Treatment of Leishmaniasis

Abstract

Treatment of Leishmaniasis is always not satisfactory despite advancement all these years. This chapter will discuss the standard treatment options like Amphotericin, oral miltefosine, topical paromycin, add more details about newer emerging drugs and alternative therapies, surgical treatment modalities for resistant cases. Will discuss few information regarding vaccines. Special precautions to be taken while travelling to endemic areas will be discussed. Management protocol for mucocutaneous and visceral type will be highlighted. Side-effects of drugs used in the treatment of Leishmaniasis will be discussed in short and measures to monitor these side effects will be discussed. Long term monitoring of relapse will also be discussed.

1. Introduction

The main goal of treatment is parasite eradication and clinical healing. Generally, parasite eradication is seen long before clinical re-epithelialization. Treatment for each case varies so it needs to be individualised depending upon various factors affecting the treatment outcome [1] (Table 1). The clinical manifestation of leishmaniasis can be broadly classified as cutaneous and visceral types. In this chapter, treatment for various clinical manifestations will be discussed in detail.

Host	Agent	Environment
Age of patient	Various species of parasite	Geographic region (endemicity)
Immune status	Drug resistance	Cost and availability of treatment
Nutritional status	Tissue tropism
Genetic background
Presence of intercurrent disease (e.g.; HIV infection)
Site and severity of infection
Toxicity of therapeutic options

Table 1.

Factors affecting the treatment outcome.

2. Treatment of leishmaniasis

Choice of treatment depends on the clinical presentation. Treatment options vary from a mere observation in spontaneously healing lesions, topical/local therapy and parenteral treatment.

Old world leishmaniasis caused by Leishmania major resolves spontaneously in 2–4 months whereas Leishmania tropica resolves by 6–15 months. New World leishmaniasis caused by resolves spontaneously in 3–4 months in 75% of cases [2]. Single lesions can be managed with local treatment options like heat therapy, cryotherapy and topical preparations. For cutaneous and mucocutaneous lesions, the drugs of choice are pentavalent antimony and miltefosine. Amphotericin B is considered the drug of choice for visceral leishmaniasis (Table 2).

Cutaneous leishmaniasis
Drugs of choice	Sodium stibogluconate Miltefosine
Alternatives	Systemic; Liposomal amphotericin Amphotericin B Pentamidine Fluconazole Topicals -; Paromomycin 15% and MBCL 12% ointment Paromomycin 15% and gentamicin 0.5% cream Heat therapy Cryotherapy with liquid nitrogen Intralesional Alternatives; sodium stibogluconate (Pentostam) meglumine antimoniate (Glucantime)
Mucocutaneous leishmaniasis
Drugs of choice	Sodium stibogluconate; Liposomal amphotericin; Amphotericin B; Miltefosine
Alternative	Pentamidine
Visceral leishmaniasis
Drugs of choice	liposomal amphotericin B
Alternatives	Miltefosine; Paromomycin; Pentavalent antimonials; Amphotericin B

Table 2.

Treatment recommendations for leishmaniasis.

3. Indications of systemic treatment

1. Lesions over face, genitalia, over joints

2. Mucosal lesions

3. Immunocompromised host

4. Single lesion >5 cm in size

5. > 4 lesions (~1 cm in size)

6. Persistent, progressive, deep, sporotrichoid, and secondarily infected lesions

7. Markedly enlarged lymph nodes

8. New World leishmaniasis caused by Leishmania braziliensis complex

Drugs used in systemic treatment

4. Pentavalent antimonials

The pentavalent antimonials [3] are the drug of choice for the treatment of cutaneous leishmaniasis (both old world and new world). Given as a single daily dose via the intravenous or intramuscular route. It is used only in areas (East Africa, Central Asia and South America) where the species causing the disease are still sensitive to this drug.

4.1 Drugs and dose

Sodium stibogluconate (Pentostam) IM/IV 20 mg/kg/day for 15 to 20 days.

Meglumine antimoniate (Glucantime) IM/IV 20 mg/kg/day for 20 days.

4.2 Mechanism of action

Leishmania amastigote converts the pentavalent form of SSG to a toxic trivalent form by a specific reductase enzyme. This in turn promotes the efflux of glutathione and reduced thiols within the parasite and increases oxidative damage. Other action includes inhibition of glycolysis and oxidation of fatty acids of the parasite. Accumulation of SSG within macrophages is responsible for its prolonged inhibitory action against the parasite.

4.3 Adverse events

The most serious side effects are cardiotoxicity and nephrotoxicity. Most patients on antimony will develop pancreatitis (either subclinical or severe abdominal pain). The dose-dependent side effects include pain at the injection site, myalgia, hepatitis, bone marrow suppression, QT prolongation, headache, fatigue, rash, and nausea, vomiting, metallic taste. These problems resolve with a reduction in the dose of antimonial. Other side-effects include sterile abscess, stiffness in the injected muscle, mental symptoms.

Relative contraindication: >60% resistance is seen in species in India and Nepal, hence not used as a first-line drug.

5. Oral miltefosine

This drug [4] is a derivative of alkyl phosphocholine with potent activity against leishmaniasis. It is the FDA-approved drug for the treatment of mucosal and visceral leishmaniasis due to L. braziliensis, Leishmania guyanensis, and Leishmania panamensis.

Dose (Table 3).

Weight	Dose
Adult >50 kgs	150 mg/day
Adult >12 years weighing >25 kgs	50 mg BID
Adult >12 years weighing <25 kgs	50 mg OD
Children (2–11 years)	2.5 mg/kg/day (as 10 mg capsules)

Table 3.

Dose of miltefosine according to age and bodyweight.

Available as 10 and 50 mg capsules.

Dose-1.5 to 2.5 mg/kg/day for 28 days orally up to 150 mg/day.

5.1 Mechanism of action

As a phosphocholine analogue, it is thought to interfere with cell-signalling pathways, and it may interfere with parasite lipid biosynthetic enzyme synthesis. Mutation limiting the transport of drug into cell membrane can cause resistance to its action. This can be overcome by combination treatment with liposomal Amp B or paromomycin.

5.2 Adverse events

Diarrhoea, anorexia, nausea, vomiting, reproductive toxicity in animals. These are common reactions during the first week of treatment so the drug should be taken in divided doses with meals to diminish nausea, vomiting, diarrhoea. Miltefosine is known to cause reversible nephrotoxicity and hepatotoxicity, hence monitoring (once a week) of renal and liver function tests is recommended during the treatment period.

5.3 Contraindications

Pregnancy (teratogenic) and lactation. The female patient should avoid pregnancy during and till 3 months after stopping treatment.

6. Amphotericin B (AMB)

Amphotericin B [5] is the first-line drug for visceral leishmaniasis and the second choice of drug for mucocutaneous leishmaniasis. Can be used in leishmaniasis associated with HIV disease, pregnancy and breastfeeding patients.

6.1 Dose and formulations

This drug is available in two forms- a less expensive formulation with deoxycholate (AMB-DOC) and a highly expensive form incorporated with liposomes (L-AMB). Since the toxicity is less with L-AMB it is most commonly used for treatment and research purposes.

6.2 Dose of L-AMB

Indian subcontinent: 10 mg/kg or 3 mg/kg/day for 5 consecutive days (total 15 mg/kg).

Mediterranean region: Two infusions of 10 mg/kg for children was found to be successful.

Other regions: Total dose of 18-21 mg/kg.

6.3 Mechanism of action

Binding to sterols present in parasite’s membrane causing a change in permeability. This drug highly concentrates in the reticuloendothelial cells in the spleen and liver, hence best suited for visceral leishmaniasis.

6.4 Adverse events

Infusion reaction like fever, chills, pain all over the body, dyspnoea occurs due to raised cytokines levels of Interleukin and TNF- alpha. Other side effects of amphotericin include nephrotoxicity, hypokalaemia and anaemia. Liposomal amphotericin is less toxic than amphotericin.

7. Paromomycin

It is an [6] aminoglycoside antibiotic that has been tried in the treatment of visceral leishmaniasis in India and Africa. It shows a promising cure in areas with species resistant to SSG. Moreover, it is less expensive, easy to administer than AMB.

Dose: 11 mg/kg/day given as intramuscular injection for 21 days.

Adverse drug effect: ototoxicity, injection site pain, the reversible elevation of serum transaminase, renal toxicity (rare).

Adverse effects and laboratory monitoring of the above mentioned drugs has been discussed in (Table 4).

Drug	Adverse events	Laboratory Monitoring for toxicity
Amphotericin B	Infusion related reactions, hypokalaemia, hypomagnesemia, nephrotoxicity and anaemia	CBC, RFT, LFT, serum electrolytes. ECG and urinalysis –baseline and twice weekly.
Liposomal amphotericin B	Same as above but better tolerated than amphotericin B. Infusion related reactions to liposomal amphotericin B also can be caused by pseudollergy due to liposome-induced complement activation	Same as above
Pentavalent antimonials: sodium stibogluconate meglumine antimoniate	Myalgia, large joint arthralgia, headache, malaise, fatigue, anorexia, nausea commonly noted as treatment progresses. Laboratory abnormalities are usually reversible includes elevated Aminotransferases, lipase/amylase values. ECG abnormalities (e.g. Non-specific ST-T wave changes, QTc prolongation) Pancytopenia	Baseline and weekly monitoring of serum chemistry values; (Aminotransferases, lipase/amylase, potassium, creatinine, BUN, glucose), CBC and ECG
Miltefosine	GI symptoms, dizziness/motion sickness, scrotal pain, decreased or absent ejaculate, nephrotoxicity, hepatotoxicity	Renal function, hepatic function and CBC –baseline and weekly monitoring

Table 4.

Adverse effects and laboratory monitoring of major anti-leishmanial drugs.

8. Combination therapy

A combination of two drugs [7] in the treatment of leishmaniasis has been tried to overcome the drug resistance, to achieve higher efficacy and cure rate, for better compliance and to reduce the overall dose, cost and side effect of each drug.

The following 3 combinations have been tested in various studies:

1. L-AMB (5 mg/kg daily as single i.v dose) + oral miltefosine daily for 7 days

2. L-AMB (5 mg/kg daily as single i.v dose) + Paromomycin (i.m) daily for 10 days

3. Oral miltefosine daily for 7 days + Paromomycin (i.m) daily for 10 days

9. Other miscellaneous drugs used in the treatment of leishmaniasis

Antimony resistance can be overcome by combining antimonials with paromomycin, pentoxifylline, allopurinol, IFN-γ, granulocyte-macrophage colony-stimulating factor, azithromycin and topical imiquimod.

Pentamidine

It causes the inhibition [8] of the active transport system and the mitochondrial topoisomerase II which in turn leads to parasitic death.

Dose: 2 to 4 mg/kg/day IM or IV on alternate days for 4 to 7 days.

Adverse events

Hypotension and hypoglycaemia are serious side effects of this drug. Hence it is recommended in antimony-resistant/ contraindicated or when serious hepatic or cardiac side-effects occur during antimonial therapy.

Oral azoles

Mechanism of action- Azoles block ergosterol synthesis and cause the accumulation of 14-methyl sterols leading to inhibition of leishmaniasis growth.

DOSE: Fluconazole 200 mg daily for 6 weeks.

Ketoconazole 600 mg daily for 28 days (not used now).

Allopurinol

A combination of a low dose of meglumine antimoniate (30 mg/kg/day) with allopurinol (20 mg/kg/day) was found to be effective in the treatment of cutaneous leishmaniasis. The addition of allopurinol increases the antimonial effect of meglumine antimonials [9].

Doxycycline

Doxycycline, [10] though it’s not the first choice of medication, still is considered equally efficacious to pentavalent antimony. It is known to have good intracellular penetration and acts directly on the body of leishmania. Due to its anti-inflammatory effect, there will be immediate relief in signs of local inflammation. Oral route of administration, low cost, easy availability and ack of major adverse effects, make doxycycline a good alternative option in the treatment of leishmaniasis. It is given in the dose of 200 mg/day.

Azithromycin

The efficacy of [11] azithromycin is questionable. It has been used in children, pregnant females and elderly patients when other classical drugs are contraindicated. Dose of 500 mg daily for 10 days, repeated every 1 to 2 months. Total of 3–4 cycles given.

Zinc sulphate

It acts by Boosting of Th1 reaction as well as phagocytosis of parasites.

Dose-2.5 to 10 mg/kg/day orally for 30 to 40 days.

Others: Rifampicin, dapsone, terbinafine, metronidazole, cotrimoxazole, nifurtimox, quinolones, pyrimethamine, anti-IL10 has been reported in the treatment of leishmaniasis [12].

10. Drugs used in topical therapy

1. Paromomycin 15% and MBCL (methyl benzethonium chloride)12% ointment

It is applied topically twice a day for 10 days and the cycle is repeated after 10 days of the waiting period. Methlybenzethonium itself has some antileishmanial activity and it helps in the penetration of paromomycin. Topical preparation may cause local inflammation [13].

1. Paromomycin 15% and gentamicin 0.5% cream

Applied topically once a day for 20 days [14].

11. Heat therapy

This treatment [15] is done in a single session. Under aseptic precautions, the lesion is anaesthetized with 2% lidocaine. With the ThermoSurgery instrument (fork-like applicator), heat is applied at 50° C for 30 seconds. This will cover an area of 3x 4 mm. Then the applicator is moved to an adjacent area and the same heat is applied, this process is continued until the lesion is fully covered. The entire session takes about 4-5 min. The lesion should then be covered with a gauze bandage. This is FDA approved for the treatment of cutaneous leishmaniasis.

12. Cryotherapy with liquid nitrogen

Freeze (15–20 secs) thaw (20-60secs) freeze (15-20 sec) cycle is followed until 1-2 mm of normal circumferential skin is frozen. A total of 3 applications will be given once in 3 weeks.

13. Intralesional antimonial therapy

Sodium stibogluconate (100 mg antimony/ml) or meglumine antimoniate is injected into all sides of the lesion until it blanches on alternate days. A total of 10 injections is given. This treatment is combined with cryotherapy for better results [16]

Other local therapy options: Surgical excision, curettage, laser ablation, photodynamic therapy, sodium chloride (moist wound therapy), topical azoles, topical glyceryl trinitrate, topical amphotericin B, intralesional interferon-gamma and intralesional metronidazole [17].

14. Assessing response to treatment

Clinical symptoms will take time to improve in cutaneous leishmaniasis. Time taken vary from patient to patient. After effective treatment, it takes around 4 to 6 weeks for the ulcer to show signs of healing, which includes re-epithelialization, reduction in the size of the ulcer, reduction of signs of local inflammation. Healing continues till 12 weeks’ time, at which decisions about continued observation versus retreatment should be made. Because of the chances of relapse in cutaneous leishmaniasis, complete responses are not measured until 6 to 12 months after successful therapy.

15. Treatment of leishmaniasis in returned traveller

Intravenous or intralesional treatment with sodium stibogluconate and other less frequently used agents resulted in resolution for most of these patients. Avoiding blood donation for 1 year is recommended in travellers from endemic areas with a history or suspicion of leishmaniasis [18].

16. Prevention of leishmaniasis

The first step in prevention is promotion and use of personal protective measures like use of protective clothing (wear long-sleeved shirts, long pants, and socks), usage of permethrin-treated bed nets, insect repellents containing 30–35% N, N-diethyl-3-methylbenzamide (DEET); avoid visits to endemic areas; staying indoors in the evening as during this time the sandflies are most active.

17. Vaccines

Preventive [19] vaccines are the best and most cost-effective protective measure against pathogens and are saving millions of lives every year around the world. The development of the Leishmania vaccine has proven to be a difficult and challenging task, because of the inadequate knowledge of parasite pathogenesis and the complex immune responses needed for protection. Killed/live attenuated / plasmid DNA based vaccines with or without bacilli Calmette-Guerin seems to be useful in endemic areas. But none of the vaccines is FDA approved for safe prophylactic use in humans. A vaccine for dogs is available and approved.