Q J Med 2000; 93: 733-737
© 2000 Association of Physicians
The role of rifampicin in the management of cutaneous leishmaniasis
From the Departments of Medicine and 1 Skin & VD, S.P. Medical College 2 Veterinary Public Health Department, College of Veterinary and Animal Science, Bikaner, India
Received 20 June 2000 and in revised form 4 September 2000
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Summary |
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We assessed the efficacy of rifampicin in the treatment of cutaneous leishmaniasis (oriental sore) using a double-blind placebo-controlled study. We studied 46 patients with cutaneous leishmaniasis, of whom 23 received rifampicin (group A) and another 23 received placebo (group B) for a period of 4 weeks. Each patient was assessed clinically for size of lesion, type of lesion, duration of lesion, number of lesions, and distribution of lesions, initially, and at the end of 1 week, 2 weeks and 4 weeks. Biochemical tests including enzyme studies were done to detect any toxic effects of the drug. Group A patients received rifampicin 1200 mg/day in two divided doses and group B patients received two doses of an identical placebo capsule. Seventeen (73.9%) of the 23 patients receiving rifampicin had complete healing. Two (8.6%) had partial healing and four (17.3%) showed no response, whereas out of 23 patients receiving placebo one patient (4.3%) showed complete healing, eight (34.7%) patients showed partial healing and 14 (60.98%) patients showed no healing or exacerbation of lesion. The difference was statistically significant in favour of response to rifampicin. This dose of rifampicin was well-tolerated and no side-effects were seen in any patient. In cases of cutaneous leishmaniasis where injectable treatment is not feasible or not acceptable, as in cases of multiple lesions, rifampicin is a better alternative oral treatment. It is simple to administer, cheap, more effective and less toxic than other available oral drugs, and well-tolerated by patients.
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Introduction |
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Cutaneous leishmaniasis is a vector-borne parasitic disease caused by a number of different Leishmania species. Infection is acquired in the tropics and subtropics following the bite of an infected sand fly. Clinical manifestation of disease are governed by the characteristics of the infecting Leishmania species, host and the host's immune response to the parasite. Infection can be limited to the skin or mucous membrane in localized cutaneous leishmaniasis (LCL), diffuse cutaneous leishmaniasis (DCL) or mucosal leishmaniasis (ML).1
Cutaneous leishmaniasis is prevalent in different parts of India, but distribution of the disease is not uniform. It has also been reported from Bikaner (in the north-west of India) at endemic levels.2–5 The lesions are usually seen on the exposed parts of body such as face, hands and legs (Figure 1
) and recovery after the treatment usually leaves a disfiguring dark-coloured scar and pitted area over the affected body parts.6
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Different treatment regimens are available for the management of cutaneous lesions and many authors have also recommended no treatment for disease.7 The process of spontaneous healing usually occurs after 6 months from the onset of disease.8 For many years, patients have been treated with sodium stibogluconate, a pentavalent antimonial compound but this treatment is less than adequate because of prolonged intravenous therapy, drug toxicity, and frequent need of hospitalization for the full treatment course (usually 20 days). Pentamidine is also used in alternative to sodium stibogluconate. Intralesional berbarin sulphate is also used but is more painful and leaves scars after healing.
Various oral medications such as ketoconazole, itraconazole, metronidazole, allopurinole, dapsone, etc. have also been tried but their effects were not constant. As the prolonged injectable treatment modalities for oriental sore are not well-accepted by patients, and other available drugs are not effective, we studied the effect of rifampicin as an oral treatment for oriental sore, because it was effective in some earlier reports.9,10
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Methods |
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Fifty cases of cutaneous leishmaniasis were randomly selected from the Department of Dermatology between January 1999 and May 1999. Biopsies were taken from the edge of the skin lesion, and were stained with Giemsa's stain. The diagnosis was confirmed by demonstrations of LT bodies (amastigote stage of L. tropica under oil immersion). Informed consent was obtained from all adult participants and from parents or legal guardians for minors. The protocol was approved by the ethical committee of the unit. The patients received either rifampicin (1200 mg/day) in two divided doses or placebo in a double-blind placebo-controlled fashion for 4 weeks. Detailed history and clinical examination including, duration of disease, site, number, type and distribution of lesions were noted in a proforma. Laboratory investigations including TLC, DLC, serum bilirubin, SGOT, SGPT were carried out before starting the treatment and at the end of 1 week, 2 weeks and 4 weeks after initiating treatment. All these data were collected on special proforma and the study was kept double-blind. At the end of 4 weeks, the files were decoded, and the patients were divided into two groups: group A, receiving rifampicin; and group B, receiving placebo. The results with rifampicin were compared with those obtained with placebo, and were statistically evaluated using SPSS version 7.0. Clinical and parasitological evaluations of the patients were performed at the end of the treatment period and 4 weeks post treatment. A cure was defined as complete healing and disappearance of the lesion or reversible hypopigmentation at the site of lesion. Incomplete or partial healing was defined as a reduction in the size of a lesion and the absence of parasites on smear. A treatment failure or non-healing was defined as the absence of any change in the lesion and persistence of parasites on smear.
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Results |
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A total of 50 cases were selected between January 1999 and May 1999. Microscopy of formalin-fixed Giemsa-stained skin biopsies confirmed intracellular amastigotes in all patients. In group A (who received rifampicin) out of 25 cases, only 23 completed the study, and two were lost during follow-up. In group B (who received placebo) out of 25 cases, only 23 completed the course and two withdrew due to exacerbation of lesions. These two patients were treated by other therapeutic regimen. All these four cases were not included in the study. The demographic data of patients and baseline characteristics of both the groups were similar, as shown in Table 1
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The results of treatment with rifampicin and placebo after 4 weeks duration are shown in Table 2
, from which it is evident that 17 (73.9%) patients had complete healing of lesions in the rifampicin group (Figure 2) and one patient (4.3%) in the placebo group while non-healing was more common in the placebo group (60.98%) than in the rifampicin group (17.3%). The drug was very well tolerated, and there were no derangements of liver function tests or other side-effects during the therapy.
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Discussion |
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Cutaneous leishmaniasis is being reported from almost every part of the world. Clinical diagnosis is sometimes difficult, because occasionally it resembles other skin diseases such as leprosy, lupus vulgaris, wart, simple ulcer, etc. and definitive diagnosis is possible only by demonstration of organisms from the lesion. Depending on the availability of laboratory backup, the species should be identified by molecular methods. Serological and leishmanin skin tests become positive in 4–6 weeks but are unreliable, because they may not distinguish between leishmaniasis and Trypanosoma cruzi infections and may demonstrate cross-reactivity at low titres in malaria, toxoplasmosis and amoebiasis.11 Serological testing is an insensitive means for diagnosing cutaneous leishmaniasis because antibody titres are only minimally elevated, except in patients who have DLC.12 All the cases in this study were diagnosed by skin biopsies which were stained with giemsa stain, showing LT bodies under oil immersion.
There are very few options for the treatment of cutaneous leishmaniasis, and the commonly-used treatment with antimonial compounds require daily parenteral administration and frequent need for hospitalization. It is also associated with many adverse effects, including those related to musculoskeletal symptoms, liver and bone-marrow toxicity, pancreatitis and electrocardiographic abnormalities. Intravenous catheter-related complications were also observed in patients who were administered intravenous sodium stibogluconate for 20 days.13 Sodium stibogluconate can also be given locally, however it is painful and is not acceptable to patients with multiple lesions. Drug toxicity is also very common with the use of pentamidine and amphotericin B for treatment of cutaneous leishmaniasis.
Apart from the different types of injectable treatment, various workers had tried different types of oral medication for the management of cutaneous leishmaniasis, including metronidazole, cotrimoxazole, allopurinol, dapsone, ketoconazole, and itraconazole, but their response is not uniform. In an earlier study, the use of metronidazole did not show major clinical improvement in cutaneous leishmaniasis.14,15 A study from Northern Algeria observed good results with ketoconazole16 but in other studies it was almost entirely ineffective in patients with CL caused by L. tropica and L. aethiopica.17–19 A recently-reported out-patient study of parenteral sodium stibogluconate therapy for cutaneous leishmaniasis revealed re-epithelization at the end of treatment.11 All patients developed transient musculoskeletal symptoms and asymptomatic hepatitis.
Rifampicin was used earlier by various workers for management of cutaneous leishmaniasis and showed promising results.9,10 Salim and Kandil used rifampicin (1200 mg/day) in a series of 46 patients with cutaneous leishmaniasis,9 and 41 patients who completed the course underwent resolution of their lesions. The other five either failed to re-attend or failed to complete their treatment. Many other workers have questioned the efficacy of a short-term course of rifampin therapy for cutaneous leishmaniasis.20 The effect of rifampicin is through its property of blocking RNA synthesis by specifically binding and inhibiting DNA-dependent RNA polymerase. The drug is generally very well-tolerated and the common adverse effects are gastrointestinal upset and derangement of liver functions. In our study, re-epithelization appeared in 19 cases (17+2) and no adverse effect was observed in any patient receiving rifampicin. The results of our study are also comparable to the best available injectable regimen, and it does not require close monitoring of the patients, thus the drug rifampicin is a very effective, easily available, cost-effective, safe and very well-tolerated oral alternative for the treatment of cutaneous leishmaniasis.
This short-term preliminary study provides some useful data about the efficacy of rifampicin in the treatment of cutaneous leishmaniasis, and provides a basis for further multicentre studies with similar protocol on a larger group of patients with longer duration of treatment.
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Notes |
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Address correspondence to Professor D.K. Kochar, C-54, Sadul Ganj, Bikaner, Rajasthan, India 334003. e-mail: masoom{at}zeenext.com
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References |
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