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E-IJD-THERAPEUTIC ROUND
Year : 2014  |  Volume : 59  |  Issue : 6  |  Page : 631
Efficacy of intralesional amphotericin B for the treatment of cutaneous leishmaniasis


Department of Dermatology, Cutaneous Leishmaniasis Research Center, School of Medicine, Imam Reza Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Date of Web Publication30-Oct-2014

Correspondence Address:
Ahmad Reza Taheri
Cutaneous Leishmaniasis Research Center, Imam Reza Hospital, School of Medicine, Mashhad University of Medical Sciences, Mashhad
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.143571

Clinical trial registration IRCT201105223862N7

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   Abstract 

Background: Antimoniate compounds have been used as gold standard treatment for cutaneous leishmaniasis since many years ago, but with increase in incidence of drug as well as individual contraindications, more attention has been given to alternative treatments. Aim: The aim of this study was to evaluate the efficacy of intralesional amphotericin B as an alternative treatment for cutaneous leishmaniasis in Mashhad, Iran, during 2007-2009. Materials and Methods: Non-random sampling from both sexes and without any age limitation of cases eligible for this alternative treatment was done. Size and induration of lesions were measured before beginning and weakly during the treatment. Amphotericin B (2 mg/ml) was injected into lesions weekly for up to 12 weeks and the cases were followed up for the treatment responses, possible side effects and recurrence of the disease. Results: A total of 93 patients with a mean age of 20.81 ± 15.26 years were included in this study. At the end of 12 th week, 61.4% of the patients were recovered completely (more than 90% reduction in size and induration), 21.6% had partial remission (60-90% reduction in size and induration), and 17% had less than 60% reduction in size and induration of skin lesions. Injection side effects were insignificant and did not lead to premature discontinuation of treatment in any patients. Conclusion: Weekly intralesional injection of amphotericin B looks promising, considering the fact that most of the patients in this study were resistant to antimoniates.


Keywords: Amphotericin B, antimoniate compounds, cutaneous leishmaniasis


How to cite this article:
Goyonlo VM, Vosoughi E, Kiafar B, Nahidi Y, Momenzadeh A, Taheri AR. Efficacy of intralesional amphotericin B for the treatment of cutaneous leishmaniasis. Indian J Dermatol 2014;59:631

How to cite this URL:
Goyonlo VM, Vosoughi E, Kiafar B, Nahidi Y, Momenzadeh A, Taheri AR. Efficacy of intralesional amphotericin B for the treatment of cutaneous leishmaniasis. Indian J Dermatol [serial online] 2014 [cited 2022 Sep 28];59:631. Available from: https://www.e-ijd.org/text.asp?2014/59/6/631/143571

What was known?
Antimoniates are standard treatment for cutaneous leishmaniasis. Systemic amphotericin B is known as a second-line treatment for visceral and mucocutaneous leishmaniasis.



   Introduction Top


Cutaneous leishmaniasis (CL) is a protozoan infection of skin caused by different species of Leishmania genus. The parasite is transmitted by the bite of sand flies to skin and replicated in the phagocytes. [1] Localized inflammatory response to parasite constitute the skin lesions. [2] L. Brazilensis and L. Mexicana species in the New World [3] and L. Tropica, L. Major and L. aethiopica species in the Old World are responsible for the disease. [2] Worldwide, more than 2 million new cases of leishmaniasis are reported each year. One tenth of the world's population is expected to be at risk of infection. However, more than 90% of CL cases happen in only six countries including: Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria. [4] Global incidence of CL is increasing probably due to improvement in diagnosis and reporting, [5],[6],[7] inadequate control of the disease vector, increased co-infection and transmission with immunosuppressive states such as HIV infection, [8] and increase in resistance to anti-leishmaniasis drugs. [9]

Often the lesions of CL heal spontaneously with scar formation. However, treatment is recommended to accelerate cure, to reduce the scar formation especially at cosmetically important sites of the body, and to prevent potential dissemination of the disease. [10] Also, in the case of L. tropica-induced CL treatment may eliminate the parasite source.

Antimoniate compounds have been used to treat CL since 1950 and are considered as the most appropriate drug and the first line of treatment. [11],[12] The standard treatment is the systemic injection of 20 mg/kg meglumine antimoniate (MA) per day [13],[14] but for patients with limited lesions, the weekly intralesional injection of MA has acceptable response in about 60-80% of cases and is considered as a good alternative for the painful and daily intramuscular injection of MA unless there are concerns about the lesion size and location. In addition, less amounts of drug are used with intralesional injection that reduce the potential toxic effects. [15],[16] Except for allergic reactions, intralesional injection does not have any unavoidable side effects and is considered as a safe treatment. Nowadays, with an increase in the resistance to antimoniate and continuous growth in the disease prevalence in the world, alternative therapies including amphotericin B have been highly considered. [17]

Systemic injection of amphotericin B has been used for disseminated leishmaniasis (visceral and mucocutaneous form) for a long time. [18],[19],[20] Since 2007, intralesional injection of amphotericin B has been used as an alternative therapy for CL in dermatology department of Imam Reza hospital in Mashhad, being started by Poorheydari's team. [21] She described the amphotericin B injection effects on the 34 patients who were resistant or allergic to meglumine antimoniate. [21] Afterwards, this treatment has been used for more cases but the treatment results and its effects have not been analyzed yet. This study aims to describe the efficacy of the treatment with amphotericin B and the possible side effects on the patients treated by intralesional amphotericin B injections in the dermatology department of Imam Reza hospital since 2007.


   Material and Methods Top


This prospective study was done on the patients referred to the dermatology department of Imam Reza hospital from 2007 to 2009. Non-random sampling from both sexes and any age was done. The patients considered for this study had confirmed diagnosis of CL based on skin smear or lesion biopsy. Intralesional amphotericin B injection was chosen based on clinical course and history of antimoniates resistance or side effects.

The patients' age, sex, and skin lesion information including clinical features, location, number of lesions, and disease duration before the treatment, previous treatment and history resistance to antimoniate were recorded in specific forms. The resistance to antimoniate was defined as being unresponsive to systemic, IM injection of antimoniate for 20 days or interalesional injection of it for at least 12 weeks. CL lesions were classified as urban, rural and lupoid type according to clinical features and examiners observation; it was urban if the size of lesions was less than 3-4 cm, the number of lesions was ≤3, and there was no ulceration and lymphatic dissemination. It was lupoid if duration of disease had been more than 24 months before admission, and it was rural if the size of lesions was more than 3-4 cm, the number of lesions was >3, and there was ulceration and or lymphatic dissemination. Size and induration of lesions were measured before beginning and then weakly during the treatment. At the end of the study, the obtained results were categorized as: Complete remission (more than 90% reduction in inflammation and indurations), partial remission (60-90% reduction in inflammation and indurations), and no response (less than 60 percent reduction in inflammation and indurations). Also, the patients were assessed for side effects, complications, and recurrence during the treatment and the followed up 1-13 months.


   Results Top


Ninety-three patients were included in this study for intralesional amphotericin injection. Seventy-nine (84.94%) of them were unresponsive to interalesional meglomine antimoniate (Glucantime) injections, which is generally the first choice of treatment in Iran.

As seen in [Table 1], the mean age of the patients was 20.81 ± 15.26 years, 47.3% of them were males and 52.7% were females. Most of lesions were observed in head and neck (55.73%), 26% of the cases had lesions in more than one area.

Regarding the disease duration, 19 patients (20.4%) had disease for less than 6 months, before the admission while 46 patients (49.5%) from 6 to 12 months and 28 patients (30.1%) for more than 12 months before the admission had the disease.

According to the manufacturer's recommendations, amphotericin B was diluted with 10 ml distilled water and kept safe from light with opaque coverage. This solution can be stored up to 1 week at 4-8 ºC. Following the protocol of Poorheidari study, [21] 0.1-0.3 ml from this solution (depending on the size of lesions) was again diluted with 2-3 parts of distilled water and then injected intralesionally. The patients were treated with intralesional amphotericin B once a week until the lesion resolves completely. The average number of the amphotericin injections was 10.31 ± 5.41. The average duration of the patient treatment and follow-up was 4.87 ± 4.24 months. The treatment results after 1, 4, 8, and 12 weeks are shown in Graph 1.

As seen in Graph 1, at the end of 12 weeks, 61.4% of the patients recovered completely (more than 90% reduction in the size and induration), 21.6% of the patients had partial remission (60-90% reduction in the size and induration), and 17% of the patients had less than 60% reduction in the size and induration of the skin lesions. [Figure 1]a and b illustrate a patients treated by this modality.
Figure 1: Pre (a) and post (b) treatment images of a CL case treated with 7 weekly intralesioal injections of amphotericin B. Note the complete re-epithelialization and more that 90% reduction in erythema and induration

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The highest rates of complete remission were seen in the patients with rural type of CL (66.7%) and also in those who were referred for the treatment in less than 6 months after onset of the disease. The treatment results at the end of 12 weeks in terms of type of leishmaniasis and disease duration before the treatment are shown in [Table 2].
Table 1: Patients' demographic information and characteristics of cutaneous lesions

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Table 2: Treatment results at the end of 12 weeks in terms of type of leishmaniasis and duration of disease

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Recurrence was observed in nine cases which happened in 6 months (six cases), 6-12 months (two cases) or more than 12 months (one case) after the end of the treatment [Table 3]. The highest rates of recurrence were seen in lupoid type (five cases) and urban type (four cases). There was no recurrence in the rural types. As seen in [Table 4], the injections side effects were negligible and did not lead to premature discontinuation of the treatment in any patients.
Table 3: Disease recurrence after treatment

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Table 4: Injections side effects

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   Discussion Top


Amphotericin B is an antifungal and antiparasitic drug with broad spectrum of activities against the organisms with ergosterol in their membranes. It is commonly used as a systemic agent with intravenous administration. However, because of its toxic effects on the body organs particularly kidney, it is generally used only after other treatments have failed. [22],[23] Since toxic side effects of a drug greatly decrease with topical administration, [7],[24],[25] intralesional injection of amphotericin for CL is regarded as an alternative treatment especially in the areas with high prevalence of resistance to antimoniate. [2]

Several studies have emphasized the effect of amphotericin in the treatment of CL. In the study conducted by Vardy, [26] systemic injection of amphotericin B was found effective in a placebo-controlled trial in the treatment of the CL caused by L. Major. A survey was done by Wortmann et al.[27] in USA on 20 patients with CL who were infected by five different species in five different countries. Their study showed that 80% of the patients had complete remission after 21 days treatment with liposomal amphotericin B. Also, in the study done by Solomon et al.[28] in Israel, 11 (84%) of the 13 patients infected with L. Tropica had complete recovery in 2 months after being treated with intravenous liposomal amphotericin B. Also, Layegh et al.[29] compared the treatment with topical application of liposomal amphotericin B lotion versus intralesional antimoniate in Iran. 56.4% improvement in the group treated with amphotericin B was reported versus 67.6% in the group treated with antimoniate. Also, in the study done by Poorheidari, [21] 72.5% complete remission was reported in 34 patients treated with intralesional amphotericin B in Iran.

The present study described therapeutic results for intralesional injection of amphotericin B for 93 cases of CL in Iran of whom 84.94% were resistant to antimoniate. It must be noted that liposomal amphotericin B is very expensive and is not easily available in Iran. Regarding the low socio-economic level of the infected people in this study, we used intralesional amphotericin B for our study as a feasible and less expensive alternative to antimoniate. 61.4% of the patients had complete recovery after 12 weeks treatment that is more than the observed positive result (56.4%) in the group treated with amphotericin B lotion by Layegh et al.[29] However, the observed result is less than the result of the study done by Poorheidari [21] in Iran and also less than the other results obtained outside of Iran [27],[28] as explained above.

We showed intralesional amphotericin B had an efficacy comparable to the intralesional antimoniate reported by Layegh et al. with the same kind of CL epidemiologically. [29] However, in Kashani's study in Tehran, [30] classic treatment with antimoniate (systemic injection of 20 mg/kg/days) had 86.66% complete recovery, while in a systematic review in 2009 by Khatami et al.[31] 97% recovery was reported.

The lower toxic side effects with topical injection is due to a much lower doses of drug absorb and reached sensitive internal organs such as kidneys compared to systemic administration. [2] In our study, the amphotericin B injection complications were low and insignificant and did not lead to discontinuation of the treatment in any cases as other research works confirm it as well. [26],[27]

We concluded that intralesional amphotericin B is a promising alternative therapy for CL considering that 84.94% of these patients were resistant to antimoniate and we observed 61.4% complete improvement of lesions.


   Limitations Top


Our study had two main limitations. The study was not randomized controlled trial. We did not determine the parasite species by molecular methods.

 
   References Top

1.Alrajhi AA. Cutaneous leishmaniasis of the Old World. Skin Ther Lett 2003;8:1-4.  Back to cited text no. 1
    
2.Berman JD. Human leishmaniasis: Clinical, diagnostic, and chemotherapeutic developments in the last 10 years. Clin Infect Dis 1997;24:684-703.  Back to cited text no. 2
    
3.Grimaldi G Jr, Tesh RB, McMahan Pratt D. A review of the geographic distribution and epidemiology of leishmaniasis in the new word. Am J Trop Med Hyg 1989;41:687-725.  Back to cited text no. 3
    
4.Desjeux P. Leishmaniasis: Current situation and new perspectives. Comp Immunol Microbial Infect Dis 2004;27:305-18.  Back to cited text no. 4
    
5.Garnier T, Croft SL. Topical treatment for cutaneous leishmaniasis. Curr Opin Investig Drugs 2002;3:538-44.  Back to cited text no. 5
    
6.Desjeux P. The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg 2001;95:239-43.  Back to cited text no. 6
    
7.Yadón ZE, Quigley MA, Davies CR, Rodrigues LC, Segura EL. Assessment of Leishmaniasis notification system in Santiago del Estero, Argentina, 1990-1993. Am J Trop Med Hyg 2001;65:27-30.  Back to cited text no. 7
    
8.Molina R, Gradonil L, Alvar J. HIV and transmission of leishmania. Ann Trop Med Parasitol 2003;97 Suppl 1:29-45.  Back to cited text no. 8
    
9.Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microb Rev 2006;19:111-26.  Back to cited text no. 9
    
10.Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet 2005;366:1561-77.  Back to cited text no. 10
    
11.Leboit A, Winstroub R. Leishmaniasis. In: Dover JS, editor. Cutaneous medicine and surgery. Philadelphia: WB Sanders; 1996. p. 1163-71.  Back to cited text no. 11
    
12.Layegh P, Rahsepar S, Rahsepar AA. Systemic meglumine antimoniate in acute cutaneous leishmaniasis: Children versus adults. Am J Trop Med Hyg 2011;84:539-42.  Back to cited text no. 12
    
13.Ghosen SH, Kuban AK. Leishmaniasis and other protozoan infections. In: Wolff K, Goldsmith LA, Gilchrest BA, Valler AS, Leffell DJ, editors. Fitzpatrick's dermatology in General Medicine. 7 th ed. USA: McGraw-Hill; 2012. p. 2001-11.  Back to cited text no. 13
    
14.Berman JD, Edwards N, King M, Grogl M. Biochemistry of Pentostam resistant leishmania. Am J Trop Med Hyg 1989;40:159-64.  Back to cited text no. 14
    
15.Tallab TM, Bahamdam KA, Mirdad S, Johargi H, Mourad MM, Ibrahim K, et al. Cutaneous leishmaniasis: Schedules for intralesional treatment with sodium stibogluconate. Int J Dermatol 1996;35:594-7.  Back to cited text no. 15
    
16.Salmanpour R, Razmavar MR, Abtahi N. Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment of cutaneous leishmaniasis. Int J Dermatol 2006;45:1115-6.  Back to cited text no. 16
    
17.Al-Mohammed HI, Chance ML, Bates PA. Production and characterization of stable amphotericin-resistant amastigotes and promastigotes of Leishmania mexicana. Antimicrob Agents Chemother 2005;49:3274-80.  Back to cited text no. 17
    
18.Croft SL, Yardley V. Chemotherapy of leishmaniasis. Curr Pharm 2002;8:319-42.  Back to cited text no. 18
    
19.Jha TK, Giri YN, Singh TK, Jha S. Use of amphotericin B in drug-resistant cases of visceral leishmaniasis in north Bihar, India. Am J Trop Med Hyg 1995;52:536-8.  Back to cited text no. 19
    
20.Thakur CP. A single high dose treatment of kala-azar with Ambisome (amphotericin B lipid complex): A pilot study. Int J Antimicrob Agents 2001;17:67-70.  Back to cited text no. 20
    
21.Poorheidari N. Thesis: Efficacy of intralesional Amphotericin B for treatment of cutaneous leishmaniasis in patients referred to Dermatology clinic of Imam Reza hospital during 2007-2008. Iran: Mashhad University of Medical Sciences; 2008.  Back to cited text no. 21
    
22.Frankenburg S, Glick D, Klaus S, Barenholz Y. Efficacious topical treatment for murine cutaneous leishmaniasis with ethanolic formulations of amphotericin B. Antimicrob Agents Chemother 1998;42:3092-6.  Back to cited text no. 22
    
23.Giri OP. Amphotericin B therapy in kala-azar. J Indian Med Assoc 1993;91:91-3.  Back to cited text no. 23
    
24.Aerdts SJ, van Dalen R, Clasener HA, Festen J, van Lier HJ, Vollaard EJ. Antibiotic prophylaxis of respiratory tract infection in mechanically ventilated patients. A prospective, blinded, randomized trial of the effect of a novel regimen. Chest 1991;100:783-91.  Back to cited text no. 24
    
25.Bent JP 3 rd , Kuhn FA. Antifungal activity against allergic fungal sinusitis organisms. Laryngoscope 1996;106:1331-4.  Back to cited text no. 25
    
26.Vardy D, Barenholz Y, Cohen R, Zvulunov A, Biton A, Klaus S, et al. Topical amphotericin B for cutaneous Leishmaniasis. Arch Dermatol 1999;135:856-7.  Back to cited text no. 26
    
27.Wortmann G, Zapor M, Ressner R, Fraser S, Hartzell J, Pierson J, et al. Liposomal Amphotericin B for treatment of cutaneous leishmaniasis. Am J Trop Med Hyg 2010;83:1028-33.  Back to cited text no. 27
    
28.Solomon M, Pavlotsky F, Leshem E, Ephros M, Trau H, Schwartz E. Liposomal amphotericin B treatment of cutaneous leishmaniasis due to Leishmania tropica. J Eur Acad Dermatol Venereol 2011;25:973-7.  Back to cited text no. 28
    
29.Layegh P, Rajabi O, Jafari MR, Emamgholi Tabar Malekshah P, Moghiman T, Ashraf H, et al. Efficacy of Topical Liposomal Amphotericin B versus Intralesional Meglumine Antimoniate (Glucantime) in the treatment of cutaneous Leishmaniasis. J Parasitol Res 2011;2011:656523.  Back to cited text no. 29
    
30.Kashani MN, Sadr B, Nilforoushzadeh MA, Arasteh M, Babakoohi S, Firooz A. Treatment of acute cutaneous leishmaniasis whit intralesional injection of meglumine antimoniate: Comparison of conventional technique with mesotherapy gun. Int J Dermatol 2010;49:1034-7.  Back to cited text no. 30
    
31.Khatami A, Firooz A, Gorouhi F, Dowlati Y. Systematic review of New World cutaneous leishmaniasis: Several points. Int J Dermatol 2009;48:201-2.  Back to cited text no. 31
    

What is new?
· Intralesional amphotericin B is an effective and safe treatment in cutaneous leishmaniasis
· Intralesional amphotericin B can be considered as a good alternative in the cases of resistant or allergic to antimoniates.


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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