SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. General Treatment Considerations for CL and ML
  4. Species based Treatment of CL
  5. Treatment of Mucocutaneous or Mucosal Leishmaniasis
  6. Treatment in Special Groups
  7. Declaration of Interests
  8. References

Background

Treatment of cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) in travelers is still controversial. Over the last decade, national and international consortia have published recommendations for treating CL in travelers. These guidelines harmonize many issues, but there are some discrepancies.

Methods

Leishmania parasites causing CL can now be genotyped by polymerase chain reaction techniques for detecting Leishmania DNA. Therefore, treatment recommendations can now be species based rather than based on geographical exposure. To review the evidence on which the recommendations were based, “LeishMan” (Leishmaniasis Management), a group of experts from 13 institutions in eight European countries, performed a PubMed (MEDLINE) literature search and considered unpublished evidence and the experts' own personal experiences. The Oxford evidence grading system was used to evaluate the information.

Results and Conclusion

In this article, the authors provide practical treatment recommendations for imported CL and ML in Europe, drawn up from the review by the European experts.

Treatment of cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) in travelers is still controversial. Current treatment recommendations are based on data from endemic regions, which may not be applicable to travelers who have different exposure rates and immunity toward Leishmania parasites.

Leishmania parasites causing CL can now be genotyped by polymerase chain reaction (PCR) techniques for detecting Leishmania DNA. Therefore, species-based treatment guidelines are now possible and are increasingly replacing previous guidelines that were based on geographical exposure. Species-oriented treatment guidelines for imported CL have been drawn up by national advisory bodies (Germany, France, UK, and WHO) and by several authors.[1-9] The WHO 2010 recommendations are mainly written for endemic countries and not for travelers.[9] Important differences exist between these guidelines, often because of insufficient evidence to support the recommendations. In this article, we provide practical treatment recommendations for imported CL and ML in Europe, drawn up from the review by the European expert group, “LeishMan” (Leishmaniasis Management).[10] To review the evidence on which recommendations are based, LeishMan performed a PubMed (MEDLINE) literature search using the key words “CL” and “treatment,” to select for controlled clinical trials published between 1962 and 2013 and using “mucosal/mucocutaneous leishmaniasis,” to select clinical trials published between 1960 and 2013. The search included articles published in English, French, German, and Spanish. In addition, LeishMan included unpublished evidence and the expert group's own personal experiences.

The Oxford evidence grading system was applied when reviewing information. The highest ranking A was assigned to randomized controlled trials in representative patient groups. Randomized controlled trials in less homogenous patient groups (small numbers, different species included) as well as cohort trials and case-control studies in representative patient groups were given a ranking B. Cohort trials or case-control studies in less homogenous patient groups, as well as case series of representative patient groups were given a ranking C. Case series of less homogenous patient groups and expert opinion were ranked as D.

General Treatment Considerations for CL and ML

  1. Top of page
  2. Abstract
  3. General Treatment Considerations for CL and ML
  4. Species based Treatment of CL
  5. Treatment of Mucocutaneous or Mucosal Leishmaniasis
  6. Treatment in Special Groups
  7. Declaration of Interests
  8. References

Patient Evaluation Before Treatment

CL lesions range from a single limited skin lesion, that may heal spontaneously, to large and multiple locally destructive skin lesions, which may spread to or involve mucosa. So, treatment depends on the clinical aspect of the lesion and the infecting species. Mucosal spread may affect the nostrils, the nasal septum, and the oral mucosa. Referral to an Ear, Nose, and Throat specialist may be warranted.

The possibility of CL being part of visceral leishmaniasis (VL) occurs rarely but should be considered if the patient has fever and hepatosplenomegaly and laboratory markers of VL infection (pancytopenia, positive Leishmania antibody titers). This clinical presentation is more likely if a patient has underlying immunosuppression.

Definition of Healing and Follow-Up

Cutaneous lesions usually heal within a month after starting treatment with pentavalent antimonials, either by local infiltration [Old World cutaneous leishmaniasis (OWCL)] or given systemically [New World cutaneous leishmaniasis (NWCL)], but large ulcers may take longer. Treatment failure is present when reepithelialization is incomplete 3 months after starting therapy. A relapse is defined as the reappearance of the ulcer after complete healing, or a renewed increase in the indurated area of a nodular lesion. Parasitological confirmation is not required, except in clinically complex cases. In such cases, parasite identification (by microscopy and or culture) is preferred, as Leishmania DNA can be detected by PCR in lesions several years after successful treatment.[11, 12] A follow-up visit at 3 and at 12 months is required to ascertain complete cure.

General Considerations: Local Versus Systemic Treatment for CL

The choice for topical or systemic treatment is determined by the following factors.

  • 1. Risk of developing mucosal leishmaniasis
  • This is the main reason for recommending systemic treatment in all patients with CL from the New World (except Leishmania mexicana infections). Recent data suggest that the risk is higher when lesions are (i) infected with Leishmania braziliensis or Leishmania panamensis, (ii) acquired in Bolivia, (iii) multiple (>4), large (>4–6 cm2), (iv) present for >4 months, (v) localized above the belt, (vi) associated with acquired or induced immunosuppression, and (vii) treated inappropriately.[13] Whether local treatment predisposes patients to ML (compared to systemic treatment) has never been studied systematically, but there are no reports on ML developing in NWCL patients treated with paromomycin or methylbenzethonium chloride ointment or with local infiltration with antimonials.[13]
  • If none of the above risk factors are present in patients with NWCL, the risk of developing ML is probably low. Local treatment is thus an option for those who can comply and for whom long-term follow-up is feasible. Experts in Latin America have recently adopted this stance and studies evaluating local therapy for NWCL are underway.
  • 2. Failure of prior local treatment
  • Local treatment includes topical treatment with ointment, cryotherapy, and intralesional injection with antimonials. Failure to respond may indicate the need for systemic treatment.
  • 3. Size, number, and localization of lesions
  • Lesions that are multiple and large, that affect the nose, lips, eyelids, or ears, or that are located close to small joints are, for practical reasons, less suited for local therapy.
  • 4. Lymphatic spread
  • It is not clear whether local lymphadenopathy and lymphangitis is an absolute indication for systemic treatment. It may indicate extra-dermal parasite spread and thus a risk of subsequent ML. In studies with local treatment, concomitant lymphadenopathy was either an exclusion criterion[14, 15] or was not reported.[16-18] It is therefore unknown whether lymphatic spread of leishmaniasis responds to local treatment.
  • 5. Toxicity of systemic treatment
  • Table 1 summarizes the adverse events associated with current systemic treatment options, based on data from CL and ML studies conducted mainly in young and otherwise healthy patients. Adverse events may be more severe and frequent in patients with comorbidities such as cardiac, renal or hepatic disease, diabetes mellitus, or immunosuppression. Miltefosine has a very long half-life and is still detectable in blood samples 6 months after a standard 28-day treatment.[40] Women of childbearing age should adopt contraceptive measures during treatment and for 4 months after treatment completion.[41]
Table 1. Drugs and follow-up for treatment of cutaneous leishmaniasis
DrugAdverse effectManagement/Follow-up
  1. ULN, upper limit of normal value.

Systemic pentavalent antimonials

Cardiac toxicity with reversible ECG alterations is seen in 30%–60%

- Repolarization alterations affecting T wave and ST segment

- Prolongation of the corrected QT interval

- Fatal arrhythmias have not been documented in CL patients treated with the usual dose ≤20 mg Sb/kg[19-23]

- Hypokalemia associated with risk of arrhythmias

ECG checks 1–2 every week

Interruption of treatment if

- Significant arrhythmias

- QTc longer than 0.5 second (age-adapted limits in children)

- QTc longer than 0.45 second: monitoring/dose reduction

- Concave ST segment

- Potassium weekly

 Hepatotoxicity seen in 50%, reversible

Transaminases weekly

Treatment interruption if transaminases higher than five times the upper limit of normal value (ULN)[24]

 Hematotoxicity (anemia, leukopenia, thrombopenia)[25]Hemoglobin, leukocytes, and platelets weekly
 Pancreatitis can occur either very early in therapy (and is then often symptomatic) or more progressively during the course of therapy. Serum levels of amylase and lipase may decline despite continued treatment with antimonials

Amylase and lipase after 48 h of treatment and then weekly

Treatment interruption if serum amylase levels became >4 times the ULN or lipase levels of >15 times the ULN, regardless of symptoms. Therapy can be resumed once these values tend significantly toward normal value[26, 27]

 Subjective complaints: musculoskeletal symptoms, headache, gastrointestinal complaints, pain at the injection site 
 Rare complications: glomerulonephritis, acute renal failure,[28] peripheral nephritis,[29] exfoliate dermatitis, herpes zoster,[30] hypersensitivity syndrome[31]Weekly examination of urine, creatinine
PentamidineAseptic abscess (accidental contact of pentamidine with the subcutaneous tissue)Pentamidine has to be given by infusion or injected slowly and strictly intramuscular with a long needle (50 mm)
 Hypoglycemia, diabetes, proteinuriaFasting glycemia and urine for proteinuria and glycosuria have to be checked before every injection and 3 weeks and 2 months after the last injection[32]
 Rhabdomyolysis[33, 34]CK in case of clinical signs of rhabdomyolysis such as myalgia or kidney failure
 Hypotension[35, 36]The blood pressure and heart rate have to be measured before and after the injection (every 15 min for 1 h)[32] less frequent when administered by slow infusion
 Subjective complaints: myalgia, nausea and gustative abnormalities, headache, pain at the injection site, abdominal pain[36] 
MiltefosineSubjective complaints: nausea (36%), vomiting up to 40% often during the first week, motion sickness (29%), headache (27%), diarrhea (6%–16%), vomiting (32%–38%)[37, 38] 
 Impaired renal function: Creatinine increased above the normal range in 32%, in 31% <1.5 times the upper limit of normal, and in 1% between 1.5 and 3 times the upper limit of normal[37]Creatinine weekly
 Hepatotoxicity: The AST was elevated in 8% and the ALT in 10% but always less than 2.5 times the upper limit of normal value.[37]Transaminases weekly
 Teratogenic, subtherapeutic miltefosine concentrations in the blood beyond 4 months after treatmentAvoid pregnancy until 4 months after end of treatment
 Discoloration of sperma 
KetoconazoleHepatotoxicity reversible, usually mild,[39] sometimes severe

Transaminases weekly

Treatment interruption if transaminases higher than five times ULN

 Diminution of testosterone values (70%), but without diminution of libido or beard growth[39]Reversible, no controls needed
 Subjective complaints: abdominal pain, headache, nausea, fever, and malaise[39] 
FluconazoleHepatotoxicity

Transaminases

Treatment interruption if transaminases higher than five times ULN

 Allergic skin reactions 
 Hematotoxicity (anemia, leukopenia, thrombopenia)Hemoglobin, leukocytes, and platelets
 Subjective complaints: headache, gastrointestinal complaints 
Liposomal amphothericin B

Renal toxicity

Hypokalemia

Creatinine and potassium before each infusion

Avoid other potential nephrotoxic drugs

 Infusion-related reactions including chest pain, flank pain, dyspnea, flushing urticariaMay be partially prevented by hydrocortisone
 Nausea, anorexia, vomiting 

Species based Treatment of CL

  1. Top of page
  2. Abstract
  3. General Treatment Considerations for CL and ML
  4. Species based Treatment of CL
  5. Treatment of Mucocutaneous or Mucosal Leishmaniasis
  6. Treatment in Special Groups
  7. Declaration of Interests
  8. References

Treatment of L. major

  • a.
    Up to three lesions, not cosmetically disfiguring, patients not immunosuppressed, option acceptable to patient:
  • No antileishmanial treatment; simple wound care
  • b.
    Up to three lesions with diameters <30 mm—local treatment:
  1. “Flash” cryotherapy plus local infiltration with antimonials [A][42-46]
  2. 15% Paromomycin or 12% methylbenzethonium chloride ointment bid for 10 to 20 days [A][47-51]
  3. Local heat therapy (50°C for 30 seconds) [A][52-55]
  • c.
    More than three lesions, diameter >30 mm, delicate location, and/or refractory to local treatment:
  1. Miltefosine (50 mg tid × 28 days) [B][56-58]
  2. Fluconazole (200 mg bid × 6 weeks) [C][59-61]
  3. Liposomal amphotericin B (18 mg/kg total dose: 3 mg/kg/day, days 1 to 5 and at day 10) [D][62]
  4. Systemic pentavalent antimonial (Sb 20 mg/kg) and pentoxifylline (3 × 400 mg/20 days) [A] or systemic pentavalent antimonial (Sb 20 mg/kg for 10–20 days) [D][55, 57, 63-65]

Watchful waiting is a critical requirement. Studies reported spontaneous cure rates of 53% at 8 weeks,[66] from 40% to 90% at 3 months[67] and close to 100% at 12 months.[2] However, CL acquired in Afghanistan often does not heal spontaneously and may require systemic treatment.[56]

In a large study of 634 patients with CL (L. major or Leishmania tropica), combining cryotherapy and intralesional injection with antimonials (Figures 1 and 2) had better cure rates (89%–91%) than either cryotherapy (57%–68%) or intralesional antimonials alone (44–75%).[42, 45, 46] Local heat therapy (50°C for 30 seconds) had a cure rate comparable to that of systemic pentavalent antimonials (Sb 20 mg/kg for 10 days) (48% vs 54%, n = 54).[55] Compared to intralesional antimonials the cure rates of local heat application were superior (81% vs 55%, n = 116)[54] (83% vs 74%, n = 382),[53] or similar (98% vs 94%, n = 100).[52] Local heat therapy is a promising method for local treatment and is a valuable option for centers with necessary equipment (ie, Thermomed Device). Topical application of an ointment containing 15% paromomycin and 12% methylbenzethonium chloride appears to be more effective than an ointment with 15% paromomycin plus 10% urea, but also causes more local inflammation.[68] A newly developed topical aminoglycoside formulation is more effective than a placebo among Tunisian patients and French travelers (L. major), with cure rates consistently above 80% at 3 months.[48, 51]

image

Figure 1. Procedure for intralesional treatment with pentavalent antimony.[46] Advance the needle while injecting under pressure in the dermis, covering the whole lesion including the center.

Download figure to PowerPoint

image

Figure 2. Procedures for superficial cryotherapy and/or intralesional injection of antimony. The lesion is first swabbed with antiseptics several minutes before starting the procedure. (A) Cryotherapy: cryotherapy with liquid nitrogen is then applied on the lesion (A1) and immediate borders (A2)—ideally with a sprayer—3- to 5-second blanching is obtained. (B and C) Intralesional injection: Antimony as formulated for parenteral administration by the manufacturer (B) is injected into the lesion (C1) and should induce blanching of the borders (C2, arrows), until the lesion is entirely swollen (before procedure C3, end of procedure C4). The procedure is usually repeated 2 to 10 times at 2 to 8 day intervals.

Download figure to PowerPoint

Miltefosine at 150 mg daily for 28 days is a treatment option for patients who have not responded to intralesional pentavalent antimonials. In treatment studies of L. major CL (three studies, n = 81) cure rates of miltefosine had a mean of 93% (range: 87% to 100%).[56-58] This was somewhat superior to the 85% cure rates of systemic meglumine antimoniate (20 mg/kg for 14 days).[57]

In OWCL, the efficacy of systemic pentavalent antimony is poorly documented.[69] In an open, uncontrolled study (pentavalent Sb 20 mg/kg for 10 days), cure rates ranged from 52% to 87% at 3 weeks[55, 57, 63-65] and was 90% at 12 months.[55] Systemic Sb treatments had the same cure rate as a placebo.[70] Adding allopurinol (15–20 mg/kg/daily for 20 days) produced only marginally better cure rates than Sb alone (80% vs 74%),[64] but when used in combination with pentoxifylline three times 400 mg daily for 20 days, the cure rate improved significantly (26/32 = 81% vs 16/31 = 52%).[63]

Fluconazole (200 mg daily for 6 weeks) was a well-tolerated treatment for L. major leishmaniasis in Saudi Arabia, with a cure rate of 79% (63/80) versus 34% (22/65) for the placebo group at 3 months.[59] Unfortunately, this favorable result could not be reproduced elsewhere.[60] Increasing the dosage of fluconazole to 400 mg daily produced a higher cure rate (81%) than fluconazole 200 mg daily (48%) at 2 months, but with increased adverse events rate. Adverse events included raised serum creatinine or liver enzymes (4%), cheilitis (45%), and nausea (10%) leading to treatment interruption.[61]

Ketoconazole, another imidazole compound, showed an acceptable cure rate of 70% (5/8) in a small case series.[71] It was superior to intralesional antimonials in a study with L. major and L. tropica CL, with cure rates of 89% (57/64) and 72% (23/32), respectively.[72] No placebo controlled studies exist with ketoconazole.

Treatment of L. tropica, Leishmania infantum/donovani, and Leishmania aethiopica

  • a.
    Up to three lesions, not cosmetically disfiguring and patients not immunosuppressed, option acceptable to patient:
  • Simple wound care
  • b.
    Up to three lesions with diameter <30 mm—local treatment:
  1. Local infiltration with antimonials with or without cryotherapy [A] [42, 45, 46]
  2. 15% Paromomycin/12% methylbenzethonium chloride ointment bid for 10 to 20 days [D]
  3. Local heat therapy (50°C for 30 seconds) [A][54, 73]
  • c.
    More than three lesions, diameter >30 mm, delicate location, and/or refractory to local treatment:
  1. Liposomal amphotericin B (18 mg/kg total dose: 3 mg/kg/day, days 1 to 5 and at day 10) [C][62, 74]
  2. Miltefosine (50 mg tid × 28 days) [D][75-77]
  3. Pentavalent antimonials (Sb 20 mg/kg for 10–20 days) (+/− allopurinol) [C][73, 78-80]

Treatment data are scarce for L. tropica and nearly non-existent for L. infantum/donovani or L. aethiopica CL lesions. Spontaneous cure for L. tropica CL is estimated at 1% to 10% at 3 months, 68% at 12 months, and close to 100% at 6 months to 3 years.[2, 79]

As mentioned above, cryotherapy combined with intralesional antimonials (see Figures 1 and 2) produced excellent cure rates in L. major or L. tropica CL and may be successful in L. aethiopica and L. infantum/donovani CL as well.[42, 45, 46, 81] Thermotherapy and photodynamic therapy were effective in L. tropica and L. major CL and is a valuable option for centers with the necessary equipment (ie, Thermomed Device).[54, 55, 82]

Liposomal amphotericine (AmBisome, 3 mg/kg/day for five consecutive days and at day 10, with a total dose of 18 mg/kg) had a cure rate of 84% in 13 travelers and immigrants with L. tropica CL.[74]

For L. tropica, L. major, and L. infantum/donovani CL, experience with miltefosine is limited to case reports[75-77, 83, 84] and small case series, with all patients cured.[58] Two patients with L. infantum ML were completely cured with miltefosine.[85, 86] Cure rates of systemic antimonials in L. tropica CL ranged from 41% to 55%,[73, 78-80] but were not studied for L. infantum/donovani CL. For L. tropica CL, adding allopurinol (15–20 mg/kg/day for 20 days) increased cure rates to 46%, compared with 24% in the antimony-only group.[87] According to European experts, systemic pentavalent antimonials are effective for treating complex CL lesions and are recommended in some national guidelines.[2, 5, 88]

There are no systematic treatment studies of L. aethiopica. Cryotherapy has been widely used. Liposomal Amphothericin B and miltefosine were used successfully in some cases.[89]

Treatment of L. panamensis

Although many experts consider L. guyanensis and L. panamensis as a single species complex, we analyzed them separately, since trials were performed on each species. As knowledge of the taxonomy of Leishmania increases, there may be justification for merging recommendations in the future.

  • a.
    Single or few lesion(s), not cosmetically disfiguring, lesions with diameter <30 mm, no lymphatic spread, option acceptable to patient—local treatment considered:
  1. 15% Paromomycin/12% methylbenzethonium chloride ointment [B][14, 16]
  2. Local heat therapy [A][90]
  • b.
    Multiple lesions or large single lesion—systemic treatment:
  1. Miltefosine (50 mg tid × 28 days) [A][91-94]
  2. Pentamidine isethionate (4 mg/kg, three infusions over 5 days) [A][35, 95]
  3. Ketoconazole (600 mg × 28 days) [B][39]
  4. Pentavalent antimonials (Sb 20 mg/kg for 20 days) [A][35, 90, 96, 97]

Data on local treatment are scarce. In a group of 52 patients infected mainly with L. panamensis, topical treatment with 15% paromomycin or 12% methylbenzethonium chloride ointment od or bid for 20 days produced cure rates of 90% at 3 months and of 85% after 1 year. Reinfections could not be distinguished from relapses.[16] This topical treatment (once daily for 30 days; n = 29; cure rate 79%) was inferior to systemic treatment with systemic pentavalent antimonials (20 mg/kg od for 10 days; n = 36; cure rate 92%).[14] However, because of toxicity and the lack of superiority to other drug regimens, systemic pentavalent antimonials are no longer the treatment of choice. As cure rates with thermotherapy were mediocre (14/24 = 58%) and inferior to systemic meglumine antimoniate (23/32 = 72%), thermotherapy cannot yet be proposed as a first line treatment.[90]

Cure rates with miltefosine were variable (60%–94%),[91-94] but superior to a placebo in one study (91% vs 38%).[93] Compared to pentavalent antimonials, cure rates with miltefosine treatment were similar in Colombia (18/30; 60% vs 23/32; 72%),[94] but higher in 43 patients from Brazil (92% vs 63%).[92]

Pentamidine was tested in different dosages (two to six injections of 2 to 4 mg/kg) in patients with predominantly L. panamensis CL. Cure rates were comparable with pentavalent antimonials (96% vs 91%) and were highest with dosages of three to five times, 4 mg/kg (96%).[35, 95]

Treatment of L. guyanensis

  • a.
    Single lesion, not cosmetically disfiguring, no lymphatic spread and infection not acquired in Bolivia:
  • No data on local treatment: no recommendation possible
  • b.
    All other cases—systemic treatment:
  1. Pentamidine isethionate (4 mg/kg: three infusions over 5 days) [A].[33, 35, 36, 95, 98-100]
  2. Miltefosine (50 mg tid × 28 days) [B][101]

Pentamidine is the first line treatment for L. guyanensis CL in French Guyana, Surinam, and Brazil, with cure rates around 90%.[35, 95, 98, 100, 36, 33] Although these studies included many patients (>2,000 patients), most are retrospective observations and different dosages were used. Cure rate was lower (77%) in a study from Surinam, possibly due to a very low follow-up rate.[102] For L. guyanensis acquired in North-East Brazil, the cure rate was higher with miltefosine (40/56; 71%) than with meglumine antimoniate group (16/28; 57%).[101]

Treatment of L. braziliensis, Leishmania peruviana

L. braziliensis and L. peruviana species are genetically very similar. Data on treatment come from studies of L. braziliensis CL.

  • a.
    Single or few lesion(s), not cosmetically disfiguring, lesion with diameter <30 mm, no lymphatic spread, not from Bolivia—local treatment possible:
  1. Local infiltration with antimonials +/− cryotherapy [B][17]
  2. 15% Paromomycin/12% methylbenzethonium chloride ointment [B]18,88
  3. Thermotherapy [A][90]
  • b.
    All other cases—systemic treatment:
  1. Pentavalent antimonials (Sb 20 mg/kg for 20 days) [A] [37, 90, 93, 94, 103-105]
  2. Liposomal amphotericin B (18 mg/kg total dose: 3 mg/kg/day, days 1 to 5 and at day 10) [B][62, 106]
  3. Miltefosine (only Bolivia, Brazil) (50 mg tid ×  28 days) [C][105, 107]

Local treatment with intralesional antimonials was only reported in one study involving 74 patients with L. braziliensis CL. Cure rate without relapse or development of ML was 80%.[17] For CL due to L. braziliensis (75%) and L. mexicana (25%), topical treatment with 15% paromomycin/12% methylbenzethonium chloride ointment (n = 35) was more effective than placebo (n = 33; response rate at 12 weeks was 91% vs 39%)[18] and had a cure rate of 76% after 8 weeks (n = 53)[108] but was not compared to systemic treatment with pentavalent antimonials. In studies of topical treatment of NWCL, patients were followed up either until healed[108, 109] or until a year after treatment.[14, 16, 18] Although none developed ML, the observation periods were too short and the sample size too small to assess that risk accurately. Since cure rates of thermotherapy were mediocre (31/95 = 53%) and inferior to those of systemic meglumine antimoniate (34/52 = 65%), thermotherapy cannot yet be proposed as a first line treatment.[90]

Pentavalent antimonials are the principal treatment for L. braziliensis CL.[19, 26, 110-112] Cure rates range from low (50%)[113, 114] to excellent (96%–100%).[97, 104, 115] The variation may be attributed to strain and site differences.[113] In CL patients infected with L. peruviana (n = 46), 76% were cured with systemic antimonials.[116, 117]

Liposomal amphotericin B has been used after treatment failure in immunocompromised patients and when pentavalent antimonials are contraindicated. Case series in travelers and immigrants showed that AmBisome (3 to 5 mg/kg daily for five consecutive days and a sixth dose on day 10, cumulative doses 18–30 mg/kg) cured 29 of 34 (85%) patients with L. braziliensis CL in Israel[106, 118] and 12 of 14 (86%) patients in Germany.[119] Using similar cumulative doses, AmBisome had a cure rate of about 84% in patients with OWCL (n = 10) and NWCL lesions (n = 10) alike.[62]

Treatment with miltefosine has been disappointing, with cure rates varying with the geographical origin of the infection. A small series from Guatemala had unacceptably low cure rates (33%) compared to placebo (8%).[93] However, cure rates were comparable to that of pentavalent antimonial treatment in Colombia (60% vs 65%, n = 93)[94] and Bolivia (88% vs 94%, n = 57),[105] and slightly better in Brazil (75% vs 53%, n = 90).[107] Differences in drug susceptibility in some subspecies of L. braziliensis may account for the wide cure rate variation observed (Table 2).

Table 2. Drug properties
DrugSpecial precautionsAdministrationDosageDurationHalf-lifeMetabolic and elimination pathwaysPregnancy categorybRenal function impairment
  1. Category A: No fetal risk, Category B: Relatively safe to use during pregnancy, Category C: fetal risk is unknown, Category D: Some evidence of fetal risk, Category X: Causes abnormalities.

  2. a

    Bi-phasic elimination, typically relating to the distribution and elimination phase of the drug.

  3. b

    Pregnancy categories.

Systemic pentavalent antimonials

Age >60 years

Cardiopathy

Liver disease

Renal impairment

Pancreatitis

IM / IV20 mg/kg of Sb[5] base equivalent

(10)-20 days

ML: 28 days

Approximately 2 h and 33–76 haRenal excretionUnknownDose adjustment[144]
Pentamidine

Renal impairment

Liver disease

Pancreatitis

Diabetes

IV (IM)4 mg/kg base3Approximately 9–13 h and approximately 28 daysaSmall extent renal excretion (4%–17% in 24 h)CNot indicated due to nephrotoxicity
MiltefosinePregnancyOral150 mg/day28 days7 days and 31 daysaPhospholipasesTeratogenic (contraception required until 4 months post-treatment)No dose adjustment indicated
KetoconazoleLiver diseaseOral600 mg/day28 days2 h and 8haHepatic; mainly biliary excretionCNo dose adjustment indicated
Fluconazole Oral400 mg/day6 weeks30 hHepatic; mainly renal excretionCCrCl <50 mL/min: 50% of daily dose
Liposomal Amphotericin B IV3 mg/kg/day, days 1–5, 10; 18 mg/kg total dose Terminal: 152 hNo extensive metabolism; very little renal and biliary excretionBClose monitoring of renal function, if progressive: daily dose reduction (eg, 50%)

Fluconazole has only been evaluated in small series of L. braziliensis CL patients and different dosage schemes have been used. Cure rates increased with dosage, from 75% at 5 mg/kg (n = 8) to 93% at 6.5 mg/kg (n = 14) and to 100% at 8 mg/kg (n = 8), respectively. Surprisingly, no significant adverse events were reported.[120] Because of a lack of solid evidence and intolerance at higher doses (400 mg/day) reported in patients with L. major, experts are reluctant to recommend fluconazole for L. braziliensis CL at present.

Treatment of L. mexicana

  • a.
    Up to three lesions not requiring immediate therapy, not cosmetically disfiguring and option acceptable to patient:
  • No antileishmanial medication, simple wound care, mostly self-limiting
  • b.
    More than three lesions with diameter<30 mm— local treatment:
  1. Cryotherapy/local infiltration with antimonials
  2. 15% Paromomycin/12% methylbenzethonium chloride ointment[18, 108]
  • c.
    More than three lesions with diameter >30 mm, delicate location and/or refractory to topical treatment—systemic treatment:
  1. Ketoconazole (600 mg/day × 28 days) [B][104]
  2. Miltefosine (50 mg tid × 28 days) [B][93]
  3. Pentavalent antimonials (Sb 20 mg/kg for 20 days) [D]

Published data on systemic treatment of L. mexicana CL are scarce, and have involved small patient groups only. Ketoconazole produced superior cure rates at 13 weeks compared to placebo (8/9; 89% vs 9/16; 56%) and to pentavalent antimonials (8/9; 89% vs 5/7; 71%).[104] Miltefosine had only limited efficacy (9/14; 64%)[93] and fluconazole was not tested.

Treatment of Other NWCL Species: Leishmania naiffi, Leishmania lainsoni, Leishmania amazonensis, Leishmania venezuelensis

Only a few case reports provide some data regarding the treatment.

L. naiffi: In Surinam, patients with five small lesions in total were successfully treated with pentamidine[121] and three small lesions in two patients disappeared without treatment.[122] Therefore, L. naiffi CL calls for a “wait and see” policy when only a few non-cosmetically disfiguring lesions are present.

L. amazonensis: Genetically speaking, this subspecies is closely related to L. mexicana, which suggests that a similar treatment approach could be used. However, there are no data to support this.

L. venezuelensis and L. lainsoni: Treatment data are not available. Cases were mostly treated as L. braziliensis.

Treatment of Mucocutaneous or Mucosal Leishmaniasis

  1. Top of page
  2. Abstract
  3. General Treatment Considerations for CL and ML
  4. Species based Treatment of CL
  5. Treatment of Mucocutaneous or Mucosal Leishmaniasis
  6. Treatment in Special Groups
  7. Declaration of Interests
  8. References

Systemic treatment is mandatory in ML cases; the spread and localization makes local treatment impractical or ineffective.

Old World Mucosal Leishmaniasis

  1. Miltefosine (50 mg tid × 28 days) [D][85, 86, 123]
  2. Pentavalent antimonials (Sb 20 mg /kg for 20–28 days) [D][124, 125]
  3. Liposomal amphotericin B (21–40 mg/kg total dose) [D][123, 124]

There have not been any controlled studies on treating OWML and the treatment options mentioned above were successfully used and reported in case reports.[85, 123, 124] There are no comparative studies between the treatment options and preference is guided by practical considerations, such as drug availability and costs.

New World Mucosal Leishmaniasis

  1. Pentavalent antimonials (Sb 20 mg/kg/day for 28–30 days) [A].[126, 127] Addition of pentoxyfilline (400 mg tid for 30 days) [A][128-130]
  2. Liposomal amphotericin B [C][126, 127] (30–40 mg/kg total dose)
  3. Miltefosine (150 mg od × 28 days) [B][131, 132]

Pentavalent antimonials are still the gold standard of treatment,[127, 133] with an overall cure rate of 88%.[127] Increasing the dosage beyond 20 mg Sb/kg/day for 30 days did not improve the already high cure rate of 91%. However, recurrence rates were high for all dosages used (22% to 25%).[126]

Destructive mucosal lesions contain few parasites, while tumor necrosis factor (TNF) levels are high. This suggests that an unmodulated immune response with increased production of pro-inflammatory cytokines (IL 10) is responsible for the tissue damage. Pentoxyfilline downregulates TNF-α and inhibits leukocyte migration and adhesion. Combining antimonials (20 mg/kg Sb/day for 30 days) with pentoxifylline (400 mg/tid for 30 days) cured 9 of 10[130] and 2 of 2[129] patients with refractory mucosal leishmaniasis. In a small controlled randomized study, 11 of 11 ML patients treated with the above combination were cured, whereas 5 of 12 (42%) patients treated with antimonials only required a second course of antimonials. Time lapse to cure was 83 days in the pentoxyfylline or antimonials treatment group and 145 days in the “antimonials only” group. No relapses were seen in either group at the follow-up visit 2 years later. Pentoxifylline is well tolerated, with only mild adverse effects (gastrointestinal symptoms and arthralgia).[128]

Amphotericin B deoxycholate (2 to 3 mg/kg/day for 20 days) is effective in NWML.[127] Treatment of ML with liposomal amphotericin B (total dose ranging from 34 to 50 mg/kg) cured all patients in a small study in Brazil.[134] The newer formulations of amphothericin B (colloid dispersion, liposomal) had better cure rates (12/12; 100%) than amphothericin B deoxycholate (5/8; 63%), and higher rates of treatment completion (12/13; 92% vs 8/17; 53%).[126]

In NWML (mainly caused by L. braziliensis), miltefosine cured 83% of patients with mild disease (ie, nasal mucosa) and 58% of patients with more extensive disease (involving pharynx, larynx, and palate).[131] Prolonging treatment from 4 to 6 weeks did not substantially increase cure rates (71% to 75%).[132]

Reported Differences Between ML Due to New World and Old World Species

Five reviews involving 43 patients[85, 123, 125, 135, 136] with Mediterranean ML (L. infantum/donovani), mostly reported as case reports, indicate some differences between NWML and OWML:

  1. The nasal cavity was affected in over 90% of NWML cases, but only in 15% of Mediterranean ML cases.
  2. Patients with ML acquired in the Mediterranean region had a better prognosis than those who acquired ML in Latin America. 17 of 17 (100%) patients with OWML treated with meglumine antimoniate (Sb 20 mg /kg for 20–28 days) were healed, but one of them had a relapse a year later.
  3. About half of the patients with ML due to Old Word species had some kind of immunosuppression.
  4. In NWML, destructive lesions with few parasites and high levels of TNF have been reported. In Mediterranean ML, a high parasite burden was found in the lesions.[135]
  5. Host factors might also play a role: more destructive NWML lesions were observed in African descendants than in Latinos. However, a paucity of parasites and a pronounced inflammatory response was observed in lesions from both racial groups.[137]

Treatment in Special Groups

  1. Top of page
  2. Abstract
  3. General Treatment Considerations for CL and ML
  4. Species based Treatment of CL
  5. Treatment of Mucocutaneous or Mucosal Leishmaniasis
  6. Treatment in Special Groups
  7. Declaration of Interests
  8. References

Children

In general, the guidelines above also apply to children.[138] A common problem is CL caused by L. infantum in the face of a child. One is reluctant to do infiltrations on the faces of children younger than 7 years. Small nodular lesions may be left alone or treated with cryotherapy only and multiple or large lesions can be treated with fluconazole or with miltefosine (2.5–3 mg/kg).

Pregnancy

CL is not known to affect the fetus. As none of the systemic treatments are known to be safe during pregnancy, systemic treatment should be withheld until after delivery; topical treatment may be applied before.[139] However, whether intralesional injections of antimony or topical paromomycin are completely safe during pregnancy is not known. Simple wound care or physical methods like cryotherapy, thermotherapy, or CO2 laser are preferred, despite the low level of evidence for efficacy. The lesions of pregnant women with L. braziliensis CL are larger than in non-pregnant women and have a cauliflower-like appearance rather than the typical well-demarcated ulcer with raised border.[139] In rare situations when lesion location, size, impact and persistence, despite local therapy, require systemic therapy, liposomal amphotericin B probably has the best benefit : risk ratio.

Patients Receiving Immunosuppressive Treatment or Coinfection With HIV

In most patients treated with a TNF-α antagonist, methotrexate or prednisone, the clinical presentation is similar to that of healthy persons; however, there might be some differences. The last exposure to leishmaniasis from an endemic region might date back several years, and multiple lesions, ML, disseminated CL, or the combination with VL, have been reported. The lesions usually respond well to antileishmanial treatment. If possible, immunosuppressive treatment should be discontinued until after the skin lesion has healed and then restarted under close observation.[140, 141]

HIV-positive patients with CL should be carefully assessed for coexisting VL. Localized CL in HIV-infected individuals tends to be associated with minimal immunosuppression and is clinically identical to CL in HIV-negative CL patients, but has a higher rate of recurrence after treatment. However, relevant immunosuppression due to HIV facilitates dissemination and may lead to disseminated CL and to VL.[142]

Outlook

Since these treatment recommendations are based on data from patients in endemic regions, they may not apply to travelers[143] who have different exposure rates and immunity toward Leishmania parasites; an international survey in travelers is ongoing. Data on species, detailed molecular description, clinical presentation, morbidity, and response to treatment for CL and ML in travelers will be studied in a multicenter and multinational study so that the recommendations can be adapted accordingly.

Declaration of Interests

  1. Top of page
  2. Abstract
  3. General Treatment Considerations for CL and ML
  4. Species based Treatment of CL
  5. Treatment of Mucocutaneous or Mucosal Leishmaniasis
  6. Treatment in Special Groups
  7. Declaration of Interests
  8. References

P. B. has accepted support for research and has served on advisory board for Sanofi-Aventis. The other authors state that they have no conflicts of interest to declare.

References

  1. Top of page
  2. Abstract
  3. General Treatment Considerations for CL and ML
  4. Species based Treatment of CL
  5. Treatment of Mucocutaneous or Mucosal Leishmaniasis
  6. Treatment in Special Groups
  7. Declaration of Interests
  8. References
  • 1
    Boecken G, Sunderkotter C, Bogdan C, et al. Diagnosis and therapy of cutaneous and mucocutaneous leishmaniasis in Germany. J Dtsch Dermatol Ges 2011; 9:151.
  • 2
    Bailey MS, Lockwood DN. Cutaneous leishmaniasis. Clin Dermatol 2007; 25:203211.
  • 3
    Blum J, Desjeux P, Schwartz E, et al. Treatment of cutaneous leishmaniasis among travellers. J Antimicrob Chemother 2004; 53:158166.
  • 4
    Schwartz E, Hatz C, Blum J. New world cutaneous leishmaniasis in travellers. Lancet Infect Dis 2006; 6:342349.
  • 5
    Blum JA, Hatz CF. Treatment of cutaneous leishmaniasis in travelers 2009. J Travel Med 2009; 16:123131.
  • 6
    Mitropoulos P, Konidas P, Durkin-Konidas M. New World cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. J Am Acad Dermatol 2010; 63:309322.
  • 7
    Goto H, Lindoso JA. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther 2010; 8:419433.
  • 8
    Buffet PA, Rosenthal E, Gangneux JP, et al. Therapy of leishmaniasis in France: consensus on proposed guidelines. Presse Med 2011; 40:173184.
  • 9
    Control of the Leishmaniases Report of a Meeting of the WHO Expert Committee on the Control of Leishmaniases, Geneva, 22–26 March 2010. Control of the Leishmaniases 2010; 949.
  • 10
    Blum J. LeishMan: harmonising diagnostic and clinical management of leishmaniasis in Europe. Euro Surveill 2013; 18:62.
  • 11
    Schubach A, Haddad F, Oliveira-Neto MP, et al. Detection of Leishmania DNA by polymerase chain reaction in scars of treated human patients. J Infect Dis 1998; 178:911914.
  • 12
    Mendonca MG, de Brito MEF, Rodrigues EHG, et al. Persistence of Leishmania parasites in scars after clinical cure of American cutaneous leishmaniasis: is there a sterile cure? J Infect Dis 2004; 189:10181023.
  • 13
    Blum J, Lockwood DNJ, Visser L, et al. Local or systemic treatment for New World cutaneous leishmaniasis? Re-evaluating the evidence for the risk of mucosal leishmaniasis. Int Health 2012; 4:153163.
  • 14
    Armijos RX, Weigel MM, Calvopina M, et al. Comparison of the effectiveness of two topical paromomycin treatments versus meglumine antimoniate for New World cutaneous leishmaniasis. Acta Trop 2004; 91:153160.
  • 15
    Soto JM, Toledo JT, Gutierrez P, et al. Treatment of cutaneous leishmaniasis with a topical antileishmanial drug (WR279396): phase 2 pilot study. Am J Trop Med Hyg 2002; 66:147151.
  • 16
    Krause G, Kroeger A. Topical treatment of American cutaneous leishmaniasis with paramomycin and methylbenzethonium chloride: a clinical study under field conditions in Ecuador. Trans R Soc Trop Med Hyg 1994; 88:9294.
  • 17
    Oliveira-Neto MP, Schubach A, Mattos M, et al. Intralesional therapy of American cutaneous leishmaniasis with pentavalent antimony in Rio de Janeiro, Brazil—an area of Leishmania (V.) braziliensis transmission. Int J Dermatol 1997; 36:463468.
  • 18
    Arana BA, Mendoza CE, Rizzo NR, et al. Randomized, controlled, double-blind trial of topical treatment of cutaneous leishmaniasis with paromomycin plus methylbenzethonium chloride ointment in Guatemala. Am J Trop Med Hyg 2001; 65:466470.
  • 19
    Herwaldt BL, Berman JD. Recommendations for treating leishmaniasis with sodium stibogluconate (Pentostam) and review of pertinent clinical studies. Am J Trop Med Hyg 1992; 46:296306.
  • 20
    Antezana G, Zeballos R, Mendoza C, et al. Electrocardiographic alterations during treatment of mucocutaneous leishmaniasis with meglumine antimoniate and allopurinol. Trans R Soc Trop Med Hyg 1992; 86:3133.
  • 21
    Wise ES, Armstrong MS, Watson J, Lockwood DN. Monitoring toxicity associated with parenteral sodium stibogluconate in the day-case management of returned travellers with new world cutaneous leishmaniasi. PLoS Negl Trop Dis 2012; 6:e1688.
  • 22
    Ribeiro AL, Drummond JB, Volpini AC, et al. Electrocardiographic changes during low-dose, short-term therapy of cutaneous leishmaniasis with the pentavalent antimonial meglumine. Braz J Med Biol Res 1999; 32:297301.
  • 23
    Lawn SD, Armstrong M, Chilton D, et al. Electrocardiographic and biochemical adverse effects of sodium stibogluconate during treatment of cutaneous and mucosal leishmaniasis among returned travellers. Trans R Soc Trop Med Hyg 2006; 100:264269.
  • 24
    Hepburn NC, Siddique I, Howie AF, et al. Hepatotoxicity of sodium stibogluconate in leishmaniasis. Lancet 1993; 342:238239.
  • 25
    Hepburn NC. Thrombocytopenia complicating sodium stibogluconate therapy for cutaneous leishmaniasis. Trans R Soc Trop Med Hyg 1993; 87:691.
  • 26
    Aronson NE, Wortmann GW, Johnson SC, et al. Safety and efficacy of intravenous sodium stibogluconate in the treatment of leishmaniasis: recent U.S. military experience. Clin Infect Dis 1998; 27:14571464.
  • 27
    Gasser RA Jr Magill AJ, Oster CN, et al. Pancreatitis induced by pentavalent antimonial agents during treatment of leishmaniasis. Clin Infect Dis 1994; 18:8390.
  • 28
    Rodrigues ML, Costa RS, Souza CS, et al. Nephrotoxicity attributed to meglumine antimoniate (Glucantime) in the treatment of generalized cutaneous leishmaniasis. Rev Inst Med Trop Sao Paulo 1999; 41:3337.
  • 29
    Brummitt CF, Porter JA, Herwaldt BL. Reversible peripheral neuropathy associated with sodium stibogluconate therapy for American cutaneous leishmaniasis. Clin Infect Dis 1996; 22:878879.
  • 30
    Wortmann GW, Aronson NE, Byrd JC, et al. Herpes zoster and lymphopenia associated with sodium stibogluconate therapy for cutaneous leishmaniasis. Clin Infect Dis 1998; 27:509512.
  • 31
    Jeddi F, Caumes E, Thellier M, et al. Drug hypersensitivity syndrome induced by meglumine antimoniate. Am J Trop Med Hyg 2009; 80:939940.
  • 32
    Hellier I, Dereure O, Tournillac I, et al. Treatment of Old World cutaneous leishmaniasis by pentamidine isethionate. An open study of 11 patients. Dermatology 2000; 200:120123.
  • 33
    Lightburn E, Morand JJ, Meynard JB, et al. Management of American cutaneous leishmaniasis. Outcome apropos of 326 cases treated with high-dose pentamidine isethionate. Med Trop (Mars) 2003; 63:3544.
  • 34
    Delobel P, Pradinaud R. Rhabdomyolysis associated with pentamidine isethionate therapy for American cutaneous leishmaniasis. J Antimicrob Chemother 2003; 51:13191320.
  • 35
    Soto-Mancipe J, Grogl M, Berman JD. Evaluation of pentamidine for the treatment of cutaneous leishmaniasis in Colombia. Clin Infect Dis 1993; 16:417425.
  • 36
    Nacher M, Carme B, Sainte MD, et al. 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 2001; 95:331336.
  • 37
    Soto J, Berman J. Treatment of New World cutaneous leishmaniasis with miltefosine. Trans R Soc Trop Med Hyg 2006; 100(Suppl 1):S34S40.
  • 38
    Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for the treatment of Indian visceral leishmaniasis. Trans R Soc Trop Med Hyg 2006; 100(Suppl 1):S26S33.
  • 39
    Saenz RE, Paz H, Berman JD. Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis. Am J Med 1990; 89:147155.
  • 40
    Dorlo TP, van Thiel PP, Huitema AD, et al. Pharmacokinetics of miltefosine in Old World cutaneous leishmaniasis patients. Antimicrob Agents Chemother 2008; 52:28552860.
  • 41
    Dorlo TPC, Balasegaram M, Lima MA, et al. Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine. J Antimicrob Chemother 2012; 67:19962004.
  • 42
    Asilian A, Sadeghinia A, Faghihi G, et al. 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 2004; 43:281283.
  • 43
    Faris RM, Jarallah JS, Khoja TA, et al. Intralesional treatment of cutaneous leishmaniasis with sodium stibogluconate antimony. Int J Dermatol 1993; 32:610612.
  • 44
    Tallab TM, Bahamdam KA, Mirdad S, et al. Cutaneous leishmaniasis: schedules for intralesional treatment with sodium stibogluconate. Int J Dermatol 1996; 35:594597.
  • 45
    Eldarouti MA, Alrubaie SM. Cutaneous leishmaniasis—treatment with combined cryotherapy and intralesional stibogluconate injection. Int J Dermatol 1990; 29:5659.
  • 46
    Salmanpour R, Razmavar MR, Abtahi N. Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment of cutaneous leishmaniasis. Int J Dermatol 2006; 45:11151116.
  • 47
    el On J, Halevy S, Grunwald MH, et al. Topical treatment of Old World cutaneous leishmaniasis caused by Leishmania major: a double-blind control study. J Am Acad Dermatol 1992; 27:227231.
  • 48
    Ben Salah A, Buffet PA, Morizot G, et al. WR279,396, a third generation aminoglycoside ointment for the treatment of Leishmania major cutaneous leishmaniasis: a phase 2, randomized, double blind, placebo controlled study. PLoS Negl Trop Dis 2009; 3:e432.
  • 49
    el On J, Livshin R, Paz ZE, et al. Topical treatment of cutaneous leishmaniasis. J Invest Dermatol 1985; 291:12801281.
  • 50
    Asilian A, Jalayer T, Nilforooshzadeh M, et al. Treatment of cutaneous leishmaniasis with aminosidine (paromomycin) ointment: double-blind, randomized trial in the Islamic Republic of Iran. Bull World Health Organ 2003; 81:353359.
  • 51
    Ben Salah A, Ben Messaoud N, Guedri E, et al. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med 2013; 368:524532.
  • 52
    Bumb RA, Prasad N, Khandelwal K, et al. Long-term efficacy of single-dose radiofrequency-induced heat therapy vs. intralesional antimonials for cutaneous leishmaniasis in India. Br J Dermatol 2013; 168:11141119.
  • 53
    Safi N, Davis GD, Nadir M, et al. Evaluation of thermotherapy for the treatment of cutaneous leishmaniasis in Kabul, Afghanistan: a randomized controlled trial. Mil Med 2012; 177:345351.
  • 54
    Sadeghian G, Nilfroushzadeh MA, Iraji F. Efficacy of local heat therapy by radiofrequency in the treatment of cutaneous leishmaniasis, compared with intralesional injection of meglumine antimoniate. Clin Exp Dermatol 2007; 32:371374.
  • 55
    Aronson NE, Wortmann GW, Byrne WR, et al. A randomized controlled trial of local heat therapy versus intravenous sodium stibogluconate for the treatment of cutaneous Leishmania major infection. PLoS Negl Trop Dis 2010; 4:e628.
  • 56
    van Thiel PP, Leenstra T, Kager PA, et al. Miltefosine treatment of Leishmania major infection: an observational study involving Dutch military personnel returning from northern Afghanistan. Clin Infect Dis 2010; 50:8083.
  • 57
    Mohebali M, Fotouhi A, Hooshmand B, et al. Comparison of miltefosine and meglumine antimoniate for the treatment of zoonotic cutaneous leishmaniasis (ZCL) by a randomized clinical trial in Iran. Acta Trop 2007; 103:3340.
  • 58
    Rahman SB, ul Bari A, Mumtaz N. Miltefosine in cutaneous leishmaniasis. J Coll Physicians Surg Pak 2007; 17:132135.
  • 59
    Alrajhi AA, Ibrahim EA, De Vol EB, et al. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 2002; 346:891895.
  • 60
    Morizot G, Delgiudice P, Caumes E, et al. Healing of Old World cutaneous leishmaniasis in travelers treated with fluconazole: drug effect or spontaneous evolution? Am J Trop Med Hyg 2007; 76:4852.
  • 61
    Emad M, Hayati F, Fallahzadeh MK, et al. 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 2011; 64:606608.
  • 62
    Wortmann G, Zapor M, Ressner R, et al. Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis. Am J Trop Med Hyg 2010; 83:10281033.
  • 63
    Sadeghian G, Nilforoushzadeh MA. Effect of combination therapy with systemic glucantime and pentoxifylline in the treatment of cutaneous leishmaniasis. Int J Dermatol 2006; 45:819821.
  • 64
    Momeni AZ, Reiszadae MR, Aminjavaheri M. Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate. Int J Dermatol 2002; 41:441443.
  • 65
    Firdous R, Yasinzai M, Ranja K. Efficacy of glucantime in the treatment of Old World cutaneous leishmaniasis. Int J Dermatol 2009; 48:758762.
  • 66
    Nassiri-Kashani M, Firooz A, Khamesipour A, et al. A randomized, double-blind, placebo-controlled clinical trial of itraconazole in the treatment of cutaneous leishmaniasis. J Eur Acad Dermatol Venereol 2005; 19:8083.
  • 67
    Morizot G, Kendjo E, Mouri O, et al. Travelers with cutaneous leishmaniasis cured without systemic therapy. Clin Infect Dis 2013; 57:370380.
  • 68
    Bryceson AD, Murphy A, Moody AH. Treatment of “Old World” cutaneous leishmaniasis with aminosidine ointment: results of an open study in London. Trans R Soc Trop Med Hyg 1994; 88:226228.
  • 69
    Khatami A, Firooz A, Gorouhi F, et al. Treatment of acute Old World cutaneous leishmaniasis: a systematic review of the randomized controlled trials. J Am Acad Dermatol 2007; 57:33529.
  • 70
    Belazzoug S, Neal RA. Failure of meglumine antimoniate to cure cutaneous lesions due to leishmania-major in Algeria. Trans R Soc Trop Med Hyg 1986; 80:670671.
  • 71
    Weinrauch L, Livshin R, Even-Paz Z, et al. Efficacy of ketoconazole in cutaneous leishmaniasis. Arch Dermatol Res 1983; 275:353354.
  • 72
    Salmanpour R, Handjani F, Nouhpisheh MK. Comparative study of the efficacy of oral ketoconazole with intra-lesional meglumine antimoniate (Glucantime) for the treatment of cutaneous leishmaniasis. J Dermatol Treat 2001; 12:159162.
  • 73
    Reithinger R, Mohsen M, Wahid M, et al. Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: a randomized, controlled trial. Clin Infect Dis 2005; 40:11481155.
  • 74
    Solomon M, Pavlotsky F, Leshem E, et al. Liposomal amphotericin B treatment of cutaneous leishmaniasis due to Leishmania tropica. J Eur Acad Dermatol Venereol 2011; 25:973977.
  • 75
    Neub A, Krahl D, Stich A, et al. Cutaneous infection with Leishmania infantum in an infant treated successfully with miltefosine. J Dtsch Dermatol Ges 2008; 6:10611064.
  • 76
    Tappe D, Muller A, Stich A. Resolution of cutaneous old world and new world leishmaniasis after oral miltefosine treatment. Am J Trop Med Hyg 2010; 82:13.
  • 77
    Killingley B, Lamb LE, Davidson RN. Miltefosine to treat cutaneous leishmaniasis caused by Leishmania tropica. Ann Trop Med Parasitol 2009; 103:171175.
  • 78
    Firooz A, Khamesipour A, Ghoorchi MH, et al. Imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis: a randomized assessor-blind controlled trial. Arch Dermatol 2006; 142:15751579.
  • 79
    Munir A, Janjua SA, Hussain I. Clinical efficacy of intramuscular meglumine antimoniate alone and in combination with intralesional meglumine antimoniate in the treatment of old world cutaneous leishmaniasis. Acta Dermatovenerol Croat 2008; 16:6064.
  • 80
    Zerehsaz F, Salmanpour R, Handjani F, et al. 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 1999; 38:610612.
  • 81
    Negera E, Gadisa E, Hussein J, et al. 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 2012; 106:496503.
  • 82
    Junaid AJ. Treatment of cutaneous leishmaniasis with infrared heat. Int J Dermatol 1986; 25:470472.
  • 83
    Faber WR, Wonders J, Jensema AJ, et al. Cutaneous leishmaniasis with lymphadenopathy due to Leishmania donovani. Clin Exp Dermatol 2009; 34:E196E198.
  • 84
    Poeppl W, Walochnik J, Pustelnik T, et al. Short report: cutaneous leishmaniasis after travel to Cyprus and successful treatment with miltefosine. Am J Trop Med Hyg 2011; 84:562565.
  • 85
    Neumayr ALC, Walter C, Stoeckle M, et al. Successful treatment of imported mucosal leishmania infantum leishmaniasis with miltefosine after severe hypokalemia under meglumine antimoniate treatment. J Travel Med 2012; 19:124126.
  • 86
    Stoeckle M, Holbro A, Arnold A, et al. Treatment of mucosal leishmaniasis (L. infantum) with miltefosine in a patient with Good syndrome. Acta Trop 2013; 128:168170.
  • 87
    Esfandiarpour I, Alavi A. Evaluating the efficacy of allopurinol and meglumine antimoniate (Glucantime) in the treatment of cutaneous leishmaniasis. Int J Dermatol 2002; 41:521524.
  • 88
    Boecken G, Weitzel T, Sunderkotter C, et al. Diagnosis and therapy of cutaneous and musculocutaneous Leishmaniasis in Germany. J Dtsch Dermatol Ges 2009; 7(Suppl 7):s1s38.
  • 89
    Zanger P, Kotter I, Raible A, et al. Case report: successful treatment of cutaneous leishmaniasis caused by leishmania aethiopica with liposomal Amphothericin B in an immunocompromised traveler returning from eritrea. Am J Trop Med Hyg 2011; 84:692694.
  • 90
    Lopez L, Robayo M, Vargas M, Vélez ID. Thermotherapy. An alternative for the treatment of American cutaneous leishmaniasis. Trials 2012; 13:58.
  • 91
    Soto J, Toledo J, Gutierrez P, et al. Treatment of American cutaneous leishmaniasis with miltefosine, an oral agent. Clin Infect Dis 2001; 33:E57E61.
  • 92
    Rubiano LC, Miranda MC, Arenas SM, et al. Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children. J Infect Dis 2012; 205:684692.
  • 93
    Soto J, Arana A, Toledo J, et al. Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis 2004; 38:12661272.
  • 94
    Velez I, Lopez L, Sanchez X, et al. Efficacy of miltefosine for the treatment of American cutaneous leishmaniasis. Am J Trop Med Hyg 2010; 83:351356.
  • 95
    Soto J, Buffet P, Grogl M, et al. Successful treatment of Colombian cutaneous leishmaniasis with four injections of pentamidine. Am J Trop Med Hyg 1994; 50:107111.
  • 96
    Ballou WR, McClain JB, Gordon DM, et al. Safety and efficacy of high-dose sodium stibogluconate therapy of American cutaneous leishmaniasis. Lancet 1987; 2:1316.
  • 97
    Wortmann G, Miller RS, Oster C, et al. 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 2002; 35:261267.
  • 98
    Lai AFE, Vrede MA, Soetosenojo RM, et al. Pentamidine, the drug of choice for the treatment of cutaneous leishmaniasis in Surinam. Int J Dermatol 2002; 41:796800.
  • 99
    Neves LO, Talhari AC, Gadelha EPN, et al. A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for the treatment of cutaneous leishmaniasis by Leishmania guyanensis. An Bras Dermatol 2011; 86:10921101.
  • 100
    Roussel M, Nacher M, Fremont G, et al. 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 2006; 100:307314.
  • 101
    Chrusciak-Talhari A, Dietze R, Chrusciak TC, et al. 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 2011; 84:255260.
  • 102
    van der Meide WF, Sabajo LOA, Jensema AJ, et al. Evaluation of treatment with pentamidine for cutaneous leishmaniasis in Suriname. Int J Dermatol 2009; 48:5258.
  • 103
    Andersen EM, Cruz-Saldarriaga M, Llanos-Cuentas A, et al. Comparison of meglumine antimoniate and pentamidine for Peruvian cutaneous leishmaniasis. Am J Trop Med Hyg 2005; 72:133137.
  • 104
    Navin TR, Arana BA, Arana FE, et al. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 1992; 165:528534.
  • 105
    Soto J, Rea J, Balderrama M, et al. Efficacy of miltefosine for Bolivian cutaneous leishmaniasis. Am J Trop Med Hyg 2008; 78:210211.
  • 106
    Solomon M, Pavlotzky F, Barzilai A, et al. Liposomal amphotericin B in comparison to sodium stibogluconate for Leishmania braziliensis cutaneous leishmaniasis in travelers. J Am Acad Dermatol 2013; 68:284289.
  • 107
    Machado PR, Ampuero J, Guimaraes LH, et al. Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial. PLoS Negl Trop Dis 2010; 4:e912.
  • 108
    Weinrauch L, Cawich F, Craig P, et al. Topical treatment of New World cutaneous leishmaniasis in Belize: a clinical study. J Am Acad Dermatol 1993; 29:443446.
  • 109
    Soto J, Fuya P, Herrera R, et al. Topical paromomycin/methylbenzethonium chloride plus parenteral meglumine antimonate as treatment for American cutaneous leishmaniasis: controlled study. Clin Infect Dis 1998; 26:5658.
  • 110
    Marsden PD. Mucosal leishmaniasis (“espundia” Escomel, 1911). Trans R Soc Trop Med Hyg 1986; 80:859876.
  • 111
    Jones TC, Johnson WD Jr Barretto AC, et al. Epidemiology of American cutaneous leishmaniasis due to Leishmania braziliensis braziliensis. J Infect Dis 1987; 156:7383.
  • 112
    Herwaldt BL. Leishmaniasis. Lancet 1999; 354:11911199.
  • 113
    Romero GA, Guerra MV, Paes MG, et al. 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 2001; 65:456465.
  • 114
    Almeida R, D'Oliveira A Jr Machado P, et al. Randomized, double-blind study of stibogluconate plus human granulocyte macrophage colony-stimulating factor versus stibogluconate alone in the treatment of cutaneous Leishmaniasis. J Infect Dis 1999; 180:17351737.
  • 115
    Seaton RA, Morrison J, Man I, et al. Out-patient parenteral antimicrobial therapy—a viable option for the management of cutaneous leishmaniasis. Q J Med 1999;92: 659667.
  • 116
    Arevalo J, Ramirez L, Adaui V, et al. Influence of Leishmania (Viannia) species on the response to antimonial treatment in patients with American tegumentary leishmaniasis. J Infect Dis 2007; 195:18461851.
  • 117
    Llanos-Cuentas A, Tulliano G, Araujo-Castillo R, et al. Clinical and parasite species risk factors for pentavalent antimonial treatment failure in cutaneous leishmaniasis in Peru. Clin Infect Dis 2008; 46:223231.
  • 118
    Solomon M, Baum S, Barzilai A, et al. Liposomal amphotericin B in comparison to sodium stibogluconate for cutaneous infection due to Leishmania braziliensis. J Am Acad Dermatol 2007; 56:612616.
  • 119
    Harms G, Scherbaum H, Reiter-Owona I, et al. Treatment of imported New World cutaneous leishmaniasis in Germany. Int J Dermatol 2011; 50:13361342.
  • 120
    Sousa AQ, Frutuoso MS, Moraes EA, et al. High-dose oral fluconazole therapy effective for cutaneous leishmaniasis due to leishmania (Vianna) braziliensis. Clin Infect Dis 2011; 53:693695.
  • 121
    van Thiel PPAM, van Gool T, Kager PA, et al. Case report: first cases of cutaneous leishmaniasis caused by leishmania (Viannia) naiffi infection in Surinam. Am J Trop Med Hyg 2010; 82:588590.
  • 122
    van der Snoek EM, Lammers AM, Kortbeek LM, et al. Spontaneous cure of American cutaneous leishmaniasis due to Leishmania naiffi in two Dutch infantry soldiers. Clin Exp Dermatol 2009; 34:E889E891.
  • 123
    Richter J, Hanus I, Haussinger D, et al. Mucosal Leishmania infantum infection. Parasitol Res 2011; 109:959962.
  • 124
    Faucher B, Pomares C, Fourcade S, et al. Mucosal Leishmania infantum leishmaniasis: specific pattern in a multicentre survey and historical cases. J Infect 2011; 63:7682.
  • 125
    Kharfi M, Fazaa B, Chaker E, et al. Mucosal localization of leishmaniasis in Tunisia: 5 cases. Ann Dermatol Venereol 2003; 130:2730.
  • 126
    Amato VS, Tuon FF, Imamura R, et al. 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 2009; 23:10261034.
  • 127
    Amato VS, Tuon FF, Bacha HA, et al. Mucosal leishmaniasis—current scenario and prospects for treatment. Acta Trop 2008; 105:19.
  • 128
    Machado PR, Lessa H, Lessa M, et al. Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis. Clin Infect Dis 2007; 44:788793.
  • 129
    Bafica A, Oliveira F, Freitas LA, et al. American cutaneous leishmaniasis unresponsive to antimonial drugs: successful treatment using combination of N-methilglucamine antimoniate plus pentoxifylline. Int J Dermatol 2003; 42:203207.
  • 130
    Lessa HA, Machado P, Lima F, et al. Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Am J Trop Med Hyg 2001; 65:8789.
  • 131
    Soto J, Toledo J, Valda L, et al. Treatment of Bolivian mucosal leishmaniasis with miltefosine. Clin Infect Dis 2007; 44:350356.
  • 132
    Soto J, Rea J, Valderrama M, et al. Efficacy of extended (six weeks) treatment with miltefosine for mucosal leishmaniasis in Bolivia. Am J Trop Med Hyg 2009; 81:387389.
  • 133
    Franke ED, Llanos-Cuentas A, Echevarria J, et al. Efficacy of 28-day and 40-day regimens of sodium stibogluconate (Pentostam) in the treatment of mucosal leishmaniasis. Am J Trop Med Hyg 1994; 51:7782.
  • 134
    Amato VS, Tuon FF, Camargo RA, et al. Short report: can we use a lower dose of liposomal amphotericin b for the treatment of mucosal American leishmaniasis? Am J Trop Med Hyg 2011; 85:818819.
  • 135
    Aliaga L, Cobo F, Mediavilla JD, et al. Localized mucosal leishmaniasis due to Leishmania (Leishmania) infantum: clinical and microbiologic findings in 31 patients. Medicine (Baltimore) 2003; 82:147158.
  • 136
    Garcia de Marcos JA, Dean FA, Alamillos GF, et al. Localized Leishmaniasis of the oral mucosa. A report of three cases. Med Oral Patol Oral Cir Bucal 2007; 12:E281E286.
  • 137
    Walton BC, Valverde L. Racial differences in Espundia. Ann Trop Med Parasitol 1979; 73:2329.
  • 138
    Dorlo TPC, Huitema ADR, Beijnen JH, et al. Optimal dosing of miltefosine in children and adults with visceral leishmaniasis. Antimicrob Agents Chemother 2012; 56:38643872.
  • 139
    Morgan DJ, Guimaraes LH, Machado PR, et al. Cutaneous leishmaniasis during pregnancy: exuberant lesions and potential fetal complications. Clin Infect Dis 2007; 45:478482.
  • 140
    Zanger P, Kotter I, Kremsner P, et al. Tumor necrosis factor alpha antagonist drugs and leishmaniasis in Europe. Trop Med Int Health 2011; 16:172.
  • 141
    Neumayr A, Buffet P, Visser L, et al. Clinical aspects and management of cutaneous leishmaniasis in rheumatoid patients treated with TNF-alpha antagonists. TMAID 2013; Epub ahead of print.
  • 142
    Alvar J, Aparicio P, Aseffa A, et al. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 2008; 21:334.
  • 143
    Mosimann V, Neumayr A, Hatz C, et al. Cutaneous Leishmaniasis in Switzerland—first experience with species specific treatment. Infection 2013; Epub ahead of print.
  • 144
    Buffet P, Deray G, Grogl M, et al. Tolerance and pharmacokinetics of antimony in a patient with renal-failure. Nephrol Dial Transplant 1995; 10:1477.