Print version ISSN 0036-4665
Rev. Inst. Med. trop. S. Paulo vol.46 no.3 São Paulo May/June 2004
Azitromicina no tratamento da leishmaniose mucosa
Mario León Silva-Vergara; Luciana de Almeida Silva; Frederico Ricardo Zago Maneira; Achilles Gustavo da Silva; Aluízio Prata
Departamento de Clínica Médica, Disciplina de Doenças Infecciosas e Parasitárias, Faculdade de Medicina do Triângulo Mineiro-FMTM, Uberaba, MG, Brasil
This report describes three elderly patients with mucosal form of American tegumentary leishmaniasis associated with chronic cardiopathy. Due to the known toxicity of classical drugs with activity against Leishmania sp., the patients received three oral courses of azithromycin therapy in single 500 mg daily dose during ten days, every other month. All lesions healed after the third series. One of the patients relapsed and a new series of azithromycin was prescribed. Azithromycin may be an alternative drug for the treatment of leishmaniasis in special situations due to its optimal mucosal and intraphagocyte concentration, single daily posology, high tolerance and oral administration. The mechanism of this drug on Leishmania sp. is unknown at present.
Keywords: Mucosal leishmaniasis; Azithromycin; Chronic cardiopathy.
O presente relato descreve três pacientes idosos com leishmaniose mucosa de longa evolução, os quais eram portadores de cardiopatia crônica. Pela alta freqüência de efeitos secundários e tóxicos dos medicamentos utilizados no tratamento clássico, esses pacientes receberam azitromicina. Este medicamento foi administrado pela via oral, em dose única diária de 500 mg, durante dez dias, em três séries com intervalo de um mês. Em todos, houve cicatrização das lesões depois da terceira série. Um dos pacientes apresentou recidiva após seis meses e uma nova série de azitromicina fez regredir novamente o quadro. Azitromicina pode ser uma alternativa para o tratamento das leishmanioses, principalmente pela concentração adequada em mucosas e nos fagócitos, posologia única diária, boa tolerância e administração oral.
The pentavalent antimonial (glucantime®) and sodium stibogluconate (pentostam®) are drugs of choice for treatment of American tegumentary leishmaniasis1,5,11. However, the therapeutical response in mucosal forms is less than that obtained in the cutaneous ulcers and, usually, several series of antimonial are required for complete clinical healing2,5,8,9,18. Amphotericin B and pentamidin therapy is the second choice, because of their toxicity and side effects, although their efficacy is similar to that of those antimonial by-products14,15,16,20.
Clinical trial with nifurtimox did not show a proper response in the treatment of the mucosal form of American tegumentary leishmaniasis4, and the use of pentavalent antimonial associated with pentoxiphylin was preliminarly effective in patients with mucosal forms, refractory to antimonial alone7.
Azithromycin, a macrolide by-product of large use in clinical practice, proved to be experimentally effective against Leishmania major,6 and, more recently, in open clinical assay, an efficacy of 85% in 20 patients with leishmaniasis cutaneous forms was reported13. Another study in Manaus, Brazil, where Leishmania viannia guyanensis is endemic, showed low efficacy in 26 patients that received this drug (unpublished data)17.
The present work describes three Brazilian elderly patients with mucosal leishmaniasis and associated chronical cardiopathy. Due to the latter condition they received azithromycin.
CLINIC CASE REPORT
Patient 1 - J. P. M., 76 year-old, male, born and resident in São Francisco de Sales, Minas Gerais, an endemic area of leishmaniasis. He presented a-four-year ulcerocrusty lesion in the right nostril and bloody rhinorrhea. Montenegro test was positive (12 mm) and biopsy showed chronical inflammation with giant cells and granuloma formation, presenting necrosis areas and mononuclear cells. No leishmania or other parasites were observed. Because of a previous history of chronical cardiopathy with heart failure, he received dapsone, and during six months his lesion was scarred, after, the lesion relapsed and Amphotericin B was considered. A week later, renal failure developed and this drug therapy was replaced by low doses of pentavalent antimonial. Within a few days, clinical and electrocardiographic examination revealed evidence of antimonial toxicity. The therapy was then discontinued and the patient received oral azithromycin 500 mg/day, during ten days in three series every other month. After 120 days, complete healing of the lesion occurred and at clinical monthly follow-up during one year no relapse was observed.
Patient 2 - C. J. S., 80 year-old, male, born and resident in Porteirinha, Minas Gerais, an endemic area of leishmaniasis. He referred upper and progressive dysphagia for several months. He presented granulomatous pervasive morula-like lesion, jeopardizing hard and soft palate, uvula and oropharynx. The lesion was friable and recovered with a white secretion. Total collapse of the nose had ocurred some years ago alongside chronical cardiopaty. The histopathological oropharynx lesion exam showed amastigotes forms of Leishmania sp into macrophages. Montenegro test was not performed. Previously, he had irregularly used pentavalent antimonial, unsuccessfully. He received azithromycin 500 mg/day per oral via, during 10 days in three series every other month. His lesions evolved for clinical healing, but six months later, relapse was noticed. Therefore, a new course of azithromycin 500 mg/day during 10 days was required, and remission was observed after three months, but no follow-up was possible, in spite of several patient recalls.
Patient 3 - E. F. O., 76 year-old, female, born and resident in Araçuaí, Minas Gerais, an endemic area of leishmaniasis. She presented ulcerovegetative lesions in the upper lip, hard and soft palate and oropharynx for eighteen months. She referred upper and progressive dysphagia, easy bleeding of lesions at minimal traumatisms and weight loss due to the dysphagia. Clinical exam revealed edema, infiltration and remarkable protraction of the upper lip, and together with total collapse of the nares, which had occurred several years ago. Besides, the patient referred chronical heart failure. Montenegro reaction resulted positive (14 mm) and lip ulcer biopsy showed chronical inflammation characterized by perivascular infiltrate with limphocytes, plasmocytes and histiocytes, and scattered granuloma formation. No amastigotes or other microrganisms were observed. She received azithromycin 500 mg/day per oral via, during 10 days, in three courses every other month. There was complete regression of the lesions in the fourth month of treatment, normal nourishing and weight. Gain. At 12 months follow-up she was asymptomatic.
The treatment of the mucosal form of American tegumentary leishmaniasis presents some problems regarding the variable response to antimonials which, like other classical drugs, are all administered by parenteral via for long periods, and frequently have toxic and side effects, mainly nephro and cardiotoxicity1,3,11. This fact becomes more evident in old patients, since they often present cardiopathies and other underlying diseases. Therefore, contraindications to use these drugs are common and patient hospitalization is often needed2,7,10. In such cases, other anti-leishmania therapeutic alternatives become relevant. A favourable clinical response to azithromycin was described to the cutaneous forms of American tegumentary leishmaniasis caused by Leishmania viannia brasiliensis13. The authors treated 20 patients who received 500 mg of azithromycin daily per oral via for 3, 5 or 10 days or 1,000 mg daily for two days. Similar courses were repeated when necessary, until full re-epitelization. Healing time ranged from 60 days in six (30%) of patients to 120 days in four (20%) of them13.
These results supported the use of azithromycin in these three elderly patients with chronic mucous lesion suggestive of American tegumentary leishmaniasis. Besides, they presented chronic cardiopathy and had been receiving anticongestive therapy for a long time.
Only one of three patients had leishmaniasis diagnosis confirmed by biopsy. The others presented suggestive clinical lesion together with a Montenegro positive test and successful response to treatment with this drug. Nevertheless, other diseases might be considered although no other microrganisms were seen at histopathological examination.
Despite the early good response, six months later, patient 2 presented clinical relapse, and a new course with azithromycin healed the lesions. No side effects were observed in these cases and similar results were previously reported13. These authors used the same dosage for a short time. On the other hand, TEIXEIRA (2003)17 observed diarrhea in 60% of the cases, abdominal pain in 28%, and headache and nauseas in 12% of 26 patients with cutaneous leishmaniasis receiving azithromycin during 20 days (unpublished data).
A favorable response obtained in these cases may support the anti-leishmania activity of this macrolide on mucosal leishmaniasis, especially if considering some outstanding advantages of it: therapeutical response observed over ten years of its use for several infectious diseases, good tolerance, high levels of drug into mucosae and phagocytes, and a single daily oral dose10,12,19.
In accordance with KROLEWIECKI et al.6, the azithromycin's mode of action against Leishmania sp is unknown at present. It might be through either direct effect on parasite or by immune and inflammatory modulation response. Nevertheless, clinical randomized and controlled studies are necessary to evaluate the azithromycin efficacy in mucosal and other clinical presentations of American tegumentary leishmaniasis.
We thank Maria Rita de Souza and Angela Azor for revising this manuscript in English and to FUNASA for financial support.
1. BERMAN, J.D. - Human leishmaniasis: clinical diagnostic and chemotherapeutic developments in the last 10 years. Clin. infect. Dis., 24: 684-703, 1997. [ Links ]
2. BRASIL. MINISTÉRIO DA SAÚDE. FUNDAÇÃO NACIONAL DA SAÚDE - Manual de controle da leishmaniose tegumentar americana. Brasília, FNS, 2000. [ Links ]
3. FRANKE, E.D.; LLANOS CUENTAS, A.; ECHEVARRIA, J. et al. - Efficacy of 28-day and 40-day regimens of sodium stibogluconate (pentostam) in the treatment of mucosal leishmaniasis. Amer. J. trop. Med. Hyg., 51: 77-82, 1994. [ Links ]
4. GUERRA, M.F.; MARSDEN, P.D.; CUBA, C.C. & BARRETTO, A.C. - Further trials of nifurtimox in mucocutaneous leishmaniasis. Trans. roy. Soc. trop. Med. Hyg., 75: 335-337, 1981. [ Links ]
5. HERWALDT, B. & BERMAN, J.D. - Recommendations for treating leishmaniasis with sodium stibogluconate (pentostam) and review of pertinent clinical studies. Amer. J. trop. Med. Hyg., 46: 296-306, 1992. [ Links ]
6. KROLEWIECKI, A.J.; LEON, S.; SCOTT, P. & ABRAHAM, D. - Activity of azithromycin against Leishmania major in vitro and in vivo Amer. J. trop. Med. Hyg., 67: 273-277, 2002. [ Links ]
7. LESSA, H.A.; MACHADO, P.; LIMA, F. et al. - Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Amer. J. trop. Med. Hyg., 65: 87-89, 2001. [ Links ]
8. MARSDEN, P.D. - Mucosal leishmaniasis ("Espundia" Escomel 1911). Trans. roy. Soc. trop. Med. Hyg., 80: 859-876, 1986. [ Links ]
9. MARSDEN, P.D. - Mucosal leishmaniasis due to Leishmania (Viannia) braziliensis L(V)b in Três Braços, Bahia, Brazil. Rev. Soc. bras. Med. trop. 27: 93-101, 1994. [ Links ]
10. NEU, H.C. - Clinical microbiology of azithromycin. Amer. J. Med., 91(suppl. 3A): 12S-18S, 1991. [ Links ]
11. OLLIARO, P.L. & BRYCESON, A.D.M. - Practrical progress and new drugs for changing patterns of leishmaniasis. Parasit. today, 9: 323-328, 1993. [ Links ]
12. PETERS, D.H.; FRIEDEL, H.A. & McTAVISH, D. - Azithromycin. A review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy. Drugs, 44: 750-799, 1992. [ Links ]
13. PRATA, A.; SILVA-VERGARA, M.L.; COSTA, L. et al. - Efficacy of azithromycin in the treatment of cutaneous leishmaniasis. Rev. Soc. bras. Med. trop., 36: 65-69, 2003. [ Links ]
14. SAMPAIO, S.A.P.; GODOY, J.T.; PAIVA, L.; DILLON, N.L. & LACAZ, C.S. - The treatment of American (mucocutaneous) leishmaniasis with amphotericin B. Arch. Derm., 82: 627-635, 1960. [ Links ]
15. SAMPAIO, R.N.R. & MARSDEN, P.D. - Tratamento da forma mucosa da leishmaniose sem resposta a glucantime com anfotericina B lipossomal. Rev. Soc. bras. Med. trop., 30: 125-128, 1997. [ Links ]
16. SOTO-MANCIPE, J.; GROGL, M. & BERMAN, J. - Evaluation of pentamidine for the treatment of cutaneous leishmaniasis in Colombia. Clin. infect. Dis., 16: 417-425, 1993. [ Links ]
17. TEIXEIRA, A.C. - Avaliação da eficácia da azitromicina no tratamento da leishmaniose cutânea em Manaus, Amazonas, Brasil. Uberaba, 2003. (Dissertação de Mestrado - Faculdade de Medicina do Triângulo Mineiro). [ Links ]
18. WHO (WORLD HEALTH ORGANIZATION)/OPS (ORGANIZACIÓN PANAMERICANA DE LA SALUD - Leishmaniasis en las Américas. Situación actual y alternativas para su control. Washington, Oficina Sanitária Panamericana, Oficina Regional de la Organización Mundial de la Salud, 1996. [ Links ]
19. WILDFLEUER, A.; LAUFEN, H. & ZIMMERMANN, T. - Uptake of azithromycin by various cells and its intracellular activity under in vivo conditions. Antimicrob. Agents Chemother., 40: 75-79, 1996. [ Links ]
20. YARDLEY, Y. & CROFT, S.L. - A comparison of the activities of three amphotericin B lipid formulations against experimental visceral and cutaneous leishmaniasis. Int. J. Antimicrob. Agents, 13: 243-248, 2000. [ Links ]
Prof. Dr. Mario León Silva-Vergara
Av. Getúlio Guaritá, s/nº, Caixa Postal 118
38001-970 Uberaba, MG, Brasil
Tel.: 55-34-3318-5255/86, Fax: 55-34-3318-5279
Received: 23 December 2003
Accepted: 14 May 2004
Financial support by FUNASA