Approach

The treatment of leishmaniasis is complex and, after discussing the primary drug options more generally, discussion is grouped by major clinical syndromes. It is important to recognise that the available literature on treatment varies in methodology with relatively few well-controlled clinical trials and a diversity of treatment endpoints.

For all types of leishmaniasis, parasite and host factors can influence treatment outcomes. Not only can treatment outcomes vary by species but there can be differences seen within a single species from different geographical regions. For example, the response to treatment of visceral leishmaniasis (VL) caused by Leishmania donovani varies significantly between South Asia and East Africa, with liposomal amphotericin-B being preferred in the former and pentavalent antimonial compounds retaining higher efficacy in the latter.[107] Host factors that influence the response to treatment include nutritional status and the presence of immunocompromise, such as HIV/AIDS.

In addition to treating the parasite, consideration has to be given to managing co-infections and/or supportive care, particularly in VL. The goal of therapy in all forms of leishmaniasis is clinical cure, recognising that Leishmania parasites likely persist after treatment.[108][109]

General considerations for choosing therapy include regional efficacy, safety, availability, and cost, with the latter two often driving management decisions in low-resource settings.

Anti-leishmanial drugs

Amphotericin-B

  • Liposomal amphotericin-B is the preferred formulation for the treatment of leishmaniasis, when available. Its use is limited by cost, availability, and the requirement of a cold chain. It is approved in Europe and the US for VL; use in other types of leishmaniasis is off-label. Liposomal amphotericin-B is generally well tolerated with adverse effects including infusion-related reactions (e.g., chills, fever), nausea, vomiting, hypokalaemia, and renal insufficiency.[110][111][112]

  • Amphotericin deoxycholate is an option if the liposomal formulation is not available; adverse effects are similar but more frequent and severe, and administration is more complicated.[113][114]

  • Other lipid formulations of amphotericin-B, if available, have been less rigorously studied and appear to be inferior to liposomal amphotericin-B.[115]

  • Amphotericin-B is the only anti-leishmanial with safety data in pregnancy.

Miltefosine

  • Miltefosine is the only oral anti-leishmanial available.

  • Use of miltefosine is limited by:

    • High risk for teratogenicity in pregnancy. Women require a negative pregnancy test and effective contraception during treatment and for at least 5 months after completion of treatment

    • Significant gastrointestinal adverse effects including nausea, vomiting, and abdominal pain

    • Natural or emerging resistance in some regions.[116][117]

  • Miltefosine is approved in the US (but not in Europe) for use in:

    • VL caused by Leishmania donovani

    • Cutaneous leishmaniasis (CL) due to Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis

    • Mucosal leishmaniasis (ML) due to Leishmania braziliensis.

Pentavalent antimonial compounds

  • Antimonials are the oldest available medications for the treatment of leishmaniasis. However, the adverse-effect profile with the high doses required makes their use less appealing.

    • Adverse effects are common and include decreased appetite, nausea, vomiting, abdominal pain, myalgias, arthralgias, headache, generalised weakness, and malaise. Laboratory abnormalities include cytopenias, elevated aminotransferases, and elevated amylase and lipase.

    • Severe adverse effects include pancreatitis, QT prolongation (potentially leading to cardiac arrhythmias including torsades de pointe), and sudden death.

    • Pentavalent antimonial compounds have been shown to be embryotoxic in rats and associated with a high rate of spontaneous abortions in humans.[118][119][120]

  • Specific drugs include sodium stibogluconate and meglumine antimonate. Branded products are generally preferred due to more reliable content and less toxicity.[121]

  • In the US, there are no Food and Drug Administration (FDA)-approved pentavalent antimonial compounds currently available. In Europe, sodium stibogluconate is licensed for use in all major forms of leishmaniasis.

  • Significant regional differences in efficacy have been seen, with a high level of resistance in South Asia.[122]

Paromomycin

  • Paromomycin is an aminoglycoside that can be administered topically in CL or intramuscularly in VL, and is often used in combination with another agent.

  • Neither intramuscular nor topical preparations of paromomycin are approved for use in the US or Europe. Oral preparations in the US are approved for other indications and can be used to compound topical ointments, but this use is off-label.

  • When used topically, paromomycin can cause mild to moderate local-site reactions including redness, pain, swelling, burning, and itching. Adverse effects with systemic paromomycin include significant injection-site pain, elevated aminotransferases, renal insufficiency, and reversible ototoxicity.

  • Safety data are lacking for paromomycin in pregnancy.

Pentamidine

  • Use is generally limited to specific situations in CL and secondary prophylaxis among immunocompromised patients.

  • Pentamidine is available in the US, but use is off-label in leishmaniasis. It is approved in Europe for the treatment of CL.

  • Adverse effects are significant and include diabetes mellitus, pancreatitis, gastrointestinal symptoms, hypotension, QT prolongation, electrolyte disturbances, nephrotoxicity, hepatotoxicity, cytopenias, and rhabdomyolysis. These effects are mitigated when drug is administered intralesionally for cutaneous leishmaniasis.

  • There are no data on the safety of pentamidine in pregnancy.

Other drugs such as azole antifungals may have a role in some specific situations.

Cutaneous leishmaniasis: general principles

The appropriate management is individualised for each CL patient. The Infectious Diseases Society of America (IDSA)/American Society of Tropical Medicine and Hygiene (ASTMH) guidelines classify cutaneous leishmaniasis as either simple or complex.[8]

  • Simple CL:

    • No mucosal involvement and parasite species not associated with ML

    • ≤4 lesions <1 cm

    • Location feasible for local therapy and/or non-exposed skin (not cosmetically important)

    • Immunocompetent host

    • Lesions resolving without therapy.

  • Complex CL:

    • Parasite species caused by species associated with ML

    • Local subcutaneous nodules

    • Large regional adenopathy

    • >4 lesions generally >1 cm

    • Individual lesion ≥5 cm

    • Size or location makes local therapy infeasible and/or lesion of the face, fingers, toes, joints, or genitalia

    • Immunocompromised host

    • Failure of local therapy

    • Unusual syndromes (leishmaniasis recidivans, diffuse cutaneous leishmaniasis, or disseminated leishmaniasis).

In high-resource settings, parasitological diagnosis with species-level identification is optimal to guide management and should be obtained. In low-resource settings, attempt should still be made to confirm the diagnosis to the extent possible due to the significant adverse effects associated with treatment.[123][124][125] In cases where the species cannot be determined, knowledge of regional (old world versus new world) and local prevalence patterns may help in guiding therapy. For example, a patient with CL from the 'mucosal belt' of Bolivia, Brazil, and Peru may be at higher risk of mucosal spread and so consideration might be given to monitoring patients without a clear species-specific diagnosis for the development of mucosal disease after management of the primary skin lesion(s).

Simple CL may require only watchful waiting or, to accelerate cure, can be managed with local therapies or potentially azole antifungals. Complex CL generally requires systemic therapy to prevent disability and social stigma, and/or to prevent parasite dissemination (e.g., mucosal leishmaniasis [ML]) or relapse.

For all cases of ulcerative CL, care should be taken to ensure proper wound management including washing of ulcer(s) and applying barrier ointment. The presence of warmth, redness, pain, and/or purulent discharge should prompt for the evaluation and management of a secondary bacterial infection. Evidence of healing often begins with flattening, and large ulcers may not be completely healed by the end of therapy. CDC: parasites – leishmaniasis Opens in new window

Treatment recommendations for specific situations are given below; however, most trials on the treatment of CL have been poorly designed and reported, resulting in a lack of clear evidence for potentially beneficial treatments. There is a need for large, well-conducted studies that evaluate long-term effects of current therapies, and evaluate recurrence rates of cutaneous leishmaniasis and its progression to mucosal disease.[126][127]

Cutaneous leishmaniasis: specific treatment

Simple cutaneous leishmaniasis

For simple CL, options include watchful waiting, local therapies, or less toxic systemic medications.

Most cases of CL, particularly among Old World species, will resolve spontaneously within 18 months; therefore, it is important to decide whether or not treatment is truly indicated.[107][128] This decision must be individualised considering factors such as whether healing has already begun, impairments of wound healing, risk of secondary infections, patient preference, whether there is evidence of impaired cell-mediated immunity, and availability/expertise in treatment.

Among those who undergo treatment, options for local therapy include cryotherapy, thermotherapy, and topical or intralesional medications. Before any local therapy is started, any crust should be removed, if present.[8]

  • Cryotherapy: involves freezing the lesion and surrounding 1 to 2 mm of healthy skin with liquid nitrogen until it is white in appearance, allowing the area to thaw, and freezing again. The IDSA/ASTMH guidelines recommend a cryotherapy session every 3 weeks up to three times total.[8] The per lesion efficacy of cryotherapy is 67% across all regions, and is statistically the same as intralesional antimonial compounds.[129] Adverse effects include transient pain and redness as well as hypopigmentation.

  • Thermotherapy: utilises heat administered to the lesion(s), often in a single treatment, resulting in a second-degree burn and requiring local anaesthesia. A meta-analysis showed 73% efficacy across all regions, equivalent to systemic antimonial therapy but with fewer adverse effects.[130] Efficacy may be even higher in the Old World, with cure rates as high as 94% in Leishmania tropica.[107] Adverse effects include cellulitis, redness, and pain at the treatment site, and US guidelines recommend utilising topical antibiotics post-procedurally for several days.[8] This treatment modality requires the use of special equipment and operator training on this equipment, which limits its broad applicability.

  • Topical paromomycin: the best studied topical medication for the treatment of CL. The efficacy varies in the literature with the precise formulation; therefore, commercial and compounded versions may not be equivalent to what is reported. Paromomycin may be used alone or in combination with methylbenzethonium chloride, urea, or gentamicin.[126]

    • In the Old World disease with ulcerative Leishmania major an overall cure rate of approximately 80% was seen (with or without the addition of gentamicin) compared with 57% in the vehicle only arm.[131]

    • In two studies in the New World among lesions caused by L panamensis, L guyanensis, or L braziliensis, similar paromomycin products had cure rates of 77% to 79%.[132][133]

    • Older studies in the New World have shown lower rates of efficacy (approximately 50%) with various different paromomycin formulations; however, the cure rates with systemic pentavalent antimonial compounds in these studies were similar (74%) to topical paromomycin in newer studies.[134]

    • In Panama, 3% of patients treated with topical paromomycin developed mucosal disease that required systemic treatment.[132] The risk of mucosal disease among patients with Viannia subgenus parasites remains a significant concern warranting close monitoring if topical treatment is chosen versus opting for systemic therapy initially.

  • Intralesional therapy: involves injecting lesions with an anti-leishmanial drug, most commonly pentavalent antimonial compounds. Pain with injection can be significant. In the Old World, the best results are seen by combining intralesional sodium stibogluconate with cryotherapy, with cure rates of 89% to 91% reported.[107] While the evidence in the New World is less robust and concerns for ML remain, a meta-analysis showed pooled efficacy of 75%, but with a preference for meglumine antimonate (efficacy 82%) rather than sodium stibogluconate, which is preferred in the Old World.[135] Sodium stibogluconate is available for intralesional use in Europe, but is not available in the US. Pentamidine can also be used intralesionally.[136]

  • Other methodologies such as photodynamic therapy or CO₂ laser therapy are potential alternative local therapies, but limited evidence prevents making recommendations regarding their use. [Figure caption and citation for the preceding image starts]: Intralesional injection for the treatment of cutaneous leishmaniasisImage courtesy of the World Health Organization [Citation ends].com.bmj.content.model.Caption@5c37b375

Generally, systemic therapy is reserved for complex disease, but azole antifungal therapy may be an option in simple CL.

  • Fluconazole, itraconazole, and ketoconazole have been evaluated and are available globally, although use in CL is off-label in both the US and Europe.

  • All have gastrointestinal adverse effects and a risk of hepatotoxicity, but ketoconazole carries a warning related to the risk of life-threatening hepatotoxicity and QT prolongation that could lead to fatal arrhythmias.

  • A systematic review did not find enough evidence to recommend any of the azole antifungals routinely, but in the New World pooled efficacy for ketoconazole in the treatment of Leishmania mexicana was as high as 89%, suggesting this as a potential option in Mexico and parts of Central America with appropriate monitoring of adverse effects.[137]

Complex cutaneous leishmaniasis

In complex CL, systemic therapy is preferred due to the extent or location of the lesion(s), prior failure of local therapy, and/or the risk of dissemination.

  • Miltefosine: a more recent option for CL. It is approved for Viannia subgenus parasites in the New World, but even in that context there is variability regionally. Cure rates in Brazil, Bolivia, and Colombia range from 71% to 91% for Viannia species, but in Guatemala the cure rate was only 33% for L braziliensis.[138]

  • Pentavalent antimonial compounds (sodium stibogluconate, meglumine antimonate): generally effective but less favourable due to the associated toxicity and duration of treatment. In Old World disease, cure rates range as high as 98% for L major and as low as 41% for L tropica. In the New World, efficacy ranges from 77% to 90%, but significant levels of treatment failure are seen among parasites of the Viannia subgenus, especially L braziliensis, and also in certain geographical regions such as L mexicana in Guatemala, or among Leishmania species in the southern jungle regions of Peru bordering with Bolivia.[138]

  • Liposomal amphotericin-B: likely effective for complex CL, but data are limited to observational studies and several small trials. Retrospective data from various regions range from 46% to 84% cured, but small trials in Bolivia had rates of 85% to 100%.[138]

  • Pentamidine: has a limited role in treating CL in the New World caused by L guyanensis in French Guiana and Suriname with cure rates generally of 84% to 90% reported.[139][140] Intravenous injection is preferred over intramuscular injection as increased efficacy is seen with intravenous administration (85% cure with intravenous versus 51% with intramuscular).[141] Another potential use is intralesional pentamidine in Bolivia with a reported efficacy of 73%, but this may not impact the risk of mucosal spread.[136] However, combination of this same regimen with 28 days of miltefosine resulted in 92% cure rates and has the advantage of systemic treatment, albeit with increased duration and cost.[142] In other settings, the adverse effects and relatively lower efficacy of pentamidine typically preclude its use. This may be due in part to underdosing based on the salt (isethionate) versus the base.[143]

The treatment of other complex forms of CL including disseminated leishmaniasis, diffuse cutaneous leishmaniasis, and leishmaniasis recidivans should be guided by experts as treatment can be challenging and data are limited.

  • Liposomal amphotericin-B has been used with reasonable success in disseminated leishmaniasis (cure rate of 75%).[144]

  • For diffuse cutaneous leishmaniasis, the Pan American Health Organization recommends treatment in a referral centre and lists pentavalent antimonial compounds, pentamidine, or miltefosine as potential options.[145] However, cure in these patients can be challenging to achieve.

  • Leishmaniasis recidivans can be frustrating to treat.[8] One potential regimen combines a pentavalent antimonial compound with allopurinol for 30 days.[146] Liposomal amphotericin and miltefosine are often used.

Pregnant patients

  • Treatment of simple and complex cutaneous disease in pregnant patients is highly individualised. If possible, treatment should be deferred until after pregnancy, even exophytic lesions; however, there may be an increased risk of preterm birth and stillbirth in untreated CL patients.[147]

  • Theoretical concerns for transplacental transmission of CL exist based on studies in mice, but this has not been reported in humans.[148]

  • Local therapies are generally preferred to systemic therapies if possible, noting that intralesional therapies can lead to systemic absorption.

  • Amphotericin-B is the preferred agent if systemic therapy is required due to its relative safety compared with other options.

  • Pentavalent antimonial compounds have increased risks of miscarriage and early delivery, generally precluding their use during pregnancy.

Mucosal leishmaniasis

Patients with ML should always receive treatment with systemic therapy. Robust data are limited and treatment efficacy varies, requiring an individualised approach to therapy. Options for therapy include pentavalent antimonial compounds, amphotericin-B formulations, miltefosine, and pentamidine. The Pan American Health Organization classifies the evidence of all options as low or very low, but gives its strongest recommendation to pentavalent antimonial compounds.[145][149]​ The US guidelines do not stratify among the alternatives other than classifying pentamidine as a lesser alternative.[8]

  • Pentavalent antimonial compounds are a reasonable first choice in patients able to tolerate the course. Efficacy varies from 58% with sodium stibogluconate to 88% with meglumine antimonate. Some studies have added adjuncts such as pentoxifylline or interferon-gamma, but evidence for this is weak.[124]

  • Amphotericin-B formulations are an alternative, particularly for treatment failure, relapse, or intolerance of pentavalent antimonial compounds. Liposomal amphotericin-B has less data, but is preferred when available in light of better safety and tolerability.[8] In a retrospective series from Brazil, the cure rate was 93% for patients treated with liposomal amphotericin-B.[150]

  • If this treatment fails, miltefosine can be used, but cure rates are low apart from in clinically mild disease.[151]

Pregnant patients

  • Amphotericin-B is preferred due to the better safety profile.

Visceral leishmaniasis: general principles

The main objective of treatment is prevention of death and achievement of long-term clinical cure. Eradication of parasites is unlikely in most patients, as evidenced by disease reactivation years after initial clinical cure and by the post-treatment persistence of parasites in a significant proportion of patients when highly sensitive detection methods (e.g., polymerase chain reaction) are used.[82][152]

As in CL, there are parasite factors (often corresponding to species and/or geographical region) and host factors that should be considered when determining a treatment course for an individual. All patients with symptomatic disease should be treated. It is unknown whether the treatment of latent VL infection would prevent the development of symptomatic disease and it is not recommended, especially in light of the toxicities of available treatments.

In addition to the treatment of Leishmania, management must address frequent complications such as volume depletion, malnutrition, anaemia, and concomitant bacterial infections (e.g., pneumonia) or parasitic infections (e.g., malaria).

Visceral leishmaniasis: treatment in immunocompetent patients

Amphotericin-B formulations

  • Outside of East Africa, liposomal amphotericin-B is the treatment of choice, with clinical cure in >90% with varying regimens.[8][107][138]

  • For L donovani in India, liposomal amphotericin-B was demonstrated to be reasonably safe and had a 96% cure rate in clinical trials.[153] Multiple subsequent studies including over 2500 patients treated with liposomal amphotericin-B across South Asia have shown similar or higher efficacy.[154][155][156][157][158]

  • In East Africa, higher doses of liposomal amphotericin-B are required to treat L donovani and have achieved a clinical cure in >90% despite most of these patients being complex (e.g., pregnancy, relapse, advanced disease, or extremes of age).[159][160]

  • Leishmania infantum (also known as Leishmania chagasi) is also preferentially treated with liposomal amphotericin-B.[138] Most efficacy data are from the Mediterranean region, but a study in Brazil supports the use of liposomal amphotericin-B over pentavalent antimonial compounds and modelling demonstrates the cost-effectiveness of this approach.[161][162]

Combination therapy

  • The combination of pentavalent antimonial compounds with paromomycin is highly effective for the treatment of VL due to L donovani in East Africa, with cure rates of 90% to 95%.[160][163] This drug combination should not be used in patients >50 years of age or those with HIV due to decreased cure rates of 81% and 56%, respectively.[163] As parenteral paromomycin is not available in Europe or the US, it is unusual to see this regimen used outside of East Africa.

  • In South Asia, the combinations of liposomal amphotericin-B with short courses of miltefosine or paromomycin, or miltefosine with paromomycin, are highly effective alternatives to amphotericin-B.[157][158][164]

Other monotherapy options

  • Miltefosine monotherapy is an alternative option. In South Asia, initial results were excellent, but after 10 years of use a decline in efficacy was observed and now use is generally as an alternative or in combination with other drugs. Effectiveness of monotherapy in East Africa and South America is also suboptimal.[138]

  • Pentavalent antimonial compounds can be used for L donovani in East Africa, or in L infantum with decent efficacy, but they are considered second-line when other options are not available. Drug resistance in South Asia precludes their use in the subcontinent.[107]

  • While paromomycin monotherapy has been demonstrated as 95% to 98% effective when compared with amphotericin-B or as a single arm in South Asia in limited studies, other safer and equally efficacious options make this a lower-tier option even in areas where it is available.[165][166]

Patients who do not respond to, or who relapse after, initial therapy should receive full treatment with an anti-leishmanial drug (or a combination of anti-leishmanial drugs) from a different class. However, if the initial treatment was with liposomal amphotericin-B, retreatment with amphotericin-B, potentially at higher total doses, is appropriate.[8][107]

Pregnant patients

  • Treatment is essential, because untreated VL can be fatal to both mother and fetus.

  • Limited data suggest that liposomal amphotericin-B is a safe and effective treatment option.[8][119]

  • Use of pentavalent antimonial compounds in pregnancy should generally be avoided due to an increased risk of miscarriage or preterm delivery, and there are no safety data on paromomycin in pregnancy.[8] However, if no other options are available, treatment with these medications (alone or in combination) may be an option under expert guidance only.

  • Miltefosine must be avoided due to fetal risk.

Visceral leishmaniasis: treatment in immunocompromised patients

Immunocompromise among VL patients is most commonly due to HIV co-infection followed by iatrogenic immunosuppression (e.g., solid organ transplant recipients). Immunocompromising conditions not only increase the risk of developing symptomatic disease but also decrease the chance of initial cure while increasing the risk of relapse.[167][168] A comprehensive approach of treating the parasite, managing immunosuppression, monitoring for relapse, and, potentially, administering secondary prophylaxis is essential.

HIV/AIDS

  • Lifelong antiretroviral therapy should be initiated or continued in all patients with HIV infection according to current local guidelines.

  • Liposomal amphotericin-B is generally regarded as the best option for patients with VL and HIV infection.[8][169]​​[170] A higher total dose is used in patients who are immunocompromised. However, even with higher doses, treatment can be unsatisfactory and relapse is common. A published trial in East Africa showed only a 55% efficacy for liposomal amphotericin-B monotherapy among patients with a median CD4 count of 69 cells/microlitre.[171]

  • Combination therapy should be considered in this context. In the trial of liposomal amphotericin-B in East Africa discussed above, the second arm showed 88% efficacy with the combination of liposomal amphotericin-B and miltefosine among patients with a median CD4 count of 54 cells/microlitre.[171] In India, the combination of miltefosine and liposomal amphotericin-B was associated with 96% efficacy compared to miltefosine monotherapy at 85%.[172] The combination of sodium stibogluconate and paromomycin, highly effective in non-HIV-co-infected East Africans, had only a 56% cure rate and probably should be avoided unless it is the only option.[163] The World Health Organization (WHO) suggests liposomal amphotericin-B plus miltefosine over liposomal amphotericin-B monotherapy in people with HIV co-infection in East Africa and South East Asia.[62]

  • Pentavalent antimonial compounds are an alternative in patients with HIV infection; however, increased mortality has been observed when compared with amphotericin-B, and higher rates of severe adverse reactions have been observed.[173][174][175]

Secondary prophylaxis in HIV/AIDS

  • Secondary prophylaxis with anti-leishmanial drugs should be given to all patients with a CD4 count <200 to 350 cells/microlitre (the higher CD4 cut-off is recommended by the Pan American Health Organization) due to the high risk of relapse.[8][145][169][170]​ There is no consensus on the best regimen, but guidelines do recommend various options.

  • A prospective study of pentamidine prophylaxis in East Africa had a 46% relapse rate at 1 year among those with CD4 counts <200 cells/microlitre compared with an historically observed relapse rate of 60% to 70% when prophylaxis was not used.[176]

  • It is unclear when secondary prophylaxis should end. Some guidelines suggest stopping after CD4 counts reach >200 to 350 cells/microlitre, whereas others recommend indefinite therapy as the risk for relapse continues. Regardless, careful monitoring for relapse is essential in all patients with HIV infection.[8][169]

  • In East Africa, relapse rates have been shown to be high even among those with CD4 counts >200 cells/microlitre, with history of prior relapse being a significant predictor of future relapse or death.[176]

  • In East Africa, a 37% relapse rate was observed over a 2 year follow-up after 12-18 months of pentamidine prophylaxis, mainly in those with a low basilar CD4 count.[177]

Other forms of immunosuppression

  • Includes solid organ transplant patients, lymphatic or haematological malignancy, or treatment with immunosuppressants for other indications.

  • If patients are on immunosuppressants for other indications, consider decreasing the dose or stopping these medications, if possible, although this is based on expert opinion and not on strong data.[168]

  • Treatment has been accomplished with multiple regimens, but liposomal amphotericin-B is recommended, particularly in solid organ transplant patients.[8][145]

  • While relapse is common, particularly among solid organ transplant patients (approximately 25%), data are not clear on the role of secondary prophylaxis. The IDSA/ASTMH guidelines recommend against secondary prophylaxis among those without a prior relapse, but in a small retrospective case-control study, risk of relapse decreased by 27% among those on secondary prophylaxis.[8][178] Consider secondary prophylaxis on an individual basis, especially among patients with a history of prior relapse for whom the immunosuppressive condition is ongoing.

Among all immunosuppressed patients who relapse, treatment with liposomal amphotericin-B is reasonable, even among those who received this as primary therapy, because failure in this setting is thought to be immunological rather than a result of drug resistance. Alternatively, other options or combination therapies can be tried.[8]

Pregnant patients

  • Treatment is essential because untreated visceral leishmaniasis can be fatal to both mother and fetus.

  • Limited data suggest that liposomal amphotericin-B is a safe and effective treatment option.[8][119] The other forms of amphotericin may be used if liposomal amphotericin is unavailable.

Post-kala-azar dermal leishmaniasis

There are few controlled studies on the management of post-kala-azar dermal leishmaniasis. Mild-to-moderate post-kala-azar dermal leishmaniasis (PKDL) self-heals in the majority of patients of East African descent within 3 to 12 months. Treatment is indicated for East African patients with severe or non-self-healing PKDL, in Indian PKDL, and in patients who are immunocompromised.[6]

  • In South Asia, miltefosine is the recommended first-line treatment for PKDL.[170] A meta-analysis demonstrated concern for declining efficacy, which is being observed even at 12 weeks of therapy, and concerns for safety (e.g., ocular disorders including blindness, ulcerative keratitis, blurred vision, photophobia) with longer courses of treatment.[179][180]

  • Amphotericin-B is considered second-line in South Asia.[170] Liposomal amphotericin-B has shown some efficacy in limited studies in the region.[181][182] However, molecular analysis demonstrated resurgence of parasites 6 months after treatment with liposomal amphotericin-B, but not with miltefosine.[183]

  • In India, combination liposomal amphotericin-B and 45 days of miltefosine therapy showed 100% efficacy versus 90 days of miltefosine monotherapy (75% efficacy).[184]

  • When treatment is required in East Africa, pentavalent antimonial compounds are still being used commonly.

Pregnant patients

  • Liposomal amphotericin-B is preferred due to safety concerns, particularly with miltefosine and pentavalent antimonial compounds.

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