Wilde E, et al. (1995) Liposomal amphotericin B (AmBisome) in the treatment of complicated kala-azar under field conditions. Clin Infect Dis 21: 188–193.
  143. 143. Ritmeijer K, Dejenie A, Assefa Y, Hundie TB, Mesure J, et al. (2006) A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis in an Ethiopian population with high prevalence of HIV infection. Clin Infect Dis 43: 357–364 CID39077 [pii];10.1086/505217 [doi].
  144. 144. Anabwani GM, Ngira JA, Dimiti G, Bryceson AD (1983) Comparison of two dosage schedules of sodium stibogluconate in the treatment of visceral leishmaniasis in Kenya. Lancet 1: 210–213 S0140-6736(83)92588-6 [pii].
  145. 145. Chulay JD, Bhatt SM, Muigai R, Ho M, Gachihi G, et al. (1983) A comparison of three dosage regimens of sodium stibogluconate in the treatment of visceral leishmaniasis in Kenya. J Infect Dis 148: 148–155.
  146. 146. Chunge CN, Owate J, Pamba HO, Donno L (1990) Treatment of visceral leishmaniasis in Kenya by aminosidine alone or combined with sodium stibogluconate. Trans R Soc Trop Med Hyg 84: 221–225.
  147. 147. Collin S, Davidson R, Ritmeijer K, Keus K, Melaku Y, et al. (2004) Conflict and kala-azar: determinants of adverse outcomes of kala-azar among patients in southern Sudan. Clin Infect Dis 38: 612–619 10.1086/381203 [doi];CID32101 [pii].
  148. 148. Hurissa Z, Gebre-Silassie S, Hailu W, Tefera T, Lalloo DG, et al. (2010) Clinical characteristics and treatment outcome of patients with visceral leishmaniasis and HIV co-infection in northwest Ethiopia. Trop Med Int Health 15: 848–855 TMI2550 [pii];10.1111/j.1365-3156.2010.02550.x [doi].
  149. 149. Moore E, O'Flaherty D, Heuvelmans H, Seaman J, Veeken H, et al. (2001) Comparison of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis in Kenya. Bull World Health Organ 79: 388–393.
  150. 150. Seaman J, Pryce D, Sondorp HE, Moody A, Bryceson AD, et al. (1993) Epidemic visceral leishmaniasis in Sudan: a randomized trial of aminosidine plus sodium stibogluconate versus sodium stibogluconate alone. J Infect Dis 168: 715–720.
  151. 151. Seaman J, Mercer AJ, Sondorp HE, Herwaldt BL (1996) Epidemic visceral leishmaniasis in southern Sudan: treatment of severely debilitated patients under wartime conditions and with limited resources. Ann Intern Med 124: 664–672.
  152. 152. Squires KE, Rosenkaimer F, Sherwood JA, Forni AL, Were JB, et al. (1993) Immunochemotherapy for visceral leishmaniasis: a controlled pilot trial of antimony versus antimony plus interferon-gamma. Am J Trop Med Hyg 48: 666–669.
  153. 153. Veeken H, Ritmeijer K, Seaman J, Davidson R (2000) A randomized comparison of branded sodium stibogluconate and generic sodium stibogluconate for the treatment of visceral leishmaniasis under field conditions in Sudan. Trop Med Int Health 5: 312–317 tmi555 [pii].
  154. 154. Davidson R, di Martino L, Gradoni, Giacchino R, Russo R, et al. (1994) Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial. Q J Med 87: 75–81.
  155. 155. Davidson RN, di Martino L, Gradoni L, Giacchino R, Gaeta GB, et al. (1996) Short-course treatment of visceral leishmaniasis with liposomal amphotericin B (AmBisome). Clin Infect Dis 22: 938–943.
  156. 156. di Martino L, Davidson RN, Giacchino R, Scotti S, Raimondi F, et al. (1997) Treatment of visceral leishmaniasis in children with liposomal amphotericin B. J Pediatr 131: 271–277 S0022347697003259 [pii].
  157. 157. Harms G, Schonian G, Feldmeier H (2003) Leishmaniasis in Germany. Emerg Infect Dis 9: 872–875.
  158. 158. Kafetzis DA, Velissariou IM, Stabouli S, Mavrikou M, Delis D, et al. (2005) Treatment of paediatric visceral leishmaniasis: amphotericin B or pentavalent antimony compounds? Int J Antimicrob Agents 25: 26–30 S0924-8579(04)00349-8 [pii];10.1016/j.ijantimicag.2004.09.011 [doi].
  159. 159. Ranawaka RR, Weerakoon HS (2010) Randomized, double-blind, comparative clinical trial on the efficacy and safety of intralesional sodium stibogluconate and intralesional 7% hypertonic sodium chloride against cutaneous leishmaniasis caused by L. donovani. J Dermatolog Treat 21: 286–293 10.3109/09546630903287445 [doi].
  160. 160. Shamsi Meymandi S, Zandi S, Aghaie H, Heshmatkhah A (2011) Efficacy of CO(2) laser for treatment of anthroponotic cutaneous leishmaniasis, compared with combination of cryotherapy and intralesional meglumine antimoniate. J Eur Acad Dermatol Venereol 25: 587–591 JDV3781 [pii];10.1111/j.1468-3083.2010.03781.x [doi].
  161. 161. Bumb RA, Mehta RD, Ghiya BC, Jakhar R, Prasad N, et al. (2010) Efficacy of short-duration (twice weekly) intralesional sodium stibogluconate in treatment of cutaneous Leishmaniasis in India. Br J Dermatol 163: 854–858 BJD9865 [pii];10.1111/j.1365-2133.2010.09865.x [doi].
  162. 162. Ghosn S (1979) Evaluation of sodium stibogluconate in the treatment of cutaneous leishmaniasis in Syria. Curr Med Res Opin 6: 280–283 10.1185/03007997909109438 [doi].
  163. 163. Harms G, Chehade AK, Douba M, Roepke M, Mouakeh A, et al. (1991) A randomized trial comparing a pentavalent antimonial drug and recombinant interferon-gamma in the local treatment of cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 85: 214–216.
  164. 164. Esfandiarpour I, Alavi A (2002) Evaluating the efficacy of allopurinol and meglumine antimoniate (Glucantime) in the treatment of cutaneous leishmaniasis. Int J Dermatol 41: 521–524 1526 [pii].
  165. 165. Firooz A, Khamesipour A, Ghoorchi MH, Nassiri-Kashani M, Eskandari SE, et al. (2006) Imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis: a randomized assessor-blind controlled trial. Arch Dermatol 142: 1575–1579 142/12/1575 [pii];10.1001/archderm.142.12.1575 [doi].
  166. 166. Layegh P, Rahsepar S, Rahsepar AA (2011) Systemic meglumine antimoniate in acute cutaneous leishmaniasis: children versus adults. Am J Trop Med Hyg 84: 539–542 84/4/539 [pii];10.4269/ajtmh.2011.10-0002 [doi].
  167. 167. Alkhawajah AM, Larbi E, Al-Gindan Y, Abahussein A, Jain S (1997) Treatment of cutaneous leishmaniasis with antimony: intramuscular versus intralesional administration. Ann Trop Med Parasitol 91: 899–905.
  168. 168. Moosavi Z, Nakhli A, Rassaii S (2005) Comparing the efficiency of topical paromomycin with intralesional meglumine antimoniate for cutaneous leishmaniasis. Int J Dermatol 44: 1064–1065 IJD2597 [pii];10.1111/j.1365-4632.2004.02597.x [doi].
  169. 169. Shazad B, Abbaszadeh B, Khamesipour A (2005) Comparison of topical paromomycin sulfate (twice/day) with intralesional meglumine antimoniate for the treatment of cutaneous leishmaniasis caused by L. major. Eur J Dermatol 15: 85–87.
  170. 170. Solomon M, Baum S, Barzilai A, Pavlotsky F, Trau H, et al. (2009) Treatment of cutaneous leishmaniasis with intralesional sodium stibogluconate. J Eur Acad Dermatol Venereol 23: 1189–1192 JDV3157 [pii];10.1111/j.1468-3083.2009.03157.x [doi].
  171. 171. Belazzoug S, Neal RA (1986) Failure of meglumine antimoniate to cure cutaneous lesions due to Leishmania major in Algeria. Trans R Soc Trop Med Hyg 80: 670–671.
  172. 172. Firdous R, Yasinzai M, Ranja K (2009) Efficacy of glucantime in the treatment of Old World cutaneous leishmaniasis. Int J Dermatol 48: 758–762 IJD4072 [pii];10.1111/j.1365-4632.2009.04072.x [doi].
  173. 173. Momeni AZ, Reiszadae MR, Aminjavaheri M (2002) Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate. Int J Dermatol 41: 441–443 1527 [pii].
  174. 174. Sadeghian G, Nilforoushzadeh MA (2006) Effect of combination therapy with systemic glucantime and pentoxifylline in the treatment of cutaneous leishmaniasis. Int J Dermatol 45: 819–821 IJD2867 [pii];10.1111/j.1365-4632.2006.02867.x [doi].
  175. 175. Asilian A, Sadeghinia A, Faghihi G, Momeni A, Amini HA (2003) 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. Ann Trop Med Parasitol 97: 493–498 10.1179/000349803225001373 [doi].
  176. 176. Faghihi G, Tavakoli-kia R (2003) Treatment of cutaneous leishmaniasis with either topical paromomycin or intralesional meglumine antimoniate. Clin Exp Dermatol 28: 13–16 1169 [pii].
  177. 177. Faris RM, Jarallah JS, Khoja TA, al-Yamani MJ (1993) Intralesional treatment of cutaneous leishmaniasis with sodium stibogluconate antimony. Int J Dermatol 32: 610–612.
  178. 178. Iraji F, Vali A, Asilian A, Shahtalebi MA, Momeni AZ (2004) Comparison of intralesionally injected zinc sulfate with meglumine antimoniate in the treatment of acute cutaneous leishmaniasis. Dermatology 209: 46–49 10.1159/000078586 [doi];78586 [pii].
  179. 179. Mujtaba G, Khalid M (1999) Weekly vs. fortnightly intralesional meglumine antimoniate in cutaneous leishmaniasis. Int J Dermatol 38: 607–609.
  180. 180. Nilforoushzadeh MA, Jaffary F, Moradi S, Derakhshan R, Haftbaradaran E (2007) Effect of topical honey application along with intralesional injection of glucantime in the treatment of cutaneous leishmaniasis. BMC Complement Altern Med 7: 13 1472-6882-7-13 [pii];10.1186/1472-6882-7-13 [doi].
  181. 181. Sadeghian G, Nilforoushzadeh MA, Siadat AH (2006) A comparison between intralesional hypertonic sodium chloride solution and meglomine antimoniate in the treatment of cutaneous leishmaniasis. Egyptian Dermatology Online Journal 2: 8.
  182. 182. Sadeghian G, Nilfroushzadeh MA, Iraji F (2007) Efficacy of local heat therapy by radiofrequency in the treatment of cutaneous leishmaniasis, compared with intralesional injection of meglumine antimoniate. Clin Exp Dermatol 32: 371–374 CED2405 [pii];10.1111/j.1365-2230.2007.02405.x [doi].
  183. 183. Sharquie KE, Al-Talib KK, Chu AC (1988) Intralesional therapy of cutaneous leishmaniasis with sodium stibogluconate antimony. Br J Dermatol 119: 53–57.
  184. 184. Sharquie KE (1995) A new intralesional therapy of cutaneous leishmaniasis with hypertonic sodium chloride solution. J Dermatol 22: 732–737.
  185. 185. Sharquie KE, Najim RA, Farjou IB (1997) A comparative controlled trial of intralesionally-administered zinc sulphate, hypertonic sodium chloride and pentavalent antimony compound against acute cutaneous leishmaniasis. Clin Exp Dermatol 22: 169–173.
  186. 186. Sharquie KE, al-Hamamy H, el-Yassin D (1998) Treatment of cutaneous leishmaniasis by direct current electrotherapy: the Baghdadin device. J Dermatol 25: 234–237.
  187. 187. Nilforoushzadeh MA, Jaffary F, Reiszadeh MR (2006) Comparative effect of topical trichloroacetic acid and intralesional meglumine antimoniate in the treatment of acute cutaneous leishmaniasis. Int J Pharm 2: 633.
  188. 188. Aram H, Leibovici V (1987) Ultrasound-induced hyperthermia in the treatment of cutaneous leishmaniasis. Cutis 40: 350–353.
  189. 189. Asilian A, Sharif A, Faghihi G, Enshaeieh S, Shariati F, et al. (2004) Evaluation of CO laser efficacy in the treatment of cutaneous leishmaniasis. Int J Dermatol 43: 736–738 IJD2349 [pii];10.1111/j.1365-4632.2004.02349.x [doi].
  190. 190. Asilian A, Iraji F, Hedaiti HR, Siadat AH, Enshaieh S (2006) Carbon dioxide laser for the treatment of lupoid cutaneous leishmaniasis (LCL): a case series of 24 patients. Dermatol Online J 12: 3.
  191. 191. Layegh P, Yazdanpanah MJ, Vosugh EM, Pezeshkpoor F, Shakeri MT, et al. (2007) Efficacy of azithromycin versus systemic meglumine antimoniate (Glucantime) in the treatment of cutaneous leishmaniasis. Am J Trop Med Hyg 77: 99–101 77/1/99 [pii].
  192. 192. Nilforoushzadeh MA, Jaffary F, Ansari N, Siadat AH, Nilforoushan Z, et al. (2008) A comparative study between the efficacy of systemic meglumine antimoniate therapy with standard or low dose plus oral omeprazole in the treatment of cutaneous leishmaniasis. J Vector Borne Dis 45: 287–291.
  193. 193. Zerehsaz F, Salmanpour R, Handjani F, Ardehali S, Panjehshahin MR, et al. (1999) A double-blind randomized clinical trial of a topical herbal extract (Z-HE) vs. systemic meglumine antimoniate for the treatment of cutaneous leishmaniasis in Iran. Int J Dermatol 38: 610–612.
  194. 194. Dietze R, Milan EP, Berman JD, Grogl M, Falqueto A, et al. (1993) Treatment of Brazilian kala-azar with a short course of amphocil (amphotericin B cholesterol dispersion). Clin Infect Dis 17: 981–986.
  195. 195. Dietze R, Fagundes SM, Brito EF, Milan EP, Feitosa TF, et al. (1995) Treatment of kala-azar in Brazil with Amphocil (amphotericin B cholesterol dispersion) for 5 days. Trans R Soc Trop Med Hyg 89: 309–311.
  196. 196. Badaro R, Nascimento C, Carvalho JS, Badaro F, Russo D, et al. (1994) Recombinant human granulocyte-macrophage colony-stimulating factor reverses neutropenia and reduces secondary infections in visceral leishmaniasis. J Infect Dis 170: 413–418.
  197. 197. Navin TR, Arana BA, Arana FE, Berman JD, Chajon JF (1992) Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 165: 528–534.
  198. 198. Vargas-Gonzalez A, Canto-Lara SB, Damian-Centeno AG, Andrade-Narvaez FJ (1999) Response of cutaneous leishmaniasis (chiclero's ulcer) to treatment with meglumine antimoniate in Southeast Mexico. Am J Trop Med Hyg 61: 960–963.
  199. 199. Silveira FT, Lainson R, Shaw JJ, de Souza AA, Ishikawa EA, et al. (1991) Cutaneous leishmaniasis due to Leishmania (Leishmania) amazonensis in Amazonian Brazil, and the significance of a negative Montenegro skin-test in human infections. Trans R Soc Trop Med Hyg 85: 735–738.
  200. 200. Andersen EM, Cruz-Saldarriaga M, Llanos-Cuentas A, Luz-Cjuno M, Echevarria J, et al. (2005) Comparison of meglumine antimoniate and pentamidine for peruvian cutaneous leishmaniasis. Am J Trop Med Hyg 72: 133–137 72/2/133 [pii].
  201. 201. Arevalo I, Tulliano G, Quispe A, Spaeth G, Matlashewski G, et al. (2007) Role of imiquimod and parenteral meglumine antimoniate in the initial treatment of cutaneous leishmaniasis. Clin Infect Dis 44: 1549–1554 CID41565 [pii];10.1086/518172 [doi].
  202. 202. Arevalo J, Ramirez L, Adaui V, Zimic M, Tulliano G, et al. (2007) Influence of Leishmania (Viannia) species on the response to antimonial treatment in patients with American tegumentary leishmaniasis. J Infect Dis 195: 1846–1851 JID37644 [pii];10.1086/518041 [doi].
  203. 203. Correia D, Macedo VO, Carvalho EM, Barral A, Magalhaes AV, et al. (1996) [Comparative study of meglumine antimoniate, pentamidine isethionate and aminosidine sulfate in the treatment of primary skin lesions caused by Leishmania (Viannia) braziliensis]. Rev Soc Bras Med Trop 29: 447–453.
  204. 204. Hepburn NC, Tidman MJ, Hunter JA (1994) Aminosidine (paromomycin) versus sodium stibogluconate for the treatment of American cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 88: 700–703.
  205. 205. Krolewiecki AJ, Romero HD, Cajal SP, Abraham D, Mimori T, et al. (2007) A randomized clinical trial comparing oral azithromycin and meglumine antimoniate for the treatment of American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. Am J Trop Med Hyg 77: 640–646 77/4/640 [pii].
  206. 206. Llanos-Cuentas A, Tulliano G, Araujo-Castillo R, Miranda-Verastegui C, Santamaria-Castrellon G, et al. (2008) Clinical and parasite species risk factors for pentavalent antimonial treatment failure in cutaneous leishmaniasis in Peru. Clin Infect Dis 46: 223–231 10.1086/524042 [doi].
  207. 207. Machado-Pinto J, Pinto J, da Costa CA, Genaro O, Marques MJ, et al. (2002) Immunochemotherapy for cutaneous leishmaniasis: a controlled trial using killed Leishmania (Leishmania) amazonensis vaccine plus antimonial. Int J Dermatol 41: 73–78 1336 [pii].
  208. 208. Miranda-Verastegui C, Llanos-Cuentas A, Arevalo I, Ward BJ, Matlashewski G (2005) Randomized, double-blind clinical trial of topical imiquimod 5% with parenteral meglumine antimoniate in the treatment of cutaneous leishmaniasis in Peru. Clin Infect Dis 40: 1395–1403 CID34933 [pii];10.1086/429238 [doi].
  209. 209. Navin TR, Arana BA, Arana FE, de Merida AM, Castillo AL, et al. (1990) Placebo-controlled clinical trial of meglumine antimonate (glucantime) vs. localized controlled heat in the treatment of cutaneous leishmaniasis in Guatemala. Am J Trop Med Hyg 42: 43–50.
  210. 210. Oliveira-Neto MP, Schubach A, Mattos M, Goncalves-Costa SC, Pirmez C (1997) A low-dose antimony treatment in 159 patients with American cutaneous leishmaniasis: extensive follow-up studies (up to 10 years). Am J Trop Med Hyg 57: 651–655.
  211. 211. Oliveira-Neto MP, Schubach A, Mattos M, Goncalves-Costa SC, Pirmez C (1997) Treatment of American cutaneous leishmaniasis: a comparison between low dosage (5 mg/kg/day) and high dosage (20 mg/kg/day) antimony regimens. Pathol Biol (Paris) 45: 496–499.
  212. 212. Oliveira-Neto MP, Mattos MS (2006) An alternative antimonial schedule to be used in cutaneous leishmaniasis when high doses of antimony are undesirable. Rev Soc Bras Med Trop 39: 323–326 S0037-86822006000400001 [pii].
  213. 213. Romero GA, Guerra MV, Paes MG, Macedo VO (2001) Comparison of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis and L. (V.) guyanensis in Brazil: therapeutic response to meglumine antimoniate. Am J Trop Med Hyg 65: 456–465.
  214. 214. Seaton RA, Morrison J, Man I, Watson J, Nathwani D (1999) Out-patient parenteral antimicrobial therapy–a viable option for the management of cutaneous leishmaniasis. QJM 92: 659–667.
  215. 215. Soto J, Valda-Rodriquez L, Toledo J, Vera-Navarro L, Luz M, et al. (2004) Comparison of generic to branded pentavalent antimony for treatment of new world cutaneous leishmaniasis. Am J Trop Med Hyg 71: 577–581 71/5/577 [pii].
  216. 216. Velez I, Lopez L, Sanchez X, Mestra L, Rojas C, et al. (2010) Efficacy of miltefosine for the treatment of American cutaneous leishmaniasis. Am J Trop Med Hyg 83: 351–356 83/2/351 [pii];10.4269/ajtmh.2010.10-0060 [doi].
  217. 217. Franke ED, Wignall FS, Cruz ME, Rosales E, Tovar AA, et al. (1990) Efficacy and toxicity of sodium stibogluconate for mucosal leishmaniasis. Ann Intern Med 113: 934–940.
  218. 218. Franke ED, Llanos-Cuentas A, Echevarria J, Cruz ME, Campos P, et al. (1994) Efficacy of 28-day and 40-day regimens of sodium stibogluconate (Pentostam) in the treatment of mucosal leishmaniasis. Am J Trop Med Hyg 51: 77–82.
  219. 219. Llanos-Cuentas A, Echevarria J, Cruz M, La Rosa A, Campos P, et al. (1997) Efficacy of sodium stibogluconate alone and in combination with allopurinol for treatment of mucocutaneous leishmaniasis. Clin Infect Dis 25: 677–684.
  220. 220. Llanos-Cuentas A, Echevarria J, Seas C, Chang E, Cruz M, et al. (2007) Parenteral aminosidine is not effective for Peruvian mucocutaneous leishmaniasis. Am J Trop Med Hyg 76: 1128–1131 76/6/1128 [pii].
  221. 221. Soto J, Rea J, Valderrama M, Toledo J, Valda L, et al. (2009) Efficacy of extended (six weeks) treatment with miltefosine for mucosal leishmaniasis in Bolivia. Am J Trop Med Hyg 81: 387–389 81/3/387 [pii].
  222. 222. Hendrickx EP, Agudelo SP, Munoz DL, Puerta JA, Velez Bernal ID (1998) Lack of efficacy of mefloquine in the treatment of New World cutaneous leishmaniasis in Colombia. Am J Trop Med Hyg 59: 889–892.
  223. 223. Martinez S, Marr JJ (1992) Allopurinol in the treatment of American cutaneous leishmaniasis. N Engl J Med 326: 741–744 10.1056/NEJM199203123261105 [doi].
  224. 224. Martinez S, Gonzalez M, Vernaza ME (1997) Treatment of cutaneous leishmaniasis with allopurinol and stibogluconate. Clin Infect Dis 24: 165–169.
  225. 225. Palacios R, Osorio LE, Grajalew LF, Ochoa MT (2001) Treatment failure in children in a randomized clinical trial with 10 and 20 days of meglumine antimonate for cutaneous leishmaniasis due to Leishmania viannia species. Am J Trop Med Hyg 64: 187–193.
  226. 226. Rubiano LC, Miranda MC, Muvdi AS, Montero LM, Rodriguez-Barraquer I, et al. (2012) Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children. J Infect Dis 205: 684–692 jir816 [pii];10.1093/infdis/jir816 [doi].
  227. 227. Saenz RE, Paz H, Berman JD (1990) Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis. Am J Med 89: 147–155 0002-9343(90)90292-L [pii].
  228. 228. Wortmann G, Miller RS, Oster C, Jackson J, Aronson N (2002) A randomized, double-blind study of the efficacy of a 10- or 20-day course of sodium stibogluconate for treatment of cutaneous leishmaniasis in United States military personnel. Clin Infect Dis 35: 261–267 CID011553 [pii];10.1086/341406 [doi].
  229. 229. Ballou WR, McClain JB, Gordon DM, Shanks GD, Andujar J, et al. (1987) Safety and efficacy of high-dose sodium stibogluconate therapy of American cutaneous leishmaniasis. Lancet 2: 13–16.
  230. 230. Lai A Fat E, Vrede MA, Soetosenojo RM, Lai A Fat R (2002) Pentamidine, the drug of choice for the treatment of cutaneous leishmaniasis in Surinam. Int J Dermatol 41: 796–800 1633 [pii].
  231. 231. Nacher M, Carme B, Sainte MD, Couppie P, Clyti E, et al. (2001) Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana. Ann Trop Med Parasitol 95: 331–336 10.1080/00034980120064355 [doi].
  232. 232. Roussel M, Nacher M, Fremont G, Rotureau B, Clyti E, et al. (2006) Comparison between one and two injections of pentamidine isethionate, at 7 mg/kg in each injection, in the treatment of cutaneous leishmaniasis in French Guiana. Ann Trop Med Parasitol 100: 307–314 10.1179/136485906X105561 [doi].
  233. 233. Chrusciak-Talhari A, Dietze R, Chrusciak Talhari C, da Silva RM, Gadelha Yamashita EP, et al. (2011) Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania (Viannia) guyanensis in Manaus, Brazil. Am J Trop Med Hyg 84: 255–260 84/2/255 [pii];10.4269/ajtmh.2011.10-0155 [doi].