Treatment of Cutaneous Leishmaniasis in Travelers 2009

Leishmaniasis is an infection caused by intracellular protozoan parasites of the genus Leishmania and it is transmitted by various species of sand flies. Apart from disseminated visceral leishmaniasis (kala azar), nodules, patches/plaques, ulcerative skin lesions, and destructive mucosal inflammation comprise the wide range of clinical manifestations. With regard to cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML), the parasite species are divided into Old World (Southern Europe, the Middle East, Asia, and Africa) and New World leishmaniasis (Latin America). While most of the Old World species cause benign cutaneous disease, a variety ranging from mild cutaneous disease to severe mucosal lesions is seen among the American species. CL is one of the 10 leading presentation diseases among tourists from tropical countries with skin diseases and was found in 3% of travelers with skin disorders. 1 Because of the broad clinical spectrum of CL and resemblance with common skin diseases such as bacterial or fungal infections and tumors, the correct diagnosis is initially often missed. However, a delayed diagnosis may lead to mucosal spread. Furthermore, treatment of the various species may be different and a suboptimal treatment may cause a prolonged course of the disease and may be associated with disfiguring scars. 2,3 The broad availability of polymerase chain reaction (PCR) allows a rapid determination of species. A species‐specific treatment approach has been evaluated for many species and is widely applied in many centers. 4–9 These treatment options need to be regularly adapted integrating new knowledge and data. This manuscript focuses on new aspects of established compounds and on new drugs such as miltefosine and the combination of traditional compounds with immunomodulators. Recent data focusing on genetic differences of individual species between regions are integrated and region‐specific treatment recommendations for Leishmania braziliensis10,11 and Leishmania guyanensis12 CL are given. In many cases of Old World CL, topical treatment can be used as first‐line treatment. In most New World CL, systemic treatment is indicated because of the risk of mucosal spread. The criteria for the use of systemic treatment respecting the aspect of the lesion and the species is summarized inTable 1. The different treatment options for CL and ML according to species, their application mode, dosage schedule, adverse effects, and management are summarized inTables 2 and 3. The indications for systemic treatment 7 The indications for systemic treatment 7 Drugs and follow up for treatment of CL ECG = electrocardiogram; ULN = upper limit of normal. Drugs and follow up for treatment of CL ECG = electrocardiogram; ULN = upper limit of normal. Treatment by species Categories reflecting the quality of evidence on which the following recommendations are based: 1. Randomized controlled trial in representative collective: A. 2. Randomized controlled trial in partially representative (small patient number, different species included) collective. Cohort trial or case‐control study in representative collective: B. 3. Cohort trial or case‐control study in partially representative collective, series of cases in representative collective: C. 4. Series of cases in partially representative (small patient number, different species included) collective, informal expert opinion, other information: D. Treatment by species Categories reflecting the quality of evidence on which the following recommendations are based: 1. Randomized controlled trial in representative collective: A. 2. Randomized controlled trial in partially representative (small patient number, different species included) collective. Cohort trial or case‐control study in representative collective: B. 3. Cohort trial or case‐control study in partially representative collective, series of cases in representative collective: C. 4. Series of cases in partially representative (small patient number, different species included) collective, informal expert opinion, other information: D. Pentavalent antimonials[meglumine antimoniate (MA) and sodium stibogluconate] have been used for decades for the treatment of CL of the New World and are the gold standard for other drugs. The biochemical basis for their effectiveness is unknown but may involve inhibition of ATP synthesis. They are still the best documented treatment and are used as first‐line treatment for most New World Leishmania species and for patients with severe Old World leishmaniasis in most travel clinics. The dosage is usually given in Sb equivalents (mg/kg). Some centers administer daily ambulatory treatment without substantial rates of complications. 62 Laboratory abnormalities such as liver function tests or amylase are very common and should be monitored as shown inTable 1. Reversible electrocardiogram (ECG) alterations are seen in 30% to 60% and may occur without evidence of myocardial damage. 13–15 Recent reports on QTc prolongation in a patient with low serum potassium and underlying cardiac disease to 587 msec 16 and in a child 63 underline the importance of ECG testing before and during treatment (Table 1). Patients with underlying cardiac disease or with risk of electrolyte disorders such as diuretics or diarrhea should be hospitalized for continuous observation. Pentamidine, an aromatic diamidin, is the first‐line treatment of L guyanensis in French Guyana, Surinam, and Brazil and can be used as an alternative to the pentavalent antimonials. Pentamidine mesylate (Lomidine) was mainly used in the past. Currently, pentamidine isethionate (Pentacarinat) is the only available drug. Unfortunately, the dosage of pentamidine mesylate (Lomidine) is usually given in pentamidine base and the one of pentamidine isethionate (Pentacarinat) in salt; 4 mg of pentamidine isethionate salt correspond to 2.3 mg base. Thus, the previous (base) dosages can only be compared to the recent dosages (salt) after correcting for the base or salt. For L guyanensis, similar cure rates were found for seven daily injections of 120 mg of pentamidine mesylate (Lomidine) and 300 mg of pentamidine isethionate (corresponding to 173 mg base) weekly for 3 to 5 weeks (87% vs 94%). The respective relapse rates were 10.6% and 10%. 40 Recently, an elevation of the creatinine kinase (CK) was observed with much higher doses of pentamidine isethionate (two injections of 7 mg salt/kg = 4 mg base/kg; second course in case of treatment failure). In 85% of these patients, the CK was extensively elevated (>5,000 IU/L, normal value 25–195 IU/L) indicating rhabdomyolysis, but clinical symptoms of rhabdomyolysis such as muscle pain, weakness, or renal failure, were not observed. 25 In an additional study with single‐dose pentamidine isethionate (7 mg salt/kg = 4 mg base/kg), substantially increased CK elevation (>1,000 U/L, range 1,032–9,312 U/L, normal <160 U/L) was observed in 19 of 26 patients. 26 In most studies, CK was not tested. It is not clear if the higher dosage of pentamidine and/or the intramuscular application is the cause of CK elevation or if rhabdomyolysis was overseen because of lack of symptoms and lack of testing in previous studies. Pentamidine isethionate in the dosage of 4 mg/kg (salt) intramuscularly daily for 7 days is the treatment of choice for human African Trypanosomiasis. In a previous and a recent trial with about 200 patients, no rhabdomyolysis was reported. Because of this risk of rhabdomyolysis, an alternative treatment would be preferable. The only validated alternative treatment for L guyanensis CL would be pentavalent antimony. But its cure rate after 6 months was disappointingly low (26.3%). 64 However, in a recent study in Peru, the cure rate after 6 months of pentavalent antimony was much higher (91.7%). A part from study design differences, these differences could be explained by genetic differences within individual species. 12 Because of the long lasting good experience in respect to efficacy and safety and because of the lack of a validated alternative, pentamidine has to be considered as first‐line treatment of L guyanensis CL in French Guyana, Surinam, and Brazil. In Peru, pentavalent antimony could be used as first‐line treatment. Because of the unclear correlation of high‐dose pentamidine and CK, repeated doses of pentamidine [three to four doses of 4 mg/kg pentamidine salt (Pentacarinat) on alternate days or weekly as intravenous infusion] 40,41 can be proposed, but CK and kidney function have to be controlled before every injection. Miltefosine, a phosphocholine analog, is a new promising oral agent for visceral leishmaniasis. An increasing number of studies shows its efficacy in Old World and New World CL and ML. The same dose of 2.5 mg/kg/d for 28 days was used for CL and ML. The most important adverse events are nausea (36%), vomiting (32%–38%), motion sickness (29%), headache (27%), and diarrhea (6%–16%). 29,30 However, vomiting lasted less than 3 days in most patients and did usually not lead to a discontinuation of treatment. Creatinine increased above the normal range in 32%, in 31% <1.5 times the upper limit of normal, and in 1% between 1.5 and 3 times the upper limit of normal. 30 The aspartate aminotransferase was elevated in 8% and the alanine aminotransferase in 10% but always less than 2.5 times the upper limit of normal. 30 Treatment with miltefosine is reported in only a small number of patients with Old World CL. The cure rate (26 of 28 = 92.9%) of miltefosine was superior to the cure rate (25 of 31 = 83.1%) of meglumine antimoniate (20 mg/kg for 14 days) in patients with Leishmania major CL. However, four patients in the miltefosine group stopped treatment because of severe vomiting. 56 In a small nonrandomized trial with L major and Leishmania tropica miltefosine (n= 15) had a cure rate of 100% at the end of treatment and 87% after 6 months and was superior to meglumine antimoniate (20 mg/kg for 28 days) with a cure rate of 93% at the end of treatment and 67% after 6 months. 57 In the mouse model, four L tropica isolates resistant to meglumine antimoniate from Iran were shown to be sensitive to miltefosine and to paromomycin. 65 In L major CL, miltefosine appears to be a valuable option and may be superior to meglumine antimoniate for 14 days. However, the high price and adverse events such as vomiting limit its use. The alternative for oral treatment is fluconazole (Table 3). The limited data do not allow a judgment of the efficacy against Leishmania infantum and L tropica. Miltefosine shows promising effects on Leishmania panamensis(91%–94% cure rate), but only a limited effect against Leishmania mexicana(60%). 10,66 It failed to cure L braziliensis infections (33%) in Guatemala. 10 Interestingly, the cure rates of miltefosine of L braziliensis infections in Bolivia (88%) were much higher than in Guatemala and similar to meglumine antimoniate (94%), 11 but antimony cured more rapidly. It appears that subspecies of L braziliensis respond differently to miltefosine. Thus, this drug needs to be evaluated in different regions. In New World ML (mainly L braziliensis), the cure rate of miltefosine was 83% in patients with mild disease (ie, nasal mucosa) and 58% in patients with more extensive disease (involving pharynx, larynx, and palate). In a nonrandomized contemporary group with ML treated with amphothericin B (45 injections of 1 mg/kg applied every other day), the cure rate was only 50%. 44 Miltefosine is a valuable option for L panamensis. However, the high costs and poor tolerability limit its use. Ketoconazole (Table 2) is a less expensive and better tolerated alternative for oral treatment, even if the efficacy was slightly inferior (76% cure rate). 31 For L braziliensis, meglumine antimoniate is still the treatment of choice, but miltefosine can be used as alternative, mainly in patients with ML. The antifungal agent amphothericin B is active against Leishmania species. Its main disadvantage is the high incidence of adverse reactions (hyperpyrexia, severe malaise, hypotension, thrombophlebitis, azotemia, renal tubular damage, hypokaliaemia, anemia, and hepatitis). The development of several amphothericin B lipid formulations with lower toxicities than the free drug has proved to be useful in the treatment of visceral leishmaniasis, but the appropriate doses for CL and ML are still under debate. Liposomal amphothericin B is mainly used in patients with resistance or contraindications for pentavalent antimonials. In ML, good response has been observed with dosages between 2 and 3 mg/kg for at least 20 days. 60,61 Even in the absence of a randomized study, there are now sufficient data to support recommendation of liposomal amphothericin B. The high cost limits its use as first‐line treatment for ML. The imidazoles and the structurally related triazoles were introduced as antifungal drugs, but also have an antileishmanial activity. They have the advantage of oral administration and few adverse effects. Fluconazole was well tolerated and showed promising results in L major leishmaniasis in Iran with a cure rate of 36% at day 50 and 88% at day 90 compared to the corresponding cure rates of 10% and 66% in the placebo group. 55 Unfortunately, these good responses of fluconazole could not be reproduced: the cure rate of 44% at day 50 was similar to published data of spontaneous healing but was not compared to a placebo group. 67 Because of different interpretation of cure rate and different geographic regions, these data do not allow additional conclusions. In the same study, five patients with L infantum lesions had treatment failure with fluconazole. 67 The efficacy of itraconazole is doubtful. The clinical cure rates 200 mg of itraconazole daily for 8 weeks (59%) was similar to the placebo group (53%) in patients with L major CL. 68 Studies with small patient numbers from the 1980s and early 1990s showed that ketoconazole has an acceptable cure rate for L panamensis(76%), 31 for L mexicana(eight of nine patients), 34 and for L major(70%). 69,70 However, these studies comprised only limited patient numbers and were not confirmed by recent studies. Fluconazole is the imidazole of first choice for treatment of L major infections and ketoconazole for L panamensis infections. 31 Because of only limited data on L infantum with treatment failure in all cases, fluconazole cannot be suggested for treating L infantum leishmaniasis. The efficacy of azithromycin is limited. 71–73 However, it was successfully applied in the dosage of 500 mg daily during 10 days, in three to four cycles every 1 to 2 months in a child (L infantum) 74 and in three elderly patients with ML and contraindication to classical drugs. 75 Therefore, the use of azithromycin is limited to patients with treatment failure or contraindications for all other options such as small children, pregnant women, or patients with underlying severe disease. Topical immunomodulators are ineffective given alone but may improve the efficacy of a standard treatment such as meglumine antimoniate if given in combination. Imiquimod (1(2methylpropyl)‐1H‐imidazo(4,5‐c)quinolin‐4‐amine) is widely used against genital warts caused by the human papillomavirus. It acts as an immune response modifier through stimulation of a local immune response at the site of application on the cutaneous genital warts, resulting in wart regression and resolution. It has no direct activity against leishmaniasis but was shown to improve the efficacy of pentavalent antimonials. With CL (L peruviana) 12 patients resistant to MA responded to the combination of MA plus imiquimod (5% cream topically, applied every other day for 20 days). 76 Seven patients with New World leishmaniasis (species unknown) all had a clinical cure, whereas only four of seven patients in the placebo group were cured. 77 The addition of imiquimod to MA did not improve the cure rate but induced a more rapid healing in 40 patients suffering from L peruviana or L braziliensis CL. 78 However, in Old World leishmaniasis due to probably L tropica, the addition of imiquimod did not improve the cure rate of meglumine antimoniate for 14 days. 79 Human granulocyte–macrophage colony‐stimulation factor (GM‐CSF) is commercially available (molgramostim). It has to be diluted to a final concentration of 10 μg/mL and to be applied on the ulcer as follows: ulcers are cleansed with 0.9% sodium chloride solution and are sprinkled with 1 mL of GM‐CSF working solution, providing a final dose between 1 and 2 μg/cm2 of ulcer area. A nonadhesive hydrophobic wound compress is secured over the area with a cotton bandage and a short stretch compression bandage. The application of 200 μg of GM‐CSF into the lesion at enrollment and 1 week later decreased the time of healing significantly and was—apart from minor local reactions—well tolerated. 80 The mean healing time was shorter (43 days) in the GM‐CSF (three applications per week for 3 weeks) group than in the placebo group (104 days). 81 Five patients who had received three or more courses of antimony without success could be healed with 1 to 2 mL of the GM‐CSF solution (10 μg/mL) associated with standard parenteral antimony. 82 The addition of an immunomodulating topical treatment to antimonials appears to be promising, but additional studies with other Leishmania species are needed. The additional workload of local application and bandages is compensated by a quicker achievement of healing, a better cure rate and cure in patients with lesions refractory to MA. The data are insufficient to compare imiquimod and GS‐CFS. In patients with refractory lesions or lesions needing a quick treatment (face), the addition of an immune modulator may be tried. In mucosal destructive lesions, a paucity of parasites and high levels of tumor necrosis factor (TNF) are observed, and the tissue damage is related to an unmodulated immune response with increased production of proinflammatory cytokines such as interleukin‐10. Pentoxyfilline is known to downregulate TNF‐α and to decrease leukocyte migration and adhesion. In 10 patients with refractory ML, the combination therapy of pentoxifylline (3 × 400 mg for 30 days) and antimony (20 mg/kg of Sb for 30 days) induced cure. 59 Another 11 patients with ML treated with the same combination were cured, whereas 5 of 12 patients (41.6%) in the placebo group (only antimony) required a second course of antimony. The healing time in the pentoxifylline group was 83 days compared with 145 days in the placebo group. No relapses were documented in either group at the 2‐year follow‐up visit. 83 A satisfactory response with quick cure of skin lesions of two patients with New World CL unresponsive to antimonial drugs was observed after treatment with pentoxifylline and antimony. 84 The combination of antimony and pentoxifylline was superior to antimony and placebo also in patients with L major CL: complete improvement, partial improvement, and poor response to treatment were 81.3%, 12.5%, and 6.2% in the trial group and 51.6%, 29%, and 19.4% in the control group, respectively. 85 The addition of pentoxifylline to MA is well tolerated and only mild adverse effects (gastrointestinal symptoms and arthralgia) were attributed to pentoxyfilline. 83,85 The combination of MA and pentoxifylline is superior to MA alone and is suggested for relapsing and severe ML. 83 There are no data on the combination of pentoxifylline with other drugs such as amphothericin B and miltefosine. With a clinical cure could be in patients with refractory ML, but such is not treatment with treatment, 90 or combination of with meglumine antimoniate were successfully applied in However, treatment was not applied in patients with Old World CL in and the 8 probably because the are not available in these or the have no to these was used only in the treatment needs clinical experience and and is limited to centers with a high number of CL patients. An with plus chloride appears to be more than the combination of plus 10% but more local has antileishmanial may cause a local and appears to improve the of paromomycin. The main for this topical treatment is the of into the Topical formulations may be applied for the clinical of L braziliensis CL. The lesions of pregnant with CL are than in and in to the presentation of a ulcer with lesions are often of a Because pentavalent are treatment is and topical treatment is In patients with contraindications for the treatment such as small children, 74 pregnant women, or patients with underlying severe disease, 75 azithromycin can be an option its limited available tests to the species allow species‐specific diagnosis of the and a species‐specific treatment. However, most studies were in regions and different responses to treatment cannot be in Thus, a study a is to the of disease and to treatment in The that have no of