Review

Therapy of cutaneous leishmaniasis

Samuel A. Lee(1,2) and Rodrigo Hasbun c3)

There have been many treatment modalities used for the therapy of cutaneous leishmaniasis. Although treatment
need not be given for cosmetically insignificant lesions, which are often self-limited, therapy is usually indicated for
larger, cosmetically significant and disfiguring lesions, and lesions which progress. This review summarizes the published
evidence in support of the numerous therapeutic options that have been employed for cutaneous leishmaniasis.
Int J Infect Dis 2003; 7: 86-93

INTRODUCTION bvaziliensis panamensis, and L. braziliensis guyanensis)

Leishmania species are protozoa1 parasites of the order
Kinetoplastida, which give rise to a number of distinct
clinical syndromes, ranging from self-limited cutaneous
lesions to progressive visceral disease and death. There
have been more than 20 species identified, most of which
cause zoonotic infections, but which can also cause
disease in humans in endemic areas. Numerous rodent
and canine species serve as reservoirs, and sandflies
serve as vectors. Rare cases of congenital or transfusion-
related transmission have also been reported. Cutaneous
leishmaniasis is classified into two different clinical syn-
dromes: New World if it is acquired in the Americas, and
Old World if it is acquired in Africa, Asia, the Middle
East, or Europe. This discussion will focus on reviewing
the clinical evidence supporting various options for the
treatment of cutaneous leishmaniasis (CL), particularly
the Old World form.
Epidemiology
Over 350 million people live in endemic areas, and
the WHO has estimated the prevalence of CL to be
12 million cases/year and that of CL to be 1.5-2.0 million
cases/year, although the true prevalence and incidence
may be considerably higher, due to underrep0rting.l
Old World CL is usually due to L. major, L. tropica,
or L. aethiopica? New World CL is usually caused by
members of the L. mexicana complex (L. mexicana
mexicana, L. mexicana amazonensis, L. mexicana
venezuelensis), and New World mucocutaneous leish-
maniasis is usually caused by members of the L.
bvaziliensis complex (L. braziliensis braziliensis, L.
(‘)Infectious Diseases Section, Yale University
New Haven, CT, USA; (*&‘A Connecticut Healthcare
Haven, CT, USA; (3)Infectious Diseases Section, Tulane
School of Medicine, New Orleans, LA, USA.
Address correspondence to Samuel A. Lee, Infectious
VA Connecticut Healthcare System, 950 Campbell Ave., Bldg 8 (Ill-I),
West Haven, CT 06516, USA.
E-mail: Samuel.lee@yale.edu
Corresponding Editor: Jonathan Cohen, Brighton,
(Table 1).
CL is usually sporadic in nature, but can occasionally
occur in an epidemic pattern, e.g. when large groups of
susceptible persons migrate to an endemic area (i.e.
military personnel). Old World CL due to L. major is
found in rural desert areas of central Asia, the Middle
East, and northern Africa. It causes lesions that tend
to be large and ‘wet’ in appearance. The primary
reservoir consists of desert rodents. Old World CL due
to L. tropica is endemic to urban areas of the Middle
East, the Mediterranean, India, Pakistan, and central
Asia. The lesions tend to be ‘dry’, with a central crust.
Old World CL caused by L. aethiopica is found in the
Ethiopian highlands and Kenya, where it causes both
simple CL and diffuse CL.
Pathogenesis
Leishmanial infections are transmitted via the bite of
infected female sandflies of the genera Phlebotomus,
Lutzomyia, or Psychodopygus. The parasite lives as an
extracellular, flagellated promastigote in the gut of the
insect. After multiplication and differentiation in the
sandfly gut, approximately 1 week later the infectious
promastigotes migrate to the proboscis. Following
inoculation into the skin of a mammalian host, the
parasite exists within lysosomes of mononuclear
phagocytes as an intracellular amastigote, characterized
by a large eccentric nucleus and a mitochondrial
structure called a kinetoplast.The clinical and histologic
appearance of the CL skin lesions is related to an
interaction between the host’s immune response and the
virulence factors of the different Leishmania species.
The clinical spectrum of CL ranges from an entity called
School of Medicine, diffuse CL, where there is a scarce immune response
System, West and heavily parasitized macrophages, to leishmaniasis
University recidivans, where there is a strong mononuclear cell
response, with few amastigotes.
Diseases Section,
Clinical features
Thus, CL presents as a spectrum of disease ranging from
UK single, chronic ulcerative lesions (‘oriental sores’) to
 Therapy of cutaneous leishmaniasis I Lee et al 87

Table 1. Leishmaniasis: clinical syndromes and geographic distribution

Syndrome Most common species Distribution

Cutaneous leishmaniasis
Old World L. major Rural desert areas of
Asia, Middle East, and
northern Africa
L. tropica Urban areas of Middle East,
Mediterranean, India, Pakistan,
and central Asia.
L. aethiopica Ethiopian highlands, Yemen,
and Kenya
New World L. mexicana Central and South America
L. braziliensis America
L. chagasi
L. peruviana Peru, Argentina
L. panamensis Panama, Costa Rica, Colombia
L. venezuelensis Venezuela
Mucocutaneous leishmaniasis L. braziliensis Central and South America
(espundia)
Visceral leishmaniasis L. donovani India, China, Nepal, Pakistan,
East Africa
L. chagasi Latin America
L. amazonensis Brazil

disseminated nodular lesions (‘diffuse’ CL). The typical
lesion appears as an erythematous papule at the site of
inoculation which increases in size and ulcerates. The
lesions are round with a raised border. Wet lesions are
covered with an exudate, and may become secondarily
infected with bacteria or fungi. Other lesions are dry
with central crusting. Old World CL is frequently self-
limited, eventually resolving without treatment. However,
scarring associated with the lesions is difficult to predict
on initial presentation, and can be disfiguring, parti-
cularly in Old World CL.
There are two forms of chronic CL: diffuse CL
and leishmaniasis recidivans. Diffuse CL is rare, and
is associated with L. aethiopica, L. arnazonensis,
L. mexicana, and other minor species. In this condition,
there is an absence of cellular immune responses, and
heavily parasitized macrophages are abundant in the
dermis. The cutaneous lesion begins as a non-ulcerative
papule, followed by migration of the organisms to other
sites, resulting in disseminated nodules. Areas of
involvement can be extensive, and the lesions could be
permanent. Leishmaniasis recidivans is a relapsing form
of CL caused by L. tropica, and is seen mostly in Iran
and central Asia. There is an intense cellular immune
response to Leishmania antigen; on skin biopsy, a dense
mononuclear infiltration with few amastigotes is seen.
It usually affects the face, and it can last for several
decades.
HIV co-infection with Leishmania species can alter
the epidemiology, diagnosis, and response to therapy.3
Visceral leishmaniasis is an important opportunistic
infection in patients with HIV/AIDS, and cutaneous
leishmaniasis can present atypically with multiple
cutaneous lesions and mucosal involvement.4 Con-
ventional therapy in patients with HIV/AIDS and
leishmaniasis is associated with a higher relapse rate,
and therefore secondary prophylaxis is recommended.5
Diagnosis
The diagnosis of CL is confirmed by identification
of amastigotes in tissue or culture of promastigotes.
The two most common media utilized in culture are a
modified Novy-MacNeal-Nicolle medium (NNN) and
Schneider’s Drosophila medium enriched with fetal calf
serum. Growth of most organisms occurs within
l-2 weeks, although cultures should be maintained for
4 weeks. Demonstration of parasites in the skin can
be accomplished by slit-incision along the ulcer edge,
whereby exposed tissue and fluid are scraped onto a
slide or culture medium. Skin biopsy by a standard
punch biopsy can also be done at the most inflamed
edge of a lesion. Giemsa staining allows the best visual-
ization of the parasite.
Speciation is usually only available from research
laboratories, the Centers for Disease Control (Atlanta,
USA), or the European reference center in Montpelier,
France. Methods of speciation include isoenzyme
analysis, kinetoplast DNA hybridization, and use of
monoclonal antibody detection. Serologic testing is
of limited utility in CL. Intradermal skin testing
(Montenegro test) using killed Leishmania antigens can
be of utility in some cases, and is available through the
WHO. The sensitivity of Leishmania skin testing is high,
but in endemic areas it lacks specificity, because it does
not distinguish between current and past infections.6
Because of the difficulties with current diagnostic
strategies, recent studies have focused on the develop-
88 International Journal of Infectious Diseases
ment of polymerase chain reaction (PCR) methods for
the diagnosis of leishmaniasis by amplification and
detection of ribosomal or kinetoplast target DNA.6,7
Weigle et al6 compared a PCR method for detection
of kinetoplast DNA in biopsy specimens with three
conventional diagnostic methods, and found, in 255
patients with acute CL lesions, that the sensitivity of
PCR (75.7%) was significantly better than that of
Giemsa-stained lesion scrapings (46.7%), biopsy culture
(.55.3%), and aspirate culture (46.3%), and all three
conventional methods combined (70.2%).
Overview of treatment modalities
The decision on whether to treat CL depends on the
location and extent of the lesion, and whether mucosal
leishmaniasis is a possibility. However, if the lesion is in
a cosmetically unacceptable area or is not healing,
specific treatment is indicated. An incredibly diverse
array of therapeutic agents has been tried for the
treatment of CL, in part due to the geographic and
clinical diversity of leishmaniasis, the lack of a com-
pletely reliable mode of treatment, often with significant
side effects, and a paucity of rigorous clinical trials
studying these agents.8-11 The pentavalent antimony (Sb)
compounds sodium stibogluconate (Pentostam, Glaxo-
Wellcome, Research Triangle Park, North Carolina, USA)
and meglumine antimoniate (Glucantime, Rhone-
Poulenc, Paris, France) remain the mainstay of therapy
for most forms of leishmaniasis. Other major treatments
use physical modalities (heat, cryosurgery), local or
intralesional injections, various anti-infective agents
(Dapsone, metronidazole, trimethoprim-sulfamethox-
azole), amphotericin B, pentamidine, allopurinol, azoles,
immunotherapy (i.e. interferon-y), and a variety of
miscellaneous agents.
Pentavalent antimony (Sb)
Sodium stibogluconate is available in the USA from the
CDC (telephone: 404-639-3670, business hours, 404-639-
2888, non-business hours) through an investigational
drug protocol. It is also available in Europe, Africa, and
India. Meglumine antimoniate is used in Latin America
and in French-speaking countries in Africa. There is
extensive experience in the use of Sb in the treatment of
leishmaniasis, although it is not clear how comparable in
terms of efficacy and toxicity the different formulations
are. In the only study to compare sodium stibogluconate
and meglumine antimoniate for the treatment of CL,
Deps et all2 conducted a single-blind, randomized study
of 63 patients with localized CL, and found that efficacy
was similar but hepatic and pancreatic toxicity was
higher in the sodium stibogluconate arm. However, the
preparation of sodium stibogluconate used in this study
may have been unusually toxic.
Sb has had variable success in the treatment of Old
World CL, and because the disease is often self-limited,
I Volume 7, Number 2.2003
Sb can be avoided in many circumstances. Thus, few
studies have been done specifically with Sb and Old
World CL. Chulay et ali3 used high-dose Sb at
18-20 mg/kg twice daily for the treatment of three
patients with CL caused by L. aethiopica in Kenya,
which usually responds poorly to conventional dosing
with Sb. All patients had a good long-term response.
Belazzoug et al I4 treated approximately 400 school
children in Algeria with Sb (given intramuscularly)
or placebo, and found no significant differences in
response rates (48% versus 55% respectively). Few
details, however, were included in the publication.
El-Safi et alI5 reported their experiences with the
treatment of CL, giving approximately 110 patients
Sb (600 mg/day for 21-30 days), and achieving clinical
cure in all but two patients.
The recommended dose of Sb is 20 mgikg per
day for 20 days (for CL) or 28 days (for visceral
leishmaniasis). Important side effects include cardio-
toxicity (prolongation of QT,, ST-T wave changes),
biochemical and, less commonly, clinical pancreatitis,
arthralgias, myalgias, nausea/vomiting, liver transaminase
abnormalities, pancytopenia, and, rarely, renal toxicity.
Gasser et all6 reported a small prospective study of 17
patients treated with Sb for CL, in which 16 patients
developed an increase in pancreatic enzymes and 12
developed clinical pancreatitis, although pancreatitis
resolved with discontinuation of therapy.
Local heat or cold therapy
Junaid17 reported his experience of treating 178 patients
with CL in Iraq using a heat-generating device creating
a temperature of 55°C for 5 min. One hundred and sixty-
two patients responded well to a single application of
heat. Aram and Leibovici18 used local hyperthermia to
42°C for 2-3 min induced by ultrasound to treat 18
patients with CL in Israel. Twenty-two lesions (78.5%)
in 13 patients resolved completely over 5-10 weeks.
Both of these uncontrolled studies reported minimal
side effects. Navin et all9 conducted a randomized trial
of 66 patients in Guatemala with proven New World
CL divided into three treatment arms: meglumine
antimoniate (850 mg/day for 15’ days), localized heat
from a radiofrequency generator (50°C for 30 s, three
weekly treatments), and placebo. Cure rates were 16
(73%) 16 (73%), and 6 (27%), respectively. Velasco-
Castrejon et alzOtreated 201 patients with CL in Mexico
with heat therapy. A localized current field-radio-
frequency device was used to give a single application
of heat at 50°C for 30 s. Of 191 patients evaluated at
8 weeks of follow-up, 172 (90%) were cured.
Bassiouny et alzl used a CO2 cryomachine to treat
30 patients with histologically confirmed CL in Egypt
in an uncontrolled trial, reporting that all patients
were cured without scarring at 4-5 weeks. Applications
generally lasted for 30-60 s, and most cases resolved
with a single treatment. Serial biopsies confirmed killing

of the parasite. Leibovici and Aram treated 14 patients
with confirmed CL in Israel with liquid nitrogen in an
uncontrolled study. All lesions were cured clinically and
parasitologically at 3-8 weeks, without scarring or
relapse at 4 months. Despite these promising results, in
a larger, unblinded trial, Al-Gindan et a123 treated 88
patients with cryosurgery but achieved a cure rate of
only 27%, as compared to 41% with Sb and 30% with
ketoconazole. Side effects included hypopigmentation,
and some patients developed satellite lesions.
El Darouti and Rubaie24 compared cryotherapy,
intralesional Sb and combined cryotherapy and
intralesional Sb in a total of 44 patients in an unblinded
study in the United Arab Emirates. The combination
therapy group achieved a 100% cure rate at 6 weeks,
compared to 68% in the cryotherapy group, and 44% in
the intralesional Sb group.
Topical and intralesional therapies
Paromomycin ointment has been studied by several
groups in the treatment of Old World CL, as a topical
preparation of low toxicity. However, some paromomycin
ointments are formulated with dimethylsulfoxide
(DMSO), w h’ich is a potentially toxic irritant. El-Safi et
a125 performed a double-blind study comparing lo-day
courses of paromomycin (16 patients) and placebo (15
patients), and found no significant difference in the
response rates, although when individual lesions
were compared, a significant difference was found.
El-On et a12’j compared paromomycin and 15%
methylbenzethonium chloride (MBCl), paromomycin
and 12% MBCl, and placebo, in a randomized, double-
blind, crossover study in 39 patients. Both treatment
arms had a combined cure rate of 74.2% versus 26.6%
in the placebo group. No difference was found between
the two treatment arms. Two more recent randomized,
placebo-controlled trials of paromomycin in Old World
CL have not had similar success. In a study by Ben
Salah et a1,27 115 patients with confirmed CL due to
L. major in Tunisia were randomized to paromomycin
ointment (57) or placebo (58) for 2 weeks. There was
no difference in adverse effects. Although there was a
trend for parasitologic improvement (negative smears)
at day 15, this difference was not apparent at days 45 and
105.
In a study by Asilian et a1,28251 patients with CL
were randomized to paromomycin ointment (125)
or placebo (125) for 2 weeks. Paromomycin ointment
was well tolerated. Although at days 15 and 105 (but
not at day 45) there was parasitologic improvement
in the treatment group, no clear clinical benefit was
observed.
Larbi et a129performed a randomized, double-blind
study of topical clotrimazole versus miconazole for
30 days for the treatment of CL in 54 patients (151
lesions) in Saudi Arabia. Of 89 lesions treated with
clotrimazole, 15.7% healed fully, and 47.2% were reduced
Therapy of cutaneous leishmaniasis I Lee et al 89
in size, versus 0.0% and 35.5% in the miconazole group.
No significant side effects were observed.
In vitro experiments have demonstrated the para-
tidal activity of nitric oxide against Leishmania.30 Nitric
oxide is synthesized in macrophages, and diffuses
well into skin tissues. S-nitroso-N-acetylpenicillamine
(SNAP) is a compound that generates the production of
nitric oxide. Lopez-Jaramillo et a131 used SNAP cream
every 4 h while the patients were awake for 10 days for
the treatment of 16 patients with CL in Ecuador. At 30-
day follow-up, all lesions were healed and new skin
was observed. In contrast, Davidson et a132 treated 42
patients with CL with a topical cream that induces the
generation of nitric oxide. In this approach, nitric oxide
is generated non-enzymatically by the acidification of
nitrite (KN02) by ascorbic acid or salicylic acid. Only 11
(28%) patients showed clinical improvement, and only
5 (12%) were cured at 2 months.
Soto et a133 used a combined regimen of topical
paromomycin (15%) and MBCl (12%) twice a day for
10 days plus intramuscular or intravenous meglumine
antimoniate for 3 or 7 days in Colombian patients with
CL. In the cohort of 20 patients who received the
injectable meglumine, the cure rate was 90% versus
42% in those who received it for only 3 days.
Intralesional treatment of CL with Sb has been
used to minimize the systemic effects of the medication.
Faris et a134 conducted an uncontrolled study using
intralesional Pentostam in 710 patients with confirmed
CL in Saudi Arabia. Most lesions required eight
injections for resolution, although some required up to
24 injections. Seventy-two per cent of lesions were
cured, 23.9% improved, and 4.1% worsened. Side effects
were limited to pain at the injection site and hyper-
pigmentation.
Tallab et a135conducted a prospective dose-ranging
study of 96 patients (129 lesions) with confirmed CL in
Saudi Arabia with intralesional Sb. Their results suggest
that alternate-day or weekly injections of Sb for a
total of three injections was more effective than daily
injection. The final complete cure rate was 99.2% after
additional injections were given. Good results with
intralesional Sb have also been obtained in New World
CL.36
Cohen and Livshin37 treated a total of 50 CL lesions
in 31 patients with intralesional injections of emetine
hydrochloride, and obtained a cure rate of 100%. The
injections were administered weekly or bi-weekly, and
the amount of emetine injected varied from 10 to
160 mg, depending on the size of the lesion.
Anti-infective agents
Several conventional anti-infective agents have been
tried for the treatment of CL, including dapsone,
rifampin with or without isoniazid, metronidazole, and
trimethoprim-sulfamethoxazole (TMP-SMX). Dogra
et a138conducted the first study of dapsone (50 patients)
90 International Journal of Infectious Diseases I Volume 7, Number 2.2003
versus an untreated control group (15 patients) in India.
Forty of 50 patients in the treatment group were
clinically cured after 21 days of treatment, and no
clinical improvement was seen in any members of the
control group.The only side effect from the dapsone was
nausea (14%). Following this, Dogra39 conducted a
double-blind study of 120 patients, comparing oral
dapsone (60 patients) or placebo (60 patients) for
6 weeks. Of the patients receiving dapsone, 49/60 (82%)
were cured. Side effects included nausea (nine patients)
and anemia (three patients). In the placebo group, O/60
showed spontaneous healing in the 6-week study period.
Rifampin has shown some efficacy in the treatment
of CL, with or without isoniazid. Livshin et a140
compared rifampin alone to rifampin with isoniazid in
39 patients with CL in Israel. The duration of therapy
varied from 14 to 60 days. At both 1 and 2 months
after beginning therapy, no major difference was found
between the two groups (52.9% versus 55%, respec-
tively). Other studies have shown variable success rates
with rifampin, ranging from 0% to 80%.
There are various case reports and case series
describing the use of metronidazole and TMP-SMX for
the treatment of CL with variable success.r”
Amphotericin B was found between the allopurinol and placebo groups.
Amphotericin has been used since its introduction into
clinical medicine in 1955 as an alternative to Sb, with
high cure rates, but significant toxicities.li Although it is
considered an effective alternative to Sb, there is a
paucity of published trials regarding its use in CL.
Liposomal formulations of amphotericin have demon-
strated in vitro efficacy against experimental CL in
mice,41 and several case reports have described its
successful use in leishmaniasis.
Pentamidine
Pentamidine has also proven to be efficacious in the
treatment of leishmaniasis, including Old World CL.8
Like amphotericin B, it is considered a traditional
alternative to Sb, but its use is limited by its toxicities.
Soto-Mancipe et a142 randomized 92 patients with
New World CL to four treatment arms: intramuscular
meglumine antimoniate (10 mg/kg b.i.d. for 20 days),
intramuscular pentamidine (2 mgikg q.o.d. in seven
doses), oral itraconazole (200 mg b.i.d. for 28 days), or
no treatment. Cure rates were as follows: meglumine
antimoniate 21/23 (91%), pentamidine 23/24 (96%),
itraconazole approximately 25 %, and placebo 14/22
(36%, not including six patients lost to follow-up). A side
arm of the study assessed intramuscular pentamidine at
a lower dose (2 mg/kg q.o.d. in four doses), reporting
cure in 14/19 patients (74%). The results of this study
were difficult to interpret, due to a relatively high
number of patients lost to follow-up or violating the
treatment protocol.
Allopurinol
Allopurinol is metabolized to toxic nucleosides by
the Leishmania parasite. Martinez and Marr43 con-
ducted an open-label, randomized study of 110 patients,
comparing allopurinol plus meglumine antimoniate
versus meglumine alone in New World CL in Colombia.
All patients had proven L. braziliensis panamensis
infection. Allopurinol was given at 20 mg/kg per day
in four divided doses for 15 days; meglumine was
administered at 20 mg/kg for 1.5 days. Cure rates were
as follows: meglumine alone 36%, allopurinol and
meglumine 74%, allopurinol alone 80%, and untreated
0%. No major toxic effects were observed.
These results must be interpreted with caution,
however, as there was an unusually low cure rate in the
group treated with Sb alone.44 Velez et a145 conducted
a randomized, partially double-blind, controlled trial
using allopurinol alone to treat CL in Colombia,
enrolling 187 patients. Patients were randomly assigned
to receive either allopurinol(20 mg/kg q.d. for 28 days),
placebo tablets (for 28 days), or intramuscular glucantime
(20 mglkgiday for 20 days). One hundred and fifty-seven
patients (86%) were evaluated. Cure rates were as
follows: allopurinol ?8/55 (33%) placebo 17146 (37%)
and glucantime 52156 (93%). No significant difference
The use of allopurinol in combination with Sb
has also been specifically addressed. Momeni and
Aminjavaheri46 conducted an uncontrolled trial of
allopurinol and meglumine antimoniate in 25 patients
with recurrent CL unresponsive to previous therapy, and
a duration of disease greater than 2 years. Twenty-four
of 25 patients responded well to treatment, and no
relapse occurred at l-year follow-up. No significant side
effects were noted. Martinez et a147conducted an open-
label, randomized, controlled study in Colombia in 100
patients, comparing stibogluconate (49 patients) versus
stibogluconate and allopurinol (51 patients) in the
treatment of CL. Cure rates were 39% for Sb, and 71%
for Sb and allopurinol, which was statistically significant.
Azoles
Azoles interfere with leishmanial cell membrane
biosynthesis. Ketoconazole has been used in the treat-
ment of Old World CL, with mixed results. Weinrauch
et a148 report treating approximately 100 patients with
CL in Israel, with a cure rate of approximately 70% in
cases due to L. major after 4-6 weeks of treatment with
200-400 mg of ketoconazole. Results were poor in cases
of CL due to L. tropica or L. aethiopica. Ketoconazole
has been used with success in New World CL as well.
Saenz et a149obtained comparable cure rates in a small
study comparing ketoconazole and Pentostam (16/21
versus 13/19, respectively). In a larger study, Navin
et a150randomized 120 patients to ketoconazole (600 mg
q.d. for 28 days), Pentostam, and placebo. Treatment

outcome depended on the particular species involved.
For L. braziliensis, response rates were 24125 for Sb, and
7/23 for ketoconazole. For L. mexicana, response rates
were 417 for Sb, and 8/9 for ketoconazole.
Singh et a151 reported poor results in a small trial
involving 16 patients with CL in India. Patients were
given ketoconazole at 200 mg b.i.d. for 10 weeks. Of 14
patients completing the study, no patients showed any
improvement. Alsaleh et al52 compared dosages of
ketoconazole in the treatment of CL in Kuwait.
Eighteen patients received 600 mg and 15 patients
received 800 mg of ketoconazole daily, with cure rates of
12/15 (80%) and 9/11(82%), respectively, inpatients com-
pleting the study, and minimal side effects. Ozgoztasi
and Baydar53 compared topical paromomycin and oral
ketoconazole in Turkey in an open-label, randomized
study enrolling 72 patients. Cure rates were 15/40 (37.5%)
in the paromomycin group and O/32 (0.0%) in the
ketoconazole group.
Itraconazole has shown promising results in several
earlier case reports54 and small pilot studies.55-57
Momeni et als8 conducted a randomized, double-blind
study comparing itraconazole (7 mg/kg/day) and placebo
for 3 weeks in the treatment of CL in Iran. One hundred
and forty patients were enrolled, and 131 patients
completed treatment, from an area endemic for
L. major. Cure rates were 59% in the itraconazole
group, and 44.3% in the placebo group, although
statistical significance was not achieved. No difference
was found in adverse effects.
Terbinafine
Terbinafine is an antifungal agent of the allylamine
group that inhibits ergosterol synthesis. Bahamdan
et a159 administered terbinafine at a dose between
250 mglday and 500 mglday for 4 weeks to 27 patients
with CL. Of the 14 patients who finished the study,
10 (71.5%) showed a clinical response (either partial
or complete cure). No side effects were reported.
Gonzalez-Ruperez et al 6o have also reported the
successful use of terbinafine in one HIV-positive patient
with localized CL.
Miltefosine
Miltefosine (hexadecylphosphocholine), an agent that
has been studied in oncologic clinical trials, has
been used in the therapy of visceral and cutaneous
leishmaniasis. Jha et a161 administered miltefosine
loo-150 mg/day for 28 days to 90 Indian patients with
visceral leishmaniasis, achieving a cure rate of 96%.
Most recently, Soto et a162 enrolled 72 Colombian
military personnel with CL into an open-label, rising-
dose, phase II trial. The cure rate for patients receiving
133-150 mg/day miltefosine was 94%. Motion sickness
was seen in 40% of the patients, but it did not interfere
with their normal duties.
Therapy of cutaneous leishmaniasis I Lee et al 91
Immunotherapy
The roots of immunotherapy lie in the still used ancient
practice of leishmanization, in which material from an
active lesion of CL is inoculated into the arm or buttock
to produce a self-limited lesion in an inconspicuous site.
Vaccines utilizing killed Leishmania antigens are still
under investigation. Interferon-y has shown promise
when combined with Sb in the treatment of visceral,
mucocutaneous or cutaneous leishmaniasis. Harms
et a1(j3 conducted a randomized, prospective trial
comparing intralesional glucantime and intralesional
interferon-y in 40 patients in Syria. Interferon-y alone
showed mixed effectiveness. Arana et al64 conducted
a randomized, double-blind trial of 66 patients in
Guatemala, comparing meglumine for 20 days,
meglumine for 10 days, and meglumine for 10 days plus
interferon-y. Meglumine was given intravenously, and
interferon or placebo was given subcutaneously (five
injections in total). Cure rates were 19/21 (90%), 18/20
(90%), and 22/22 (lOO%), respectively. However, there
was no statistically significant difference in response
rates between the three groups.
CONCLUSION
The optimal approach to the treatment of CL remains
a challenge, as systemic therapy is expensive and
associated with significant toxicities. Definitive recom-
mendations are hampered by the self-limited nature of
many cases of CL, and a paucity of rigorously designed
clinical trials. Sb remains the standard therapy for CL
that requires treatment, despite its significant toxicities.
In New World CL, the ability of L. braziliensis to
progress to mucocutaneous disease necessitates systemic
therapy. Pentamidine, amphotericin B and azoles are
also effective as systemic therapy. Local and topical
therapies, such as topical paromomycin or intralesional
Sb, may be useful in cases where cosmetic aspects are
of less concern, particularly in Old World CL, although
some specific therapeutic modalities may not be widely
available. Immunotherapy and vaccine development
represent a promising avenue of continued research.
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