Cutaneous leishmaniasis: Treatment

INTRODUCTION — Leishmaniasis consists of a complex of vector-borne diseases caused by a heterogeneous group of protozoa belonging to the genus Leishmania; it is transmitted by sand fly vectors [1]. There is a broad array of clinical leishmaniasis syndromes; among these, the clinical course, treatment options, response to therapy, and prognosis are all highly variable. Treatment choices are complicated by the paucity of well-controlled comparative trials and lack of standardized outcome measures [2,3].

Old World cutaneous leishmaniasis (CL) consists mainly of L.L. major and L.L. tropica. Less common species include L.L. infantum and L.L. aethiopica (table 1). New World CL consists mainly of L.L. mexicana, L.L. amazonensis, and Viannia subgenus (table 1). The Leishmania subgenus Mundinia has been described in areas typically not considered endemic for leishmaniasis, such as Thailand, Myanmar, Ghana, and the Caribbean [4]. Of these Leishmania species, infection due to L.V. braziliensis, L.V. panamensis, and L.V. guyanensis are considered complicated due to risk for mucosal leishmaniasis (ML), although other species can cause ML as well. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)

The treatment of CL and ML is reviewed here. The clinical features, diagnosis, epidemiology, and control are discussed separately. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis" and "Cutaneous leishmaniasis: Epidemiology and control".)

CUTANEOUS LEISHMANIASIS

Clinical approach

Uncomplicated versus complicated infection — The approach to management of cutaneous leishmaniasis (CL) begins with establishing the clinical severity of infection.

Features of uncomplicated CL include [1]:

●Infection with species not likely to be associated with mucosal leishmaniasis (ML)

●No mucosal involvement

●Single lesion or a few lesions

●Small lesion size (eg, <1 cm)

●Immunocompetent host

Features of complicated CL include [1,5]:

●Infection with species associated with ML (primarily Viannia subgenus, especially in the "mucosal belt" of Bolivia, Peru, and Brazil)

●More than four lesions of significant size (eg, >1 cm)

●Individual lesions ≥5 cm

●Subcutaneous nodules

●Regional adenopathy >1 cm size (somewhat controversial)

●Size or location of lesions for which local treatment is not feasible

●Lesions on face, fingers, toes, or genitalia

●Immunosuppressed host

●Clinical failure of local therapy after two to three months posttreatment

Forms of CL that should be managed as complicated infection with expert consultation include:

●Leishmaniasis recidivans (due to L.L. tropica)

●Disseminated CL (due to L.V. braziliensis)

●Diffuse CL (due to L.L. mexicana, L.L. amazonensis, or L.L. aethiopica)

●Infections due to L.L. aethiopica [6]

Whom to treat — The objective of CL treatment is clinical cure not parasitologic cure. Many CL infections eventually resolve clinically without treatment, and not all patients who undergo treatment demonstrate elimination of parasitic infection [7]. Treatment decisions must include consideration of individual risks and benefits (which can be complex given the large number of parasite species with variable clinical syndromes), complications, rates of spontaneous resolution, and patient preference [8]. CL in children is common, but most clinical trial data derives from treatment of adults [9,10]. (See 'Uncomplicated versus complicated infection' above and "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)

Clinical observation (in the absence of treatment) is reasonable for immunocompetent patients with uncomplicated lesions that are healing spontaneously whose infection is either known to be caused by a Leishmania species not associated with increased risk for ML or whose species is unknown but whose infection was acquired outside of areas with Leishmania species associated with increased risk for ML (table 1 and figure 1) [1]. The decision to pursue this approach should be made in conjunction with patient involvement. Reconsideration of treatment is warranted for patients managed with clinical observation who do not heal in four to six weeks. (See 'Assessing risk for mucosal disease' below and 'Clinical follow-up' below.)

Local therapy is reasonable for patients with uncomplicated CL who are not already healing spontaneously and/or who would like to pursue therapeutic intervention. Local therapy is appropriate for management of Old World CL as well as for treatment of New World CL caused by species unlikely to cause disseminated infection [1]. (See 'Local therapy' below.)

Systemic therapy is warranted for patients with complicated CL, for immunocompromised patients, for patients with spontaneously healing or recently healed lesions whose infection is known to be caused by a Leishmania species associated with increased risk for ML, and for patients with healing lesions whose species is unknown but whose infection was acquired within an area with Leishmania species associated with increased risk for ML [1]. Systemic therapy is also warranted for patients with less common syndromes including leishmaniasis recidivans, diffuse cutaneous leishmaniasis, and disseminated cutaneous leishmaniasis. (See 'Overview of therapeutic approaches' below and 'Assessing risk for mucosal disease' below and "Cutaneous leishmaniasis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

The benefits of treatment include accelerated healing of skin lesions [11,12], reduced likelihood of recurrence (especially in the setting of subsequent immune compromise), diminished severity of skin scarring and attendant emotional concerns [13,14], and reduced risk for metastatic infection (which is important for individuals with immune compromise and/or for individuals with infection due to Viannia subgenus) [15]. In addition, in the setting of infection due to the anthroponotic species L.L. tropica, treatment may reduce the reservoir for transmission.

Consequences of no treatment or suboptimal treatment include scarring, superinfection, persistence of a chronic wound, and, for some Leishmania species, ML that may be destructive or disfiguring. In immunocompromised individuals, dissemination may occur.

Assessing risk for mucosal disease — In general, for Old World CL infection (eg, due to L.L. tropica or L.L. major) and for New World CL infection due to L.L. mexicana, the concern for later complications is relatively low and the lesions often heal in months. CL acquired in Central America north of Costa Rica, where Viannia subgenus is less frequently associated with ML, may not always require systemic therapy.

Systemic treatment for patients with CL acquired in the Americas south of Nicaragua is warranted, particularly in the setting of infection acquired in Brazil, Peru, or Bolivia. For these cases, a detailed nasal and oral examination must be performed to exclude mucosal involvement, which could modify treatment dosing and duration. Sampling of the skin lesion with culture and polymerase chain reaction (PCR) should be pursued as species identification may guide assessment for risk of later mucosal dissemination.

The use of systemic therapy to reduce risk of ML is based on observational evidence; lower rates of ML have been observed among patients who completed CL therapy than among those who received partial or no treatment [15,16]. However, subsequent development of ML has been observed among individuals treated with antimonials [15,17]. A re-evaluation of the limited evidence base provides a summary of the available published clinical experience [2,18]. These risks and benefits should be reviewed with patients, and a determination regarding treatment approach should be made based on individual circumstances. Patients should be counseled about the signs and symptoms of relapse or of ML and should be followed for at least three to five years.

Overview of therapeutic approaches — Therapeutic agents and dosing for treatment of CL are summarized in the table (table 2) [2,3].

The approach to treatment of CL is often influenced by the agents available [2,3]. In the United States, there is one therapeutic agent with approval for treatment of CL by the US Food and Drug Administration (FDA); oral miltefosine is indicated for treatment of L.V. braziliensis, L.V. guyanensis, and L.V. panamensis. Other readily available treatment modalities include cryotherapy and thermotherapy. Relatively few dermatologists have experience treating CL via cryotherapy, and success correlates with experience. Thermotherapy devices may be less accessible; less skill with these devices is required for treatment success.

Available systemic agents in the United States include miltefosine, azoles, amphotericin deoxycholate, and liposomal amphotericin. The efficacy of azoles is limited, and the duration of treatment is prolonged. Therefore, many use parenteral liposomal amphotericin B given accessibility and short duration, even though evidence for efficacy is limited and the optimal dose remains uncertain. Use of amphotericin deoxycholate is limited by duration and toxicity but is quite effective.

In the United States, pentavalent antimonials and topical paromomycin are not available commercially but, meglumine antimoniate may be obtained via investigator-initiated investigational new drug (IND) protocol. Instructions on how to initiate the process to obtain these therapeutic agents can be found on the American Society of Tropical Medicine and Hygiene website.

Drug resistance varies by region; the same species may have variable response to a given drug depending on the geographic location. In addition, in some endemic areas, access to costly drugs and to species-level diagnosis for guiding treatment is limited. A species-directed review of treatment for CL in travelers provides evidence to support species identification to target therapy [19].

For New World CL, the Pan American Health Organization (PAHO) has issued updated GRADE guidelines, which heavily rely on the 2020 Cochrane review of interventions for American CL and ML [2,20]. The uptake of these recommendations remains to be seen given the significant changes in the guidelines, including marginalization of systemic pentavalent antimonial drugs except for ML, use of intralesional and topical therapy even in ML-causing species, elevation of miltefosine in both adults and children, and no recommendation to identify species prior to therapy. The Infectious Diseases Society of America (IDSA) guidelines remain available to guide practice [21]. It is important to take into account that no therapy offers more than moderate efficacy and guidelines balance that fact with the cultural and societal values and restrictions in different parts of the world. Drug availability also affects the choice of treatment. For example, antimonial drugs are not easily available in the United States, topical paromomycin is relegated to poorly tested compounded formulations, and miltefosine is expensive, difficult to dose in heavier individuals, and not available in all dosing formulations in the United States. Furthermore, trials of miltefosine continue to show geographic differences in efficacy. PAHO, IDSA, and our recommendations value an individualized approach to care of localized CL. The appeal of better tolerated, nonparenteral agents with shorter courses has contributed to the emphasis of establishing guidelines for treatment of CL and ML, although the evidence base for steering the development of these guidelines remains thin.

Local therapy — Local therapy is warranted for patients with uncomplicated CL (see 'Whom to treat' above). Local therapy is appropriate for management of Old World CL as well as for treatment of New World CL caused by species unlikely to cause disseminated infection (table 1 and figure 1) [1,22]. In one series including 105 returned travelers to France with primarily L.L. major and L.L. infantum, 62 percent were managed without systemic therapy; cure rates were 92 percent for wound care only and 79 percent for local therapy [23]. There are few studies of intralesional therapy in New World CL acquired in the mucosal belt, but no ML cases were noted in follow-up [24,25].

Eschar(s) overlying ulcers should be debrided and secondary wound infection managed prior to administration of local therapy to maximize treatment effect [1]. Patients with subcutaneous nodules, regional adenopathy, and infection due to species associated with mucosal involvement should not be treated with local therapy alone, as it is less likely to control the infection.

The efficacy of local cryotherapy is greatest using a treatment approach combining cryotherapy immediately followed by intralesional pentavalent antimony (Sb^V), which is widely used globally but is not available in the United States. Use of cryotherapy alone is appropriate for relatively small, nonulcerated lesions of recent onset. Thermotherapy alone can be used as an alternative to cryotherapy for management of patients with uncomplicated Old World or New World CL presenting with few and relatively small (≤25 mm) lesions. Thermotherapy and cryotherapy can also be used for follow-up management of residual lesions not fully healed after systemic treatment; in addition, both are acceptable for use during pregnancy and breastfeeding.

Topical paromomycin may be used for treatment of ulcerative lesions due to L.L. major or non-ML-associated Central American species; it is not generally used in conjunction with cryotherapy or thermotherapy. In Israel, use of topical paromomycin for treatment of L.L. tropica was effective in 70 percent of cases, so less than in L.L. major, but it could still be considered in individual patient situations [26]. In the United States, the availability of topical paromomycin is limited to a compounded ointment prepared from capsules; the efficacy of such preparations is uncertain, and they have not been studied in clinical trials. WR279,396 (a topical cream containing 15% paromomycin and 0.5% gentamicin) is no longer available.

Intralesional therapy with pentamidine [27] or amphotericin [28] has been used successfully for treatment of both Old World CL and New World CL, in contrast to the more commonly used pentavalent antimonial drugs [29].

Photodynamic therapy is a relatively new therapy; thus far, it appears promising, although data are limited [30].

Specific agents for local therapy are discussed further below. (See 'Local therapy' below.)

Oral systemic therapy — Oral systemic agents include azoles and miltefosine (table 2).

In some cases, azoles can be used as systemic therapy, although the efficacy of azole therapy is limited and treatment failure is common. Clinical circumstances in which azoles have been used successfully include lymphocutaneous spread in the setting of non-ML-associated infection and cases in which the scope of cutaneous involvement is not amenable to local therapy. Fluconazole and ketoconazole may be useful for treatment of L.L. major, L.L. mexicana, and possibly L.V. panamensis. Azoles may be used in combination with cryo- or thermotherapy for treatment of L.L. major with lymphocutaneous involvement.

Oral miltefosine has reasonable efficacy against many New World CL species (compared with pentavalent antimonials). Data are limited regarding use of miltefosine for Old World CL, but it appears to have some efficacy. In the United States, miltefosine is available and FDA approved; this drug has become the treatment of choice for New World CL due to Viannia species.

Oral systemic therapy is discussed further below. (See 'Oral systemic therapy' below.)

Parenteral systemic therapy — Parenteral agents for treatment of CL include pentavalent antimonials, amphotericin, and pentamidine (table 2). The optimal agent depends on individual clinical circumstances.

Both pentavalent antimonials and amphotericin derivatives have activity against Old World and New World CL. Antimonials historically are generally the mainstay of systemic parenteral therapy of CL, given observed success with antimonials and toxicity associated with use of amphotericin B deoxycholate. Small clinical series note liposomal amphotericin treatment efficacy of 80 to 85 percent [31-33], but a European series including 41 patients (treated with a median cumulative dose of 20 mg per kg) noted only 46 percent were healed at 90 days post treatment [34]; the efficacy of liposomal amphotericin was greatest in patients with L. infantum infection and least in patients with Viannia infection. Pentamidine is used largely for treatment of infection due to L.V. guyanensis but is generally a secondary therapy due to its adverse effect profile.

There are two parenteral pentavalent antimony agents: sodium stibogluconate and meglumine antimoniate. Historically, the antimonial drugs have good efficacy for reducing risk of progression to mucosal disease in New World CL. Parenteral Sb^V has been the local standard of care for infection due to Viannia subgenus acquired in South America, especially in the mucosal belt, except for known foci of high antimonial resistance such as Madidi National Park, Bolivia, Manu National Park, and Puerto Maldonado, Peru. This may change with the PAHO guideline updates recommending use of miltefosine in adults and children. Treatment with systemic antimonials is also appropriate in the setting of complicated Old World CL that has not responded to local therapy. In the United States, antimonial drugs are available only via an investigator-initiated IND protocol; instructions on how to obtain these drugs are available through the American Society of Tropical Medicine and Hygiene website.

Amphotericin B deoxycholate has the greatest efficacy against CL (based on case series, not controlled trials), but its use is somewhat limited by toxicity. Liposomal amphotericin circumvents some of the toxicity and may permit a shorter duration of treatment; further studies are needed to fully evaluate its use for treatment of CL, including the appropriate dose and duration. Liposomal amphotericin has become a commonly used agent for treatment of CL in regions where available.

Parenteral systemic therapy is discussed further below. (See 'Parenteral systemic therapy' below.)

Specific therapeutic agents

Local therapy — An overview of local therapy is discussed above. (See 'Local therapy' above.)

Cryotherapy — Use of cryotherapy is often restricted to Old World disease since there is no risk for metastases and less lymphocutaneous involvement with these species. Cryotherapy may be used for infection of recent onset (less than three months' duration), disease with relatively few and relatively small lesions (<3 cm), nodular lesions, and for individuals who cannot use systemic treatment. The efficacy of cryotherapy in clinical trials ranges from 53 to 100 percent; the efficacy is increased when cryotherapy is used in combination with intralesional pentavalent antimonials [35-38].

In general, cryotherapy with liquid nitrogen consists of a freeze, thaw, freeze cycle, which causes intracellular ice to form, destroying cells, and leads to localized ischemic necrosis. It is important to treat into normal-appearing tissue around the lesions. One series including 293 patients in Saudi Arabia described a method of cryotherapy involving placement of a cotton-tipped applicator with liquid nitrogen directly on the lesion, freezing 15 to 20 seconds (until 1 to 2 mm of circumferential normal appearing skin appears frozen), thawing 20 to 60 seconds, and freezing again [39]. This sequence was repeated at three-week intervals up to three times or until healing occurred.

Adverse effects of cryotherapy include erythema, edema of the perilesional area, occasional blistering, permanent hypopigmentation (in dark-skinned individuals), hyperpigmentation, and scar.

Thermotherapy — Dermatotrophic leishmaniasis species, such as L.L. mexicana, L.L. major, and L.L. tropica, are thermosensitive; their ability to replicate is limited at higher temperatures [40]. Heat treatment of cutaneous leishmaniasis can be delivered by several methods; a radiofrequency instrument, ThermoMed, has received FDA approval for this purpose. Studies evaluating efficacy of radiofrequency thermotherapy for treatment of CL due to L.L. major, L.L. tropica, L.V. panamensis, and L.V. braziliensis have observed clinical cure rates of 54 to 73 percent at two to three months following treatment [41-44].

The radiofrequency instrument is portable, battery operated, and delivers superficial heat to 50°C via a set of prongs placed directly on the lesion. The treatment is painful, and local anesthesia is required. Prongs are touched to the lesion for 30-second heat intervals in a grid pattern over the lesion as well as a 1 to 2 mm border of normal-appearing skin. Most trials have used a single treatment session, although up to three treatments have been reported. The probes are not disposable and require sterilization between patients.

Thermotherapy can cause second-degree burns; up to a week of topical antibiotic therapy and a wound dressing are warranted. Local pain at the site lasts approximately 24 hours and is comparable to sunburn. Other adverse effects include blistering, oozing, and erythema. In general, the cosmetic outcome is relatively good; little permanent hypopigmentation or significant keloid formation has been observed following thermotherapy, in contrast with cryotherapy.

Thermotherapy alone should not be used for lesions with potential for lymphocutaneous or mucosal spread. It should not be used directly over superficial nerves, cartilage, eyelids, nose, or lips.

Intralesional pentavalent antimony — Intralesional injection of sodium stibogluconate or meglumine antimoniate is a reasonable approach for treatment of localized CL lesions ≤1 cm (table 2) [20]. The treatment is most effective for management of lesions due to CL species not associated with mucosal or lymphocutaneous involvement. The optimal dosing regimen is uncertain; few randomized controlled trials have been performed [35,45-47]. We favor injection of 0.2 to 5 mL per session every three to seven days (up to three weeks between treatments is also acceptable) in combination with cryotherapy [5,48]. A total of five to eight treatment sessions (or until clinical healing is observed) is appropriate. The efficacy depends on the technical skill of the treating provider and close follow-up for continued treatments.

Treatment consists of injection of up to five sites per lesion with a 25- to 27-gauge needle, for an estimated dose of 0.1 mL per cm². The needle should be advanced while injecting under pressure into the upper and mid-dermis of the lesion and border circumferentially, until the lesion is blanched (picture 1). The procedure is painful; in adults, lidocaine/prilocaine cream may be used, while children may need to be anesthetized. Treatment may be repeated up to five to eight times or until healed. Adverse effects include local allergic reaction, pain, edema, pruritus, and transient erythema. Intralesional antimony should be avoided on fingers, nose, ear, eyelid, and near lip.

This route of antimonial administration is not available in the United States except by investigator-IND protocol (and can be accessed through the American Society of Tropical Medicine and Hygiene website).

Topical paromomycin — Topical paromomycin (also called aminosidine) is an aminoglycoside in the form of an ointment or cream (table 2). Topical paromomycin is most useful for treatment of ulcerative infection due to L.L. major with small (≤5 cm), relatively few lesions in the absence of lymphocutaneous involvement. A meta-analysis of 14 trials with 1221 patients treated with topical paromomycin noted that paromomycin ointment had therapeutic activity against both Old World and New World CL (relative risk [RR] for clinical cure versus placebo 2.58 versus 1.01) [49]. For treatment of Old World CL, the efficacy of topical paromomycin is comparable with that of intralesional antimonials. For treatment of New World CL, topical paromomycin is inferior to parenteral antimonial therapy (RR 0.67; 95% CI 0.54-0.82) [49]. However, a Cochrane systematic review concluded that there was no difference in cure rates for paromomycin ointment compared with vehicle for treatment of Old World CL [3].

Formulations of topical paromomycin differ in efficacy and include preparations with methylbenzethonium or gentamicin. An ointment consisting of 15% paromomycin and 12% methylbenzethonium (Leishcutan) was effective among 87 percent of 67 patients with CL due to L.L. major [50]. Adverse effects included localized pain, skin irritation, and edema. This preparation is not so effective for treatment of CL due to L.L. tropica [26]. An ointment of 15%/10% urea in soft white paraffin has been studied in Iran and Tunisia; efficacy was insufficient [51,52].

WR279,396 is a topical cream consisting of 15% paromomycin and 0.5% gentamicin in a hydrophilic base [49,53-55]. The drug is administered once daily for 20 days. It has been studied in Panama, Colombia, and Tunisia (L.L. major and L.V. panamensis primarily) and shown to have cure rates of 71 to 99 percent [49,53-55]. Following treatment, the scar is usually not retracted. Side effects include erythema and mild pain. The formulation WR279,396 is no longer available.

Topical paromomycin can be compounded in the United States using oral capsules. A home brewed topical ointment can be compounded using 15% paromomycin and 12% methylbenzethonium in soft white paraffin; however, the performance characteristics for this formulation are not known. In addition, WR279,396 cream can be approximated by compounding Unibase ointment with 15% (free base) paromomycin sulfate, 0.5% gentamicin sulfate, 6.75% urea, and purified water (42.2 percent) [1].

Photodynamic therapy — Photodynamic therapy (PDT) destroys tissue by generating reactive oxygen species, which interfere with normal cell function. Treatment consists of administration of a photosensitizing compound (such as with 5-aminolaevulinic acid) that selectively accumulates in the target tissue, followed by irradiation [30].

PDT is a relatively new therapy; thus far, it appears promising, although data are limited. In one trial including 60 patients with Old World CL treated with PDT, paromomycin, or placebo, complete cure after two months was observed more frequently among patients treated with PDT than the other groups (93, 41, and 13 percent, respectively) [56]. The cosmetic results of PDT were good, with superficial or minimal scar.

Oral systemic therapy — An overview of oral systemic therapy is discussed above. (See 'Oral systemic therapy' above.)

Azoles — Azole drugs alter biosynthesis of ergosterol, thereby modifying the components of the Leishmania parasite membrane (table 2) [57]. The use of azoles is limited to specific circumstances depending on geography and the infecting species. Parasite speciation is important to tailor the approach to azole therapy. Ketoconazole has reasonable clinical efficacy for treatment of CL due to L.L. mexicana, L.V. panamensis, and L.L. major but has significant risks of hepatotoxicity or QT prolongation [12,58,59]. Fluconazole is effective against L.L. major in Saudi Arabia, although L.L. major in North Africa and Iraq appears to be less responsive to fluconazole; higher doses may improve efficacy.

Ketoconazole was more effective than sodium stibogluconate for treatment of L.L. mexicana infection (89 versus 57 percent, respectively) in one study including 120 Guatemalan patients with CL [12]. However, for treatment of L. braziliensis infection, ketoconazole was less effective than sodium stibogluconate (30 versus 96 percent, respectively) [12]. In a study including 96 Iranian patients with CL (likely L.L. major), clinical cure rates were higher with ketoconazole than with intralesional meglumine antimoniate (89 versus 72 percent, respectively) [58].

Fluconazole is effective against L.L. major in Saudi Arabia. In one study including 209 patients with L.L. major infection in Saudi Arabia, healing was observed more frequently among patients who received fluconazole (200 mg daily for six weeks) than placebo (59 versus 22 percent) [60]. However, L.L. major in North Africa and Iraq appears to be less responsive to fluconazole [61]. In some circumstances, fluconazole may be more effective at higher doses than lower doses. Among 120 patients with L.L. major in Iran, the relative risk of healing was higher among patients on fluconazole 400 mg daily than among patients on fluconazole 200 mg daily (RR 4.57; 95% CI 1.99-10.46) [62].

Fluconazole is not effective for treatment of CL due to L.V. braziliensis or L.V. guyanensis [63,64]. In one randomized trial including 53 patients infected with L.V. braziliensis and treated with fluconazole (6.5 to 8 mg/kg orally per day) or Sb^V (20 mg/kg parenterally per day), healing at two months among patients treated with fluconazole was observed in only 22 percent of cases [63].

Posaconazole was successful in a case report of a traveler with a single nodular lesion due to L.L. infantum [65].

Miltefosine — Miltefosine is an oral alkylphosphocholine drug known as hexadecylphosphocholine; it has activity against cutaneous, mucosal, and visceral leishmaniasis (VL) (table 2) [66]. Miltefosine interacts with parasite membrane constituents and can affect lipid-dependent cell signaling pathways by inhibiting Akt (also known as protein kinase B) [67]. Miltefosine also interferes with glycosylphosphatidyl inositol anchors [67]. In 2014, the FDA approved miltefosine for the treatment of ML, VL due to L.L. donovani, and CL due to L.V. braziliensis, L.V. guyanensis, and L.V. panamensis for individuals >12 years old.

Most data available for use of miltefosine address treatment of New World CL. The efficacy of miltefosine for treatment of New World CL varies both by species and by geography within a particular species [68,69]. Miltefosine appears to have clinical utility for treatment of L.V. panamensis, L.V. guyanensis, L.L. mexicana, and L.V. braziliensis infection in Colombia and Brazil [2,70-75]. Miltefosine shows efficacy in the treatment of L.V. braziliensis in Bolivia (70 to 88 percent) and Brazil (75 percent) but not in Guatemala (45 percent) [70,76,77].

Data on use of miltefosine for treatment of Old World CL are limited [68,69,78-80]. Among 63 Iranian patients with L.L. major infection, the efficacy of miltefosine and intramuscular meglumine antimoniate were comparable (81 percent at three months after treatment) [78]. In an observational study of 95 Ethiopian patients with L.L. aethiopica, miltefosine was associated with 48.7 percent clinical cure at day 180 and 32 percent relapse rate [81].

Oral absorption of miltefosine is relatively slow, and the elimination half-life is 30.9 days [82]. In one study of serial skin biopsies performed during miltefosine treatment, the rate of parasite load decline for L.L. major and L.L. infantum was about one log/week, and high skin levels of miltefosine were demonstrated at the end of treatment [83].

Gastrointestinal effects of miltefosine include anorexia, nausea, vomiting, or diarrhea; administration of miltefosine with fatty foods may reduce these symptoms, but the effect on bioavailability is not known. Elevated serum transaminases and creatinine concentration may also occur [84]. Ocular toxicity has been described during treatment of post-kala-azar dermal leishmaniasis [85,86].The use of miltefosine is contraindicated in pregnant women [87]. Women of childbearing potential should use contraception during treatment and for five months following treatment with miltefosine [88].

Oral miltefosine has reasonable efficacy against many New World CL species (compared with pentavalent antimonials); this advantage must be weighed against adverse events, cost, and availability. The package insert cites an upper dosage limit of 150 mg per day because of poor gastrointestinal tolerability. Limited data are available for individuals >75 kg, but a lower clinical response rate has been observed in individuals receiving less than 2.5 mg/kg per day.

Parenteral systemic therapy — An overview of parenteral systemic therapy is discussed above. (See 'Parenteral systemic therapy' above.)

Parenteral pentavalent antimony — There are two parenteral pentavalent antimony agents: sodium stibogluconate (sodium antimony gluconate, Pentostam) and meglumine antimoniate (N-methyl glucamine antimoniate, Glucantime) (table 2) [89,90]. The pentavalent antimonial drugs affect adenosine triphosphate (ATP) synthesis, and it has been suggested that they inhibit glycolysis, affecting fatty acid oxidation [91]. Sodium stibogluconate has been identified to have effects on cell signaling, leading to increased interferon-gamma production in Leishmania-infected macrophages [92].

The parenteral pentavalent antimony agents generally can be considered clinically equivalent, though it is important to note that they contain different antimony concentrations; sodium stibogluconate contains 100 mg/mL Sb^V and meglumine antimoniate contains 81 mg/mL Sb^V [93-96]. For decades, these drugs have been a standard therapy for CL; they are especially important for management of infection with potential for mucosal progression [20]. This is particularly important in the setting of clinical unresponsiveness to therapy, which requires higher doses and longer duration of therapy and can result in increased toxicity.

More data are available regarding use of parenteral antimonials for treatment of New World CL than for treatment of Old World CL [12,59,97]. One meta-analysis including 1150 patients with New World CL noted a comparable cure rate with pentavalent antimonials and pentamidine (76 percent) [98]. No differences in efficacy between species were observed (although most infections were due to L.V. braziliensis), but there were differences in efficacy between regions, with greater efficacy in Colombia than Brazil (91 versus 71 percent, respectively) [98]. It has been observed that early treatment of New World CL (eg, treatment of patients with only superficial ulceration and/or less than 30 days of illness) with parenteral antimonials does not prevent ulceration and is associated with high rates of treatment failure [11].

The efficacy of parenteral antimonials for treatment of Old World CL is 60 to 80 percent [99]. Among 64 Iranian patients with likely L.L. major, combination therapy with meglumine antimoniate plus pentoxifylline was more likely to be associated with a complete response rate than meglumine antimoniate plus placebo (81 versus 52 percent) [100].

Pentavalent antimonial drugs are administered by intramuscular or intravenous routes for systemic therapy. Dosing for sodium stibogluconate or meglumine antimoniate consists of 20 mg Sb^V/kg/day (there is no upper limit in contrast with the information in the package insert) in a single daily dose infused over 15 to 30 minutes for 20 days. Expert consultation regarding dose should be pursued for management of patients with obesity. Pentavalent antimonials accumulate in renal insufficiency. The rate of antimony clearance is higher in children than adults, which may explain why lower antimonial response rates have been observed among children compared with adults [101,102].

Adverse effects include myalgias and arthralgias (these generally occur after seven days of therapy), early elevation of pancreatic enzymes (though clinical pancreatitis occurs less frequently), rash, nausea, abdominal pain, fatigue, headaches, elevated transaminases, mild leukopenia, and nonspecific ST wave changes on electrocardiography [103-107]. Less common findings include anemia, thrombocytopenia, reactivation of herpes simplex and varicella-zoster viruses, and QT prolongation [108]. Rare but serious side effects include angioedema and severe pancreatitis [109]. In general, most effects are reversible, and management is symptomatic; nonsteroidal drugs may be administered for musculoskeletal pain [107]. In the setting of elevated pancreatic enzymes, the drug should be held for a few days until levels normalize. In general, weekly electrocardiogram and blood counts should be monitored during therapy, in addition to serum concentrations of creatinine, amylase, lipase, and transaminases. The pentavalent antimonial drugs are contraindicated during pregnancy and breastfeeding [110,111].

The therapeutic response to treatment of leishmaniasis is influenced by multiple factors, including pharmacologic factors, the host immune status, and the variable biology of Leishmania species. These factors confound correlation of clinical outcomes with drug susceptibility and the possibility of resistance [112]. Diminished response to pentavalent antimony has been observed among L.V. braziliensis, L.L. tropica, and L.L. aethiopica, with some geographic variability. Failure of pentavalent antimonial drugs has been associated with increased duration of skin lesions, multiple lesions, age of patient, large lesions, parasite species, and concomitant helminth infection [113,114].

In the United States, sodium stibogluconate is not available and meglumine antimoniate is only available through an investigator-initiated IND protocol; instructions can be accessed through the American Society of Tropical Medicine and Hygiene website. Since alternative options such as oral miltefosine and liposomal amphotericin B have less serious adverse events than antimonial drugs, these options have become preferred in practice. The use of intralesional pentavalent antimonial drugs is still recommended, however.

Amphotericin B — There are two formulations of amphotericin B used in the treatment of CL: amphotericin B deoxycholate and liposomal amphotericin B (Ambisome) (table 2). Amphotericin B is a polyene antibiotic; the drug binds to ergosterol precursors in preference to host cholesterol, leading to increased parasite membrane permeability resulting in cell death [115].

Use of amphotericin B deoxycholate is limited by long duration of intravenous therapy (hours of infusion daily for 20 to 30 days) and potential irreversible nephrotoxicity. Liposomal amphotericin B consists of amphotericin incorporated into liposomes that targets to the drug to macrophages, where the parasite is concentrated; the preparation is also associated with lower rates of nephrotoxicity than amphotericin B deoxycholate. Case series data suggest that patients with ML may benefit from treatment with liposomal amphotericin [116-118]; this data might be extrapolated to suggest that CL patients treated with liposomal amphotericin may have decreased risk for future ML, although further study is needed. Other lipid amphotericin agents have not been studied sufficiently for treatment of CL, but reports suggest they may not have equivalent efficacy [119,120]. (See 'Mucosal leishmaniasis' below.)

Adverse effects of amphotericin B include nephrotoxicity, hypokalemia, anemia, peripheral vein phlebitis, and fever with rigors related to infusion. The risk of nephrotoxicity associated with amphotericin B may be increased among patients previously treated with pentavalent antimonials; saline loading may reduce nephrotoxicity [121]. In addition, baseline QT prolongation may be potentiated in the setting of hypokalemia induced by amphotericin B, which can lead to cardiac arrhythmia; a wash-out period of at least two weeks between the two treatments (antimonials and amphotericin) is warranted [122,123]. Additional side effects associated with liposomal amphotericin treatment in CL include infusion-related chest or flank pain, dyspnea, urticaria, and flushing [124].

Dosing of amphotericin B deoxycholate for treatment of cutaneous leishmaniasis is 0.5 to 1 mg/kg/day or every other day for a cumulative dose of 15 to 30 mg/kg; the World Health Organization recommends 0.7 mg/kg/day for 25 to 30 days [5]. Dosing of liposomal amphotericin is uncertain; it is unclear whether the dosing regimen for visceral leishmaniasis is optimal for treatment of CL [119,120,125]. Some efficacy has been observed with administration of relatively short course of liposomal amphotericin (3 mg/kg for five consecutive days and a sixth dose on day 10); a European case series showed an initial healing response at three months of only 46 percent [32,34].

Data on the efficacy of amphotericin relative to antimonials are limited [32,126,127]. In a controlled trial of low-dose liposomal amphotericin (1.5 mg Sb^V/kg/day for five doses) versus meglumine antimoniate (20 mg/kg/day intravenously for 20 doses) among 35 Brazilian patients with cutaneous leishmaniasis, cure rates were 50 and 100 percent, respectively [127]. In a case series including patients with L.V. braziliensis CL, 34 patients were treated with liposomal amphotericin (3 mg/kg/day for six doses) and 34 patients treated with sodium stibogluconate (20 mg/kg/day for three weeks). Healing was observed in 97 and 71 percent of patients, respectively, and liposomal amphotericin was better tolerated than sodium stibogluconate [32]. In smaller series including patients with Old World CL, 84 percent responded to liposomal amphotericin (3 mg/kg/day for six or more doses) [124,128].

Pentamidine — Pentamidine isoethionate is an alternative parenteral treatment for cutaneous leishmaniasis (table 2). It is an aromatic diamidine compound; its mechanism of action is thought to be through interference with DNA synthesis, modifying the Leishmania kinetoplast morphology and causing fragmentation of mitochondrial membranes [129]. Its many adverse effects have relegated it to a secondary therapy, largely reserved for L.V. guyanensis infection acquired in the Guyanas [20].

Data are limited regarding use of pentamidine for treatment of Old World CL. In one small series of 11 European patients with infections due to L.L. tropica, L.L. major, or L.L. infantum, treatment with pentamidine (4 mg/kg intramuscularly every other day for three doses) resulted in 73 percent clinical response [130].

There are more data regarding use of pentamidine for treatment of New World CL than Old World CL [131]. Pentamidine appears to have greatest efficacy against L.V. guyanensis infection acquired in Guyana, French Guiana, and Suriname; among several studies with different regimens and endpoints (including more than 1000 patients cumulatively), efficacy ranged 73 to 95 percent [132-137]. In studies in Colombia, higher total dose (either more doses or higher dose) was linked to efficacy of 96 percent [138,139]. The appropriate dose for pentamidine isethionate is 7 mg/kg weekly for three doses [140]; the intravenous route of administration is preferred for efficacy [141].

Pentamidine has a significant adverse event profile, including drug-induced pancreatitis leading to insulin-dependent diabetes, dysglycemia (especially reversible hypoglycemia), hypotension, QT prolongation, hyperkalemia, cytopenias, nephrotoxicity, and elevated liver-associated enzymes. Other adverse events reported include pain at the injection site, sterile abscesses, dysgeusia, myalgias (increased creatine phosphokinase levels), nausea, and headache.

Clinical follow-up — Patients should be followed for 6 to 12 months to evaluate for relapse; patients at risk for ML should be followed for at least two years [1]. Treatment response is generally assessed by physical appearance. A careful nasal and oropharyngeal examination should also be performed. Lesion sampling for parasitologic assessment is not necessary if the lesion appears to be healing clinically.

Healing of CL is slow and continues after treatment has been completed; lesions are rarely completely healed at the end of treatment. The first sign of healing is usually flattening of the skin lesion. A paradoxical increase in the local inflammatory response may be seen in the first two to three weeks of treatment and can be difficult to differentiate from therapeutic failure. By four to six weeks following treatment, the lesion size should be decreased by more than 50 percent, with improvement in edema and inflammation. Ulcers should be reepithelializing, and no new lesions should be appearing [142]. Ulcers are generally reepithelialized or "clinically cured" approximately three months following treatment [2,3].

Relatively little improvement or worsening while on therapy (usually seen at the border of a healed lesion) suggests an inadequate response and should prompt additional therapy (but not necessarily a different agent or approach). Additional therapy is also warranted if there is incomplete healing by three months after completion of treatment. For management of patients who relapse or do not respond to treatment, consultation with a leishmaniasis expert is warranted.

Patients with symptoms such as chronic nasal stuffiness, epistaxis, or hoarseness or findings such as septal perforation should prompt evaluation for ML, including referral to a specialist for endoscopic otorhinolaryngologic examination if relevant.

Wound care — Ulcerative CL is a chronic wound [143]. Secondary bacterial infection inhibits healing, permits further enlargement of the lesion, and can cause surrounding cellulitis. Lesions should be gently cleaned daily with mild soap and water. If purulence is observed, the overlying eschar should be debrided to a clean base. A thin layer of a petroleum-based ointment should be applied after bathing. Occlusive dressings are not needed but can be used if there is associated wound drainage [144]. Trauma may interrupt healing or cause lesions to develop at sites of trauma remote to initial lesion. Cosmetic surgery and/or skin grafts should be postponed until at least a year after successful healing [145].

MUCOSAL LEISHMANIASIS — Mucosal leishmaniasis (ML) occurs most frequently in the New World and is characterized by mucosal destruction. (See "Cutaneous leishmaniasis: Clinical manifestations and diagnosis", section on 'Mucosal leishmaniasis'.)

Cure is difficult unless ML is identified while mild; the goals of treatment include preventing morbidity (eg, disfigurement) and mortality (eg, from aspiration pneumonia or respiratory obstruction) [1]. There are few randomized controlled trials to guide treatment of ML; a long duration of therapy is required, and close follow-up for relapse is warranted.

Prior to initiation of therapy, a complete examination of the naso-oropharyngeal and laryngeal mucosa should be conducted by an otolaryngologist to assess the extent and clinical severity of mucosal disease. In the setting of laryngeal/pharyngeal disease and increased risk for respiratory obstruction (as indicated by symptoms, otolaryngologic and/or radiographic examination), inpatient monitoring and prophylactic corticosteroid therapy are warranted at the time of treatment initiation; these may reduce the risk of cyanosis, dyspnea, and need for emergent tracheostomy [1].

There are few randomized controlled trials to guide treatment of ML; a long duration of therapy is required, and close follow-up for relapse is warranted [146]. Therapeutic options for treatment of ML include parenteral pentavalent antimony drugs, amphotericin B including liposomal amphotericin, and miltefosine (used for treatment of Bolivian ML) (table 3) [5]:

●In general, initial management of ML should consist of parenteral therapy. The recommended treatment option by the PAHO is pentavalent antimony in combination with pentoxifylline for synergistic activity [2,20,74,147]. However, the efficacy of pentavalent antimonials in ML is variable depending on geography, severity of presenting infection, parasite species, and duration of treatment [148-150].

●The use of amphotericin B deoxycholate is somewhat limited by toxicity, though case series have demonstrated that it is associated with a better response rate and lower relapse rate than pentavalent antimony. The toxicity of liposomal amphotericin B is less than amphotericin B deoxycholate and is comparable with that of antimonials, though data are limited regarding the optimal dose and duration of therapy; its use is also limited by cost.

●Miltefosine has demonstrated good efficacy in the treatment of Bolivian ML and is US Food and Drug Administration approved for use in ML due to L.V. braziliensis.

●Pentamidine is rarely used to treat ML given its adverse effect profile during a long course of treatment [151].

A systematic review including 68 studies and 271 patients with ML noted an overall treatment efficacy of 67 percent [152]. Pentavalent antimonial drugs were the most commonly used agents; the efficacy among Brazilian, Peruvian, and Panamanian patients was 88, 51, and 51 percent, respectively. In a retrospective review of 140 Brazilian patients, meglumine antimoniate was administered to approximately half of patients with a cure rate of 91 percent and a recurrence rate of 22 percent [116]. Primary resistance to antimonials was observed in 14 percent of cases; most resistance was related to use of doses <10 mg/kg and shorter duration of therapy.

Among 23 Brazilian patients with L.V. braziliensis, patients treated with sodium stibogluconate (20 mg/kg/day for 30 doses) plus pentoxifylline (400 mg orally three times daily for 30 days) healed faster than those treated with sodium stibogluconate alone (100 versus 40 percent healing at six months following treatment) [147]. The benefit of pentoxifylline may be related to its ability to downregulate tumor necrosis factor (TNF)-alpha production, which is expressed in high levels in ML lesions.

Amphotericin B deoxycholate has therapeutic activity for ML. Among Brazilian and Bolivian patients with mucosal disease, 90 to 96 percent who completed therapy (1 mg/kg until healing, in combination with hydrocortisone) were clinically cured [153,154]. Complete healing was observed among eight Brazilian patients treated with liposomal amphotericin (total dose 35 mg/kg) with two years of follow-up [155]. Among 32 Brazilian patients treated with liposomal amphotericin (1 to 4 mg/kg/day to cumulative dose of 2500 mg) 26 were healed at a mean of 55.6 months follow-up; in the same case series 14 of 25 patients treated with pentavalent antimonial drug healed [156].

Miltefosine is effective for treatment of ML due to L.V. braziliensis in Bolivia. Among 72 patients treated with miltefosine (2.5 mg/day for 28 doses with one-year follow-up), the efficacy for mild and moderate disease was 83 and 58 percent, respectively [157]. A follow-up study extending the duration of therapy to six weeks increased the cure rate to 75 percent [158]. A case series of 40 Brazilian patients with ML showed that those with complete healing four years after treatment were 16 of 18 of those treated with miltefosine and 12 of 14 treated with meglumine antimonate [146].

Data are limited regarding treatment of ML due to Old World species such as L.L. aethiopica in Sudan/Ethiopia or L.L. infantum-chagasi infection [159,160].

Follow-up of ML after treatment should include nasopharyngeal and laryngeal visualization every three months for one year or longer in the absence of resolution. Evidence of clinical response depends on the initial presentation; signs to follow include erythema, edema, infiltration, ulceration, and tissue destruction. Septal perforation and granulomatous-appearing lesions are common. Response is usually seen during treatment, but relapses are common. Consultation with a leishmaniasis expert should be pursued in the absence of treatment response. In some cases, surgical reconstruction may be required; if possible, tissue grafts should be delayed for at least a year after effective treatment [145,161].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Leishmaniasis".)

SUMMARY AND RECOMMENDATIONS

●There is a broad array of clinical leishmaniasis (CL) syndromes; among these, the clinical course, treatment options, response to therapy, and prognosis are all highly variable. Treatment choices are complicated by the paucity of well-controlled comparative trials and lack of standardized outcome measures. (See 'Introduction' above.)

●Many CL infections eventually resolve clinically without treatment, and not all patients who undergo treatment demonstrate elimination of parasitic infection. The benefits of treatment include accelerated healing of skin lesions, reduced likelihood of recurrence, diminished severity of scarring, and reduced risk for metastatic infection. (See 'Clinical approach' above.)

●In general, we suggest local therapy for treatment of uncomplicated CL (Grade 2B); we suggest systemic therapy for treatment of complicated CL (Grade 2B). Features of complicated CL are summarized above. (See 'Uncomplicated versus complicated infection' above.)

●Therapeutic agents and dosing for treatment of CL are summarized in the table (table 2). The approach to treatment of CL is often influenced by the agents available. (See 'Overview of therapeutic approaches' above.)

●Local therapy is preferred for treatment of uncomplicated Old World CL and may be useful for New World CL caused by species unlikely to cause disseminated infection. Cryotherapy or thermotherapy can be used for the management of patients with uncomplicated Old World or New World CL presenting with few and relatively small (≤25 mm) lesions. Topical paromomycin cream may be used for treatment of ulcerative lesions due to L.L. major or nonmucosal leishmaniasis (ML)-associated Central American species. (See 'Local therapy' above.)

●Oral systemic agents include azoles and miltefosine (table 2). In some cases, azoles can be used as first-line systemic therapy, although the efficacy of azole therapy is limited. Oral miltefosine has reasonable efficacy against many New World CL species. Data are limited regarding use of miltefosine for Old World CL, but it appears to have some efficacy. (See 'Oral systemic therapy' above.)

●Parenteral agents for treatment of CL include pentavalent antimonials, amphotericin, and pentamidine (table 2). Both pentavalent antimonials and amphotericin derivatives have activity against both Old World and New World CL. Antimonials are the historic choice for systemic parenteral therapy of CL, given observed success with antimonials and toxicity associated with use of amphotericin B; further study of liposomal amphotericin is needed. Pentamidine is used largely for treatment of infection due to L.V. guyanensis but is generally a secondary therapy due to its adverse effect profile. (See 'Parenteral systemic therapy' above.)

●Healing of CL is slow and continues after the course of treatment has been completed. Treatment response is generally assessed by physical appearance. By four to six weeks following treatment, the lesion size should be decreased by approximately two-thirds, with improvement in edema and inflammation; ulcers should be reepithelializing, and new lesions should not appear. Relatively little improvement or worsening while on therapy suggests an inadequate response, and an alternate treatment approach should be planned promptly. (See 'Clinical follow-up' above.)

●ML occurs most frequently in the New World and is characterized by mucosal destruction. Therapeutic options for treatment of ML include parenteral pentavalent antimony drugs, amphotericin B (including liposomal amphotericin B), and miltefosine (table 3). The Pan American Health Organization (PAHO) recommends parenteral pentavalent antimony in combination with pentoxifylline for synergistic activity. The use of amphotericin B is somewhat limited by toxicity (lessened when liposomal amphotericin is used), though case series have demonstrated that it is associated with a better response rate and lower relapse rate than pentavalent antimony. (See 'Mucosal leishmaniasis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Karin Leder, who contributed to an earlier version of this topic review.

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