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Intralesional 8.33% Rifamycin infiltration; New treatment for cutaneous leishmaniasis
Available online at www.sciencedirect.com www.jdds.org
ScienceDirect Journal of Dermatology & Dermatologic Surgery 20 (2016) 39–45
Original article
Intralesional 8.33% Rifamycin infiltration; New treatment for cutaneous leishmaniasis Nameer K. Al-Sudany a,⇑, Yousif J. Ali b a
Department of Dermatology and Venereology, Al-Mustansiriya University, College of Medicine, Baghdad, Iraq b Al-Yarmouk Teaching Hospital, Baghdad, Iraq Received 30 July 2015; accepted 16 November 2015 Available online 24 November 2015
Abstract Background: Cutaneous leishmaniasis (CL) is an endemic disease in Iraq, for which many therapies had been tried, aiming to induce cure with no or minimal scaring. Rifamycin is an antibacterial agent, with the ability to inhibit bacterial DNA-dependent RNA synthesis and it is effective against extra- and intracellular microorganisms. Objective: To evaluate the effectiveness and safety of intralesional 8.33% Rifamycin infiltration in treatment of cutaneous leishmaniasis. Patients and methods: This is an open controlled therapeutic trial, carried out in the outpatient clinic of Dermatology & Venereology, Al-Yarmouk Teaching Hospital during the period between the first of December 2013 to the end of June 2014. A total of 29 patients have been enrolled in this therapeutic trial, however 4 patients were defaulted and 25 patients have completed the therapeutic trial. Fourteen (56%) were males and 11 (44%) were females, with a male to female ratio 1.27. Their ages ranged from 6 to 60 years, with a mean ± SD of 28.6 ± 14.9 years. The total number of lesions was 56 and the duration of lesions ranged between 4 and 18 weeks with a mean ± SD of 9.9 ± 4.4 weeks. The size of lesions ranged from 0.5 to 6 cm in diameter with a mean ± SD of 2.46 ± 1.17 cm. All patients have been diagnosed through history and clinical examination and the diagnosis was confirmed by skin smear and biopsy. The lesions were divided into two groups; group A treated with intralesional 8.33% Rifamycin infiltration every 2 weeks for a maximum of 5 sessions, while group B was left untreated as a control group. Follow up was every 2 weeks during the treatment period, and for 6 weeks after completing the therapeutic sessions. Results: Twenty five patients with a total of 56 lesions were completed the study period. Twenty one (37%) lesions were ulcerative and 35 (63%) were non ulcerative lesions. Ten (40%) patients had single lesion whereas 15 (60%) patients had multiple lesions. In group A, 38 (92.7%) out of 41 lesions showed a cure with 2–5 sessions with a mean ± SD of 4.9 ± 0.79 sessions, while in the control group no lesion had significantly improved or cured. At the end of the study period, only 8 out of 41 treated lesions have left trivial scars. Most of the lesions showed transient hyperpigmentation at the end of the study, but fortunately, it had disappeared in all cases few weeks later. Conclusion: Rifamycin 8.33% solution given intralesionally in cutaneous leishmaniasis is a highly effective agent with a success rate of 92.7%. For cure, it needs 2–5 local infiltrations given every two weeks. In addition to being effective, it is a safe, and less costly therapeutic option for cutaneous leishmaniasis. Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Cutaneous leishmaniasis; Rifamycin solution; Intralesional infiltration
⇑ Corresponding author. Mobile: +964 7712216414.
E-mail address: [email protected] (N.K. Al-Sudany). Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
1. Introduction Cutaneous leishmaniasis (CL) is a zoonotic disease caused by infestation with a protozoan of the genus Leishmania. The disease is endemic in Iraq and other Middle East countries (Desjeux, 1992; Neouimine, 1996).
http://dx.doi.org/10.1016/j.jdds.2015.11.001 2352-2410/Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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The parasite is transmitted to the human exclusively by the bite of infected female sand fly species of Lutzomyia and Phlebotomus (Levin et al., 1980). Although CL is a self healing disease, spontaneous cure may take several months or even years (Sharquie et al., 2001; Sharquie and Al-Talib, 1988), but invariably leaving the patient permanently scared, a stigma which can cause serious social prejudice (Sharquie and Al-Talib, 1988). An estimated 2 million new cases (1.5 million cases of cutaneous leishmaniasis and 500,000 of visceral leishmaniasis) occur annually, with about 12 million people currently infected (Magnitude of the problem, 2011). Over 90% of CL cases occur in Afghanistan, Algeria, Iran, Iraq, Saudi Arabia, Syria, Brazil and Peru (Desjeux, 2004). CL is caused by Leishmania which is a flagellated protozoan of phylum Sarcomastigophora. The vector host of CL is mosquitoes of the genus Phlebotomus, of various species like; P. papatasi, P. sergenti, and P. macedonicum (Faust, 1975; Vegas Francisco, 1976; Sarhan, 1985). Clinically the disease can be seen as dry and wet type (Ghosn and Kurban, 2008). The incubation period is relatively short (1–4 weeks) for wet type and longer (2–8 months or more) for dry type. The rash appears as a macule that rapidly becomes a painless, non-itchy papule which is dusky red in color. With time it might enlarge to become a nodule or a plaque. This stage is called dry (non ulcerative) type leishmaniasis. The lesion may become crusted at the center and then ulcerate forming the wet (ulcerative) type of leishmaniasis (Griffiths and Croft, 1980). Other forms of the disease are diffuse cutaneous leishmaniasis, leishmania recidivans, lupoid leishmaniasis and post kala-azar dermal leishmaniasis. Although CL is a self-limiting disease, it is disfiguring, therefore, the main objectives of treatment of CL are: shortening the duration of the disease, improving the cosmetic results of its scar and to cut short psychological impact on the patients (Sharquie and Al-Talib, 1988). There are different ways of treating CL that may include: 1. Local treatment: like; heat therapy (Selim et al., 1990), cryotherapy (Gurei et al., 2000), laser (Shamsi Meymandi et al., 2011), local infiltration with sodium stibogluconate (Sharquie and Al-Talib, 1988), hypertonic sodium chloride (Sharquie et al., 1994), chloroquine (Yasmin et al., 2011), zinc sulfate solution (Sharquie et al., 1997) and topical application of paromomycin (Asilian et al., 2003) and azole agents (Larbi et al., 1995). 2. Systemic treatments: like; pentavalent antimonials (Joint Formula Committee, 2014), antifungal drugs (Salmanpour et al., 2001; Momeni et al., 1996; Ghosn and Kurban, 2008), rifampicin, (Jaffar, 2006) Azithromycin, (Silva-Vergara et al., 2004) Dapsone, (AlMutaii et al., 2009) and Immunomodulating agents like oral zinc sulfate (Sharquie et al., 2001) and interferon c (Khatami et al., 2007). These therapeutic options have been associated with different success rates and may have certain side effects during or after treatment.
2. Patient and methods This is an open controlled therapeutic trial, carried out in the outpatient clinic of Dermatology & Venereology, Al-Yarmouk Teaching Hospital, Baghdad during the period between the 1st of December, 2013 to the end of June, 2014. A full history was taken from each patient regarding age, sex, occupation, residence, duration of the lesions, family history of similar lesions, history of pregnancy, and history of any previous therapy. Thorough physical examination was performed regarding the number, site, size, consistency and type of the lesions (ulcerative and non-ulcerative lesions). Regional lymphadenopathy was also checked for during examination. All patients diagnosed with CL during the study period were included in this work except patients with the following criteria: Patients received any anti–leishmanial treatment for at least one month before this study. Patients with liver disease. Patients with lesions close to the eyes or lesions involving the nose or ears. Patients with history of hypersensitivity to Rifamycin group of drugs. Patients with large-sized lesions (larger than 6 cm in diameter). Patients with large number of lesions (more than 5 lesions). Pregnant women. The ethical approval was given by the Scientific Committee of the Scientific Council of Dermatology and Venereology, Iraqi Board for Medical Specializations. All patients have been informed and fully-explained about the nature of disease and the therapy that will be used and a formal consent was taken from each patient. The diagnosis of every case was made on a clinical background and confirmed by skin smear and biopsy. The lesions have been divided into two groups: Group A: Lesions were treated with a local infiltration (intralesional) of 8.33% Rifamycin solution which was obtained in a form of readymade medication, 250 mg/3 ml ampoule. It was purchased from FARMA KOCAK Pharmaceutical and Chemical Industry, Turkey. It is injected intradermally using (26 gauge insulin needle) at an angle 45° to the lesion surface, with the injected amount at a rate of 0.5 ml per cm2). One intralesional session of Rifamycin was given every two weeks for a maximum of five total sessions. Group B: Lesions in this group have received no treatment and left as a control (an average of one control lesion for each patient with two or more lesions). All lesions were assessed for the degree of erythema, the size, and palpated to assess the degree of induration. However the main parameter of assessment was reduction in the
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size of the lesion according to the following scaling (grading) system Sharquie and Al-Talib, 1988: Slight: decrease in erythema and indurations of the lesion. Mild: reduction in the size of the lesion up to 30%. Moderate: reduction in the size of the lesion of 30–60%. Marked: reduction in the size of the lesion >60%. Total clearance of the lesion.
2.1. Both marked improvement and total clearance were considered as a clinical cure (Sharquie and Al-Talib, 1988) The size of each lesion was measured using finely calibrated tape measure in centimeter unit. For rounded lesions one diameter was taken, whereas for irregularlyshaped lesions, the two maximum diameters (length and width) were taken to calculate the mean. In each visit (every 2 weeks) the diameter of lesions were measured in addition to assessing the degree of erythema and induration, and compared with the results of previous visits to assess the degree of improvement or resolution. Photos were taken in a standardized way according to place, light exposure, and distance using Canon Power Shot SX260HS camera 12.1 Megapixel. Patients were assessed every 2 weeks and at each visit the scoring was re-assessed to estimate the degree of the response and record any local and systemic side effects. All patients were followed-up for further 6 weeks after completing their therapeutic sessions for further assessment of therapeutic results obtained and the fate of side effects if any. SPSS program (version 21) was used for descriptive (number, mean, percentage, range and standard deviation) and analytic statistics using Chi-squire (v2) and P value for data analyses. 3. Results A total of 29 patients have been enrolled in this therapeutic trial, however 4 patients with a total of 6 lesions were defaulted and 25 patients with a total of 56 lesions were completed the study period. Fourteen (56%) were males and 11 (44%) were females, with a male to female ratio 1.27. The age ranged from 6 to 60 years, with a mean ± SD of 28.6 ± 14.9 years. The youngest patient was 6 years old and the oldest patient was 60 years old. The total numbers of lesions were 56 lesions, with 21 (37.5%) ulcerative lesions and 35 (63.5%) non ulcerative lesions. The duration of the lesions was 4–18 week with a mean ± SD of 9.9 ± 4.4 weeks. The size of lesions ranged from 0.5 to 6 cm in diameter with a mean ± SD of 2.46 ± 1.17 cm. Ten (40%) patients had single lesion whereas 15(60%) patients had multiple lesions (Table 1). The most common site affected by cutaneous leishmaniasis was the upper extremities 48 (85.7%), then the lower
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extremities 5 (8.9%), while the least affected site was the face (1.8%) (Table 2). Group A, Forty one lesions were treated, 38 (92.7%) lesions showed a cure, of which, 37 (90.2%) lesions showed total clearance of the lesions and one (2.5%) lesion had marked improvement. The number of sessions ranged from 2 to 5 with a mean ± SD of 4.9 ± 0.79 sessions. The remaining 3 (7.3%) lesions showed moderate response with 5 sessions (Table 3). Thirty seven (90.2%) lesions had complete clearance with 2–4 sessions, mean ± SD of 3.83 ± 0.72 sessions, where 13 lesions totally cleared with only 2 sessions, 17 lesions by 3 and 7 lesions by 4 sessions (Figs. 1–3). This study has revealed that non ulcerative lesions were better responsive than ulcerative ones, as all 26 (100%) non ulcerative lesions versus 12 out of 15 (80%) ulcerative lesions were cured. This was statistically significant (P value = 0.017). Group B, The 15 control lesions showed no sign of improvement after completing the study period except for 2 (13.3%) lesions which showed slight clinical improvement. Table 1 The number of lesions in patients with cutaneous leishmaniasis. Number of lesions
Number of patients
Percentage (%)
Single 2 3 4 5 Total = 56
10 4 7 3 1 Total = 25
40 16 28 12 4 100
Table 2 The frequency distribution of lesions according to the site of involvement. Site
Number of lesions
Percentage (%)
Upper extremities Lower extremities Trunk Face Neck Total
48 5 2 1 0 56
85.7 8.9 3.6 1.8 0 100
Table 3 The score of response in all treated lesions of cutaneous leishmaniasis. Grade of response
Number of lesions
Percentage (%)
Number of sessions
Slight Mild Moderate Marked Total clearance No response Total
0 0 3 1 37 0 41
0 0 7.3 2.5 90.2 0 100
0 0 5 sessions 5 sessions 2–4 sessions 0
Mean ± SD sessions = 4.9 ± 0.79.
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A
B
Figure 1. A 19-year-old female with CL. (A) Before treatment, (B) After two sessions of intralesional Rifamycin injection.
A
B
Figure 2. A 34-year-old female with CL. (A) Before treatment, (B) After two sessions of intralesional Rifamycin injection (Complete clearance).
During the study period there were no systemic side effects from using Rifamycin solution intralesionally, however, regarding local side effects, mild pain at the infiltration site was encountered in 18 (72%) patients and moderate pain in 7 (28%) patients. At the end of the study only 8 (19.5%) out of 41 treated lesions have left scarring, it was slight in all cases, as none of them exceeded the size of the one third of the original lesion. Postinflammatory hyperpigmentation was seen in most of the treated lesions, however, it was transient and took just few weeks to disappear. 4. Discussion CL is a self-healing disease; however spontaneous cure may take several months or even years. Many therapeutic agents were used to shorten the duration of lesions and to prevent or minimize scarring (Sharquie and Al-Talib, 1988).
Regarding age groups affected by CL, the present work has shown that adult were more commonly involved than children (75% versus 25%), this may differ from the finding of many previous studies that had shown predominance of children involvement (Vegas Francisco, 1976; Sharquie et al., 1997; Layegh et al., 2013). However, adult more than children involvement by CL have been reported (Armijos et al., 1997). The mean age group was 28.6 ± 14.9 and this goes in parallel with many other published studies (Sharquie and Al-Talib, 1988; Yasmin et al., 2011; AlZoubaidi, 2012; Hamdi et al., 2010). Males were more affected than females in the present study with a male to female ratio 1.27. This was similarly reported by many previous studies (Yasmin et al., 2011; Armijos et al., 1997; Hamdi et al., 2010; Velez et al., 2001). Regarding the type of CL lesions, 26 (about 63%) lesions were non ulcerative versus 15 (about 37%) lesions were ulcerative. The clinical types of lesions of CL whether ulcerative or none ulcerative usually depend on the clinical
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A
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B
Figure 3. A 30-year-old male with CL. (A) Before treatment, (B) After 4 sessions of intralesional Rifamycin injection.
forms of CL i.e. wet early ulcerative versus dry late ulcerative CL, which in turn is mainly a reflection of the type of species of the causative Leishmania protozoa that differ in their pathogenicities. This study was not concerned with the clinical types of lesions regarding wet and dry varieties, but rather ulcerative and non-ulcerative lesions to detect any difference in their responsiveness to the assessed therapeutic agent. However the predominance of non-ulcerative lesions may be partly explained by the relatively early presentation of the patients enrolled in this study, as the duration of the lesions ranged from 4 to 18 weeks with a mean of 10 weeks and it is well documented that ulceration may start after 3 months of the onset of infection and it may be delayed to many month later in dry type (Ghosn and Kurban, 2008). Regarding the site of involvement by cutaneous leishmaniasis in the present study, most of the lesions were on the exposed parts of the body and in order of decreasing frequency these were; the upper extremities (85.7%), the lower extremities (8.9%), whereas only 3.6% were on the trunk. This is expected as CL is an insect-born infestation and it goes in parallel with the published literature regarding the predominance of exposed parts involvement by CL (Ghosn and Kurban, 2008; Sharquie et al., 1994, 1997). However, face involvement was rare in this study and this may be secondary to the exclusion criteria applied in which lesions around orifices like nose, eyes, and ears were excluded. A lot of therapeutic options for CL are available, however local chemical infiltrations may be considered as an appropriate method of treatment, especially for small, non-inflamed lesions that are not at risk to progress to mucocutaneous leishmaniasis (Ghosn and Kurban, 2008). Also intralesional injection of leishmaniasis sore is a traditional method of treatment recommended by the World
Health Organization in endemic areas (Hamdi et al., 2010; Dawlati, 1996; Ahmed, 1982). Many therapeutic agents given intralesionally have been tested previously with different success rates, like; Sodium stibogluconate, (Sharquie and Al-Talib, 1988) Meglumin antimoniate, (Chehade and Douba, 1990) Hypertonic sodium chloride solution (7%), Sharquie et al., 1994 Zinc sulfate solution (2%), Sharquie et al., 1997 Metronidazole, (Sharquie et al., 2004) ]Bleomycin (1%), Soyuer and Aktas, 1988 Ciprofloxacin (0.2%) Hamdi et al., 2010 and Chloroquine. (Yasmin et al., 2011). We have tried Rifamycin, which is for our best knowledge, has not been tried before for CL through intralesional infiltration. Rifamycin is an antibacterial drug and it is related to Rifampicin (both are belonging to Rifamycin group), its activity relies on the inhibition of bacterial DNA dependent RNA synthesis and it is effective against intra and extracellular located microorganism (Feklistov et al., 2008; Campbell et al., 2001). We have found a final success rate of 92.7% among patients with CL involved in this study with intralesional Rifamycin infiltration versus none of the controlled lesions. This success rate can be considered very comparable with the success rates of many effective intralesional chemical therapeutic agents previously studied like; Sodium stibogluconate antimony (94.6%) Sharquie and Al-Talib, 1988, Meglumine antimoniate (100%) Chehade and Douba, 1990; Yasmin et al., 2011, Hypertonic sodium chloride solution 7% (96%) Sharquie, 1995, Zinc sulfate solution 2% (94.8) Sharquie et al., 1997, Metronidazole 0.5% and 5% (with success rates of 85% and 87% respectively) (Sharquie et al., 2004), Chloroquine (100%) Yasmin et al., 2011, Bleomycin (100%) Soyuer and Aktas, 1988 and Ciprofloxacin 0.2% (81.5%) Hamdi et al., 2010.
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The number of sessions needed for cure of lesions ranged from 2 to 5 sessions given at 2 weeks interval, which was comparable with many other agents like; Ciprofloxacin, Metronidazole (0.5% and 5%) and Hypertonic sodium chloride solution (7%) (Hamdi et al., 2010; Sharquie et al., 2004; Sharquie, 1995). However, the number of required therapeutic sessions in this study was less than the average number of injections needed with Meglumin antimoniate and Chloroquine (Yasmin et al., 2011). Still the number of sessions needed with Sodium stibogluconate (Sharquie and Al-Talib, 1988) was less than with Rifamycin injection used in this study. Rifamycin intralesionally in addition to be effective, it is associated with insignificant side effects as only 8 out of 41 lesions ended with a scar, which is minimal in all cases and this coincides with many other successful therapeutic agents (Yasmin et al., 2011; Sharquie et al., 1997, 2004; Sharquie, 1995; Hamdi et al., 2010; Soyuer and Aktas, 1988). Most of the treated lesions (38 out of 41 lesions) with Rifamycin infiltration have left transient localized hyperpigmentation which was subsided after few weeks in all cases. Many other therapeutic agents used intralesionally in CL lesions have left similar hyperpigmentation which was transient (Yasmin et al., 2011; Sharquie et al., 1997, 2004; Sharquie, 1995). Comparing the results which have been obtained with intralesional Rifamycin used in the present work with oral Rifampicin, we have found that intralesional Rifamycin was superior to oral Rifampicin in success rate (92.7%) versus (61.8%) Jaffar (2006) and (73.9%) Kochar et al. (2000) with nearly similar duration of treatment. However the dose of Rifampicin used was too high (1200 mg/day) (Kochar et al., 2000), which may necessitate serological and biochemical assessment regarding complete blood count, liver and renal function tests before, during and after treatment (Jaffar, 2006). 5. Conclusion Rifamycin 8.33% solution given intralesionally in cutaneous leishmaniasis is a highly effective agent with a success rate of 92.7%. For cure, it needs 2-5 local infiltrations given every two weeks. In addition to being effective, it is a safe and less costly therapeutic option for cutaneous leishmaniasis. Conflict of interest There is no conflict of interest associated this study. References Ahmed, A.M., 1982. Case report: chronic cutaneous leishmaniasis successfully treated with pentostam. Iraqi Med. J. 29, 99–101. Al-Mutaii, N., Alshiltawy, M., El Khalawany, M., Joshi, A., Eassa, B., Manchanda, Y., Gomaa, S., Darwish, I., Rijhwani, M., 2009.
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N.K. Al-Sudany, Y.J. Ali / Journal of Dermatology & Dermatologic Surgery 20 (2016) 39–45 Magnitude of the problem [internet] 2011 [updated 2014 Nov 1]. Available from: http://www.who.int/leishmaniasis/burden_magnitude. leishmaniasis. Momeni, A.Z., Jalayer, T., Emamjomeh, M., Bashardost, N., Ghassemi, R.L., Meghdadi, M., 1996. Treatment of cutaneous leishmaniasis with itraconazole. Randomized double-blind study. Arch. Dermatol. 132, 784–786. Neouimine, N.I., 1996. Leishmaniasis in the eastern mediterranean region. Eastern Med. Health 2, 94–101. Salmanpour, R., Handjani, F., Nouhpisheh, M.K., 2001. Comparative study of the efficacy of oral ketoconazole with intra-lesional meglumine antimoniate (Glucantime) for the treatment of cutaneous leishmaniasis. J. Dermatolog. Treat. 12, 159–162. Sarhan, G.M., 1985. Epidemiological and Clinical Study on Cutaneous Leishmaniasis Postgraduate thesis. College of Medicine University of Baghdad. Selim, M.M., Vilasin, Z., Jaroskova, L., 1990. Leishmaniasis. In: Currently recommended treatment. Int. J. Dermatol. 29, 318–320. Shamsi Meymandi, S., Zandi, S., Aghaie, H., Heshmatkhah, A., 2011. Efficacy of CO2 laser for treatment of anthroponotic cutaneous leishmaniasis, compared with combination of cryotherapy and intralesional meglumine antimoniate. J. Eur. Acad. Dermatol. Venereol. 25 (5), 587–591. Sharquie, K.E., 1995. A new intra-lesional therapy of cutaneous leishmaniasis with hypertonic sodium chloride solution. J. Dermatol. 22, 732–737. Sharquie, K.E., Al-Talib, K., 1988. Intralesional therapy of cutaneous leishmaniasis with sodium stibogluconate antimony. Br. J. Dermatol. 119, 53–57.
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Sharquie, K.E., Hussian, A.K., Turki, K.M., 1994. Intralesional therapy of cutaneous leishmaniasis with Hypertonic Sodium Chloride Solution. J. Pan-Arab Ass. Dermatol. 5, 85–91. Sharquie, K.E., Najem, R.A., Farjou, I.B., 1997. A comparative control trail of intralesional administrated zinc sulfate, hypertonic saline chloride and pentovalent antimony compound against acute cutaneous leishmaniasis. Clin. Exp. Dermatol. 22, 169–173. Sharquie, K.E., Najm, R.A., Farjou, I.B., Al-Timimi, D.J., 2001. Oral zinc sulfate in the treatment of acute cutaneous leishmaniasis. Clin. Exp. Dermatol. 26, 21–26. Sharquie, K.E., Al-Waize, M., Al-Asser, M., 2004. Treatment of cutaneous leishmaniasis by intralesional metronidazole. Saudi Med. J. 10, 1512–1513. Silva-Vergara, M.L., Silva, L.A., Maneira, F.R.Z., Silva, A.G., Prata, A., 2004. Case report: azithromycin in the treatment of mucosal leishmaniasis. Rev. Inst. Med. Trop. Sao Paulo 46, 175–177. Soyuer, U., Aktas, E., 1988. Intra-lesional bleomycin therapy of leishmaniasis cutis. Arch. Dermatol. 124, 1571. Kerdel - Vegas Francisco. Oriental sore (Cutaneous leishmaniasis); infection and bites, parasites, arthropods and animal. In: Clinical Dermatology. Demis D. Joseph. 1976; 4:18. Velez, I.D., Hendrickx, E., Robledo, S.M., del Pilar Agudilo, S., 2001. Gender and cutaneous leishmaniasis in Colombia. Cad. Saude. Publica. 17 (1), 171–180. Yasmin, R., Khan, I., Ahmad, S.A., 2011. Response to treatment of cutaneous leishmaniasis with intralesional chloroquine vs intralesional meglumine antimoniate. J. Pak. Assoc. Dermatol. 21 (4), 270– 275.
ScienceDirect Journal of Dermatology & Dermatologic Surgery 20 (2016) 39–45
Original article
Intralesional 8.33% Rifamycin infiltration; New treatment for cutaneous leishmaniasis Nameer K. Al-Sudany a,⇑, Yousif J. Ali b a
Department of Dermatology and Venereology, Al-Mustansiriya University, College of Medicine, Baghdad, Iraq b Al-Yarmouk Teaching Hospital, Baghdad, Iraq Received 30 July 2015; accepted 16 November 2015 Available online 24 November 2015
Abstract Background: Cutaneous leishmaniasis (CL) is an endemic disease in Iraq, for which many therapies had been tried, aiming to induce cure with no or minimal scaring. Rifamycin is an antibacterial agent, with the ability to inhibit bacterial DNA-dependent RNA synthesis and it is effective against extra- and intracellular microorganisms. Objective: To evaluate the effectiveness and safety of intralesional 8.33% Rifamycin infiltration in treatment of cutaneous leishmaniasis. Patients and methods: This is an open controlled therapeutic trial, carried out in the outpatient clinic of Dermatology & Venereology, Al-Yarmouk Teaching Hospital during the period between the first of December 2013 to the end of June 2014. A total of 29 patients have been enrolled in this therapeutic trial, however 4 patients were defaulted and 25 patients have completed the therapeutic trial. Fourteen (56%) were males and 11 (44%) were females, with a male to female ratio 1.27. Their ages ranged from 6 to 60 years, with a mean ± SD of 28.6 ± 14.9 years. The total number of lesions was 56 and the duration of lesions ranged between 4 and 18 weeks with a mean ± SD of 9.9 ± 4.4 weeks. The size of lesions ranged from 0.5 to 6 cm in diameter with a mean ± SD of 2.46 ± 1.17 cm. All patients have been diagnosed through history and clinical examination and the diagnosis was confirmed by skin smear and biopsy. The lesions were divided into two groups; group A treated with intralesional 8.33% Rifamycin infiltration every 2 weeks for a maximum of 5 sessions, while group B was left untreated as a control group. Follow up was every 2 weeks during the treatment period, and for 6 weeks after completing the therapeutic sessions. Results: Twenty five patients with a total of 56 lesions were completed the study period. Twenty one (37%) lesions were ulcerative and 35 (63%) were non ulcerative lesions. Ten (40%) patients had single lesion whereas 15 (60%) patients had multiple lesions. In group A, 38 (92.7%) out of 41 lesions showed a cure with 2–5 sessions with a mean ± SD of 4.9 ± 0.79 sessions, while in the control group no lesion had significantly improved or cured. At the end of the study period, only 8 out of 41 treated lesions have left trivial scars. Most of the lesions showed transient hyperpigmentation at the end of the study, but fortunately, it had disappeared in all cases few weeks later. Conclusion: Rifamycin 8.33% solution given intralesionally in cutaneous leishmaniasis is a highly effective agent with a success rate of 92.7%. For cure, it needs 2–5 local infiltrations given every two weeks. In addition to being effective, it is a safe, and less costly therapeutic option for cutaneous leishmaniasis. Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Cutaneous leishmaniasis; Rifamycin solution; Intralesional infiltration
⇑ Corresponding author. Mobile: +964 7712216414.
E-mail address: [email protected] (N.K. Al-Sudany). Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
1. Introduction Cutaneous leishmaniasis (CL) is a zoonotic disease caused by infestation with a protozoan of the genus Leishmania. The disease is endemic in Iraq and other Middle East countries (Desjeux, 1992; Neouimine, 1996).
http://dx.doi.org/10.1016/j.jdds.2015.11.001 2352-2410/Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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The parasite is transmitted to the human exclusively by the bite of infected female sand fly species of Lutzomyia and Phlebotomus (Levin et al., 1980). Although CL is a self healing disease, spontaneous cure may take several months or even years (Sharquie et al., 2001; Sharquie and Al-Talib, 1988), but invariably leaving the patient permanently scared, a stigma which can cause serious social prejudice (Sharquie and Al-Talib, 1988). An estimated 2 million new cases (1.5 million cases of cutaneous leishmaniasis and 500,000 of visceral leishmaniasis) occur annually, with about 12 million people currently infected (Magnitude of the problem, 2011). Over 90% of CL cases occur in Afghanistan, Algeria, Iran, Iraq, Saudi Arabia, Syria, Brazil and Peru (Desjeux, 2004). CL is caused by Leishmania which is a flagellated protozoan of phylum Sarcomastigophora. The vector host of CL is mosquitoes of the genus Phlebotomus, of various species like; P. papatasi, P. sergenti, and P. macedonicum (Faust, 1975; Vegas Francisco, 1976; Sarhan, 1985). Clinically the disease can be seen as dry and wet type (Ghosn and Kurban, 2008). The incubation period is relatively short (1–4 weeks) for wet type and longer (2–8 months or more) for dry type. The rash appears as a macule that rapidly becomes a painless, non-itchy papule which is dusky red in color. With time it might enlarge to become a nodule or a plaque. This stage is called dry (non ulcerative) type leishmaniasis. The lesion may become crusted at the center and then ulcerate forming the wet (ulcerative) type of leishmaniasis (Griffiths and Croft, 1980). Other forms of the disease are diffuse cutaneous leishmaniasis, leishmania recidivans, lupoid leishmaniasis and post kala-azar dermal leishmaniasis. Although CL is a self-limiting disease, it is disfiguring, therefore, the main objectives of treatment of CL are: shortening the duration of the disease, improving the cosmetic results of its scar and to cut short psychological impact on the patients (Sharquie and Al-Talib, 1988). There are different ways of treating CL that may include: 1. Local treatment: like; heat therapy (Selim et al., 1990), cryotherapy (Gurei et al., 2000), laser (Shamsi Meymandi et al., 2011), local infiltration with sodium stibogluconate (Sharquie and Al-Talib, 1988), hypertonic sodium chloride (Sharquie et al., 1994), chloroquine (Yasmin et al., 2011), zinc sulfate solution (Sharquie et al., 1997) and topical application of paromomycin (Asilian et al., 2003) and azole agents (Larbi et al., 1995). 2. Systemic treatments: like; pentavalent antimonials (Joint Formula Committee, 2014), antifungal drugs (Salmanpour et al., 2001; Momeni et al., 1996; Ghosn and Kurban, 2008), rifampicin, (Jaffar, 2006) Azithromycin, (Silva-Vergara et al., 2004) Dapsone, (AlMutaii et al., 2009) and Immunomodulating agents like oral zinc sulfate (Sharquie et al., 2001) and interferon c (Khatami et al., 2007). These therapeutic options have been associated with different success rates and may have certain side effects during or after treatment.
2. Patient and methods This is an open controlled therapeutic trial, carried out in the outpatient clinic of Dermatology & Venereology, Al-Yarmouk Teaching Hospital, Baghdad during the period between the 1st of December, 2013 to the end of June, 2014. A full history was taken from each patient regarding age, sex, occupation, residence, duration of the lesions, family history of similar lesions, history of pregnancy, and history of any previous therapy. Thorough physical examination was performed regarding the number, site, size, consistency and type of the lesions (ulcerative and non-ulcerative lesions). Regional lymphadenopathy was also checked for during examination. All patients diagnosed with CL during the study period were included in this work except patients with the following criteria: Patients received any anti–leishmanial treatment for at least one month before this study. Patients with liver disease. Patients with lesions close to the eyes or lesions involving the nose or ears. Patients with history of hypersensitivity to Rifamycin group of drugs. Patients with large-sized lesions (larger than 6 cm in diameter). Patients with large number of lesions (more than 5 lesions). Pregnant women. The ethical approval was given by the Scientific Committee of the Scientific Council of Dermatology and Venereology, Iraqi Board for Medical Specializations. All patients have been informed and fully-explained about the nature of disease and the therapy that will be used and a formal consent was taken from each patient. The diagnosis of every case was made on a clinical background and confirmed by skin smear and biopsy. The lesions have been divided into two groups: Group A: Lesions were treated with a local infiltration (intralesional) of 8.33% Rifamycin solution which was obtained in a form of readymade medication, 250 mg/3 ml ampoule. It was purchased from FARMA KOCAK Pharmaceutical and Chemical Industry, Turkey. It is injected intradermally using (26 gauge insulin needle) at an angle 45° to the lesion surface, with the injected amount at a rate of 0.5 ml per cm2). One intralesional session of Rifamycin was given every two weeks for a maximum of five total sessions. Group B: Lesions in this group have received no treatment and left as a control (an average of one control lesion for each patient with two or more lesions). All lesions were assessed for the degree of erythema, the size, and palpated to assess the degree of induration. However the main parameter of assessment was reduction in the
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size of the lesion according to the following scaling (grading) system Sharquie and Al-Talib, 1988: Slight: decrease in erythema and indurations of the lesion. Mild: reduction in the size of the lesion up to 30%. Moderate: reduction in the size of the lesion of 30–60%. Marked: reduction in the size of the lesion >60%. Total clearance of the lesion.
2.1. Both marked improvement and total clearance were considered as a clinical cure (Sharquie and Al-Talib, 1988) The size of each lesion was measured using finely calibrated tape measure in centimeter unit. For rounded lesions one diameter was taken, whereas for irregularlyshaped lesions, the two maximum diameters (length and width) were taken to calculate the mean. In each visit (every 2 weeks) the diameter of lesions were measured in addition to assessing the degree of erythema and induration, and compared with the results of previous visits to assess the degree of improvement or resolution. Photos were taken in a standardized way according to place, light exposure, and distance using Canon Power Shot SX260HS camera 12.1 Megapixel. Patients were assessed every 2 weeks and at each visit the scoring was re-assessed to estimate the degree of the response and record any local and systemic side effects. All patients were followed-up for further 6 weeks after completing their therapeutic sessions for further assessment of therapeutic results obtained and the fate of side effects if any. SPSS program (version 21) was used for descriptive (number, mean, percentage, range and standard deviation) and analytic statistics using Chi-squire (v2) and P value for data analyses. 3. Results A total of 29 patients have been enrolled in this therapeutic trial, however 4 patients with a total of 6 lesions were defaulted and 25 patients with a total of 56 lesions were completed the study period. Fourteen (56%) were males and 11 (44%) were females, with a male to female ratio 1.27. The age ranged from 6 to 60 years, with a mean ± SD of 28.6 ± 14.9 years. The youngest patient was 6 years old and the oldest patient was 60 years old. The total numbers of lesions were 56 lesions, with 21 (37.5%) ulcerative lesions and 35 (63.5%) non ulcerative lesions. The duration of the lesions was 4–18 week with a mean ± SD of 9.9 ± 4.4 weeks. The size of lesions ranged from 0.5 to 6 cm in diameter with a mean ± SD of 2.46 ± 1.17 cm. Ten (40%) patients had single lesion whereas 15(60%) patients had multiple lesions (Table 1). The most common site affected by cutaneous leishmaniasis was the upper extremities 48 (85.7%), then the lower
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extremities 5 (8.9%), while the least affected site was the face (1.8%) (Table 2). Group A, Forty one lesions were treated, 38 (92.7%) lesions showed a cure, of which, 37 (90.2%) lesions showed total clearance of the lesions and one (2.5%) lesion had marked improvement. The number of sessions ranged from 2 to 5 with a mean ± SD of 4.9 ± 0.79 sessions. The remaining 3 (7.3%) lesions showed moderate response with 5 sessions (Table 3). Thirty seven (90.2%) lesions had complete clearance with 2–4 sessions, mean ± SD of 3.83 ± 0.72 sessions, where 13 lesions totally cleared with only 2 sessions, 17 lesions by 3 and 7 lesions by 4 sessions (Figs. 1–3). This study has revealed that non ulcerative lesions were better responsive than ulcerative ones, as all 26 (100%) non ulcerative lesions versus 12 out of 15 (80%) ulcerative lesions were cured. This was statistically significant (P value = 0.017). Group B, The 15 control lesions showed no sign of improvement after completing the study period except for 2 (13.3%) lesions which showed slight clinical improvement. Table 1 The number of lesions in patients with cutaneous leishmaniasis. Number of lesions
Number of patients
Percentage (%)
Single 2 3 4 5 Total = 56
10 4 7 3 1 Total = 25
40 16 28 12 4 100
Table 2 The frequency distribution of lesions according to the site of involvement. Site
Number of lesions
Percentage (%)
Upper extremities Lower extremities Trunk Face Neck Total
48 5 2 1 0 56
85.7 8.9 3.6 1.8 0 100
Table 3 The score of response in all treated lesions of cutaneous leishmaniasis. Grade of response
Number of lesions
Percentage (%)
Number of sessions
Slight Mild Moderate Marked Total clearance No response Total
0 0 3 1 37 0 41
0 0 7.3 2.5 90.2 0 100
0 0 5 sessions 5 sessions 2–4 sessions 0
Mean ± SD sessions = 4.9 ± 0.79.
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N.K. Al-Sudany, Y.J. Ali / Journal of Dermatology & Dermatologic Surgery 20 (2016) 39–45
A
B
Figure 1. A 19-year-old female with CL. (A) Before treatment, (B) After two sessions of intralesional Rifamycin injection.
A
B
Figure 2. A 34-year-old female with CL. (A) Before treatment, (B) After two sessions of intralesional Rifamycin injection (Complete clearance).
During the study period there were no systemic side effects from using Rifamycin solution intralesionally, however, regarding local side effects, mild pain at the infiltration site was encountered in 18 (72%) patients and moderate pain in 7 (28%) patients. At the end of the study only 8 (19.5%) out of 41 treated lesions have left scarring, it was slight in all cases, as none of them exceeded the size of the one third of the original lesion. Postinflammatory hyperpigmentation was seen in most of the treated lesions, however, it was transient and took just few weeks to disappear. 4. Discussion CL is a self-healing disease; however spontaneous cure may take several months or even years. Many therapeutic agents were used to shorten the duration of lesions and to prevent or minimize scarring (Sharquie and Al-Talib, 1988).
Regarding age groups affected by CL, the present work has shown that adult were more commonly involved than children (75% versus 25%), this may differ from the finding of many previous studies that had shown predominance of children involvement (Vegas Francisco, 1976; Sharquie et al., 1997; Layegh et al., 2013). However, adult more than children involvement by CL have been reported (Armijos et al., 1997). The mean age group was 28.6 ± 14.9 and this goes in parallel with many other published studies (Sharquie and Al-Talib, 1988; Yasmin et al., 2011; AlZoubaidi, 2012; Hamdi et al., 2010). Males were more affected than females in the present study with a male to female ratio 1.27. This was similarly reported by many previous studies (Yasmin et al., 2011; Armijos et al., 1997; Hamdi et al., 2010; Velez et al., 2001). Regarding the type of CL lesions, 26 (about 63%) lesions were non ulcerative versus 15 (about 37%) lesions were ulcerative. The clinical types of lesions of CL whether ulcerative or none ulcerative usually depend on the clinical
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A
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B
Figure 3. A 30-year-old male with CL. (A) Before treatment, (B) After 4 sessions of intralesional Rifamycin injection.
forms of CL i.e. wet early ulcerative versus dry late ulcerative CL, which in turn is mainly a reflection of the type of species of the causative Leishmania protozoa that differ in their pathogenicities. This study was not concerned with the clinical types of lesions regarding wet and dry varieties, but rather ulcerative and non-ulcerative lesions to detect any difference in their responsiveness to the assessed therapeutic agent. However the predominance of non-ulcerative lesions may be partly explained by the relatively early presentation of the patients enrolled in this study, as the duration of the lesions ranged from 4 to 18 weeks with a mean of 10 weeks and it is well documented that ulceration may start after 3 months of the onset of infection and it may be delayed to many month later in dry type (Ghosn and Kurban, 2008). Regarding the site of involvement by cutaneous leishmaniasis in the present study, most of the lesions were on the exposed parts of the body and in order of decreasing frequency these were; the upper extremities (85.7%), the lower extremities (8.9%), whereas only 3.6% were on the trunk. This is expected as CL is an insect-born infestation and it goes in parallel with the published literature regarding the predominance of exposed parts involvement by CL (Ghosn and Kurban, 2008; Sharquie et al., 1994, 1997). However, face involvement was rare in this study and this may be secondary to the exclusion criteria applied in which lesions around orifices like nose, eyes, and ears were excluded. A lot of therapeutic options for CL are available, however local chemical infiltrations may be considered as an appropriate method of treatment, especially for small, non-inflamed lesions that are not at risk to progress to mucocutaneous leishmaniasis (Ghosn and Kurban, 2008). Also intralesional injection of leishmaniasis sore is a traditional method of treatment recommended by the World
Health Organization in endemic areas (Hamdi et al., 2010; Dawlati, 1996; Ahmed, 1982). Many therapeutic agents given intralesionally have been tested previously with different success rates, like; Sodium stibogluconate, (Sharquie and Al-Talib, 1988) Meglumin antimoniate, (Chehade and Douba, 1990) Hypertonic sodium chloride solution (7%), Sharquie et al., 1994 Zinc sulfate solution (2%), Sharquie et al., 1997 Metronidazole, (Sharquie et al., 2004) ]Bleomycin (1%), Soyuer and Aktas, 1988 Ciprofloxacin (0.2%) Hamdi et al., 2010 and Chloroquine. (Yasmin et al., 2011). We have tried Rifamycin, which is for our best knowledge, has not been tried before for CL through intralesional infiltration. Rifamycin is an antibacterial drug and it is related to Rifampicin (both are belonging to Rifamycin group), its activity relies on the inhibition of bacterial DNA dependent RNA synthesis and it is effective against intra and extracellular located microorganism (Feklistov et al., 2008; Campbell et al., 2001). We have found a final success rate of 92.7% among patients with CL involved in this study with intralesional Rifamycin infiltration versus none of the controlled lesions. This success rate can be considered very comparable with the success rates of many effective intralesional chemical therapeutic agents previously studied like; Sodium stibogluconate antimony (94.6%) Sharquie and Al-Talib, 1988, Meglumine antimoniate (100%) Chehade and Douba, 1990; Yasmin et al., 2011, Hypertonic sodium chloride solution 7% (96%) Sharquie, 1995, Zinc sulfate solution 2% (94.8) Sharquie et al., 1997, Metronidazole 0.5% and 5% (with success rates of 85% and 87% respectively) (Sharquie et al., 2004), Chloroquine (100%) Yasmin et al., 2011, Bleomycin (100%) Soyuer and Aktas, 1988 and Ciprofloxacin 0.2% (81.5%) Hamdi et al., 2010.
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The number of sessions needed for cure of lesions ranged from 2 to 5 sessions given at 2 weeks interval, which was comparable with many other agents like; Ciprofloxacin, Metronidazole (0.5% and 5%) and Hypertonic sodium chloride solution (7%) (Hamdi et al., 2010; Sharquie et al., 2004; Sharquie, 1995). However, the number of required therapeutic sessions in this study was less than the average number of injections needed with Meglumin antimoniate and Chloroquine (Yasmin et al., 2011). Still the number of sessions needed with Sodium stibogluconate (Sharquie and Al-Talib, 1988) was less than with Rifamycin injection used in this study. Rifamycin intralesionally in addition to be effective, it is associated with insignificant side effects as only 8 out of 41 lesions ended with a scar, which is minimal in all cases and this coincides with many other successful therapeutic agents (Yasmin et al., 2011; Sharquie et al., 1997, 2004; Sharquie, 1995; Hamdi et al., 2010; Soyuer and Aktas, 1988). Most of the treated lesions (38 out of 41 lesions) with Rifamycin infiltration have left transient localized hyperpigmentation which was subsided after few weeks in all cases. Many other therapeutic agents used intralesionally in CL lesions have left similar hyperpigmentation which was transient (Yasmin et al., 2011; Sharquie et al., 1997, 2004; Sharquie, 1995). Comparing the results which have been obtained with intralesional Rifamycin used in the present work with oral Rifampicin, we have found that intralesional Rifamycin was superior to oral Rifampicin in success rate (92.7%) versus (61.8%) Jaffar (2006) and (73.9%) Kochar et al. (2000) with nearly similar duration of treatment. However the dose of Rifampicin used was too high (1200 mg/day) (Kochar et al., 2000), which may necessitate serological and biochemical assessment regarding complete blood count, liver and renal function tests before, during and after treatment (Jaffar, 2006). 5. Conclusion Rifamycin 8.33% solution given intralesionally in cutaneous leishmaniasis is a highly effective agent with a success rate of 92.7%. For cure, it needs 2-5 local infiltrations given every two weeks. In addition to being effective, it is a safe and less costly therapeutic option for cutaneous leishmaniasis. Conflict of interest There is no conflict of interest associated this study. References Ahmed, A.M., 1982. Case report: chronic cutaneous leishmaniasis successfully treated with pentostam. Iraqi Med. J. 29, 99–101. Al-Mutaii, N., Alshiltawy, M., El Khalawany, M., Joshi, A., Eassa, B., Manchanda, Y., Gomaa, S., Darwish, I., Rijhwani, M., 2009.
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