Mashhad University of Medical Sciences Clinical Research Development Center (MUMS) Reviews in Clinical Medicine Ghaem Hospital

Systemic Treatments of Leishmaniasis: A Narrative Review

Ahmad Reza Taheri (MD)1, Sara Sabouri Rad (MD)1, Sara Molkara (MD)2*

1Cutaneous Leishmaniasis Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. 2Resident of Dermatology, Imam Reza hospital, Mashhad University of Medical Sciences, Mashhad, Iran.

ARTICLE INFO ABSTRACT

Article type Cutaneous leishmaniasis is a prevalent parasitic infection in humans. According to the Review article reports published in several localities across the world, leishmaniasis is an endemic

Article history and is often diagnosed through the smear examination of the affected area using a Received: 18 Aug 2019 microscope.disease in certain The treatments regions in ofIran. choice Leishmaniasis for leishmaniasis is transmitted involve the through use of sandfly pentavalent bites Revised: 8 Sep 2019 antimony compounds, such as meglumine antimoniate and sodium stibogluconate. Accepted: 22 Sep 2019 However, other medications have been proposed for the treatment of leishmaniasis, and there is ongoing research for effective, less harmful treatments. This narrative Keywords Cutaneous Leishmaniasis review aimed to summarize various systemic treatments for leishmaniasis. Systemic Treatment

Please cite this paper as: Taheri AR, Sabouri Rad S, Molkara S. Systemic Treatments of Leishmaniasis: A Narrative Review. Rev Clin Med. 2019;6(3):91-97.

Introduction Leishmaniasis is a prevalent disease of trop- less and might heal within a few months, while ic and sub-tropic regions, affecting 15 million they often cause impaired function, secondary in- individuals across the globe. Based on tropism, fections or persistent wounds (5,9,10). leishmaniasis is categorized into four clinical syn- - dromes, including cutaneous, mucocutaneous, dif- taneous clearing of the wounds without interven- fuse cutaneous, and visceral leishmaniasis (1-5). tionsThere in arethe severalpatients, influential including factors immunology in the spon and Cutaneous leishmaniasis is a chronic dermal genetics, locality, number and species of the para- condition, which is characterized by several clini- site, clinical symptoms, and severity of the lesions, cal symptoms due to the variable immunity status of the host, affected area, and age of the patients. of treatment. Considering the large variability of Leishmania major and L. tropica cause urban and theseand the factors, outcome spontaneous significantly recovery affects may the prolong, course rural leishmaniasis, respectively. The organism thereby leading to the scars that care particular- was transmitted to humans by Phlebotomus pa- ly problematic in various body parts that may be patasi in the Old World and is transmitted by the of cosmetic or functional importance. The leish- Lutzomyia species in the New World (1, 4-8). maniasis lesions in such areas require immediate - treatment. Therefore, treatments are considered ythematous papules, later developing into raised, crucial to controlling the dissemination of leish- ulceratedAfter the lesions biting (2,9,10).of the fly, The lesions lesions appear are aspain er- maniasis and its transmission between individu-

*Corresponding author: Sara Molkara. This is an Open Access article distributed under the terms of the Resident of Dermatology, Imam Reza hospital, Mashhad Creative Commons Attribution License (http://creativecommons. University of Medical Sciences, Mashhad, Iran. org/licenses/by/3.0), which permits unrestricted use, distribution, E-mail: [email protected] and reproduction in any medium, provided the original work is Tel: 985138583845 properly cited.

Rev Clin Med 2019; Vol 6 (No 3) 91 Published by: Mashhad University of Medical Sciences (http://rcm.mums.ac.ir) Taheri AR et al. als (especially in case of patients with immuno- maniasis. Glucantime is administered daily via intramuscular injection, while sodium stiboglu- the key objectives of leishmaniasis treatment in- conate is administered via slow intravenous injec- cludedeficiency) the treatment and preventing of all the recurrence.patients, limiting Some the of tion. Glucantime is available in Iran. According to spread of the lesions, eradicating the reservoirs of the guidelines of the World Health Organization the Leishmania species, controlling the spread of (WHO), the prescribed dose of antimony for sys- the disease, preventing the development of large temic treatment is 20 mg/kg of pentavalent anti- scars (particularly facial scars), and preventing mony, which is equal to 75 mg/kg of glucantime. the associated complications and disease recur- - rence (11,12). tains 425 milligrams of antimony (1.5 g of glucan- Various local and systemic treatments are avail- Since each five-milliliter shot of glucantime con able for leishmaniasis, including physical inter- be prescribed per 20 kilograms of the body weight ventions (e.g., curettage, surgery, thermotherapy, oftime), patients. 1-3 five-milliliter In general, shotsthe treatment of glucantime period could for cryotherapy, and laser therapy) and medications rural and urban leishmaniasis is two and three (e.g., derivatives of antimony and nanoparticle weeks, respectively. If the signs of recovery are not treatments). Since most of these treatments have observed within four weeks after the treatment, not been thoroughly examined in the clinical the treatment is considered a failure, and systemic setting, their dependability remains uncertain. treatment with the previous dosage is prescribed Meanwhile, some of the main causes of unreliable treatment methods for leishmaniasis include the of glucantime involves the gradual increase of the high costs, poor patient compliance due to the dosageagain (18). as one The quarter,most efficient one half, approach and three to the quar use- long-term need for intramuscular/intravenous in- jections, and risk of systemic toxicity (11,13). third day, respectively, followed by the adminis- One of the main challenges that limits the treat- trationters of theof the final full dosage dose on on the the fourth first, second,day and andon- ment options for leishmaniasis is the variable wards (19). Theoretically, glucantime acts by affecting the various Leishmania species (14,15). The present bioenergetic pathways of the amastigote form of studyefficacy aimed of the to medicationssummarize various that are systemic used against treat- Leishmania and disrupting oxidation and glycol- ments for leishmaniasis. ysis processes, thereby reducing the cell levels of adenosine triphosphate (20). According to re- Literature Review Pentavalent Antimony Compounds of glucantime include musculoskeletal pain, nau- Antimony has been used in medicine for cen- seaports, and the vomiting, most significant diarrhea, clinical abdominal adverse pain, effects head- turies, and its importance has long been recog- aches, cough, pneumonitis, loss of appetite, leth- application of this element was the treatment of of glucantime treatment, complications such as leishmaniasis.nized. In the pastIn the century, 20th century, the most Gaspar significant Vianna cardiac,argy, fever, hepatological, erythema, and and hives. nephrological At the final stagesdisor- (a pioneer in the treatment of leishmaniasis) re- ders have also been reported. Among the other ported the effects of potassium antimony tartrate adverse effects of this compound are the elevation (a trivalent antimony compound) on mucocutane- of pancreatic enzymes (observation of pancreati- ous leishmaniasis. However, the widespread use tis in some cases, particularly in patients with im- of this compound in the following years revealed paired renal function), dose-dependent changes its adverse effects, which led to the cessation of its in the electrocardiogram (most commonly T-wave use. Since the 1940s, other less harmful trivalent and ST-segment changes and QT prolongation), antimony compounds have become widespread and atrial and ventricular arrhythmia rarely (21). for the treatment of leishmaniasis, which are cur- The mechanism of action of sodium stiboglu- rently among the most common treatment op- conate remains unclear. It is speculated that this tions in this regard. However, their application is drug functions through affecting the enzymes that are involved in DNA synthesis. Several side-ef- the injection of these compounds and the asso- fects have been documented for sodium stibo- ciatedassociated complications with specific affect limitations. patient Forcompliance, instance, gluconate, and reports have suggested the risk thereby leading to the development of resistance of sodium stibogluconate intolerance syndrome. in some endemic regions (16,17). Some of the associated symptoms include fever, Currently, meglumine antimoniate (glucantime) arthralgia, myalgia, edema, and gastrointestinal and sodium stibogluconate (pentostam) are the complications, which may manifest at the initial most commonly prescribed pentavalent antimony stages of treatment. It is notable that these symp- derivatives for the treatment of cutaneous leish- toms are not dose-dependent and do not justify

92 Rev Clin Med 2019; Vol 6 (No 3) Published by: Mashhad University of Medical Sciences (http://rcm.mums.ac.ir) Taheri AR et al. the cessation of treatment. On the other hand, the ous leishmaniasis, 46% of the patients were re- main symptoms of sodium stibogluconate toxicity ported to recover after receiving treatment with include cardiotoxicity, pancreatitis, hepatological liposomal amphotericin B for 90 days (37). In disorders, aplastic anemia, and nephrotoxicity another research by Mashayekhi et al. (2014), 93 on a few occasions. These symptoms are consid- ered to be severe dose-dependent complications, compounds were administered with intralesional which often occur during the second week of amphotericinpatients with B. significant After 12 weeks, resistance 61.4% to of antimony the pa- treatment (22). tients completely recovered from leishmaniasis. Pentavalent antimony derivatives have variable Similarly, another report by the same researchers degrees of success in the treatment of Old World was published on the treatment of ocular leish- cutaneous leishmaniasis. According to a review maniasis, presenting amphotericin B as a prom- study by Masmoudi et al., which was conducted ising treatment option for leishmaniasis, partic- in Tunisia during 1999-2006, the success rate of ularly in the cases with resistance to antimony the treatment with these compounds was report- derivatives (38,39). ed to be 75% (22). Another study in this regard was performed by Belazzoug and Neal (1986) in Miltefosine - Miltefosine (hexadecyl phosphocholine) is an tween the glucantime treatment group and con- oral medication, which was discovered in 1980. It Algeria, reporting no significant differences be was initially used as an antitumor agent and aban- recorded for pentavalent antimony derivatives, doned immediately since it caused hemotoxicity. whiletrols (23). the resistanceFurthermore, may drug be merely resistance an initialhas been re- Miltefosine is an analogue of alkyl phosphocho- line, which inhibits the biosynthesis of sterols and of the medication (24). phospholipids, disrupting intercellular transduc- sistance or reflect the low-dose or short-term use tion pathways. Miltefosine was investigated as an Amphotericin B anti-leishmaniasis medication in 1992, yielding Amphotericin B belongs to polyene macrolides acceptable outcomes against visceral leishman- iasis; therefore, it was prescribed for cutaneous drug in 1959. Despite the introduction of other leishmaniasis as well. Oral doses of 50-100 mg/ medicationsand was first (e.g., used azoles), as a highly amphotericin effective antifungalB remains kg are prescribed for 28 days for the treatment applicable as a potent medication for the treat- of cutaneous leishmaniasis. However, miltefosine ment of systemic fungal infections. Amphotericin may cause minor side-effects, such as gastroin- B acts through binding to membrane sterols (er- testinal problems and elevated transaminase and gosterol in fungi) and changing membrane per- creatinine levels. Since miltefosine is teratogenic, meability, thereby causing the loss of small mole- it must not be prescribed for pregnant women cules and essential ions (e.g., potassium) (25-27). (40-44). The most common side-effects of amphotericin In 2007, Mohebali et al. used miltefosine for B include anemia, low serum potassium, nausea the treatment of Leishmania major infection, and and vomiting, fever and chills, arthralgia, myalgia, the success rate was reported to be 90% (45). nephrotoxicity, neurological complications, rash- In a phase II/III randomized clinical trial, Chrus- es, and thrombophlebitis at the injection site. It is ciak-Talhari et al. (2011) used miltefosine for the notable that renal function abnormality is consid- treatment of untreated leishmaniasis in Brazil. - photericin B (28-31). receiving miltefosine therapy recovered as op- eredAmphotericin to be the most B is administered significant side-effect in the two of forms am posedAccording to 53.6% to the of findings, the patients 71.4% administered of the patients with antimony derivatives. In the mentioned study, the along with intravenous dextrose solution every otherof Fungizone day, and (dosage: liposomal 1 mg/kg/day) amphotericin via B injection, (dosage: high tolerance of the patients to the medication 3 mg/kg/day dose), which is administered via in- (46).safety of miltefosine was confirmed based on the travenous injection for 10 days for a 21-day peri- Miltefosine seems to be a superior alternative od (26, 32-35). Since liposomal amphotericin B is to antimony derivatives considering that it is oral- safer and causes fewer side-effects, it is more fre- ly administered and increases drug btolerance quently prescribed. Moreover, liposomal ampho- in patients, while causing fewer side-effects. In tericin B is used as the secondary treatment for contrast, some reports have denoted the better visceral leishmaniasis in the cases with resistance performance of antimony in this regard. If further to pentavalent antimony (36). In a study by Guery, which was conducted the treatment of leishmaniasis, this agent could be during 2008-2016 on 43 travelers with cutane- proposedclinical trials as aconfirm viable option the efficacy in the of endemic miltefosine areas. in

Rev Clin Med 2019; Vol 6 (No 3) 93 Published by: Mashhad University of Medical Sciences (http://rcm.mums.ac.ir) Taheri AR et al.

Pentamidine treated in both groups, and no recurrence was Pentamidine is an aromatic diamine molecule, observed. On the other hand, 10% of the patients which is used as an antifungal and antiprotozoal in both groups experienced infection recurrence agent in the treatment of trypanosomiasis, pneu- (54). monia caused by Pneumocystis carinii, and some Another research in this regard was performed forms of leishmaniasis. Although the exact mech- by Robledo et al. (2006) in Columbia on 63 patients anism of action remains known, it is believed that with cutaneous leishmaniasis, who were admin- the drug interferes with DNA, RNA, and protein istered with 4 mg/kg of pentamidine four times. synthesis through affecting folate. According to the obtained results, 43 patients Pentamidine is prescribed as a mesylate or is- were successfully followed-up for six months, and ethionate salt. Pentamidine isethionate, which is 86% were successfully treated after 1.5 months. the more common form of the drug, is often pre- However, treatment failure was reported in 11.6% scribed at the dosage of 4 mg/kg (equivalent to 2.3 of the patients, and only one patient experienced mg/kg of pure pentamidine) and administered via disease recurrence (55). intramuscular injection or intravenous infusion within a minimum of 60 minutes. Pentamidine Azoles isethionate is prescribed at various doses for the Azoles have been widely used in the treatment treatment of leishmaniasis, the most common of of fungal infections since late 1970s. Their key which are seven doses (2 mg/kg), which are in- mechanism of action is the inhibition and disrup- jected intramuscularly/intravenously every other tion of cytochrome P450 activity, which in turn day, or four doses (3 mg/kg), which are injected intramuscularly every other day (47-49). used as antifungals and have limited application Pentamidine has also been used for the treat- inleads the to treatment cell wall biosynthesis.of leishmaniasis. Azoles Nevertheless, are chiefly ment of visceral leishmaniasis for several years. some azoles could be used in the treatment of Old Considering its shorter course of treatment and World cutaneous leishmaniasis. Laboratory ex- length of hospital stay in the patients, as well as the low treatment costs, pentamidine is preferred category on Leishmania promastigotes (56-59). over antimony derivatives. However, pentamidine perimentsSeveral azole have compoundsconfirmed the have effects been of investigat this drug- has been reported to cause some adverse effects, ed for the treatment of leishmaniasis, including the most prevalent of which are renal disorders. - Renal disorders occur due to the reversible entry conazole (200 mg/day for six weeks), and itracon- of creatinine and nitrogenous compounds into azoleketoconazole (100-400 (200-600 mg/day mg/dayfor 6-8 weeks).for 28 days), However, flu cause acute renal failure and induce elevated liver rates of these compounds. In cases of hepatotox- enzymethe bloodstream. levels or Furthermore,anomalies in bloodpentamidine cell counts. may icity,there azolesare variable have limitedfindings application. regarding the According success Acute pancreatitis has also been rarely observed. to the literature, itraconazole has been effective The quick intravenous injection of pentamidine in the treatment of 60-70% of the patients with should be avoided since it might cause an abrupt lesions caused by Leishmania tropica (60). decline in blood pressure, as well as vertigo, head- In a recent study in this regard, a patient with aches, vomiting, tachycardia, and syncope. In ad- sporotrichoid cutaneous leishmaniasis, who was dition, gastrointestinal complications and derma- unresponsive to pentavalent antimony treatment, tological side-effects, especially at the injection was fully treated after the administration of oral site, may restrict the application of pentamidine Mohebali et al. (2002) indicated that the treat- leishmaniasis (47-49). itraconazole (61). Furthermore, the findings of asPentamidine the first drug seems of choice to be fora more the treatmentviable treat of- resulted in 79% recovery rate as opposed to only ment option for New World leishmaniasis. Non-re- 34%ment in of the patients placebo with patients L. major (45). with However, fluconazole some sponsiveness to this drug depends on the time of treatment and failure to complete the course of between azole fungicides and placebo in the treat- treatment before the complete resolution of leish- mentstudies of haveleishmaniasis reported (62). no significant differences maniasis (19, 50-53). In a study by Esther et al. (2002), which was conducted in Surinam on pa- Metronidazole tients with cutaneous leishmaniasis, 235 patients Metronidazole is a narrow-spectrum antibiotic were administered with pentamidine mesylate, in the nitroimidazole class of antibiotics, which is and 80 patients received treatment with pent- used in the treatment of the infections caused by amidine isethionate. According to the obtained results, 90% of the patients were successfully entry into anaerobic cells, metronidazole is di- protozoa and most anaerobic bacteria. Following 94 Rev Clin Med 2019; Vol 6 (No 3) Published by: Mashhad University of Medical Sciences (http://rcm.mums.ac.ir) Taheri AR et al. minished and metabolized. The toxic metabolites not as effective as glucantime in the treatment of of metronidazole cause DNA damage, and some Old World cutaneous leishmaniasis (76,77). of the common side-effects of metronidazole in- - clude blood disorders (e.g., leukopenia and neu- ing the effectiveness of rifampicin in the treatment of ConflictingOld World findingsleishmaniasis, have been with proposed the values regard with- in the range of 0-80% (78). In addition, oral zinc tachycardiatropenia), peripheral when taken neuropathy, with alcohol), disulfiram-like metallic sulfate has shown promising results in the treat- taste,reactions dry (e.g.,mouth, nausea and Stevens-Johnsonand vomiting, flushing, syndrome and ment of cutaneous leishmaniasis in Iraqi patients in rare cases (63,64). - in the other studies in this regard (19). scribed for 15-30 days for the treatment of cutane- althoughUse of nanoparticlesthese findings hashave been not beenon the confirmed rise for ousFor leishmaniasis several years, in metronidazolechildren and adults has been (15 mg/pre the treatment of dermal conditions, and their new kg/day for children and 25 mg/kg/day for adults). applications are constantly discovered. Cutaneous Retrospective studies in Tanzania have indicated leishmaniasis has not been an exception, with sev- that with the success rate of 66%, metronidazole eral studies reporting the effectiveness of gold and could be a viable option for the treatment of Old silver nanoparticles in the treatment of leishmani- World leishmaniasis (65-68). However, consid- asis, especially in combination with phototherapy ering the self-limited nature of L. tropica and L. or electromagnetic radiation therapy (79,80). major infections, this rate may be statistically in- The effectiveness of other compounds has also been investigated in the treatment of leishmania- sis, yielding controversial results. Such examples metronidazolesignificant, and on further cutaneous controlled leishmaniasis experiments (69). are antimalarial compounds, avlosulfon, sulfame- maySimilar be required results inhave order been to reportedconfirm the by effectsthe clini of- cal trials comparing the effectiveness of metroni- and systemic paromomycin. dazole and glucantime in the treatment of leish- thoxazole-trimethoprim, bleomycin terbinafine, maniasis, indicating that metronidazole is not Conclusion Given the importance of cutaneous leishmania- viewed as an alternative only (70,71). sis (especially the urban variety), all the patients significantly superior to glucantime and could be - Other Systemic Treatments tive diagnosis. In Iran, which is considered to be Allopurinol is a xanthine oxidase inhibitor, anshould endemic receive area immediate for leishmaniasis, treatment the andmost defini effec- which has been reported to be effective in the tive treatment approach for the disease should be treatment of leishmaniasis with the success rate selected based on the associated advantages and of 74% in Asia. Combined administration of allo- risks of each treatment method, as well as the ca- purinol and antimony compounds to Iranian pa- pabilities of the healthcare system, availability of tients with L. major infection has also been shown the medications, and individual conditions of the to reduce the required effective dose of antimony patients. Combination therapy is considered to be by half (72-74). the optimal treatment approach for leishmania- Doxycycline is another effective therapeutic sis, along with the minimization of the associated compound against leishmaniasis. In a study per- complications and invasiveness, in order to pre- formed in Tunisia, daily doxycycline dose of 200 vent the development of resistance and improve milligrams for 15-30 days could successfully treat patient compliance until complete recovery. 71% of the patients. Phototoxicity is considered to be the main side-effect associated with doxycy- Acknowledgements cline (75). None. Considering the high tolerance of patients with leishmaniasis, azithromycin is a feasible option for Conflict of Interest the treatment of children infected with the Leish- mania species in the endemic areas. However, a study conducted in Iran in 2003 has undermined ReferencesThe authors declare no conflict of interest. the relative effectiveness of this drug. In the men- 1. Alidadi S, Oryan A. Cutaneous leishmaniasis and the strate- gies for its prevention and control. 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