This document discusses the pharmacotherapy of cutaneous leishmaniasis. It provides details on the various treatment options including topical, intralesional, and systemic treatments. Topical treatments discussed include paromomycin ointment, imiquimod cream, and topical amphotericin B. Intralesional options include sodium stibogluconate and meglumine antimoniate injections. Systemic treatments include oral azoles like fluconazole, miltefosine, and pentavalent antimonials administered intravenously or intramuscularly. Drug combinations with antimonials are also used to enhance efficacy.

1. Pharmacotherapy of
Cutaneous Leishmaniasis
Dr. Karabi Adak
MBBS, MD

2. ---Kala azar is a deadly disease caused by the parasitic
protozoa Leishmania donovani and transmitted to
humans by the bite of infected female sand fly,
Phlebotomus argentipes.
Historical Landmarks of kala-azar & its Indian
connection-
■ The name ‘Kala-azar’ came from Sanskrit.
■ ‘Delhi boil’---- for cutaneous form of Leishmaniasis.
■ Kala-azar in Assam (Assam fever)- was first identified
by Clarke in 1882.
■ McNaught, a Civil Medical Officer of Tura,of Garo Hills
district in Assam called this disease ‘Kala-hazar’.

3. ■ William B. Leishman reported in 1900, of peculiar bodies in the
spleen pulp of a soldier who died of Dum-Dum Fever at Netely
Hospital.
■ Published in British Medical Journal in 1903 “On the Possibility of
the Occurrence of Trypanosomiasis in India”

4. ■ In July 1903, Charles Donovan reported the finding of similar
bodies from the spleen of patients suffering from prolonged fever
with splenomegaly in Madras. described them as new parasite not
Trypanosomiasis.

5. ■ The link between these organisms and kala azar was eventually
discovered by Ronald Ross----named them as Leishmania
donovani in November,1903.

6. Kala-Azar: The Indian Scenario
■ In India, it is a serious problem in Bihar, West Bengal
and eastern Uttar Pradesh.
■ Lymphadenopathy is a major presenting feature in
India.
■ The widespread co-existence of malaria and kala-
azar in India---- difficulty in diagnosis and treatment.
■ Organism developing resistance to antimony
compounds (main drug for treatment) in India.

7. Life Cycle

8. Cutaneous Leishmaniasis: Epidemiology
■ There are 1-1.5 million cases of cutaneous leishmaniasis
reported yearly world wide. There has been a sharp increase
in recorded cases over the last 10 years.
■ More than 90% of cutaneous disease occurs in Afghanistan,
Peru, Brazil, Iran, Saudi Arabia and Syria.
---Epidemiology of visceral leishmaniasis in India. Bora D. Helminthology Division, National Institute of Communicable Diseases, New
Delhi, India. Natl Med J India. 1999 Mar-Apr;12(2):62-8.

9. ■ Old World Leishmaniasis ---India/Middle
East/Africa.
--- benign, self-limiting
■ New World Leishmaniasis ---Latin America/North
America/Europe
---Broad spectrum of
conditions benign to
severe
manifestations,
including mucosal
involvement.
---Complexity of Treating New World Cutaneous Leishmaniasis. Byron Arana; Center for Health Studies. Universidad del Valle – Guatemala,

10. Prevalence of Leishmaniasis
*2018, Lancet

11. ■ Cutaneous Leishmaniasis----- often self-limiting, can result
in significant scarring / invasive, mucocutaneous disease.
Therefore, treatment may be considered to prevent these
complications.
■ Cutaneous leishmaniasis -----L. major & L.tropica
■ Visceral leishmaniasis ---L. infantum & L donovani

12. Risk Factors For Cutaneous Leishmaniasis
■ Rural >> urban.
■ Ecologic region: rainforests to arid regions.
■ Dusk to dawn (sand flies typically feed / bite at night and
during twilight hours). Sand flies do not make noise, they are
small (one-third the size of mosquitoes), and their bites might
not be noticed.
■ Travelers like ecotourists, adventure travelers, bird watchers,
soldiers, construction workers.

13. Clinical Presentation:
■ Skin lesions---occur weeks/ months after exposure.
■ Small papules to nodular plaques, ulcer, can be covered with
scales /crust. The lesions usually----painless / painful (if
infected)
■ Satellite lesions, regional lymphadenopathy.
■ The lesions heal eventually, even without treatment------
ultimately result in scarring.

15. Diagnostic tools:
■ Cutaneous scraping
■ Punch biopsy
■ Needle aspirate
■ Immunologic tests
■ PCR–species identification
■ Skin test

16. Post Kala-azar Dermal Leishmaniasis
(PKDL)
■ Recurrence in----untreated/ partially treated/even in some
adequately treated. Can occur up to 20 years after
treatment.
■ Can be hypo-pigmented macules, papules, nodules, or facial
erythema.
■ It is commonly associated with L. donovani.
■ Sodium stibogluconate alone or in combination with
Rifampicin is used for a course up to 4 months.

17. Mucocutaneous Leishmaniasis
■ Parasites spread from the skin to the mucosa of the
nose/mouth.
■ Most feared form---- produces destructive & disfiguring
lesions of the face.
■ Mainly caused by Leishmania braziliensis.
■ Treatment: long courses(30 days) of pentavalent antimonials
(20 mg/kg).
■ Combination of pentoxifylline (inhibitor of TNF-α) and a
pentavalent antimonial can also be tried.

18. When to Treat Cutaneous Leishmaniasis?
■ Cosmetically unacceptable lesions
■ Chronic lesions
■ Large lesions
■ Lesions in immunosuppressed/HIV patients
■ Lesions over joints
■ Mucosal disease
■ Multiple lesions
■ Nodular lymphangitis
■ Worsening lesions

19. Salient features about Treatment
■ Establish the species of leishmania by PCR prior to starting
treatment.
■ Leishmania major infections----heal spontaneously, do not
require treatment, but Fluconazole 200 mg/day for 6wk----
enhance healing.
■ Leishmania braziliensis---pentavalent antimonials
/Amphotericin is mandatory, due to risk of developing
mucocutaneous lesions.
Treatment options outlined for cutaneous leishmaniasis. by Elizabeth Dodds Ashley; Pharmacology Consult; Posted December
1, 2005.

20. Topical treatments and intralesional injections:
■ Intralesional injections of pentavalent antimony compounds-
--Sodium stibogluconate
--Meglumine antimoniate.
■ WHO recommends---1–3ml inj. under the edges of the lesion
until the surface has blanched. It is given every 5–7 days, for a
total of 2–5 times.

21. Other intra-lesional injections:
■ Local injections of-
---Hypertonic sodium chloride solution
---Zinc sulphate
■ Excision is not recommended because of the high risk of
local relapse and disfiguration.
Topical treatment for cutaneous leishmaniasis. Tracy Garnier & Simon L Croft. Current Opinion in Investigational Drugs 2002 3(4): PharmaPress ISSN
1472-4472.

22. Paromomycin ointments
■ Topical preparations available for cutaneous leishmaniasis are-
--
--15% paromomycin sulphate dissolved in a soft white
paraffin base in Methyl-benzothenium chloride or Urea.
■ The efficacy of the two ointments in cutaneous leishmaniasis,
per day for 10–30 days varies from 74% to 86%.
--Topical treatment for cutaneous leishmaniasis. Tracy Garnier & Simon L Croft. Current Opinion in Investigational Drugs 2002 3(4): PharmaPress ISSN
1472-4472.

23. Imiquimod
■ This is an immune response modifier that targets
preferentially monocytes and macrophages.
■ Imiquimod demonstrates a leishmanicidal activity by releasing
of nitric oxide.
■ Imiquimod 5% cream every other day for 20 days upto 8
weeks is recommended.
REVIEW- Cutaneous leishmaniasis treatment. Philippe Minodiera,, Philippe Parolab. Travel Medicine and Infectious Disease (2007) 5, 150–158. Available
at www.sciencedirect.com.

24. Topical amphotericin B
■ Colloidal dispersion of amphotericin B and cholesteryl
sulphate can also be tried as an alternative in cutaneous
leishmaniasis.
■ It is mainly effective in L. major species.
Cryotherapy
■ Cryotherapy with liquid nitrogen two cycles of 10–30 sec
freezing time are sufficient for L.tropica lesions.
Cutaneous Leishmaniasis: Recognition and Treatment. William H. Markel, And Khaldoun Makhoul. Downloaded from the American Family

25. Localized controlled heat
■ ThermoMeds is an FDA-approved device that delivers
localized radiofrequency-generated heat directly to a
lesion through prongs placed onto it.
■ Heat may be controlled locally and 500C for 30 sec are
used.
■ The procedure is painful and requires local anesthetic.
Localized controlled heat was found to be as effective as
meglumine antimoniate in some cases.
Cutaneous Leishmaniasis: Recognition and Treatment. William H. Markel, And Khaldoun Makhoul. Downloaded from the American Family Physician Web site at
www.aafp.org/afp. Copyright© 2004 American Academy of Family Physicians.

26. CO2 laser
■ Used to vaporize cutaneous leishmaniasis lesions.
■ A power of 30W (maximum 100 W) and a pulse width of 0.5–5
s, until the ulcer bed turned brown.
Photodynamic therapy
■ A 10% d-aminolevulinic acid (porphyrin compounds) emulsion
is locally applied for 4 hr. Then, irradiation was done using
570–670 nm red light. Treatment is repeated weekly.
REVIEW- Cutaneous leishmaniasis treatment. Philippe Minodiera,, Philippe Parolab. Travel Medicine and Infectious Disease (2007) 5, 150–158.
Available at www.sciencedirect.com.

27. Peter J. Weina, et al has suggested criteria for
starting systemic therapy-----
■ Lesions on the face/ear/cosmetically evident areas
■ Lesions have not healed for many months
■ Lesions over the joints
■ Lesions are present on the hands & feet
■ Local evidence of dissemination
■ Immunocompromised hosts
■ Multiple lesions (more than 5)
■ Large lesions (>4 cm)

28. Oral treatments: Azoles
■ Certain azole antifungal drugs inhibit ergosterol synthesis of
Leishmania parasites.
■ Ketoconazole (600 mg/d X 1month). Poorly tolerated. Not
used commonly. Broad spectrum.
■ Fluconazole (200 mg/d for 6 wk), commonly used.
■ Itraconazole (100–400 mg/d). Better tolerated than
ketoconazole, but more treatment failures.
Fluconazole For The Treatment Of Cutaneous Leishmaniasis Caused By Leishmania Major. A. Bdulrahman AA, Lrajhi, E. Lfaki et al. N
Engl J Med, Vol. 346, No. 12; March 21, 2002.

29. Azithromycin
■ It concentrates in tissues especially in macrophages that are
infected by Leishmania parasites.
■ Its oral administration, its long half-life, and its safety in
children is advantage for the treatment of leishmaniasis.
REVIEW- Cutaneous leishmaniasis treatment. Philippe Minodiera,, Philippe Parolab. Travel Medicine and Infectious Disease (2007) 5,
150–158. Available at www.sciencedirect.com.

30. Oral zinc sulfate
■ Sensitivities of L. major and L. tropica strains to zinc was
reported to be higher than those to pentavalent Antimony.
■ It is also delivered intralesionally with success in cutaneous
leishmaniasis.
■ Mechanisms of action are--- direct antileishmanial effect,
immunomodulatory effect, effect on macrophages function
and wound-healing effect.
REVIEW- Cutaneous leishmaniasis treatment. Philippe Minodiera,, Philippe Parolab. Travel Medicine and Infectious Disease (2007) 5, 150–
158. Available at www.sciencedirect.com.

31. Miltefosine
■ It’s a new treatment option that has recently been approved
for use in Columbia, Germany and India for treatment of
leishmaniasis.
■ This phospholipid agent was originally developed as a
therapeutic agent for breast cancer.
■ Miltefosine is an oral antitumor agent, that interferes with
cell signal-transduction pathways and inhibits phospholipids
and sterol biosynthesis.

32. ■ In India, Miltefosine (2.5 mg/kg/d for 28 days) is given
in leishmaniasis due to L. donovani.
■ Miltefosine was successfully used in an HIV infected
patient with a L. major diffuse cutaneous leishmaniasis.
■ It is not, however, without adverse effects. Elevated
transaminases and reproductive health risks do occur.

33. IM / IV drugs: Systemic antimonials
■ Systemic antimonials are generally required for the
treatment of cutaneous leishmaniasis because of the risk of
mucosal involvement.
■ WHO recommendations are 10–20 mg pentavalent
antimony/kg/day dose for 20 days, and for 30 days in
patients with mucous involvement.

34. ■ Meglumine antimoniate (Glucantime)
Dosage: 20 mg/ kg/ day for 20 days.Cure rate: around 94
percent . Eliminated by kidneys.
■ Stibogluconate
It is supplied as 100 mg/mL solution.
Dose is: 12-20 mL which is diluted in 50 mL of 5% dextrose,
infused IV over 10-15 minutes.
ADR of antimonials--- pancreatitis, hepatitis, marrow
suppression, QT prolongation, myalgias, fatigue, headache,
rash, nausea.

35. Drugs Combinations With Antimonials
■ In order to enhance the efficacy of antimony, combinations
with other drugs have been used.
■ Combination of antimony (20 mg/kg/d) and Allopurinol (20
mg/kg/d) have been proposed in cases nonresponsiveness to
antimonial drugs.
■ Oral Pentoxifylline (400 mg/day) plus pentavalent antimony
(15–20 mg/kg/d) for a month can be tried.
Treatment options outlined for cutaneous leishmaniasis. Elizabeth Dodds Ashley, PharmD, BCPS. Pharmacology Consult; Posted December
1, 2005.

36. Pentamidine
■ Pentamidine was used in visceral leishmaniasis treatment for
years, also can be tried in cutaneous leishmaniasis---
■ Two IM injections (days 1 and 4) of 4 mg/kg pentamidine-base
(7 mg/kg Pentacarinats) are used
OR
2 mg/kg IM every other day for 7 days.

37. Amphotericin B
■ Liposomal amphotericin B replaces antimony in the
treatment of pediatric VL due to L.infantum. Its role in
cutaneous leishmaniasis is still controversial.
■ Reserved for antimony failures, 2nd line drug.
■ Dosage: 0.5-1 mg/kg every other day for up to 8 wks; total
dosage is 1.5-2 g for the treatment period

38. Rifampicin
■ Rifampicin 1200mg/day for 4 weeks can heal cutaneous
leishmaniasis.
■ The effect of rifampicin is through its property of blocking
RNA synthesis by specifically binding and inhibiting DNA
dependent RNA polymerase.
---The role of Rifampicin in the management of cutaneous leishmaniasis. Kocher DK, Aseri S, Sarma BV. Q J Med, 2000; 93,
733-737.

39. Other treatment modalities
(contradictory study results)
■ Antibiotics-- kanamycin and gentamycin.
■ Immunomodulators including BCG, IFNγ and Colony
Stimulating Factors have been used.
■ Emetine, metronidazole, co-trimoxazole.
■ Vaccine-- (killed Leishmania organism with BCG as an
adjuvant) have also yielded promising results.
-- REVIEW- Cutaneous leishmaniasis treatment. Philippe Minodiera,, Philippe Parolab. Travel Medicine and Infectious Disease (2007) 5, 150–158. Available at
www.sciencedirect.com.

40. Advice/Precaution to Travelers
■ Avoid outdoor activities from dusk to dawn--- most active
time of sand flies.
■ Wear protective clothing/Apply insect repellent.
■ Sleep in air-conditioned or well-screened areas. Fans or
ventilators may also help.
■ Sand flies are small (2–3 mm)----can pass through holes in
ordinary bed nets. Effectiveness of nets can be enhanced by
treatment with Permethrin.
---Infectious Diseases Related To Travel. Barbara L. Herwaldt,
Alan J. Magill.

41. Conclusion:
■ Limited treatment options available----its important for
clinicians to understand the available agents.
■ Selection of therapeutic agent depends on the potential
treatment benefit vs. toxicities, no one is better than the
other.
■ The prognosis is related to the species.
■ The lack of comparative studies of treatment hinders
consensual recommendations.