REVIEW

New World cutaneous leishmaniasis: Updated review of

current and future diagnosis and treatment
Panagiotis Mitropoulos, DO, Pete Konidas, PharmD, and Mindy Durkin-Konidas, PharmD
South Korea

Background: Cutaneous leishmaniasis (CL) has traditionally been underrecognized and underreported.
Improved awareness is warranted as the number of cases has increased as a result of increased travel to
endemic countries, the HIV/AIDS pandemic, and the larger number of military and contract workers
deployed overseas.

Objective: We sought to present a systematic review of evidence from a gamut of research trials on the
treatment efficacy of different regimens and aggregate this knowledge for use as a guide for clinical practice
decisions.

Methods: We performed a comprehensive search of print and electronic sources to identify the
accumulated research information on New World CL.

Results: Topical treatment of New World CL lesions is generally not recommended. Findings support the
systemic administration of pentavalent antimonials as first-line treatment. Exception to this is infection with
L guyanensis in French Guiana where systemic pentamidine is suggested as first-line treatment.

Limitations: The reliability of the findings of this review of research evidence is dependent on the
individual quality and potential bias in its component principal trials. There was a conscious attempt to
only include evidence derived from randomized controlled studies, with adequate randomization,
adequate patient numbers, and complete follow-up information. However, because of the relatively small
number of such studies on New World CL, evidence from nonrandomized studies and case series studies
was also considered.

Conclusions: The pentavalent antimony compounds remain the first-line treatment choice for the
treatment of New World CL. Concerns with cost, availability, poor compliance, and systemic toxicity,
however, may compel clinicians to opt for alternative treatment modalities. Some advances in the
development of an antileishmanial vaccine have been made but none is yet available for clinic use. The
increase, over recent years, in the incidence of CL warrants an enhanced effort to increase awareness of the
disease, assure timely diagnosis, and implement effective management and treatment strategies. ( J Am
Acad Dermatol 2010;63:309-22.)

Key words: cutaneous; diagnosis; leishmaniasis; New World; treatment.

L eishmaniasis is a sandfly-borne infection that

is endemic in several countries around the
world. It results from infection with the pro-
tozoan parasite Leishmania species. The disease has
Abbreviations used:
CL:
FDA:
IL:
cutaneous leishmaniasis
Food and Drug Administration
interleukin
IM: intramuscular
From the Camp Long Troop Medical Clinic. IV: intravenous
Funding sources: None.
Conflicts of interest: None declared.
Reprint requests: Panagiotis Mitropoulos, DO, 75th Medical gained interest because of expanding international
Company, Unit 15190, Camp Humphreys, APO, AP 96297. travel, population overgrowth, the HIV/AIDS pan-
E-mail: drmitropoulos@yahoo.com. demic, and reports of increasing incidence up to
Published online March 22, 2010.
0190-9622/$36.00
500% in several endemic areas.1,2 The United States
2009 by the American Academy of Dermatology, Inc. has also seen an increasing number of leishmaniasis
doi:10.1016/j.jaad.2009.06.088 cases because more and more Americans are

309
310 Mitropoulos, Konidas, and Durkin-Konidas J AM ACAD DERMATOL
AUGUST 2010

traveling to endemic countries, and because of the minority of them progressing to muco-CL. Visceral
larger number of military and contract workers leishmaniasis and diffuse CL are also found in the
deployed overseas. aforementioned geographic regions. Although rec-
ognition of the geographic distributions of the various
EPIDEMIOLOGY parasites and their prevalence has increased during
Leishmaniasis is a disease caused by the protozoa recent years, the disease is still grossly underreported.
of the Leishmania species, which is transmitted by Estimates of the number of cases are frequently
the bite of a female sandfly. unreliable as a result of local
During their blood meal, difficulties in diagnosis and
infected sandflies inject the CAPSULE SUMMARY the frequency of subclinical
infective stage, the promasti- infections; frank disease rep-
dThis article highlights leishmaniasis
gote parasite, into the human resents only a proportion of
epidemiology and calls attention to
host. Injected promastigotes total infections.8
modern changes in its worldwide
are then phagocytized by In the Unites States more
incidence and burden.
macrophages and are trans- than 25 nonmilitary cases of
formed into amastigotes. dFactors that may impact leishmania cutaneous disease have been
These multiply in the in- geographic distribution and incidence of identified since 1980 in
fected cells and affect differ- infection are discussed. individuals living in Texas
ent tissues and, depending dBased on evidence from a number of suggesting that the disease
on the Leishmania species, randomized controlled studies, the may be endemic in that re-
cause the corresponding therapeutic efficacy of several different gion.9,10 Nevertheless, almost
clinical manifestation of the regimens against New World cutaneous all cases of leishmaniasis in
disease. leishmaniasis is assessed. the United States are thought
The disease can be classi- to have been imported from
dThe authors summarize their findings
fied several ways. A common elsewhere.
and present clinical practice guidelines
way is geographically into
for the treatment of cutaneous
New World versus Old DIAGNOSIS
leishmaniasis according to Leishmania
World disease. Old World Occurring in several forms,
species.
forms of Leishmania are leishmaniasis is generally rec-
transmitted by sandflies of dThey comment on current knowledge ognized from its cutaneous
the genera Phlebotomus and and future prospects for the form that causes nonfatal,
are endemic in Africa, Asia, development of a prophylactic vaccine. disfiguring lesions. However,
the Middle East, and the infection may result in a wide
Mediterranean. The New spectrum of clinical diseases that can be divided into
World form is transmitted mainly by flies of the genus 4 broad categories: (1) CL, (2) diffuse CL, (3) muco-
Lutzomyia that are endemic from Texas through CL, and (4) visceral leishmaniasis. The severity and
South America. Australia and the South Pacific are clinical presentation of leishmaniasis that develops
not considered leishmaniasis-endemic regions.3 depends on many factors, including the species of
The overall prevalence of leishmaniasis is esti- Leishmania involved, the number of parasites inoc-
mated to be 12 million cases worldwide, and the ulated, the site of inoculum, and the nutritional status
global incidence of all clinical forms approaches 2 and immune competence of the host.11-13
million new cases annually (1.5 million for cutaneous CL is the most common form of the disease. It is
leishmaniasis [CL] and 500,000 for visceral leishman- characterized by one or more papules, nodules, or
iasis).4 Muco-CL is estimated to develop as a compli- ulcers. The lesions are, typically, described as look-
cation of L viannia subgenus CL in 5% to 20% of ing somewhat like a volcano with a raised edge and a
untreated patients living in areas where leishmaniasis central crater. These are usually painless but can
is endemic.5,6 More than 90% of CL cases occur in become painful if they become secondarily infected.
Iran, Afghanistan, Syria, Saudi Arabia, Brazil, and Most lesions develop within a few weeks of the
Peru.2 sandfly bite, but may also appear up to several
Leishmaniasis is extremely common in many months later. Other entities in the differential diag-
regions of the Americas. In the Andean highlands noses are listed on Table I.
and the Amazon basin (Venezuela, Colombia, The confirmatory diagnosis of CL relies on the
Ecuador, Peru, Bolivia) most human infections are microscopic demonstration of the Leishmania orga-
caused by Leishmania in the viannia subgenus.7 nism in the lesion aspirate, scraping, or biopsy
Human infection causes cutaneous lesions, with a specimen. Current available diagnostic tests are
J AM ACAD DERMATOL
VOLUME 63, NUMBER 2
listed in Table II. The organisms are identified
on Giemsa and Romanowsky hematoxylin-
eosinestained smears. In tissue sections Giemsa
stains are not usually useful, but the organisms may
be highlighted with Brown-Hopps modified Gram
stain. Under ideal circumstances, species recognition
should also be sought. This is why polymerase chain
reaction is increasingly becoming the diagnostic
method of choice, because it has a high sensitivity
and gives a species-specific diagnosis, allowing spe-
cies-specific treatment.14
TREATMENT
Skin sores of CL, especially Old World CL, can heal
on their own but this can take months or even years.
Spontaneous healing, however, occurs less com-
monly in New World disease.2
If lesions are left untreated, complications, such as
spreading to contiguous mucous membranes, or
significant disfigurement, are possible. This is
particularly important in infections with species
belonging to the L viannia subgenus (L viannia
braziliensis, L viannia guyanensis, and L viannia
panamensis), which have been shown to have
greater tendency for systemic dissemination when
compared with other species.15,16 Furthermore, to
avoid long-term complications, patients with multi-
ple lesions ( $ 3); patients with large lesions
([2.5 cm); patients with lesions on the face, hands,
and feet, and over joints; and immunocompromised
individuals should be treated promptly.17
To date, there is no Food and Drug Administration
(FDA)-approved vaccine against leishmaniasis,
and the drugs available are too toxic, expensive,
and difficult to administer. Moreover, there is evi-
dence of emerging resistance of the parasites to the
commonly used drugs, such as the pentavalent
antimonials.18-20
Treatment of CL should be directed toward the
eradication of the amastigotes and reduction of the
size of the lesions with minimal scarring and toxicity.
No single treatment modality to date has been shown
to be indisputably superior to others.
Antiparasitic pentavalent antimonials, such as so-
dium stibogluconate (Pentostam, GlaxoSmithKline,
London, UK) or meglumine antimoniate (Glucantime,
Sanofi-Aventis, Bridgewater, NJ), administered intra-
venously (IV), intramuscularly (IM), or directly into
the lesions are the mainstays of therapy. However, a
high rate of adverse events, length of treatment, and
relapses in up to 25% of cases highlight the limitations
of these drugs.14
Several uncontrolled trials, predominantly invol-
ving Old World disease, have demonstrated moderate
to excellent treatment efficacy and cosmetic outcomes
Mitropoulos, Konidas, and Durkin-Konidas 311
Table I. Differential diagnoses of cutaneous
leishmaniasis
Sporotrichosis Ecthyma
Blastomycosis Malignancy
Atypical mycobacterial infection Sarcoidosis
Cutaneous tuberculosis Tularemia
Lupus vulgaris Yaws
Tertiary syphilis (gumma) Myiasis
Insect bite reaction Cutaneous anthrax
via cryotherapy or heat administration. The use of
surgical excision and curettage is rarely recommen-
ded in New World disease because of high risk of
relapse, lymphatic dissemination, and disfigurement.
Several other medications, such as allopurinol,
rifampicin, dapsone, chloroquine, and nifurtimox
have been proposed as treatment alternatives for
leishmaniasis.21-26 Their implementation, however,
is not widely accepted as treatment efficacy is not
convincing, and experience with their use is limited.
More novel preparations for the treatment of CL
are being studied, in both human and animal models,
with promising results and include the immune
regulator imiquimod, recombinant interferon, mono-
clonal antibodies, oxygenated chalcones, cyclospor-
ine, and photodynamic therapy.21,26-30
Both human and parasite genomes have been
targeted for sequence analysis. The Leishmania ge-
nome project, which began as a large-scale attempt to
sequence part of each of the transcripts of all the
genes of the organism, has been almost completed.
Sequencing of L major is finished barring only two
gaps. For L braziliensis and L infantum, a high-
quality draft sequence has been obtained.31 Although
these genome sequences have vastly increased our
knowledge of Leishmania genome content and
organization, much work remains to be done, be-
cause approximately 65% of protein-coding genes
currently lack functional assignment.31,32 The genetic
information from both human beings and parasites
will allow us to gain an understanding of the inter-
action between parasite virulence factors and host
response factors. It will be exciting to see how this
molecular knowledge of the host-parasite interaction
will facilitate targeting of new treatments.
Pentavalent antimony (sodium stibogluconate
[Pentostam] and meglumine antimoniate
[Glucantime])
This is the standard recommended treatment for
CL. Pentavalent antimonial compounds have been
the mainstay of treatment for visceral leishmaniasis,
CL, and mucosal leishmaniasis for decades. Different
312 Mitropoulos, Konidas, and Durkin-Konidas J AM ACAD DERMATOL
AUGUST 2010

Table II. Leishmaniasis diagnostic tests

Histology
Scraping, punch biopsy specimen, or aspirate Easier and most commonly used method; demonstration of
amastigotes on smear or biopsy sample, or promastigotes in aspirate

Culture
On Schneider Drosophila or NNN mediums Unreliable, as organisms are difficult to isolate especially if lesions are
old; results may take 1-3 wk depending on parasite load

Molecular techniques
PCR Enables species identification; useful in monitoring patients after
treatment; not widely available in endemic regions
Antigen detection (using monoclonal antibodies) Not widely available, expensive
DNA hybridization (for genome detection) Not used in practice; still only a research tool

Leishmanin skin test

(Montenegro skin test) Relies on delayed-type hypersensitivity response after injection of dead
promastigotes intradermally; may produce positive results in 3 mo
after appearance of lesions; result is considered positive if induration
of [5 mm develops after 48 h
Important notes:
dDoes not detect acute infection

dReaction may not be mounted in immunocompromised

dAlmost 70% of population in endemic areas will test positive

Not approved for use in the United States

Serologic tests
ELISA, IFA, DAT, K39 ELISA, strip tests Serum antibody detection can be useful in diagnosing visceral
leishmaniasis but is of no use in cutaneous disease

DAT, Direct agglutination tests; ELISA, enzyme-linked immunosorbent assay; IFA, indirect immunofluorescence; NNN, Novy-MacNeal-Nicolle;
PCR, Polymerase chain reaction.

dosage regimens have been proposed and tested
throughout the years in an attempt to discover the
minimum effective therapeutic dose with the least
toxic side effects. This has proved to be a challenge as
the daily dose of antimony and duration of therapy
had to be progressively increased to combat unre-
sponsiveness and resistance of the organisms to
therapy. Currently, the efficacy of an antimony reg-
imen at the dose of 20 mg/kg/d parenterally for a 3- to
4-week period is well established and comprises the
first-line treatment for New World CL.33-37 Exception
to this is infection with L guyanensis in French Guiana
([90% of cases of CL in French Guiana) where
pentamidine is the first-line treatment.38-41 This is
true only for French Guiana and not for the neigh-
boring or other countries where the pentavalent
antimonials are still the first-line treatment.
High cost, difficulty of administration, toxicity,
and increased morbidity still present serious limita-
tions in the treatment of leishmaniasis. In lieu of that,
several studies have investigated the efficacy of a
shorter course of treatment. In a randomized, dou-
ble-blind study, Wortmann et al42 concluded that a
10-day course of 20 mg/kg/d of IV antimony was
therapeutically equivalent and less toxic than the
standard 20-day course. Similar findings were mir-
rored in a study in Guatemala in patients infected
with L braziliensis.43 In a similar quest, Oliveira-Neto
et al44 investigated the efficacy of a lower dose
regimen (5 mg/kg/d for 30 days) in 159 individuals in
Brazil, an area of L braziliensis transmission, and
reported an 84% cure rate and no relapses within a
10-year period of follow-up. Multiple other studies
demonstrated that good results may be achieved
with use of less aggressive antimony therapy.45-47
Despite the promising results of these studies the
current recommendation stands at 20 mg/kg/d IM/IV
for 20 days as the concern exists that a shorter course
of treatment or use of lower dose may permit the
development of resistance.
Intralesional injection with pentavalent antimo-
nials has also been proposed and studied, as means
to decrease costs and the side effects associated with
IM or IV therapy. Local treatment of New World CL is,
usually, not recommended because of the possibility
of already disseminated disease, and only one study
investigating this treatment modality was found. In a
trial of 74 patients with CL from Brazil (an area of
J AM ACAD DERMATOL
VOLUME 63, NUMBER 2
L braziliensis transmission), researchers reported a
cure rate of 79.7% (59/74) 12 weeks after meglumine
(425 mg/5 mL) was injected intralesionally.48 From
the 59 healed patients, a single dose was successful
in 47 patients and 12 patients needed an additional
dose 2 weeks later. The amount injected varied
according to the lesion size and infiltration continued
until complete blanching of the lesion was achieved.
The mean lesion size in this study was 51.4 mm2 and
for this size it was estimated that 2 to 3 ampoules of
meglumine were required. No relapses or develop-
ment of mucosal lesions after a 10-year follow-up
period were disclosed.48
Pentamidine isethionate
Pentamidine, a synthetic derivative of amidine, is
primarily used in the prevention and treatment of
Pneumocystis jiroveci pneumonia, formerly known
as P carinii pneumonia. It has also been shown to
have good clinical activity against a number of
protozoa such as Leishmania, certain strains of
Trypanosoma, and Babesia, as well as certain fungi,
such as Candida albicans. The precise mode of its
antiprotozoal action is not fully understood.
Pentamidine may be used in individuals intolerant
to antimonial treatment, or in cases of antimonial
resistance. It comprises the first line of treatment (3
mg/kg/d IM every other day for 4 injections) of CL in
French Guiana where more than 90% of infections
are caused by L guyanensis.38-40 Several studies have
compared pentamidine treatment of CL versus the
gold standard antimony regimens. Andersen et al37
reported a 35% cure rate with pentamidine versus
78% with meglumine antimoniate in a study of 80
patients with CL caused by L braziliensis in Peru. On
the other hand, a study in Colombia demonstrated a
96% cure rate of CL in 51 patients who received a
total of 4 injections of 3 mg/kg/d every other day,
and a side-effect profile similar to that of the standard
antimonial therapy.49,50
The pentamidine regimen has the advantage of a
short time course. Despite this, frequent adverse
reactions with moderate morbidity have been asso-
ciated with its use, to include an unusually high rate
(50%) of hyperglycemia, most likely as a result of
pancreatic damage, and hypotension, tachycardia,
and electrocardiographic changes.21
Imidazoles/triazoles (ketoconazole,
fluconazole, itraconazole)
A number of researchers have investigated the
efficacy of the azole compounds in the treatment of
New World CL. These antifungal compounds include
two different classes: imidazoles (eg, ketoconazole)
and triazoles (eg, fluconazole, itraconazole). They all
Mitropoulos, Konidas, and Durkin-Konidas 313
share the same antifungal spectrum and mechanism
of action, but triazoles are metabolized slower,
interfere less with human sterol synthesis, and are,
therefore, less toxic than imidazoles.51 A great ad-
vantage of these compounds is that they can be
orally administered and that the side-effect profile is
considerably less toxic compared with the recom-
mended pentavalent antimonials.
Studies on use of oral ketoconazole for the treat-
ment of New World CL emphasize the importance of
speciation because the efficacy of treatment has been
shown to vary according to species. Moreover, in
vitro studies have failed to produce consistent results
on the susceptibility of each of the Leishmania
species to the azole compounds.
In a placebo-controlled trial of 120 patients from
Guatemala, a 28-day course of oral 600 mg/d keto-
conazole regimen delivered a 30% cure rate among
patients infected with L braziliensis versus 89% cure
rate among patients infected with L mexicana.36
However, the researchers recognized that the sample
size was not adequate to allow reliable evaluation of
treatment of CL caused by L mexicana.
In a separate smaller trial of 8 patients in Belize,
oral administration of 800 mg/d of ketoconazole for
28 days resulted in 100% (4/4) cure rate in those
infected by L mexicana versus 25% (1/4) in those
infected by L braziliensis.52 In all cases, clearance of
infection was confirmed by the absence of amasti-
gotes in posttreatment biopsy specimens and nega-
tive posttreatment culture findings. The modest
activity of oral ketoconazole against L mexicana,
and the substantially lower efficacy against L brazil-
iensis has, also, been demonstrated by other trials.53
In addition, in a randomized clinical trial involving
patients infected with L panamensis, treatment with
oral ketoconazole (600 mg/kg/d for 28 days) cured
76% (16 of 21) of patients versus 68% (13 of 19) in the
group treated with pentavalent antimony.54
It appears that oral ketoconazole may be effective
in the treatment of the more readily self-curing forms
of CL (cutaneous disease caused by L mexicana and
L panamensis) and, therefore, can reasonably but
cautiously be recommended as initial treatment.35
No studies on the use of fluconazole or itracona-
zole for the treatment of New World CL were found
and, therefore, these agents cannot, currently, be
recommended.
Paromomycin (aminosidine)
Paromomycin sulfate is best known for its use as
a broad-spectrum aminoglycoside antibiotic. It is
marketed as an oral antiparasitic drug and as a
topical antileishmaniasis agent. Orally, paromomy-
cin is used to treat giardiasis, amebiasis, and
314 Mitropoulos, Konidas, and Durkin-Konidas
cryptosporidiosis. Topically, it is commonly used to
treat Old World CL (L major, L tropica, L aethiop-
ica). Injectable paromomycin has been experimen-
tally used to treat visceral leishmaniasis (primarily
caused by L donovani).55
By and large, experts are hesitant to treat New
World CL with local agents because of the potential
risk of mucosal disease development, mainly asso-
ciated with infection by L braziliensis and L pan-
amensis. Strains of L mexicana, on the other hand,
have been found to be highly susceptible to paro-
momycin sulfate treatment.56 Currently, topical treat-
ment of New World CL is not recommended except
in cases of infection with L mexicana where the risk
of progression to mucosal leishmaniasis is un-
likely.15,38,57 In cases of L mexicana infection topical
15% paromomycin/12% methylbenzethonium oint-
ment may be an acceptable, less costly alternative if
first-line treatment with pentavalent antimony is not
readily available.
Several studies have been conducted investigating
the therapeutic efficacy of topical paromomycin in
New World CL. Most of the trials have been
performed by using an ointment comprising 15%
paromomycin and 12% methylbenzethonium in
white soft paraffin. Methylbenzethonium is a disin-
fectant compound that has exhibited behavior against
growth of Leishmania promastigotes and amastigotes
in vitro.58 Combination of paromomycin with 10%
urea in white soft paraffin has also been used with
evidence of little to no therapeutic efficacy.59,60
In a double-blind randomized trial in Guatemala
the clinical response rate after a 12-month follow-up
period was 88.6% (31/35) in the group treated
topically for 20 days with ointment comprising 15%
paromomycin/12% methylbenzethonium versus
39.4% (13/33) in the placebo group.59 Both L brazil-
iensis and L mexicana are known to cause infection
in Guatemala. No identification of the specific
Leishmania species was performed for this study.
The researchers, however, note that according to
data from their several other studies, which took
place in the same geographic region, most of their
patients (75%) have been infected with L braziliensis
and 25% with L mexicana. In another randomized,
controlled study in Ecuador the effectiveness of two
topical paromomycin treatments (15% paromomy-
cin/12% methylbenzethonium and 15% paromomy-
cin/10% urea) were compared with the gold
standard treatment of meglumine antimoniate.61 By
12 weeks the researchers found that the proportion
of clinically cured subjects in the meglumine anti-
moniate group (91.7%) was not significantly different
(P [ .05) when compared with 15% paromomy-
cin/12% methylbenzethonium (79.3%) and 15%
J AM ACAD DERMATOL
AUGUST 2010
paromomycin/10% urea (70%) groups. The time,
however, required for the clinical healing of the
ulcerated lesions was significantly longer when top-
ical treatment was used.61
In a large, randomized, partially double-blind
controlled trial, which included patients mostly in-
fected by L braziliensis, a combination treatment of
topical 15% paromomycin/12% methylbenzethonium
plus a short course (7 days) of injectable meglumine
was investigated. The researchers concluded that the
addition of topical paromomycin to a short course of
meglumine antimoniate in the treatment of CL does
not augment the cure response.62 The same re-
searchers, however, in an earlier cohort study, had
reported cure rates of 90% with the use of the same
regimen of topical paromomycin plus a 7-day course
of meglumine antimoniate.63 The differences in the
findings may be attributed to the Leishmania species
involved in each case, emphasizing the importance of
species identification in treating CL.
A combination of 15% paromomycin and 0.5%
gentamicin was used topically twice daily for 10 days
to treat CL in mice. For ulcers caused by L mexicana, L
panamensis, and L amazonensis, the researchers
reported 100% cure rate and no evidence of relapse.64
However, a phase II trial in human beings that was
conducted in Colombia failed to reproduce these
findings. Treatment with this combination ointment
resulted in nonstatistically significant difference in
the cure rates between those individuals who were
treated and those who were given a placebo.65
Amphotericin B
Amphotericin preparations have typically been
used in treating visceral and mucosal leishmaniasis.
It is generally not indicated for CL, except for
mucosal lesions unresponsive to antimonial ther-
apy.38 Amphotericin B is associated with infusion-
related toxicityeand thus needs to be administered
slowlyeand nephrotoxicity.21 The liposomal prepa-
rations, also administered IV, are less toxic, but also
significantly more expensive.
Few studies have been done to determine the
treatment efficacy of amphotericin B in New World CL.
Solomon et al66 reported complete clinical cure with
liposomal amphotericin B in 7 patients with cutaneous
lesions caused by L braziliensis infection. This study,
however, was nonrandomized and included relatively
few patients. Similarly, several case reports of suc-
cessful treatment of New World CL (most caused by
L braziliensis) with amphotericin B exist.67,68
No large controlled studies assessing the therapeutic
efficacy of amphotericin B preparations were found. In
addition, the use of this drug for CL in human beings
J AM ACAD DERMATOL
VOLUME 63, NUMBER 2
appears to be limited and at present time its use to treat
New World CL cannot be recommended.
Miltefosine
Miltefosine, a phosphocholine analogue, was ini-
tially developed as an antineoplastic agent. It was
found to have antileishmanial activity in vitro and in
vivo, probably via effects on cell-signaling pathways
and membrane synthesis.69,70
Miltefosine, which is administered orally, has
demonstrated very promising results in Indian vis-
ceral leishmaniasis (cure rates [ 95%) and CL in
Pakistan (cure rates comparable with pentavalent
antimony), and is undergoing clinical trials for use in
several other countries.71-73 Currently, miltefosine it
is not available in the United States.
Oral miltefosine (2.5 mg/kg/d for 28 days) was
compared with IM antimony (20 mg/kg/d for 20
days) in the treatment of CL caused by L braziliensis
in Bolivia.74 The cure rates after 6 months of follow-
up were statistically similar at 88% (36/41) in patients
who received miltefosine versus 94% (15/16) in
patients who received antimony treatment.74
A large, placebo-controlled study of miltefosine
therapy against CL in Colombia and Guatemala
revealed therapeutic outcomes that varied by the
causative species.71 In regions in Colombia where L
panamensis is common the researchers reported
cure rates with oral miltefosine (2.5 mg/kg/d for 28
days) at 91% versus 38% in the placebo group.71 The
miltefosine cure rate was comparable with treatment
with the standard pentavalent antimony treatment.
On the other hand, in regions in Guatemala where L
braziliensis and L mexicana are prevalent the cure
rate for the miltefosine-treated group was 53% versus
21% in the placebo group.71 These cure rates are
significantly inferior to the historic antimony cure
rates of more than 90%. The findings in this study
parallel the data from preceding open-label trials in
the same geographic region.75,76
Although promising, additional placebo-controlled
studies are necessary to concretely assess the value of
miltefosine in the treatment of New World CL, and its
activity against the different Leishmania species.
Imiquimod
Imiquimod is an imidazoquinoline amine that has
been approved by the FDA for the treatment of
actinic keratosis, superficial basal cell carcinoma,
and external genital and perianal warts. Sold as a 5%
cream, imiquimod has demonstrated use for treating
dermatologic diseases of both neoplastic and infec-
tious origin. Imiquimod is an immune response
modifier that increases local cytokine production,
with a subsequent activation of both the innate
Mitropoulos, Konidas, and Durkin-Konidas 315
(rapid, nonspecific) and adaptive (specific, cellular,
and humoral) immune systems.77 Imiquimod partic-
ularly induces interferon-a, but also tumor necrosis
factor-alfa, interleukin (IL)-1a, IL-6, and IL-8.78
Furthermore, imiquimod and a related compound,
resiquimod (formerly called S-28463), have been
shown to effectively stimulate leishmanicidal activity
in macrophages.79
In a randomized, double-blind clinical trial use of
imiquimod produced a 72% cure rate when the
ointment was used in conjunction with meglumine
antimoniate in 40 patients with CL who had failed to
respond to antimony alone.80 All subjects received
meglumine antimoniate (20 mg/kg/d IM or IV) and
were randomized to receive either topical imiquimod
5% cream or vehicle control every other day for 20
days. Similarly, in an open-label, prospective study in
Peru, therapy of New World CL with imiquimod plus
meglumine antimoniate produced a cure rate of 90%
at the 6-month follow-up period.81 In addition, in a
pilot study in Peru patients were randomly assigned
to receive 1 of 3 treatments: imiquimod 7.5% cream
applied topically every other day for 20 days, IV
meglumine antimoniate at 20 mg/kg/d for 20 days, or
combination therapy with both meglumine antimoni-
ate and imiquimod 7.5% cream. The investigators
determined that the combination therapy was not
only more effective (100% cure rate) compared with
the other two treatments, but also led to faster healing
and better cosmetic results.82 Several of the patients
showed initial resolution of lesions with use of
imiquimod cream alone, but all experienced relapse
after discontinuation of treatment.82
The combination therapy with imiquimod and
meglumine antimoniate is a promising alternative
regimen for the treatment of New World CL. Most of
the evidence, however, is currently derived from stud-
ies with a limited number of patients. Additional, larger
studies are needed to support the current findings.
Allopurinol
Allopurinol (4-hydroxypyrazolo[3,4-d] pyrimidine)
is a drug traditionally used for the treatment of gout. It
has been shown to inhibit the growth of Leishmania in
vitro at concentrations that are attainable in human
tissues and body fluids.83 This compound is believed
to act by prohibiting the de novo synthesis of pyrim-
idines, probably through the formation of allopurinol
ribotide, which leads to the inhibition of protein
synthesis in the Leishmania parasite.83
Data from a randomized, controlled study in
Colombia revealed a 71% cure rate in patients who
received treatment with oral allopurinol (20 mg/kg/d
for 15 days) plus stibogluconate (20 mg/kg/d for
15 days) versus patients who received stibogluconate
316 Mitropoulos, Konidas, and Durkin-Konidas
alone (39% cure rate).84 In another similar, random-
ized, controlled study the cure rate with the combina-
tion of allopurinol plus meglumine antimoniate was
reported to be 74% versus 36% for patients treated with
meglumine antimoniate alone.85 In a placebo-con-
trolled study in Ecuador, a 41% cure rate (9/21) was
observed in patients with CL who received treatment
orally with allopurinol ribonucleoside (1500 mg 34
daily) plus probenecid (500 mg 34 daily) for 28 days.
This was compared with a 96% cure rate delivered in
the group that was treated with the standard IM
pentavalent antimony regimen for 20 days.86 Most of
the evidence in studies suggest that allopurinol may be
useful in treating New World CL but only when used as
an adjunct to pentavalent antimonials.87,88
Other drugs
Agents such as rifampicin, isoniazid, dapsone,
chloroquine, cyclosporine, recombinant interferon,
nifurtimox, and monoclonal antibodies that have
found some favor in human and animal studies
involving Old World CL have not being investigated
for their efficacy against New World disease.21-27 In
addition, several novel compounds have demon-
strated leishmanicidal activity, such as antimicrobial
peptides, and a diverse number of plant extracts, such
as chalcones, alkaloids, terpenes, and phenolics.55
There is still much more to learn about the activity of
these agents. They are still on an experimental plat-
form and have not yet been evaluated in clinical trials.
Physical methods/localized therapy
Physical measures, such as cryotherapy, heat
application, curettage, electrodessication, and surgi-
cal excision have all, also, been implemented in the
treatment of early, small, cutaneous lesions in leish-
maniasis. These can be an alternative when cost and
toxic adverse effects prevent the use of the proposed
first-line agents, or when systemic therapy is contra-
indicated, such in cases of pregnancy, heart condi-
tions, and impaired renal or hepatic function.21
Topical treatment in New World CL is commonly
not recommended except in cases of infection with L
mexicana where the risk of progression to mucosal
leishmaniasis is nearly nonexistent.38,56,57 For New
World disease most of the localized treatment mo-
dalities have not been analyzed with randomized,
placebo-controlled trials, making it difficult to
suitably appraise their effectiveness, and therefore
cannot be recommended at this time.
VACCINES
Over the years several strategies for the develop-
ment of a vaccine against leishmaniasis have been
pursued but to date no FDA-approved vaccine
J AM ACAD DERMATOL
AUGUST 2010
exists.89 Nevertheless, one live Leishmania prophy-
lactic vaccine in Uzbekistan and one killed
Leishmania vaccine used as an adjunct to antimony
therapy in Brazil have been registered for clinical use
against human disease.90
The development of a vaccine against leishman-
iasis, thus far, can be divided into the following
categories: (1) live Leishmania inoculation, termed
leishmanization; (2) first-generation vaccines con-
sisting of fractions of the parasite or whole killed
Leishmania with or without adjuvants; and (3) sec-
ond-generation vaccines using live genetically mod-
ified parasites, or bacteria or viruses containing
Leishmania genes, recombinant or native fractions.91
The presence of antileishmanial antibodies alone
does not offer full protection against reinfection. It
seems, however, that cellular immune responses are
associated with at least partial acquired immunity as
evidenced in populations that have been vacci-
nated.2,92 There is a general consensus among
Leishmania vaccine researchers that parasite persis-
tence may be an important factor for the maintenance
of an effective protective immune response by the
host.93 Research evidence indicates that both CD41
and CD81 T cells are involved in protection against
leishmaniasis.94 In addition, it has been identified that
CD8 cells are required for the maintenance of long-
term vaccine-induced immunity.95 The capacity to
induce both CD41 and CD81 cell responses has,
traditionally, been known to be a feature of DNA
vaccines. However, some protein-based vaccines have
demonstrated the same capacity.96,97 Although the
vast majority of vaccines have been directed against
antigens of the infectious agent transmitted by the
arthropod vector, other vaccine approaches have been
directed to the arthropod itself.98 Scientists begin to
consider vector and pathogen as an integrated unit in
the infectious process of leishmaniasis, and sandfly
molecules together with parasite antigens are being
investigated as components in a future vaccine.98
There is only one second-generation, multianti-
gen vaccine against leishmaniasis, named MPL-SE
(monophosphoryl lipid A in a stable emulsion), that
has reached human trials. The initial safety and dose-
escalating trial, conducted in volunteers in the
United States, produced satisfactory results. There
are also ongoing trials in Brazil and Peru for patients
with CL and mucosal leishmaniasis, respectively.
MPL-SE is being developed for prophylaxis, therapy
based on studies in mice, and preliminary trials in
human beings on a compassionate basis.91
DISCUSSION
New World CL lesions are less likely to heal
spontaneously than Old World CL and, therefore,
J AM ACAD DERMATOL
VOLUME 63, NUMBER 2
prompt treatment is recommended. Systemic agents
and, specifically, the pentavalent antimonials are the
drugs of choice. Certain species belonging to the L
viannia subgenus (L viannia braziliensis, L viannia
panamensis, and L viannia guyanensis) have a
greater tendency to disseminate systemically from
the skin compared with other species.15
Subsequently, topical treatment of New World CL is
not recommended. Exception to this are cases of
infection with L mexicana where the risk of pro-
gression to mucosal leishmaniasis is minimal.15,38,57
In cases of L mexicana infection, topical 15%
paromomycin/12% methylbenzethonium ointment
is viewed as an acceptable first-line treatment.38
Lesions may also become secondarily infected and
in those cases an appropriate antibacterial agent
should be prescribed. Multiple studies have indi-
cated that treatment outcome depends on the spe-
cies involved and, therefore, species determination,
when feasible, is ideal. It should also be noted that
multiple Leishmania species may coexist during
infection. Table III summarizes the currently recom-
mended treatment modalities for New World CL
according to species. Treatment recommendations
of infection by L mexicana, L panamensis, and L
braziliensis are based on A and/or B grades of
recommendation. Table IV lists and presents expla-
nation of the different grades. The several random-
ized, controlled studies that have been performed
provide reasonably strong evidence for the thera-
peutic efficacy of the current recommendations. The
first-choice treatment for infection by L guyanensis
(total of 4 injections containing 3 mg/kg/d of pent-
amidine isethionate delivered IM every other day) is
based on a few nonrandomized trials and a larger
number of case series studies. With the fair amount
of positive reports from respected authorities and
good clinical experience, this current treatment rec-
ommendation can be classified as being based on a C
level of strength. The treatment proposal (pentava-
lent antimony 20 mg/kg/d IV or IM for 20 days) for
the rest of the species associated with New World CL
is extrapolated from research involving the previ-
ously mentioned species (L mexicana, L panamen-
sis, L braziliensis). The paucity in randomized
controlled trials and lack of other appropriate data,
currently, makes this recommendation the only sen-
sible choice.
CL lesions may not heal for several weeks after
completion of treatment. Re-epithelialization of the
lesions continues after therapy has been concluded.
Complete healing is most commonly defined as
disappearance of the induration and complete re-
epithelization of the ulcer. This is what the majority
of the aforementioned studies used to assess cure
Mitropoulos, Konidas, and Durkin-Konidas 317
rates. Relapse of lesions after treatment may occur
after 3 to 6 months. Close patient follow-up and re-
evaluation of the infection sites is essential. Hence,
reevaluation at 4 to 6 weeks posttreatment and again
at 6 months may be prudent. In addition, patients
should be advised on measures that can be taken to
prevent infection when traveling to areas with high
incidence of infection.
Combination therapies have shown promising
results with favorable toxicity profiles, and further
trials should be continued. It appears, however, that
there is more of a need to focus on screening for new
antileishmanial products rather than attempting to
optimize the activity of the already known com-
pounds. The completed genome sequence of L
major and the progress of sequencing of the rest of
the Leishmania subspecies genome should further
facilitate identification of suitable drug targets.55 On
the other hand, some argue that the drug discovery
process is hindered by the alleged reluctance of the
pharmaceutical industry to invest in discovering
treatments for diseases that mainly affect the less
economically advanced countries.99-101
Meanwhile, emerging resistance to drugs and in-
secticides, drug toxicity, financial liability, and opera-
tional difficulties impede the progress toward effective
control of leishmaniasis. Additional methods for con-
trolling leishmaniasis include eradication of the vector
(sandfly) or its habitat, destruction of animal reser-
voirs, treatment of human reservoirs, personal protec-
tive measures against sandfly bites, and early diagnosis
and treatment of cases.
Leishmaniasis is a major vector-borne disease and
is the only tropical vector-borne disease that has
been endemic to southern Europe for decades. Most
of the reported cases are caused by zoonotic visceral
leishmaniasis, but CL is also present.102 As with other
vector-borne diseases, climatic patterns are associ-
ated with the epidemiologic profile of leishma-
niasis.103 Justifiably so, the emergence of global
warming and changes in climate cycles have gener-
ated concerns regarding the future of distribution
and spread of arthropod-borne diseases not only in
Europe, but worldwide. Warmer climatic changes
may aid the dissemination of both the sandfly vector
and the pathogen northward and into higher alti-
tudes. Moreover, in currently endemic regions,
higher temperatures may lead to prolonged vector
activity periods and shorter diapause periods. This
could result in an increased number of sandfly
generations per year.
Conversely, if the climate becomes too hot and
dry for the vector to survive, the disease may disap-
pear or its incidence may significantly be reduced in
certain geographic regions.
318 Mitropoulos, Konidas, and Durkin-Konidas J AM ACAD DERMATOL
AUGUST 2010

Table III. Species-specific treatment for New World leishmaniasis

Level of
Leishmania species98 Geographic region98 Recommended treatment evidence
Subgenus mexicana
L mexicana Belize, Colombia, Costa Rica, Dominican Topical: 15% paromomycin/12% A, B
Republic, Ecuador, Guatemala, Honduras, methylbenzethonium applied twice
Mexico, Panama, United States, Venezuela daily for 20 d
Systemic: pentavalent antimony
20 mg/kg/d IV/IM for 20 d, or
ketoconazole 600 mg/d orally for 28 d
L amazonensis Bolivia, Brazil, Colombia, Costa Rica, Ecuador, Pentavalent antimony 20 mg/kg/d IV/IM C
French Guiana, Panama, Peru, Venezuela for 20 d
L venezuelensis Venezuela
L chagasi Argentina, Bolivia, Brazil, Colombia, Ecuador,
El Salvador, Guadalupe, Guatemala,
Honduras, Martinique, Mexico, Nicaragua,
Paraguay, Suriname, United States,
Venezuela
Subgenus viannia
L braziliensis Argentina, Belize, Bolivia, Brazil, Colombia, Pentavalent antimony 20 mg/kg/d A, B
Costa Rica, Ecuador, Guatemala, IV/IM for 20 d
Honduras, Nicaragua, Panama, Paraguay,
Peru, Venezuela
L panamensis Colombia, Costa Rica, Ecuador, Honduras, Pentavalent antimony 20 mg/kg/d IV/IM for A, B
Nicaragua, Panama, Venezuela 20 d, or ketoconazole 600 mg/d orally for
28 d, or combination of pentavalent
antimony (20 mg/kg/d for 15 d) and oral
allopurinol (20 mg/kg/d for 15 d)
L peruviana Peru Pentavalent antimony 20 mg/kg/d IV/IM C
L lainsoni Brazil for 20 d
L naiffi Brazil
L colombiensis Colombia, Panama, Venezuela
L shawi Brazil
L guyanensis Brazil, Colombia, Ecuador, French Guiana, Pentamidine isethionate 3 mg/kg/d IM every C
Peru, Surinam, Venezuela other day for up to 4 injections

IM, Intramuscular; IV, intravenous;

Table IV. Grading/strength of recommendations according to existing evidence

Grades/strength of
recommendation Explanation
A Based on evidence supported by $ 1 RCTs, or systematic review of trials of sufficient size to ensure
low risk of false-positive or false-negative results (narrow confidence interval)
B Based on evidence supported by good-quality cohort studies or low-quality RCT (eg, small size, \80%
follow-up) or case-control studies, including systematic reviews of case-control studies
C Based on evidence from case series, poor-quality cohort or case-control studies, or extrapolations*
from studies of A or B grading
D Evidence based on expert opinion without explicit appraisal, or based on physiology, bench research,
or troublingly inconsistent or inconclusive studies of any level

RCT, Randomized controlled trial.

*Extrapolations are where data are used in a situation that has potentially clinically important differences from original study situation.

To date, there is no compelling evidence that
sandfly and leishmaniasis distribution in Europe has
altered in response to recent climate changes. Since the
mid-1990s the worldwide geographic distribution
of leishmaniasis has expanded, and in Europe,
specifically, there has been a suggestion of a northward
spread as indicated by reports of visceral leishmaniasis
cases in northern Italy and southern Germany.104-106
This spread, however, is most likely the result of a
combination of factors, such as increased monitoring,
J AM ACAD DERMATOL
VOLUME 63, NUMBER 2
demographic changes, population movement, land
use, and possibly, changes in seasonal climate.104 In
one study in Costa Rica, researchers indicated that the
dynamics of CL are strongly associated with climate
variables, such as land temperature and certain El Nino
southern oscillation indices. They asserted that the
incidence of CL can be predicted 12 months ahead,
with an accuracy that varies between 73% and 77%.103
However, improved surveillance methods and a
more profound understanding of the relationship
between climate and disease dynamics is essential to
anticipate and recognize disease trends in the setting
of the global changes in climate and physical
environment.
In nonendemic countries, many physicians may
not readily suspect CL in individuals presenting with
skin lesions. Moreover, many health care providers
do not inquire on the travel profile of the patient
during history taking. Several medical institutions in
nonendemic countries have already observed an
escalating number of cases of New World CL.15 It is
reasonable to speculate that this is the result of
increased travel to destinations such as Central and
South America. It is not unlikely that New World CL
will emerge as an increasingly frequent imported
infection. This ought to remind all clinicians that CL
should be included in the differential diagnosis of
cutaneous ulcers in all travelers, foreign visitors, and
immigrants from leishmaniasis-endemic areas.
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