The genus Leishmania includes over 50 species, of which more than 20 are known to infect humans (Table 1). Only two Leishmania (L.) species, L. donovani and L. tropica, are primarily anthroponotic, all other species are zoonotic, with the main reservoir hosts being rodents and dogs (and other canids). Leishmania has two life-cycle stages, a flagellated (promastigote), extracellular stage in the sand fly vector and a non-flagellated (amastigote), intracellular stage in the vertebrate host (Fig. 1). Promastigotes are 15–30 µm long and 2–5 µm wide, with shape and size depending on the cell cycle stage. They have a central nucleus, an apical kinetoplast, and a 10–20 µm long flagellum (Fig. 1a). Amastigotes are oval, typically measure between 2.5 to 3.5 μm and have a rod-shaped kinetoplast located near the nucleus (Fig. 1b). In fact, amastigotes do also have a (very short) flagellum that is however only visible by electron microscopy. They can infect various phagocytic cells, such as monocytes, macrophages, dendritic cells, and neutrophils.

Leishmania species are transmitted by the bites of female sand flies (Diptera: Psychodidae: Phlebotominae), which take their blood meals preferentially on calm evenings at dusk and during the early night hours. Sand flies are small insects with a size of only 1–3 mm (Fig. 2), a low radius of activity (around 100 m and only up to 2 m above ground) and low flight capacity during wind. At least 100 of the 1000 described sand fly species are known vectors of Leishmania species [1]. The most important ones transmitting CL and MCL to humans are Phlebotomus (Ph.) neglectus, Ph. perniciosus, Ph. sergenti, and Ph. papatasi in the Old World and Lutzomyia longipalpis, Bichromomyia olmeca and Psychodopygus wellcomei in the New World. An overview of Leishmania species and their known vectors is given in Table 1.

In rare cases, infection may also be acquired by blood contacts or by transplacental transmission. In dogs, venereal transmission has been documented; it is unclear if this plays any role in humans.

Leishmaniasis is classified as a Neglected Tropical Disease and more than one billion humans live in endemic areas of potential transmission. It is estimated that up to one million new cases of CL occur annually [2]. The countries with the highest numbers of CL cases are Afghanistan, Algeria, Brazil, Colombia, Iraq, Libya, Pakistan, Peru, the Syrian Arab Republic and Tunisia, while the majority of mucocutaneous cases occur in Bolivia, Brazil, Ethiopia and Peru [2]. Leishmaniasis is endemic in all southern countries of Europe, with around 700 autochthonous human cases reported each year and many more asymptomatic infections. Autochthonous cases (at least assumed) have also been reported from several Central European countries, in humans as well as in animals [3, 4].

The incubation time may vary between 2 weeks and several months, in extreme cases of MCL even over a year. Symptoms and progression of the disease depend on the species, the localization of the infection and the immune status of the host. Generally, six clinical forms of CL and MCL can be differentiated: localized cutaneous (LCL), diffuse (DL), disseminated cutaneous (DCL), MCL, mucosal (ML), post-Kala Azar dermal leishmaniasis (PKDL). Over 90% of cases are of the LCL form, where the infection is confined to one (or a few) lesions. In DL and DCL, the infection may show a localized expansion, and in MCL, a diffuse expansion.

LCL typically affects the face and the extremities and starts with a small reddish papule around a non-healing insect bite, which rapidly (L. major) or slowly (L. tropica) grows to a nodule or plaque and then progresses to an ulcerating lesion (Fig. 3). While the ulcus is usually dry in L. tropica, lesions caused by L. major are moist with central necrosis and may also disseminate and cause secondary lesions, which may however, also derive from multiple sand fly bites. The ulcers are of irregular shape, with an elevated margin and covered with scab. They are relatively indolent and typically self-limited within 2–6 months (L. major), or 6–15 months (L. tropica), leading to life-long immunity against infections with the respective species. However, they do cause a permanent local destruction of the skin and are often associated with social stigmatization in humans. Depending on the geographical region and the immune status of the host, L. infantum can also cause LCL, in which lesions often heal very slowly.

DL is found in East Africa and Latin America; typical causative agents are L. aethiopica, L. mexicana and L. amazonensis and usually there is no ulcer, but rather subepidermal nodules of 2–4 cm in size. The infection may not heal for years and may affect large areas of the skin resulting in a lepra-like clinical picture. This form is more common in immunocompromised patients and specifically in individuals with an impaired T cell response.

MCL and ML are typically found in Brazil and Peru (Espundia), but also in a slightly different form in Central America (Chiclero¹). In Espundia, first ulcers are usually nasal (later often with oral/palatal, pharyngeal, and laryngeal involvement) and patients have a history of chronic unexplained congestion or secretions. In Chiclero, the infection typically remains limited to the ear. The first clinical sign usually is a small ulcer at the site of the insect bite, later erythema, edema, hyperemia, infiltration, nodules, erosion, ulceration, and tissue destruction (e.g., perforation of the nasal septum) may evolve. The parasites can disseminate over the lymphatic system and reach mucosal tissue, possibly years after the infection (DCL). With progressing disease, also cartilage and bone tissue may be destroyed. If left untreated, this form of leishmaniasis can be fatal.

PKDL is a late complication of VL, that may manifest even after successful treatment of the systemic infection. While the Asiatic variant is more macular, the East African variant typically presents as a papular rash stretching from the face (grade 1), over the upper part of the body (grade 2) or the entire body (grade 3). This form may resemble leprosy, but the skin nerves are not affected.

Depending on the clinical form of leishmaniasis, differential diagnosis should include various bacterial and fungal skin infections, discoid lupus erythematosus, eczema, neoplasms and skin cancer (Table 2).

Before taking the sample, the skin should be cleansed carefully, e.g., with 70% alcohol. If culture² is intended, do not use antiseptics that could affect parasite growth (e.g., iodine) and rinse with physiological saline. If biopsy specimens or deep dermal scrapings are obtained, use anesthetics (e.g., 1% lidocaine with epinephrine 1:100,000), injected through cleansed intact skin into the dermis underlying the sample area. For culture, avoid high concentrations of anesthetics as this may inhibit parasite growth. Before taking the samples, remove scabs and cellular debris from the relevant areas with a scalpel blade and achieve haemostasis by applying pressure with a sterile gauze. Detailed instructions for collecting the respective samples are given in Table 4.

While numerous commercial diagnostic test systems are available for VL, laboratory diagnostics of CL can still be challenging. In CL, the humoral immune response is typically low (exceptions: MCL and other disseminated forms), hence laboratory diagnostics mainly relies on direct detection methods. An overview of recommended and possible/additional techniques is given in Table 5.

Given that the initiation of treatment in CL is not overly time-sensitive, targeted decisions are strongly recommended – after determination of the geographical area of infection and identification of the causative parasite, preferably to the species or complex level. To facilitate clinical management, CL can be classified either into Old World cutaneous leishmaniasis (OWCL) or New World cutaneous leishmaniasis (NWCL) and into a “simple” or “complex” clinical form [8]. Simple CL is characterized by infection with a Leishmania species presumably not associated with development of ML, the presence of up to three lesions, lack of mucosal involvement, and an immunocompetent host. Complex CL is defined by the presence of an ML-associated parasitic species (e.g., L. braziliensis, L. guyanensis, L. panamensis), 4 or more lesions, lesion(s) sized larger than 4 cm or localization on face, fingers, toes, genitalia and in areas unsuitable for local treatment. In addition, an immunocompromised state of the host, failure of prior treatment(s), regional lymphadenopathy, leishmaniasis recidivans, disseminated or diffuse forms, and infection with L. aethiopica are assigned to the complex form.

Hereinafter, the available therapeutic modalities for CL are delineated. Some options, however, are not approved and, hence, have to be used “off-label”. Overall, simple OWCL, simple NWCL caused by L. mexicana, CL in pregnant women or cases with concomitant contraindications to systemic therapy can be approached with local therapeutic options. Systemic treatment is recommended for complex CL, NWCL caused by parasites of the subgenus Viannia or by L. amazonensis, ML, MCL, DL, DCL and in case of recurrence.

Paromomycin sulfate (PA) is an aminoglycoside antibiotic with leishmanicidal activity. Its mechanism of action has not been entirely elucidated, but interference with the parasites´ protein synthesis and mitochondrial function are considered the main effects.

PA can be topically administered in a 15% formulation, in combination with 12% methyl benzalkonium chloride (MBCI) (commercially available as Leshcutan® in Israel) or as a complex hydrophilic base consisting of 15% PA plus 0.5% gentamicin sulfate. Notably, formulations of 15% PA alone in 10% urea were not superior to vehicle alone. When necessary, cleaning and debridement of the lesion is recommended, followed by twice-daily application for 20 days. The entire lesion as well as the surrounding indurated border should be covered about 1 mm in height, and the use of an occlusive dressing to prevent involuntary removal is advisable.

PA-containing formulations have demonstrated efficacy in several RCTs. In OWCL caused by L. major, 20-day treatment regimens with once or twice per day applications – using PA alone or in combination with MBCI or gentamicin – achieved cure rates of 74–82% [9, 10]. Ulcerative lesions appear to benefit most, likely due to the enhanced absorption of the active ingredient. In NWCL attributable to L. braziliensis, L. panamensis and to a lesser extent to L. guyanensis, L. naiffi and other Leishmania species, once and twice daily application of PA-containing topicals for 20 days led to cure in 78–86% [11–13]. In the few comparative studies, the efficacy of topical PA in OWCL did not differ significantly from that of intralesional antimon [14]. PA-MBCI was more effective than oral ketoconazole, given at 400 mg once daily for 4 weeks, which failed to achieve cure in the comparator arm [15]. The modest cure rate reported for PA-MBCI in this particular study (38%) may be attributed to the infecting species, L. tropica. In NWCL caused by L. panamensis or L. braziliensis, topical PA was less effective than parenteral antimon [14, 16]. In L. braziliensis-positive NWCL, the efficacy of PA was relatively comparable to intralesional application of pentamidine [11].

Adverse reactions to PA were generally mild to moderate and confined to local effects. Irritancy and intolerance were more pronounced when MBCI had been included in the formulation. Systemic adverse effects associated with parenteral aminoglycoside antibiotics were absent after topical administration. Thus, topical PA provides a relatively safe and resource-efficient therapeutic option that requires minimal health-care infrastructure and can be easily self-applied by the patients. Nevertheless, the intrinsic susceptibility varies between Leishmania species. Furthermore, the treatment efficacies may differ across the formulations, which highlights the need for a standardized, homogeneous, industrially produced preparation.

Photodynamic therapy (PDT) has emerged as an attractive option for the treatment of CL, although a standardized protocol has not yet been established and the reported conditions varied considerably [17].

In general, cleaning and removal of eschars from lesions prior to PDT enhances penetration of photosensitizer and light into the infected tissues. Overall, the use of 5’aminolevulinic acid 10% or 20% or methyl aminolevulinate 16% or 20%, applied in a 1 mm thick layer onto the lesion(s) plus a 1 cm margin, as well as wavelengths of 570–670 nm, fluences of 75–100 J/cm², irradiances of 150 mW/cm² and treatment frequencies of once to twice per week have been reported.

RCTs on PDT in LC have been limited, and most available evidence has derived from case reports. In one RCT, L. tropica-positive lesions completely resolved in 76% of the patients after delivery of a total light dose of 90 J/cm² on days 1, 15, and 45. Fractionated illumination further increased the efficacy to 91% and was associated with fewer adverse events [18]. Another RCT reported that weekly PDT achieved a significantly higher cure rate (94%) of L. major-positive lesions compared to twice-daily applications of PA-MBCI (41%), when both treatments had been administered over 4 weeks [19]. German colleagues developed a method of daylight PDT, in which natural sunlight serves as light source, thereby eliminating the need for specialized equipment and reducing the required time for absorption of the photosensitizer. The total cure rate of daylight PDT on primarily small, non-ulcerated lesions in this single-center study was around 89% and all L. major- and 73% of L. tropica-positive lesions showed clinical response [20].

Pain, pruritus, erythema, edema and pigmentation have been reported as adverse effects, but these reactions were typically mild, transient and self-limiting. PDT offers the advantages of favorable cosmetic outcomes and the absence of development of drug-resistance. However, its disadvantages include the time-consuming nature of the procedure and the requirement for specialized medical equipment.

Cryotherapy, applied to the lesion and surrounding perilesional skin, induces destruction of infected tissue and intracellular amastigotes. Although the optimal number of treatment sessions has not been standardized, weekly applications for 1–3 weeks or treatments every two weeks for up to 6 weeks have generally been sufficient to achieve cure.

The reported cure rates vary widely, from 34% to 100%, reflecting substantial heterogeneity in treatment protocols and lesion characteristics across studies. The causative species included L. major, L. infantum and L. donovani or were not specified. A meta-analysis comprising eight studies conducted in OWCL and NWCL reported per lesion cure rates of 67% for cryotherapy as compared to 68% for intralesional pentavalent antimonials, thus supporting the use of cryotherapy as an effective local treatment modality [21]. Cryotherapy can also be used adjunctively to intralesional antimonials.

The most commonly reported side effects were hypo- and hyperpigmentation, erythema, edema and pain. Cryotherapy offers a rapid, low-cost treatment option that can be safely applied in pregnancy, lactation and in immunocompromised or multimorbid patients. However, liquid nitrogen may not always penetrate deeply enough to reach the dermis, where the parasites reside, potentially allowing some amastigotes to survive within the lesion.

Thermotherapy is based upon the observation that certain Leishmania species, particularly dermatotropic species, are temperature-sensitive and stop multiplication at higher temperatures. The efficacy of thermotherapy is thought to further result from increased local blood flow after heat application and, thus, an improved immune response. Several methods and devices are available to deliver localized heat, including radiofrequency, ultrasound, exothermic crystallization, infrared light and microwaves. One such device, ThermoMed®, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of CL. However, standardized treatment protocols for thermotherapy have not yet been established and it is currently difficult to confirm whether the target temperatures are consistently achieved within the affected tissues.

Due to substantial heterogeneity among the individual studies, the reported overall therapeutic efficacies ranged from 48% to 100% across a variety of Leishmania species, including L. donovani, L. infantum, L. tropica, L. braziliensis, L. guyanensis, L. panamensis, L. mexicana, L. amazonensis and L. major [22, 23]. Slightly lower rates were observed for L. braziliensis. A meta-analysis including studies from both, OWCL and NWCL, demonstrated that the overall efficacy of thermotherapy was non-inferior to systemic or intralesional pentavalent antimonials, with cure rates of 73% versus 71%, respectively, and without systemic toxicity [23].

Reported local side effects include discomfort, pruritus, burning sensations, pain, blistering, hyperpigmentation, burns and secondary infections. Thermotherapy is not suitable for skin lesions located near mucosal surfaces or over superficial nerves or cartilage. Aside from these anatomical limitations, there are no formal contraindications and the method can be safely applied in infancy, pregnancy, lactation, immunosuppressed patients and individuals with chronic underlying diseases.

Laser therapy promotes thermolysis and destruction of Leishmania-infected tissues. Various laser types, including continuous and fractional CO₂, argon, erbium glass and Nd:YAG, have been used for CL treatment [24]. However, to date, RCTs and standardized treatment protocols are still lacking.

Pentavalent antimonials, such as N-methylglucamine antimoniate (MA; Glucantime®, containing 81 mg/mL active antimony) and sodium stibogluconate (SSG; Pentostam®, Stibanate®, containing 100 mg/mL active antimony), have been the mainstay of anti-leishmanial therapy for several decades. The precise mechanism of their activity is still not fully understood. It is hypothesized that antimonials form complexes with ribonucleosides, disrupting DNA replication and transcription. Also, pentavalent antimony is reduced to a more active trivalent form within the Leishmania amastigotes, which then interacts with sulfhydryl-containing biomolecules in the parasite and thus generates oxidative stress, leading to DNA fragmentation and programmed cell death.

Pentavalent antimonials can be administered via intralesional, intramuscular or intravenous routes. Locally directed (intralesional) administration allows to deliver the anti-leishmanial substances directly to the target tissues, possibly achieving higher drug concentrations. While a standardized procedure for delivery has not yet been generally recognized, a standard protocol for antimony intralesional infiltration has been proposed [25]. Briefly, after local anesthesia, the antimony is infiltrated intradermally in a volume of 1–3 ml by inserting the needle with the bevel facing up toward the center of the lesion and subsequently retracting it backwards toward the edge while concomitantly and continuously infiltrating the drug. This procedure is repeated in a V-shaped pattern to achieve saturation of the entire lesion, including the base and the edges. Saturation is indicated by visible “blanching” of the tissues after delivery of the medication. Numbers and frequency of infiltrations as well as duration of therapy vary considerably in published studies, a regimen of once-weekly injections until the lesion has healed seems feasible. Intramuscular injections are painful, which together with the large volume required often limits its use. Intravenous administration bears the risk for thrombophlebitis. The recommended dosage for intramuscular and intravenous applications is around 20 mg per kg body weight, with no specified upper limit, given once daily for 21–28 days. Comparable efficacies for intralesional and systemic administration routes have been reported, at least for NWCL [26, 27].

Although most of the evidence for the use of antimony derivatives is sometimes weak, they continue to be the first-line treatment recommended for most forms of leishmaniasis in many countries. Cure rates ranged from 41–90% with standard doses of systemic 10–20 mg kg/day. The efficacies against the individual Leishmania species were variable, with 81% reported for L. major, 56% for L. guyanensis, 62–90% for L. braziliensis and 85% for L. panamensis [8, 28, 29]. Its use is further hampered by numerous reports describing treatment failure and disease reactivation after clinical cure, especially in patients with MCL caused by L. braziliensis, DL and DCL. In certain regions of India, Bolivia, southern Peru and Brazil, the emergence of clinical antimonial resistance has been observed.

Both, MA and SSG, show similar side effect profiles. After intralesional use, the most frequent adverse effects are pain, hyper- and hypopigmentation. Adverse effects associated with systemic administration are related to cumulative exposure and include myalgia, arthralgia, gastrointestinal discomfort, hypersensitivity reactions, pancytopenia and reversible elevation of transaminases and pancreatic enzymes. Importantly, severe adverse effects, such as nephro- and cardiotoxicity and mutagenicity, limit the use in the elderly in the presence of renal and cardiac impairment and in pregnant and lactating women. Prior to initiation and at regular intervals during systemic administration, monitoring of electrocardiographic tracing, blood cell count, electrolytes, and renal, liver and pancreatic function is strongly recommended. Due to the limitations of antimonials, it is advised that alternative therapeutic options are used as a first choice for certain clinical forms and species.

Liposomal Amphotericin B (L-AmB) (AmBisome®) is produced using Amphotericin B, a polyene antibiotic originally isolated from Streptomyces nodosum. It binds to ergosterol molecules in the cytoplasmic membrane of the Leishmania parasites, forming aqueous pores that increase membrane permeability. The subsequent ion influx contributes to the death of the parasites. Compared to the parental formulation, L-AmB has a significantly lower toxicity profile specifically in regard to nephrotoxicity or electrolyte disturbances (mainly potassium), however, due to the lack of enteral absorption, intravenous administration remains necessary. Although L-AmB has not formally been approved for CL, in most studies dosing regimens of 2–3 mg per kg body weight per day administered on days 1–5, 14, and 21 in a cumulative dose of 21 mg per kg body weight have been employed, based on the FDA-approved regimen for VL. However, the skin penetration of L-AmB has not been well studied, and species-related differences in response to L-AmB need to be considered.

Despite the lack of comparative, interventional RCTs, the efficacy of L-AmB in CL has been extrapolated from its efficacy against VL. In a meta-analysis restricted to 92 case reports and 40 case series involving OWCL and NWCL, overall treatment efficacies were estimated at 82–87% [30]. The interpretation of these findings, however, is substantially constrained by the marked heterogeneity in the study populations, treatment regimens and causative Leishmania species. Nevertheless, clinical responses to L-AmB have been reported for L. major, L. infantum/donovani, L. tropica, L. aethiopica, L. braziliensis and L. guyanensis. Retrospective and non-randomized observational studies, in OWCL and NWCL, have demonstrated efficacy rates ranging widely from 30% to 100%. One of the most frequently cited studies reported a response rate of 84% in a cohort of 20 patients with CL caused by multiple Leishmania strains, using a regimen of L-AmB at 3 mg/kg/day of for up to 10 doses over 21 days [31]. Comparative studies evaluating L-AmB versus systemically administered pentavalent antimonials have reported efficacy rates of approximately 72–88% for L-AmB compared with 55–87% for antimonials, predominantly in NWCL, but also in OWCL [32–35].

Despite its improved tolerability, systemic administration of L-AmB is largely restricted to the hospital setting and rarely performed in outpatient care. In addition to cardio-nephrotoxicity, reported side effects include fever, headache, nausea, vomiting, tremors, hypotension, hypokalemia, hypomagnesemia, allergic reactions, vision and hearing disorders. Regular monitoring of serum creatinine, blood cell counts and electrolytes is thus recommended prior to initiation and regularly throughout treatment. Although L-AmB is highly effective, its use is further limited by the high cost of the substance.

For topical use, several amphotericin B-containing formulations have been developed, such as a semi-solid oil in water emulsion containing 3% amphotericin B (termed Anfoleish), nanoliposomes containing 0.4% amphotericin B as well as drops or gel formulations containing L-AmB. While topical applications may reduce systemic toxicity of the drug, the lack of standardized formulations and the scarceness of studies currently preclude formal treatment recommendations at this time.

Pentamidine isethionate (Pentacarinat®) is an aromatic diamine that interferes with polyamine synthesis and RNA polymerase activity in Leishmania parasites, thereby inhibiting the synthesis of proteins, nucleic acids, phospholipids and folic acid. The mechanism of action may also involve a decreased mitochondrial membrane potential, resulting from drug accumulation in the mitochondria. Pentamidine is generally regarded as a less attractive treatment option because of its potentially irreversible toxicity and lower efficacy compared to other compounds. Pentamidine has not been approved by the FDA for treatment of CL. In the available studies it has been mainly administered at doses of 2–4 mg per kg body weight, up to a maximum dose of 300 mg per application, given 2–4 times weekly by intramuscular or intravenous injection.

The vast majority of available studies have been performed in NWCL, with only a few conducted in OWCL. In a systematic review comprising 26 studies with CL and 1,341 patients, the pooled cure rates derived from RCTs and observational studies ranged around 79% [36]. The treatment schedules, however, were highly heterogeneous and species-specific efficacies were difficult to decipher due to insufficient specification in the majority of the studies. Nevertheless, cures have been reported for infections with L. braziliensis, L. panamensis, L. guyanensis, L. mexicana and L. naiffi. One study investigating the routes of pentamidine administration in L. guyanensis-NWCL patients reported significantly higher cure rates following intravenous compared with intramuscular administration, with success rates of 85% versus 51%, respectively [37].

Reported adverse effects include hypo- and hyperglycemia due to pancreatic islet cell damage, electrolyte imbalances, arrhythmia, hypo- or hypertension, pancytopenia, dysgeusia, nausea, and nephro- and hepatotoxicity. Serious adverse effects have also been documented, such as the induction of insulin-dependent diabetes, renal impairment after prolonged administration and lethal cases due to severe hypotension, hypoglycemia or arrhythmia. Consequently, stringent monitoring of hepatic, pancreatic, and renal function, electrolyte levels, blood counts, and blood glucose as well as cardio-respiratory parameters, is required prior to treatment initiation and during treatment. Concurrent therapy with nephrotoxic drugs, substances inducing QT prolongation, dideoxyinosine and foscarnet is not advisable.

Miltefosine (Impavido®) is an alkylphosphocholine with broad-spectrum antiparasitic activity. Its mechanism of action is based on the intracellular accumulation of the drug within the parasites, leading to interference with the biosynthesis of ether lipids and phospholipids in cellular membranes. In 2014, miltefosine received approval by the FDA for the treatment of CL caused by L. braziliensis, L. panamensis and L. guyanensis [38]. This drug is available in 10 mg and 50 mg capsules for oral administration. The recommended daily dose for individuals above the age of 12 years is weight-dependent, consisting of 100 mg (for individuals weighing between 30–44 kg body weight) and 150 mg (for individuals with body weight ≥ 45 kg). The treatment is usually given for 28 consecutive days.

Efficacy studies showed cure rates of 82% in patients infected with L. panamensis, 48–85% against L. braziliensis (with higher response rates observed in Bolivia, Brazil, and Colombia as opposed to lower rates in Guatemala), and 67% and 77% for L. guyanensis and L. tropica, respectively [39, 40]. Other species with reported susceptibility to miltefosine include L. mexicana, L. infantum, L. aethiopica and L. major with cure rates of around 77% [41]. Comparative evaluations of miltefosine and parenteral MA in 150 patients with NWCL caused by L. guyanensis revealed the non-inferiority of miltefosine [42]. Furthermore, in antimonial-resistant L. tropica-positive patients, subsequent miltefosine treatment proved effective in 68–70% [40, 43, 44], suggesting that miltefosine may represent a second line option in cases with failure to antimonials.

Miltefosine is generally well-tolerated, however, reported side effects include nausea, vomiting, diarrhea, hepatic, renal and gastrointestinal toxicity, pruritus, headache, dizziness and somnolence. Concomitant intake with fatty food may mitigate gastrointestinal effects. Owing to its potential teratogenic effect, miltefosine is contraindicated in pregnancy, and females of reproductive potential should use effective contraception throughout treatment and for up to 5 months after end of therapy. Miltefosine is also contraindicated in patients with Sjögren–Larsson syndrome and is not recommended during lactation or in individuals with severe hepatic or renal impairment. Monitoring of renal and liver function is advised prior to treatment initiation, weekly during therapy and after therapy completion. Although miltefosine is relatively safe and comfortable for patients´ use, its high costs continue to limit the widespread use.

Imidazoles (ketoconazole) and triazoles (fluconazole, itraconazole) are antifungal compounds that exhibit high activity against Leishmania species in vitro. Azoles act by inhibiting inhibiting the cytochrome P450-dependent enzyme lanosterol 14-α-demethylase in the parasitic plasma membrane. They can be administered orally and have lower toxic profiles than pentavalent antimonials. However, their efficacy has not been consistently proven for leishmaniasis and approval for CL has therefore been lacking. The reported dosing regimens for CL include ketoconazole 600 mg daily for 28 days, fluconazole 200 mg daily for 6 weeks and itraconazole 200 mg daily for 6 weeks.

In a meta-analysis including 37 studies and 1,259 patients with OWCL and NWCL, the pooled final efficacy rates for azoles ranged between 60% and 64% [45]. No major differences were observed between the administration of ketoconazole, fluconazole and itraconazole. The treatment outcomes were relatively comparable between OWCL and NWCL, with cure rates of 66% and 62%, respectively. Species-specific analyses revealed higher efficacies for L. mexicana (89%), L. infantum (88%) and L. donovani (80%) as compared with L. major (53%) and L. braziliensis (49%). The lowest reported efficacy was observed for L. tropica (15%).

Common adverse side effects were nausea, vomiting, diarrhea, abdominal pain, pruritus, skin rash and reversible elevation of liver enzymes. For early detection of drug-induced hepatitis, monitoring of the liver function every 2 weeks is recommended. Azoles have several drug-drug interactions due to their interaction with the cytochrome p450 enzyme complex, which should be taken into account.

A variety of alternative therapeutic approaches have been explored in a limited number of studies, including topical imiquimod, hypertonic salt solutions, trichloracetic acid, intralesional metronidazole, intense pulsed light therapy and systemic agents such as azithromycin, methotrexate, cimetidine, allopurinol and newer azoles, including voriconazole, 3-imidazolyl flavanones and luliconazole. However, these interventions have produced variable and often inconsistent outcomes. Consequently, further well-designed studies are required to conclude on their therapeutic value.