New World cutaneous leishmaniasis: Updated review of current and future diagnosis and treatment

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 protozoan parasite Leishmania species. The disease has

From the Camp Long Troop Medical Clinic. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Panagiotis Mitropoulos, DO, 75th Medical Company, Unit 15190, Camp Humphreys, APO, AP 96297. E-mail: [email protected]. Published online March 22, 2010. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.06.088

Abbreviations used: CL: FDA: IL: IM: IV:

cutaneous leishmaniasis Food and Drug Administration interleukin intramuscular intravenous

gained interest because of expanding international travel, population overgrowth, the HIV/AIDS pandemic, and reports of increasing incidence up to 500% in several endemic areas.1,2 The United States has also seen an increasing number of leishmaniasis cases because more and more Americans are 309

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traveling to endemic countries, and because of the larger number of military and contract workers deployed overseas.

minority of them progressing to muco-CL. Visceral leishmaniasis and diffuse CL are also found in the aforementioned geographic regions. Although recognition of the geographic distributions of the various parasites and their prevalence has increased during EPIDEMIOLOGY recent years, the disease is still grossly underreported. Leishmaniasis is a disease caused by the protozoa Estimates of the number of cases are frequently of the Leishmania species, which is transmitted by unreliable as a result of local the bite of a female sandfly. difficulties in diagnosis and During their blood meal, CAPSULE SUMMARY the frequency of subclinical infected sandflies inject the infections; frank disease repinfective stage, the promastiThis article highlights leishmaniasis resents only a proportion of gote parasite, into the human epidemiology and calls attention to total infections.8 host. Injected promastigotes modern changes in its worldwide In the Unites States more are then phagocytized by incidence and burden. than 25 nonmilitary cases of macrophages and are transFactors that may impact leishmania cutaneous disease have been formed into amastigotes. geographic distribution and incidence of identified since 1980 in These multiply in the ininfection are discussed. individuals living in Texas fected cells and affect differsuggesting that the disease ent tissues and, depending Based on evidence from a number of may be endemic in that reon the Leishmania species, randomized controlled studies, the gion.9,10 Nevertheless, almost cause the corresponding therapeutic efficacy of several different all cases of leishmaniasis in clinical manifestation of the regimens against New World cutaneous the United States are thought disease. leishmaniasis is assessed. to have been imported from The disease can be classiThe authors summarize their findings elsewhere. fied several ways. A common and present clinical practice guidelines way is geographically into for the treatment of cutaneous DIAGNOSIS New World versus Old leishmaniasis according to Leishmania Occurring in several forms, World disease. Old World species. leishmaniasis is generally recforms of Leishmania are They comment on current knowledge ognized from its cutaneous transmitted by sandflies of and future prospects for the form that causes nonfatal, the genera Phlebotomus and development of a prophylactic vaccine. disfiguring lesions. However, are endemic in Africa, Asia, infection may result in a wide the Middle East, and the spectrum of clinical diseases that can be divided into Mediterranean. The New 4 broad categories: (1) CL, (2) diffuse CL, (3) mucoWorld form is transmitted mainly by flies of the genus CL, and (4) visceral leishmaniasis. The severity and Lutzomyia that are endemic from Texas through clinical presentation of leishmaniasis that develops South America. Australia and the South Pacific are depends on many factors, including the species of not considered leishmaniasis-endemic regions.3 The overall prevalence of leishmaniasis is estiLeishmania involved, the number of parasites inocmated 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 CL is the most common form of the disease. It is million new cases annually (1.5 million for cutaneous characterized by one or more papules, nodules, or leishmaniasis [CL] and 500,000 for visceral leishmanulcers. The lesions are, typically, described as lookiasis).4 Muco-CL is estimated to develop as a complication 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 diagregions 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 orgacaused 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 d

d

d

d

d

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listed in Table II. The organisms are identified on Giemsa and Romanowsky hematoxylineosinestained 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 species-specific treatment.14

Table I. Differential diagnoses of cutaneous leishmaniasis

TREATMENT

via cryotherapy or heat administration. The use of surgical excision and curettage is rarely recommended 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, monoclonal antibodies, oxygenated chalcones, cyclosporine, and photodynamic therapy.21,26-30 Both human and parasite genomes have been targeted for sequence analysis. The Leishmania genome 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 highquality 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, because 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 interaction 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.

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 commonly 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 multiple 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 evidence 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 sodium stibogluconate (Pentostam, GlaxoSmithKline, London, UK) or meglumine antimoniate (Glucantime, Sanofi-Aventis, Bridgewater, NJ), administered intravenously (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 involving Old World disease, have demonstrated moderate to excellent treatment efficacy and cosmetic outcomes

Sporotrichosis Blastomycosis Atypical mycobacterial infection Cutaneous tuberculosis Lupus vulgaris Tertiary syphilis (gumma) Insect bite reaction

Ecthyma Malignancy Sarcoidosis Tularemia Yaws Myiasis Cutaneous anthrax

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

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Table II. Leishmaniasis diagnostic tests Histology Scraping, punch biopsy specimen, or aspirate

Culture On Schneider Drosophila or NNN mediums

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

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)

Serologic tests ELISA, IFA, DAT, K39 ELISA, strip tests

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

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 unresponsiveness and resistance of the organisms to therapy. Currently, the efficacy of an antimony regimen 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 neighboring 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 limitations in the treatment of leishmaniasis. In lieu of that, several studies have investigated the efficacy of a shorter course of treatment. In a randomized, double-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 mirrored 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 antimonials 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

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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 development 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 associated 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

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 advantage of these compounds is that they can be orally administered and that the side-effect profile is considerably less toxic compared with the recommended pentavalent antimonials. Studies on use of oral ketoconazole for the treatment 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 ketoconazole 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 amastigotes in posttreatment biopsy specimens and negative posttreatment culture findings. The modest activity of oral ketoconazole against L mexicana, and the substantially lower efficacy against L braziliensis 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 itraconazole 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, paromomycin is used to treat giardiasis, amebiasis, and

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cryptosporidiosis. Topically, it is commonly used to treat Old World CL (L major, L tropica, L aethiopica). Injectable paromomycin has been experimentally 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 associated with infection by L braziliensis and L panamensis. Strains of L mexicana, on the other hand, have been found to be highly susceptible to paromomycin sulfate treatment.56 Currently, topical treatment of New World CL is not recommended except in cases of infection with L mexicana where the risk of progression to mucosal leishmaniasis is unlikely.15,38,57 In cases of L mexicana infection topical 15% paromomycin/12% methylbenzethonium ointment 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 disinfectant 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 braziliensis 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% paromomycin/12% methylbenzethonium and 15% paromomycin/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 antimoniate group (91.7%) was not significantly different (P [ .05) when compared with 15% paromomycin/12% methylbenzethonium (79.3%) and 15%

paromomycin/10% urea (70%) groups. The time, however, required for the clinical healing of the ulcerated lesions was significantly longer when topical treatment was used.61 In a large, randomized, partially double-blind controlled trial, which included patients mostly infected 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 researchers, 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 therapy.38 Amphotericin B is associated with infusionrelated toxicityeand thus needs to be administered slowlyeand nephrotoxicity.21 The liposomal preparations, 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 successful 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

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appears to be limited and at present time its use to treat New World CL cannot be recommended. Miltefosine Miltefosine, a phosphocholine analogue, was initially 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 visceral 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 followup 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 infectious origin. Imiquimod is an immune response modifier that increases local cytokine production, with a subsequent activation of both the innate

(rapid, nonspecific) and adaptive (specific, cellular, and humoral) immune systems.77 Imiquimod particularly 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 antimoniate 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 studies 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 pyrimidines, 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

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alone (39% cure rate).84 In another similar, randomized, controlled study the cure rate with the combination of allopurinol plus meglumine antimoniate was reported to be 74% versus 36% for patients treated with meglumine antimoniate alone.85 In a placebo-controlled 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 demonstrated 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 platform and have not yet been evaluated in clinical trials. Physical methods/localized therapy Physical measures, such as cryotherapy, heat application, curettage, electrodessication, and surgical excision have all, also, been implemented in the treatment of early, small, cutaneous lesions in leishmaniasis. 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 contraindicated, such in cases of pregnancy, heart conditions, 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 modalities 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.

exists.89 Nevertheless, one live Leishmania prophylactic 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 leishmaniasis, thus far, can be divided into the following categories: (1) live Leishmania inoculation, termed ‘‘leishmanization’’; (2) first-generation vaccines consisting of fractions of the parasite or whole killed Leishmania with or without adjuvants; and (3) second-generation vaccines using live genetically modified 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 vaccinated.2,92 There is a general consensus among Leishmania vaccine researchers that parasite persistence 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 longterm 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, multiantigen vaccine against leishmaniasis, named ‘‘MPL-SE’’ (monophosphoryl lipid A in a stable emulsion), that has reached human trials. The initial safety and doseescalating 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

VACCINES Over the years several strategies for the development of a vaccine against leishmaniasis have been pursued but to date no FDA-approved vaccine

DISCUSSION New World CL lesions are less likely to heal spontaneously than Old World CL and, therefore,

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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 progression 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 indicated that treatment outcome depends on the species 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 recommended 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 explanation of the different grades. The several randomized, controlled studies that have been performed provide reasonably strong evidence for the therapeutic efficacy of the current recommendations. The first-choice treatment for infection by L guyanensis (total of 4 injections containing 3 mg/kg/d of pentamidine 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 recommendation can be classified as being based on a C level of strength. The treatment proposal (pentavalent 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 previously mentioned species (L mexicana, L panamensis, L braziliensis). The paucity in randomized controlled trials and lack of other appropriate data, currently, makes this recommendation the only sensible 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 reepithelization of the ulcer. This is what the majority of the aforementioned studies used to assess cure

rates. Relapse of lesions after treatment may occur after 3 to 6 months. Close patient follow-up and reevaluation 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 compounds. 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 insecticides, drug toxicity, financial liability, and operational difficulties impede the progress toward effective control of leishmaniasis. Additional methods for controlling leishmaniasis include eradication of the vector (sandfly) or its habitat, destruction of animal reservoirs, treatment of human reservoirs, personal protective 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 associated with the epidemiologic profile of leishmaniasis.103 Justifiably so, the emergence of global warming and changes in climate cycles have generated 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 altitudes. 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 disappear or its incidence may significantly be reduced in certain geographic regions.

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Table III. Species-specific treatment for New World leishmaniasis Leishmania species98

Geographic region98

Recommended treatment

Subgenus mexicana L mexicana Belize, Colombia, Costa Rica, Dominican Topical: 15% paromomycin/12% 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 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 Pentavalent antimony 20 mg/kg/d L braziliensis Argentina, Belize, Bolivia, Brazil, Colombia, 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 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 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 Peru, Surinam, Venezuela other day for up to 4 injections

Level of evidence

A, B

C

A, B

A, B

C

C

IM, Intramuscular; IV, intravenous;

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

A B C D

Explanation

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) 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 Based on evidence from case series, poor-quality cohort or case-control studies, or extrapolations* from studies of A or B grading 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,

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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 Nin˜o 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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