Pentavalent Antimonials Combined with Other Therapeutic Alternatives for the Treatment of Cutaneous and Mucocutaneous Leishmaniasis: A Systematic Review

The first choice drugs for the treatment of cutaneous and mucocutaneous leishmaniasis are pentavalent antimonials, sodium stibogluconate, or meglumine antimoniate. However, the treatment with these drugs is expensive, can cause serious adverse effects, and is not always effective. The combination of two drugs by different routes or the combination of an alternative therapy with systemic therapy can increase the efficacy and decrease the collateral effects caused by the reference drugs. In this systematic review we investigated publications that described a combination of nonconventional treatment for cutaneous and mucocutaneous with pentavalent antimonials. A literature review was performed in the databases Web of Knowledge and PubMed in the period from 01st of December 2004 to 01st of June 2017, according to Prisma statement. Only clinical trials involving the treatment for cutaneous or mucocutaneous leishmaniasis, in English, and with available abstract were added. Other types of publications, such as reviews, case reports, comments to the editor, letters, interviews, guidelines, and errata, were excluded. Sixteen articles were selected and the pentavalent antimonials were administered in combination with pentoxifylline, granulocyte macrophage colony-stimulating factor, imiquimod, intralesional sodium stibogluconate, ketoconazole, silver-containing polyester dressing, lyophilized LEISH-F1 protein, cryotherapy, topical honey, and omeprazole. In general, the combined therapy resulted in high rates of clinical cure and when relapse or recurrence was reported, it was higher in the groups treated with pentavalent antimonials alone. The majority of the articles included in this review showed that cure rate ranged from 70 to 100% in patients treated with the combinations. Serious adverse effects were not observed in patients treated with drugs combination. The combination of other drugs or treatment modalities with pentavalent antimonials has proved to be effective for cutaneous and mucocutaneous leishmaniasis and for most seemed to be safe. However, new randomized, controlled, and multicentric clinical trials with more robust samples should be performed, especially the combination with immunomodulators.


Introduction
Leishmaniasis is an important zoonosis around the world, being reported that about 20,000 to 30,000 deaths occur annually as a consequence of the disease [1]. The most frequent form is cutaneous leishmaniasis (CL), which is present in several countries, mainly in the Americas, the Mediterranean basin, the Middle East, and Central Asia. An annual occurrence of 0.6 to 1.0 million new cases is estimated [2] and around 399 million of people are at risk of infection in 11 high-burden countries [1].
The pentavalent antimonials, sodium stibogluconate or meglumine antimoniate, are drugs commonly used to treat cutaneous and mucocutaneous leishmaniasis. However, the treatment with these drugs is expensive and can cause serious adverse effects, such as cardiac toxicity and elevation in the levels of hepatic enzymes [3][4][5], and, sometimes, it is ineffective or presents low cure rates [6,7]. Amphotericin B, pentamidine, fluconazole, and miltefosine can be used as second choice drugs, but they also exhibit toxicity. Moreover, the efficacy of the treatment also depends on the Leishmania species involved in the infection, since some species are more resistant to some drugs [6].
Local therapies, such as cryotherapy, CO 2 laser, thermotherapy, and photodynamic therapy, are alternatives to conventional drugs, since they are less toxic to the patient and the main adverse effects are restricted to the site of application [8][9][10][11][12][13]. However, the exclusive use of local therapy is controversial, since some New World species can lead to mucosal leishmaniasis after primarily cutaneous lesions [3].
The combination of two drugs or the combination of a local therapy with systemic therapy can be an alternative to increase the efficacy of local therapy and may decrease the collateral effects caused by the reference drugs. Some studies have evaluated the efficacy of this type of combination [14][15][16][17], being necessary prospective and multicenter studies for safer evidence. Our central question was evaluated if the combination of an alternative therapy with meglumine antimoniate presents more efficiency that only meglumine antimoniate in the treatment of cutaneous and mucocutaneous leishmaniasis. In this sense, we investigated published articles that used the combination of an alternative therapy with pentavalent antimonials in the treatment of cutaneous and mucocutaneous leishmaniasis through systematic review.  [18]. The screening of the titles and abstracts was performed by researchers (TRNB, CAM, PWN, TFPM, GCD and AVS). The MeSH (Medical Subject Headings) terms, strategy used for the search on PubMed, were also selected by these researchers based on publications on the topic at PubMed. Any disagreements were decided by consensus. The MeSH terms were validated by two experts (JVT and TGVS) and were divided into two groups: Group 1 "Antiprotozoal Agents" OR "Combined Modality Therapy" OR "Drug Therapy, Combination" OR "Treatment Outcome" OR "Amphotericin B" OR "Meglumine" OR "Protozoan Vaccines" OR "Organometallic Compounds" OR "Antimony Sodium Gluconate" OR "Antimony" OR "Pentamidine" OR "Anti-Infective Agents" OR "Medication Therapy Management" OR "Complementary Therapies"; AND Group 2 "Leishmaniasis" OR "Leishmania". The research in the Web of Knowledge database was carried out by topic, which ensures good sensitivity.

Inclusion, Exclusion Criteria, and Studies Selection.
Articles that describe a combination of therapeutic alternatives with pentavalent antimonials for cutaneous or mucocutaneous leishmaniasis were included in this review. Only original clinical trials, in English and with abstract available, were added. Other types of publications (reviews, case reports, comments to the editor, letters, interviews, guidelines, and errata) were excluded. After the search the papers initially selected were analyzed by the researchers of group 1 (TRNB, CAM, PWN, TFPM, GCD, and AVS) and disagreements about inclusion or exclusion of articles were decided by consensus. To increase the search sensitivity, the researchers in group 1 checked all references from the selected publications to retrieve other unidentified publications in the other phases of the search. The validation of selected articles was performed by four independent evaluators of group 2 (TGVS, MVCL, SMAA, and IGD).

Data Extraction.
The structure of the topics to compose the tables was organized by researchers from group 1 with the support of two experts (TGVS and JVT): Table 1 (study, area country, study design, period of study, age range or mean in years, gender, clinical forms, patients enrolled, leishmaniasis diagnosis, and statistics); Table 2 (study, Leishmania species, treatment, patients at the end, percentage of clinically healed patients or lesions, percentage of therapy failure, and percentage of relapse or recurrence); Table 3 (treatment, side effects  percentage, and study source); and Table 4 (treatment, dose, route of administration, time efficacy, safety, practice/clinical implications, and study source). The tables were completed by researchers in group 1 and then checked by researchers from group 2.

Results
Based on the inclusion criteria defined by consensus, 16 articles were selected, being from Iran (6), Peru (4), Brazil (4), Yemen (1), and Afghanistan (1) (see Figure 1). In all, 1,302 patients aged between 1 and 87 years were involved in the studies, with cutaneous or mucocutaneous leishmaniasis, being predominant the cutaneous form of the disease. The most reported species of Leishmania were L. braziliensis, L. tropica, and L. major (Table 1).
In the selected articles, pentavalent antimonials were administered in combination with different drugs or treatment modalities, which were pentoxifylline; granulocyte macrophage colony-stimulating factor; imiquimod; intralesional sodium stibogluconate; ketoconazole; nonsilver-containing Dermatology Research and Practice 3      [26]). The other authors reported cure rates below 70% and ranged from 36.4% to 66.7%. The lowest cure rate was (36.4%) in the combination of IL-MA+ silver PD (Khatami et al. 2013 [27]) ( Table 2).
No serious adverse effects were observed in patients treated with the drugs combination. For the combination of imiquimod and meglumine antimoniate, adverse effects were locally limited, being the most reported pruritus/itching, erythema, and edema. For the combination of imiquimod with sodium stibogluconate, the same was observed. Only Miranda-Verastegui et al. (2005) [23] reported elevated liver enzyme levels.
In relation to granulocyte macrophage-stimulating factor, there were no reports of side effects. With lyophilized LEISH-F1 protein in association to meglumine antimoniate, the observed side effects were induration, erythema, and tenderness; in combination with sodium stibogluconate, the presence of induration, erythema, and tenderness sites was reported, in addition to headache pyrexia and systemic malaise. The common adverse effects of the use of meglumine antimoniate and sodium stibogluconate were also observed.
To the combination of meglumine antimoniate and pentoxifylline, the common adverse effects, described in two studies, were nausea, arthralgia, dizziness, pain, and diarrhea.
In the use of intralesional sodium stibogluconate, alone or in association with other medicinal products, secondary infection, pain and swelling at injection site, and lymphatic involvement were observed. The pentavalent intralesional antimonials also showed adverse effects related to the application site, such as pain, pruritus/itching, and edema.
Intralesional sodium stibogluconate, when associated with cryotherapy, resulted in secondary infection and lymphatic involvement, in addition to the inherent symptoms of intralesional application of stibogluconate already mentioned. Meglumine antimoniate combined with silver PD presented only itching, burning, and edema, in contrast to when combined with topical honey, in which only dermatitis, caused by honey, was reported. Cryotherapy combined with meglumine antimoniate had only local adverse effects such as hyperpigmentation plus trivial scar, atrophic scar, and hypopigmentation plus trivial scar ( Table 3).
Each of the combinations was classified according to their efficacy (efficacious/likely efficacious/not efficacious) and the clinical implications (investigational/clinically useful/possibly useful) [30].
In this context, imiquimod associated with meglumine antimoniate (Miranda-Verastegui et al. 2005 [23]) and stibogluconate (Miranda-Verastegui et al. 2009 [24]) and cryotherapy-associated stibogluconate (Van-Thiel et al. 2010 [29]) were classified as clinically useful and with acceptable risk without specialized monitoring. The meglumine antimoniate associated with pentoxifylline (Machado et al. 2007) were classified as clinically useful and with acceptable risk with specialized monitoring (Machado et al. 2007 [15]). On the other hand the combination of meglumine antimoniate associated with pentoxifylline performed by Brito et al. 2017 [31] to treat cutaneous leishmaniasis caused by Leishmania braziliensis was classified as not efficacious and not useful. Meglumine antimoniate associated with omeprazole (Nilforoushzadeh et al. 2008 [26]) was classified as clinically useful and with acceptable risk with specialized monitoring.

Discussion
In this review, we saw that the majority of the combinations resulted in an elevated cure rate. Relapse or recurrence, when reported, were higher in the groups treated with the isolated drugs than in the ones treated with the drugs combination. These findings indicate that the combinations with 14 Dermatology Research and Practice pentavalent antimonials were more efficacious to prevent relapse or recurrence. Several authors have demonstrated that the combination of some drugs with pentavalent antimonial showed a higher percentage of cure.
It is known that the use of systemic meglumine antimoniate can be lead to serious adverse effects, so the application in the lesion site showed to be an efficacious and more secure alternative to treat CL. Some authors have demonstrated that the intralesional MA is as effective as the systemic MA and had few adverse effects [43][44][45]. It is important to note that, unlike in the articles included in this study, Vasconcellos et al. (2014) [46] reported that one patient presented eczema after the treatment with intralesional meglumine antimoniate. After use of oral dexchlorpheniramine, eczema and ulcer receded. Thus, the administration of intralesional MA must be carefully conducted, especially due to the possibility of occurring hypersensitivity.
For the SSG, the intralesional application has also shown good results [47,48]. The application twice a week is well tolerated and the lesions healed faster than only once a week [49].

Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF).
The granulocyte macrophage colony-stimulating factor (GM-CSF) acts in the recruitment of monocytes and neutrophils. It is produced by a wide range of cells such as macrophages, neutrophils, dendritic cells, T cells, eosinophils, fibroblasts and endothelial cells. It is also believed that it promotes the differentiation of the macrophages to a proinflammatory phenotype [50].
In view of its role in the recruitment of different types of cells, GM-CSF has been investigated for the CL treatment. In their study, Almeida et al. (2005) [19] evaluated the topical use of GM-CSF (10 g/mL) in combination with the meglumine antimoniate (20 mg/kg/day) and showed that 60% of the patients were clinically healed 50 days after the treatment start, and the remaining 40% were cured 120 days after the beginning of the treatment. Similar results were found by Santos et al. (2004) [51], when they use this combination. On the other hand, among the patients treated only with meglumine antimoniate, just 20% were clinically healed at 45 days after the start of treatment, and 100% of the patients were cured after 256 days.
In a previous study, Almeida et al. (1999) [52] showed that clinical cure in patients treated with the combination of pentavalent antimonial and GM-CSF was faster than in the control group that was treated with pentavalent antimonial alone. Possibly the factor that contributed for the quick cure associated by GM-CSF was the modulation of the immunologic balance, by inducing differentiation for the Th1 subtype [52][53][54] and activation of macrophages to kill Leishmania [55].
GM-CSF combined with pentavalent antimonial can be an alternative to treat CL, since the risk inherent to this combination is acceptable and its use deserves to be greatly investigated.

Imiquimod.
Imiquimod is an immunomodulator that was first approved to treat genital and perianal warts and then to treat actinic keratosis.
Imiquimod stimulates the immune system in different ways. It is believed that imiquimod is an agonist of the tool like receptors 7 and 8, so the stimulation of these receptors leads to the synthesis of different inflammatory mediators, such as INF-, TNF-, interleukins 1, 6, 8, 10 and 12, granulocyte colony -stimulating factor and granulocyte macrophage colony-stimulating factor [56][57][58]. In addition, the use of imiquimod also indirectly contributes to the immune response acquired, through the induction of Th1 type cytokines, such as INF-Υ [58,59]. The induction of INF-Υ an IL-12 production induces to Th1 differentiation and it is important in the control of CL.
Imiquimod has been investigated in the treatment of CL and its efficacy is controversial. Arevalo et al. (2007) [20] and Seeberger et al. (2003) [60] showed no efficacy in the use of imiquimod alone. In combination with pentavalent antimonials, imiquimod can be an adjuvant; moreover, the success in treatment with imiquimod is directly related to the concentration used. Only at the concentration of 7.5% imiquimod combined with meglumine antimoniate appears to be more effective than the antimonate alone [20]. Authors that administered imiquimod at 5% in combination with meglumine antimoniate observed that the efficacy was similar to that of patients treated with meglumine antimoniate alone [23,28].
Meymandi et al. (2011) [61] showed the combination of intralesional meglumine antimoniate and imiquimod as beneficial its resulted in a decrease in parasitic load, an increase in lymphocyte numbers, and a decrease in histiocyte aggregation in the lesion site. In addition, they observed that imiquimod alone was also ineffective.
Imiquimod appears to be a good adjuvant for pentavalent antimonial when used in the appropriate concentration. The risk involved in its use is acceptable. More evidence is needed to strengthen its application in clinical practice.

Silver-Containing Polyester
Dressing. The silver-containing polyester dressing (silver PD) is composed of hydrophobic polyamide netting with silver-coated fibers. Silver PD differs from each other by the way silver is incorporated and how it is liberated in the lesion. It is known that silver has antimicrobial activity in solutions, but it does not differentiate at pathogens from the other cells, such as fibroblast and keratinocytes [62,63].
Clinical trials using silver PD to treat CL are scarce. In this review, only one study used silver PD with this aim. No efficacy in silver PD was shown, not even combined with intralesional meglumine in the treatment of CL [27]. In this study, silver PD Atrauman Ag5 by Hartmann was used.
As mentioned before, silver can cause the death of human cells [63]. However, according to the manufacturer of the Atrauman Ag5, a higher concentration of silver is needed to lead to the death of human cells and, specifically in the case of Atrauman Ag5, the release of silver is small. Moreover this dressing released silver only when in contact with bacteria and no negative influence of the silver ions was exercised in human cells [64]. Since amastigote forms are phagocytosed by macrophages, they remaining and multiplying. The silver released by the dressing, for being in small quantities, may not be able to reach the amastigotes phagocytosed.
There are some inherent characteristics of polyester dressing that influence in their activity, such as their capacity in the release of silver [65]. Besides that, the compounds binding to silver can contribute to this activity.
The use of silver PD isolated or in combination with pentavalent antimonial needs to be further investigated due to the scarcity of studies that used silver PD to treat CL and the several factors that can influence its efficacy.

LEISH-F1+MPL-SE.
LEISH-F1+MPL-SE was the first candidate vaccine for entry in clinical trials. It was composed by recombinant fusion protein Leish-111f and an adjuvant in an oil-water emulsion (monophosphoryl lipid A -MPL). MPL is a TLR4 agonist, safely used in other vaccines, such as hepatitis [66].
In the two articles included in this review, LEISH-F1+MPL-SE was tested in combination with SSG or meglumine antimoniate in the treatment of CL. One of these Llanos Cuentas et al. (2010) [22] observed similar clinically cure in both groups; however in addition, relapse or recurrence did not occur in the combination groups. The stimulation of the immune response was greater in the LEISH-F1+MPL-SE group than in the SSG group, a fact that may have contributed to the absence of recurrences. Nascimento et al. (2010) [25], on the other hand, observed a greater clinical cure rate (80%) in the group treated with the combination of LEISH-F1+MPL-SE and meglumine antimoniate than in the groups treated with meglumine antimoniate alone (38%) or the adjuvant MPL-SE alone (50%).
LEISH-F1+MPL-SE in combination with pentavalent antimonials can be useful to treat CL, mainly because this combination appears to decrease recurrences observed with pentavalent antimony alone. The risks related to its use are acceptable therefore its use should be better explored.

Topical Honey.
Honey was used, many years ago to treat several types of lesions, but there is no consensus on its effectiveness in lesion healing. In relation to CL, there are few data on the use of honey for its treatment.
It is well established that honey has an antimicrobial action, which can act on tissues, contributing to their repair [70], and also on the immune system, having both proinflammatory and anti-inflammatory action [71].
FDA has already approved some honey-based products with different clinical indications, but some authors remain cautious regarding its clinical use for lesion healing. Jull et al. (2013) [72], in a review about the use of topical honey in the treatment of wounds, concluded that honey may delay the time of wound healing in some types of wounds, such as CL and deep burns, but it is good for moderate burns. Still, in their opinion, more clinical studies are needed to guide the use of honey in clinical practice in other types of wounds than moderate burns.
In the same line Saikaly and Khachemoune (2017) [73] concluded in their study that the use of honey seems to be beneficial to wound healing in some types of lesions and that new technologies have contributed to the understanding of the action mechanisms of honey. However, more evidence is still needed to elucidate precisely the results obtained with the use of honey.
The combination of topical honey with IL-MA to treat CL was tested by Nilforoushzadeh et al. (2007) [33] and did not show efficacy. In this study, gauze soaked in honey was used, not being mentioned the type of honey used. It is known that there are different types of honey of different constitution and that, therefore, they may have different properties [71]. The choice of dressing must also be taken into consideration, as one should choose the dressing most appropriate for the wound to be treated [70].
There are several factors related to honey that should be taken into account, such as honey type and composition, as well as the best form of application, and it deserves to be better evaluated in order to be combined with pentavalent antimonials in the treatment of CL.

Omeprazole.
Omeprazole is a drug used to treat peptic ulcer disease, due to its interference with the stomach pH. Omeprazole acts by inhibiting the human gastric K + , H + -ATPase enzyme, resulting in the disruption of acid secretion [74].
In the intracellular environment, omeprazole accumulates in the lysosomes, in the same place that the amastigotes in the macrophages. Jiang et al. (2002) [75] showed that omeprazole inhibits the K + , H + -ATPase enzyme located on the membrane surface of Leishmania, and this drug had leishmanicidal activity against Leishmania donovani intracellular amastigotes in a dose-dependent manner.
The combination omeprazole plus meglumine antimoniate was well tolerated and the authors reported no side effects, thus it may be a clinically useful alternative likely efficacious for CL treatment.

Cryotherapy.
Cryotherapy is a therapeutic modality recommended by the World Health Organization (WHO) for the treatment of CL. According to WHO, it is a recommended treatment regimen for Old World CL, combined or not with intralesional antimonial [4].
Above all, some studies showed that the combination of cryotherapy with intralesional pentavalent antimonial is more effective than the antimonial alone [11,76].
The  [32], presented a lower cure rate for the combination of cryotherapy and intralesional sodium stibogluconate or for the combination with meglumine antimoniate.
Some variables should be taken into consideration for the performance of cryotherapy, which may directly influence the efficacy of the treatment, such as the size of the lesion and the frequency of the cryotherapy sessions. Papules smaller than or equal to 1 cm, responded more quickly to cryotherapy than lesions larger than 1 cm. According to Ranawaka et al. (2011) [77], for smaller papules the cure rate was 90.5% and for the ones larger than 1 cm, it was 64.28%.
The frequency of sessions also seems to play an important role in the effectiveness of cryotherapy. When performed weekly, cure rates were high (equal or greater than 90%), either alone or in combination with pentavalent antimonials [8,77]. Application at longer time intervals may result in lower cure rates. Soto et al. (2013) [78] performed only two sessions of cryotherapy at intervals greater than 1 week and obtained a low cure rate (20%).
Another important fact to consider before the application of cryotherapy is the phototype of skin. In patients with phototype V, for example, depigmentation may occur. It is also necessary to investigate the tendency of keloid formation [77].
Cryotherapy is a clinically useful alternative and has few, but not serious, adverse effects. It has a high cure rate when considering the size of the lesion and the frequency of the sessions.

Ketoconazole.
Ketoconazole is an antifungal that interferes with the biosynthesis of ergosterol, an important cell membrane constituent, essential for the viability and survival of fungi and trypanosomatids. The target of Ketoconazole is the C14 -demethylase and, thus, it interferes with the dimethylation of the sterol and, consequently, inhibits the synthesis of ergosterol [79].
Oral ketoconazole alone has been tested for the treatment of CL for several years and has shown different cure rates [80][81][82][83]. In this review, we included the study of El-Sayed and Anwar (2010) [21], which tested the combination of intralesional sodium stibogluconate and oral ketoconazole (600 mg/day). This combination was more effective than the ketoconazole and sodium stibogluconate alone. Saenz et al. (1990) [80], using ketoconazole alone (600 mg/day), obtained a cure rate of 73% and Salamanpour et al. (2001) [82] found a cure rate of 89% in the treatment with ketoconazole (600 mg/day) alone.
Possibly the species is a determinant factor in the efficacy of ketoconazole. WHO recommends ketoconazole (600 mg/day) as the treatment regimen for CL in the New World, specifically when the etiologic agent is Leishmania mexicana, although there are reports of its efficacy in other species [4]. El-Sayed and Anwar (2010) [21] did not identify the species in their study. Saenz et al. (1990) [80] also did not identify it, but their study was conducted in Panama. Salmanpour et al. (2001) [82] [84] demonstrated that Leishmania amazonensis can up-regulate the C-14 demethylase in response to ketoconazole, which may contribute to its resistance to this drug.
Oral administration of ketoconazole combined with intralesional sodium stibogluconate for the treatment of CL is shown acceptable risk with specialized monitoring and no serious adverse effects and in administration are reported.

Pentoxifylline.
Pentoxifylline is a derivative of dimethylxanthine classified as a vasodilator agent. It exerts effects on different cell types, such as reduction of the expression of adhesion molecules with ICAM-1 in keratinocytes and Eselectin in endothelial cells, inhibition of TNF-synthesis, IL-1 and IL-6 and antifibrinolytic effects [14,85].
In particular, pentoxifylline may potentiate the action of pentavalent antimonials primarily by two mechanisms: increase in the expression of the inducible nitric oxide synthase (iNOS) and, consequently, increase in the production of nitric oxide, and anti-TNF-action [86,87]. Brito et al. (2014) [88] observed that patients treated with pentoxifylline (400 mg -3 times per day) combined with meglumine antimoniate (20 mg 5+ /kg/day) had greater TNF-suppression than those treated with meglumine antimoniate alone (20 mg 5+ /kg/day), and cure rates were higher in the combined group than in the second group. Machado et al. (2007) [15] demonstrated in their study that the combination of meglumine antimoniate (20 mg 5+ /kg/day) and pentoxifylline (400 mg -3 times per day) potentiated the effect of the meglumine antimoniate, since the combination resulted in 82% of cure in patients with mucosal leishmaniasis, while meglumine antimoniate (20 mg 5+ /kg/day) alone had a cure rate of 41.6%. Sadeghian and Nilforoushzadeh (2006) [17], in which this same combination was tested to treat cutaneous leishmaniasis (in endemic area for Leishmania major) and resulted in 81.3% cure versus 51.6% for meglumine antimoniate alone. In contrast, at the same conditions in the cited studies, Brito et al. (2017) [31] reported a cure rate of 43% for a combination of pentoxifylline and meglumine antimoniate to treat cutaneous leishmaniasis caused by Leishmania braziliensis, as divergences in cure rates may be related to intrinsic characteristics of each patient to pentoxifylline, and the specie of Leishmania.
The anti-TNF-action of pentoxifylline makes its use interesting, mainly in cases of mucosal and/or treatmentrefractory leishmaniasis, since this cytokine is the main responsible for mucosal damage. There have been reports of success in the combination of pentoxifylline and meglumine antimoniate in the treatment of treatment-refractory cases [14] and with high production of TNF- [89] or recurrent cases [90].
For Lessa et al. (2001) [14], the efficacy of the combination pentoxifylline and meglumine antimoniate should make it the second choice in the treatment, since the administration is oral and has fewer adverse effects than amphotericin B.
The efficacy of pentoxifylline in combination with meglumine antimoniate in the treatment of mucocutaneous leishmaniasis, even in cases refractory to conventional and/or recurrent treatment, added to few and not severe effects, makes this combination a good therapeutic alternative clinically useful for treatment of mucocutaneous leishmaniasis. However to treat cutaneous leishmaniasis with this combination it is necessary to take into account the species involved, since in cases caused by Leishmania braziliensis this combination showed not efficacious and not useful.

Clinical
Implications. The first choice drugs for the treatment of cutaneous or mucocutaneous leishmaniasis do not always show the expected result, so the association of these conventional drugs with others drugs or modalities of therapy, such as local therapies have good cure rates, often higher than those of the drugs of choice, and few adverse effects. Above all, the combination with immunomodulators seems to be promising, even with limited numbers study and patient it was surprisingly effective, revealing higher efficacy and few adverse effects. In the case of combination with local application therapies, the diameter of the lesion appears to be an important factor for successful treatment. In addition to efficacy, many combinations are easy to administer by the patient and without the need for specialized monitoring, what represents an advantage for use in more isolated communities.

Strengths and Limitations of the Study.
This systematic review has gone through many steps in its development. The precision in publications' search was guaranteed by two databases. Publications' identification criteria were monitored and discussed in many steps of the research to guarantee robustness and rigor of the findings. Special care was also taken for the identification of the MeSH terms, which were decided by many researchers and by consensus, providing good sensitivity and specificity. The publications' findings were organized and detailed in four tables for better clarity and quality of data. Concerning the limitations, we identified that only four of the 16 articles included in the Other limitations were the inclusion of only two databases, with publications merely in English comprising the period from 12/2004 to 6/2017. The considerable heterogeneity between the articles included, mainly due to the significant variation of both the substances used and the research regions, made it impossible to analyze the data more precisely, for example through meta-analysis. Despite these limitations, we believe the results can contribute positively for the treatment of cutaneous leishmaniasis and mucocutaneous leishmaniasis.

Conclusion
The combination of pentavalent antimonial drugs with other drugs seems to be a good alternative to conventional treatment, since they presented good cure rates, often higher than those of the drugs of choice, and few adverse effects. Therefore, this type of combination deserves to be investigated in more detail by clinical trials and prospective studies with more robust population sample to reinforce the effectiveness and safety that this alternative treatment provides to the patient.

Conflicts of Interest
The authors declare that they have no conflicts of interest.