Home » Volumes » Volume 44 March/April 2011 » American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis resistant to meglumine antimoniate, but with good response to pentamidine: a case report

American cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis resistant to meglumine antimoniate, but with good response to pentamidine: a case report

Maria Inês Fernandes Pimentel; Cibele Baptista; Évelyn Figueiredo Rubin;Érica de Camargo Ferreira e Vasconcellos; Marcelo Rosandiski Lyra; Mariza de Matos Salgueiro; Maurício Naoto Saheki; Cláudia Maria Valete Rosalino; Maria de Fátima Madeira; Aline Fagundes da Silva; Eliame Mouta Confort; Armando de Oliveira Schubach

Laboratório de Vigilância em Leishmanioses, Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ

DOI: 10.1590/S0037-86822011000200026


RESUMO

Relatamos um caso de um militar brasileiro com leishmaniose cutânea, cuja lesão reativou após dois tratamentos sistêmicos com antimoniato de meglumina. Foi tratado com anfotericina B, mas precisou interromper por intolerância à medicação. Após isolamento de Leishmania sp, seis infiltrações intralesionais de antimoniato de meglumina foram realizadas, sem resposta. Promastigotas de Leishmania sp. foram novamente isoladas. Foi submetido a tratamento intramuscular com pentamidina (4mg/kg). Parasitas da primeira e segunda biópsias foram identificados como Leishmania (Viannia) braziliensis; os da primeira biópsia eram mais sensíveis ao antimoniato de meglumina in vitro do que os da segunda biópsia. A lesão não reativou.

Palavras-chaves: Leishmaniose cutânea. Terapêutica. Resistência medicamentosa.


ABSTRACT

This is a case report of a Brazilian soldier with cutaneous leishmaniasis. The lesion relapsed following two systemic treatments with meglumine antimoniate. The patient was treated with amphotericin B, which was interrupted due to poor tolerance. Following isolation of Leishmania sp., six intralesional infiltrations of meglumine antimoniate resulted in no response. Leishmania sppromastigotes were again isolated. The patient was submitted to intramuscular 4mg/kg pentamidine. Parasites from the first and second biopsies were identified as Leishmania (Viannia) braziliensis; those isolated from the first biopsy were more sensitive to meglumine antimoniate in vitro than those isolated from the second biopsy. No relapse was observed.

Keywords: Cutaneous leishmaniasis. Therapeutics. Drug resistance.


 

 

INTRODUCTION

American tegumentary leishmaniasis (ATL) is a disease caused by protozoan parasites of the genusLeishmania. Several wild and domestic animals serve as reservoirs of the parasite and humans are the secondary host. Transmission occurs through the bite of different species of phlebotomine sand flies, which vary according to geographical region. The incubation period ranges from a few days to several months. The disease often manifests as a papule that evolves into a nodule and frequently ulcerates with a distinctive infiltrated border. A primary lesion is usually solitary, but more than one lesion might be observed1.

Leishmania (Viannia) braziliensis is widely distributed in Brazil and is mainly responsible for cutaneous leishmaniasis (CL) and for occasional mucosal or mucocutaneous presentations. The last two forms are associated with significant morbidity1.

Pentavalent antimonials (Sb5+) are considered to be the first choice drug. In Brazil, a daily dose of 10 to 20mg/kg Sb5+ administered for 20 days is recommended for CL. If no remission is observed, a second treatment is administered for 30 days. In the absence of a therapeutic response, the second drug of choice (amphotericin B) is used. The third drug of choice is pentamidine1. All of these medications are parenterally administered and may result in mild to severe side effects. Pentavalent antimonials can cause hyperamylasemia, ECG abnormalities, bone marrow suppression and hepatotoxicity, as well as constitutional symptoms, such as myalgia, arthralgia, headache, fever, nausea, vomiting, and pain at the site of drug application, when administered intramuscularly1,2. Amphotericin B may result in anemia, cardiac and nephrotoxic effects, hypokalemia, and constitutional side effects, such as nausea, vomiting, phlebitis, shivering and fever1, which sometimes require the interruption of treatment. Pentamidine is known for its cardiac toxicity, nephrotoxicity, hypotension, hypoglycemia, but the major concern is the possibility of development of diabetes mellitus1.

A case of CL caused by Leishmania (Viannia) braziliensis is reported in a Brazilian soldier, who probably acquired the disease in Ecuador during a military mission. The lesion was unresponsive to two complete courses of pentavalent antimonials and to six intralesional applications of the drug. The patient did not tolerate two different forms of amphotericin B (deoxycholate and liposomal), which caused constitutional symptoms. The lesion finally receded after treatment with 2.4g of pentamidine with minimal side effects.

 

CASE REPORT

A 35 year-old white male military officer, weighing 77kg and living in Rio de Janeiro, Brazil, had been in Ecuador between May 2005 and June 2006 on a military mission. In March 2006, a furunculoid lesion developed on his right arm, which was treated with antibiotics. The lesion increased in diameter and ulcerated and a diagnosis of CL was made (imprint positive for the parasite). The patient was treated with pentavalent antimonial (meglumine antimoniate 10mL/day for 30 days, approximately 10mg/kg Sb5+ per day), which resulted in apparent resolution of the lesion. Twenty days later, the lesion ulcerated again. Back in Brazil, the patient was submitted to a second treatment with meglumine antimoniate at the same dose for 30 days, with apparent healing of the lesion. Twenty days later, the lesion ulcerated again.

Next, the patient received 25mg of amphotericin B deoxycholate, but he did not tolerate the drug, due to high fever, malaise, headache and chills. New treatment with liposomal amphotericin B was initiated, but as the cumulative dose increased, the patient did not tolerate this drug either, again due to moderate fever, chills, myalgia, tachypnea, tachycardia, nausea and hypotension during infusion. In an attempt to minimize the adverse effects, the duration of infusion was increased to 4h and 100mg of hydrocortisone was administered during infusion and oral dipyrone was used every 6h; however, with the increasing cumulative dose, the adverse effects became more frequent and more severe, leading to suspension of the drug. A total dose of 0.775g of amphotericin B was administered over a 16-day period.

In August 2006, the patient still presented an ulcerated lesion on his right arm (Figure 1), but was otherwise in general good health. An immunoenzymatic assay for Leishmania was positive and the cutaneous Montenegro reaction was 12mm. A new skin biopsy was obtained and Leishmania sp. promastigotes were isolated by culture in NNN medium. Six attempts at intralesional injections of meglumine antimoniate at 2-week intervals were then performed, but the patient developed contact eczema throughout the lesion and the surrounding skin area following the final application. The lesion was still ulcerated and crusted (Figure 2). A new biopsy was obtained and Leishmania sp. promastigotes were again isolated. In March 2007, the patient was treated with intramuscular pentamidine isethionate at a daily dose of 4mg/kg on alternate days, receiving a cumulative dose of 2.4g over a 23-day treatment, with a brief interruption of one week due to pain and hemorrhaging at the site of injection.

 

 

 

 

Both isolates obtained during treatment with pentavalent antimonials were characterized as Leishmania (V.) braziliensis by isoenzyme electrophoresis3. In parallel, promastigote forms in the late log phase of growth were tested in vitro for sensitivity to meglumine antimoniate (Aventis-Pharma, São Paulo)4. The results showed a relevant difference between isolates, with the first isolate presenting an inhibitory concentration for 50% (IC50) of 0.26 + 0mg/mL and the second presenting an IC50 of 2.10 + 0.16mg/mL.

No laboratory alterations were detected during and after treatment with pentamidine isethionate. The patient was negative for HIV 1 and 2 and HTLV-1. The lesion remained healed after a 34-month follow-up (Figure 3).

 

 

DISCUSSION

Cutaneous leishmaniasis is a common condition among soldiers involved in military campaigns in endemic areas. Military excursions to the Amazon region play a relevant role in the local incidence of the disease5.

Success rates reported in the literature for the recommended doses of pentavalent antimonials vary widely. Many factors may influence the outcome of treatment, including drug subdoses and irregular treatment6, and the immune status of the host, with more common failures in HIV-positive patients7.

Several mechanisms have been suggested to be involved in the drug resistance of parasites. It is known that species causing leishmaniasis respond differently to treatment with pentavalent antimonials. Furthermore, some Leishmania populations may develop resistance to these drugs, probably as a result of natural clone selection8In vitro sensitivity testing of the parasites isolated after the two intramuscular treatments and after the six intralesional injections of antimonials revealed differences between the isolates. According to Azeredo-Coutinho et al9L. (V.) braziliensisstrains presented IC50 values varying from 0.8 to 9.5mg/mL and the strains isolated from patients poorly responsive to therapy showed significantly higher IC50 values than those isolated from patients who were cured after completion of the first antimonial treatment9. In the present study, the parasites isolated from the first biopsy were more sensitive to antimonials (0.26mg/mL) than those isolated after intralesional treatment (2.10mg/mL), a finding suggesting the development of resistance to the drug after successive cycles of treatment. This resistance was confirmed both in vitro and in vivo. These results suggest that even the appropriate therapeutic regimen can induce parasite resistance.

Amphotericin B has been recognized as an effective drug for the treatment of leishmaniasis, but is sometimes poorly tolerated. In Brazil, amphotericin B is the second drug of choice for the treatment of CL in the case of failure or contraindication to pentavalent antimonials1. Liposomal amphotericin B is associated with a lower frequency of side effects, but its high cost and the need for intravenous administration limit its use. The present patient did not tolerate either of the two forms of amphotericin B due to constitutional symptoms, although the total dose of the drug applied was 0.775g, approximately half the dose indicated for the treatment of CL1.

Pentamidine has been gradually accepted in several Latin American countries as an excellent alternative to pentavalent antimonials and has been recommended as the drug of choice for the treatment of CL in some countries10. The drug is highly effective and side effects are generally well tolerated, with pain at the site of drug injection, nausea, fever and bitter taste being the most frequent symptoms10. Hypotension and hypoglycemia have been reported, as well as the induction of diabetes mellitus1. Therefore, monthly serum glucose monitoring for 6 months has been recommended following the administration of a pentamidine cumulative dose higher than 1.0g1. Several studies have compared the efficacy of pentavalent antimonials and pentamidine and some of them demonstrated a better performance of the latter10.

The administration of pentamidine was well tolerated by the patient and the outcome was satisfactory. The patient presented no laboratory alterations during post-treatment follow-up and was lesion-free 34 months after the end of treatment.

 

FINANCIAL SUPPORT

This study was supported by the Secretaria Municipal de Saúde do Rio de Janeiro (convênio RJ/FIOCRUZ), FIOCRUZ, FAPERJ, CNPq, and PAPES4/FIOCRUZ.

 

REFERÊNCIAS

1. Ministério da Saúde. Manual de Vigilância da Leishmaniose Tegumentar Americana. 2ª ed. atualizada. Brasília: Ministério da Saúde; 2010.         [ Links ]

2. Aronson NE, Wortmann GW, Johnson SC, Jackson JE, Gasser Jr RA, Magill AJ, et al. Safety and efficacy of intravenous sodium stibogluconate in the treatment of leishmaniasis: recent U. S. military experience. Clin Infect Dis 1998; 27:1457-1464.         [ Links ]

3. Cupolillo E, Grimaldi Jr G, Momen H. A general classification of New World Leishmania using numerical zymotaxonomy. Am J Trop Med Hyg 1994; 50:296-311.         [ Links ]

4. Machado GM, Leon LL, De Castro SL. Activity of Brazilian and Bulgarian propolis against different species of Leishmania. Mem Inst Oswaldo Cruz 2007; 102:73-77.         [ Links ]

5. Guerra JAO, Talhari S, Paes MG, Garrido M, Talhari JM. Aspectos clínicos e diagnósticos da leishmaniose tegumentar Americana em militares simultaneamente expostos à infecção na Amazônia. Rev Soc Bras Med Trop 2003; 36:587-590.         [ Links ]

6. Rodrigues AM, Hueb M, Santos TARR, Fontes CJF. Fatores associados ao insucesso do tratamento da leishmaniose cutânea com antimoniato de meglumina. Rev Soc Bras Med Trop 2006; 39:139-145.         [ Links ]

7. Barratt G, Legrand P. Comparison of the efficacy and pharmacology of formulations of amphotericin B used in treatment of leishmaniasis. Curr Op Infect Dis 2005; 18:527-530.         [ Links ]

8. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006; 19:111-126.         [ Links ]

9. Azeredo-Coutinho RB, Mendonça SC, Callahan H, Portal AC, Max G. Sensitivity of Leishmania braziliensis promastigotes to meglumine antimoniate (glucantime) is higher than that of other Leishmania species and correlates with response to therapy in American tegumentary leishmaniasis. J Parasitol 2007; 93:688-693.         [ Links ]

10. Lai A Fat EJSK, Vrede MA, Soetosenojo RM, Lai A Fat RFM. Pentamidine, the drug of choice for the treatment of cutaneous leishmaniasis in Surinam. Int J Dermatol 2002; 41:796-800.         [ Links ]

 

 

 Address to:
Dra. Maria Inês Fernandes Pimentel
Lab. Vigilância em Leishmanioses/IPEC/FIOCRUZ
Av. Brasil 4365, Manguinhos
21040-900 Rio de Janeiro, RJ, Brasil
Phone-Fax: 55 21 3865-9609
e-mail: maria.pimentel@ipec.fiocruz.br

Received in 05/08/2010
Accepted in 16/11/2010