Mycobacterium leprae: aspectos da resistência aos fármacos na poliquimioterapia / Drug resistance in multidrug therapy for Mycobacterium leprae

Introdução: O diagnóstico da hanseníase possui números significativos que causam preocupação à saúde pública. Os casos de resistência medicamentosa nessa doença se iniciaram em meados dos anos 60 e diante do problema, a Organização Mundial da Saúde instituiu em 1981 a poliquimioterapia, associação dos antibióticos rifampicina, dapsona e clofazimina, tratamento atual de escolha. A resistência aos fármacos na hanseníase é reportada pela literatura, desvelando um obstáculo à sua eliminação. Apresentamos nessa revisão os principais aspectos da resistência medicamentosa no tratamento para hanseníase e seus impactos. Metodologia: Revisão sistemática sobre os aspectos da resistência medicamentosa utilizando a pesquisa exploratória como metodologia de abordagem. Foram pesquisados os termos resistência medicamentosa, hanseníase, recidiva, alterações genéticas e os operadores booleanos "and" e "or" na busca. Resultados e discussão: A dificuldade de tomar a medicação corretamente foi um dos principais fatores que acarretaram resistência do bacilo Mycobacterium leprae aos fármacos. Homens de países norte e sul-americanos e asiáticos foram os mais atingidos por episódios de resistência. A resistência medicamentosa é uma das principais causas de recidivas em hanseníase. O principal fármaco causador de resistência medicamentosa descrito nos trabalhos foi a dapsona (46,6%) e a maioria das alterações genéticas encontradas estão no gene rpoB; 23,2% dos registros relatados foram de resistência secundária aos fármacos e, também, sete casos de resistência múltipla a esses medicamentos. Conclusão: Os principais aspectos da resistência medicamentosa na hanseníase são os equívocos ao ingerir os medicamentos e as alterações genéticas na bactéria. Os impactos causados estão na dificuldade de refazer o tratamento, a possibilidade de nova transmissão e o aparecimento de sintomas mais graves.

Introduction: The diagnosis of leprosy has significant numbers causing public health concern. Reports of drug resistance in this disease begun in the mid-1960s and due to this problem, the World Health Organization instituted a multidrug therapy with rifampicin, dapsone, and clofazimine antibiotic association in 1981, which is currently the first-choice treatment for leprosy. Cases of drug resistance have been reported in literature, revealing an obstacle to the eradication of the disease. This paper has the purpose of presenting the key aspects and impacts of drug resistance in the treatment for leprosy. Methods: Systematic review of the drug resistance aspects using exploratory research as an approach methodology. The authors searched the terms drug resistance, leprosy, recurrence, genetic alterations, and the Boolean operators "and" and "or" between them. Results and discussion: The difficulty in taking the medication correctly was one of the key factors that led to drug resistance for Mycobacterium leprae. Men from North and South American, as well as from Asian countries, were the most affected by episodes of resistance. Drug resistance is one of the main causes of leprosy recurrences. Dapsone was the most frequently identified drug resistance in the studies (46.6%), while most of the genetic alterations were found in the rpoB gene; 23.2% of the cases were from secondary resistance episodes, and seven cases of multiple resistance were reported. Conclusion: The misconceptions when taking the treatment and the Mycobacterium leprae genetic alterations have been described as the key aspects of drugs resistance in leprosy and the impacts caused are the difficulty in redoing the treatment, the possibility of new transmission, and the appearance of more severe symptoms.

Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach

Abstract: BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). Patients and methods: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.

Reacción lepromatosa tipo I, a propósito de un caso / Type I lepra reaction: a case report

La lepra es una infección crónica, granulomatosa, producida por Mycobacterium leprae, que afecta piel y nervios periféricos. Se describen dos tipos de reacciones leprosas: tipo I y tipo II, las que corresponden a cuadros agudos que exacerban la enfermedad. Estas leproreacciones pueden ocurrir antes, durante o después del tratamiento. Se presenta el caso de un paciente masculino que acude a consultar con lesiones cutáneas y resultado de biopsia de piel con diagnóstico de lepra. Se inicia tratamiento multidroga OMS-MB1. Posteriormente presenta una leproreacción tipo I, por lo que se le realiza tratamiento con prednisona.

Leprosy is a chronic granulomatous infection of the skin and peripheral nervous system produced by Mycobacterium leprae. Two types of acute leprosy reactions have been described: type I and type II. These reactions can occur before, during or after treatment. We present the case of an adult male patient presenting with skin lesions and skin biopsy diagnostic for leprosy. A multidrug WHO-MB 1 treatment was initiated, after which he presents with type I lepra reaction requiring corticosteroids.

Adverse effects of alternative therapy (minocycline, ofloxacin, and clofazimine) in multibacillary leprosy patients in a recognized health care unit in Manaus, Amazonas, Brazil / Efeitos adversos das drogas (minociclina, ofloxacina e clofazimina) utilizadas no esquema alternativo para pacientes com hanseníase multibacilar, em unidade de referência, Manaus, Amazonas, Brasil

BACKGROUND: After the introduction of the multidrug therapy, there was a decline in the coefficients of prevalence and detection of new cases of leprosy. However, the records of drug resistance and relapses are threatening factors in leprosy control. Hence, new alternative schemes and monitoring of adverse effects to avoid treatment abandonment are important considerations. OBJECTIVE: Describe the side effects of a multidrug regimen containing minocycline, ofloxacin, and clofazimine in multibacillary leprosy patients. METHODS: We conducted a prospective, descriptive, and observational study with multibacillary patients, including cases of intolerance to standard MDT and relapses. The study was carried out at Fundação Alfredo da Matta (Alfredo da Matta Foundation), in Manaus, Amazonas, from April 2010 to January 2012. The patients received alternative therapy, which consisted of daily self-administered doses of 100mg of minocycline, 400 mg of ofloxacin, and 50mg of clofazimine and a supervised monthly dose of 300mg of clofazimine for six months, followed by eighteen months of daily doses of ofloxacin 400mg, clofazimine 50mg, and a supervised monthly dose of clofazimine 300mg. Results: Twenty-one cases were included. Mild and transitory side effects occurred in 33.3% of patients. Of the total episodes, 45.9% were attributed to ofloxacin and they included abdominal pain, nausea, vomiting, headache, and insomnia; 21.6% were due to clofazimine, with 100% of patients presenting skin pigmentation. The mean time for the development of adverse effects after beginning the therapy was 15.2 days. CONCLUSION: All patients tolerated the drugs well, and compliance was satisfactory, with no serious events. Unlike other standard MDT studies ...

FUNDAMENTOS: Após introdução do esquema poliquimioterápico padrão, houve declínio nos coeficientes de prevalência e detecção de casos novos; entretanto, os registros de resistência medicamentosa e recidivas representam ameaça para o controle da hanseníase. Dessa forma, a proposição de novos esquemas alternativos e a necessidade de monitorar efeitos adversos são importantes para evitar o abandono do tratamento. OBJETIVO: Descrever efeitos adversos do esquema alternativo contendo clofazimina, ofloxacina e minociclina em pacientes com hanseníase multibacilar. MÉTODOS: Estudo prospectivo, descritivo e observacional de casos multibacilares, incluindo recidivas ou intolerância à poliquimioterapia padrão, realizado na Fundação Alfredo da Matta, Manaus, Amazonas, de abril de 2010 a janeiro de 2012. Os indivíduos receberam a terapia composta de doses diárias auto-administradas de 100mg de minociclina, 400mg de ofloxacina e 50mg de clofazimina e mensais supervisionadas de 300mg de clofazimina por seis meses, seguidas de 18 meses de doses diárias de ofloxacina 400mg, clofazimina 50 mg e supervisionadas mensais de clofazimina 300mg. Resultados: 21 pacientes foram incluídos. Efeitos adversos leves e transitórios foram observados em 33,3% dos pacientes; 45,9% foram atribuídos à ofloxacina, como dor abdominal, náuseas, vômitos, cefaléia e insônia; 21,6% foram associados à clofazimina, com relatos e observação em 100% dos pacientes de hiperpigmentação cutânea. O tempo médio de desenvolvimento das reações adversas a partir do início do esquema foi de 15,2 dias. ...

Brazilian clinical trial of uniform multidrug therapy for leprosy patients: the correlation between clinical disease types and adverse effects

This study sought to verify the correlation between leprosy types and the adverse effects of treatment drugs. This quantitative, prospective, nested study was developed at the Dona Libânia Dermatology Centre in Fortaleza, Brazil. Data were collected from November 2007-November 2008. During this period, 818 leprosy patients were diagnosed and began treatment. Forty patients with tuberculoid leprosy (TT) were selected. Twenty patients followed a standard therapy of dapsone and rifampicin and 20 were administered dapsone, rifampicin and clofazimine (U-MDT). Twenty patients with borderline lepromatous (BL) and lepromatous leprosy (LL) were also selected and treated with U-MDT. All of the subjects received six doses. With the exception of haemolytic anaemia, there was a low incidence of adverse effects in all the groups. We did not observe any differences in the incidence of haemolytic anaemia or other side effects across groups of patients with TT, BL or LL treated with U-MDT.

Efetividade da vitamina E sobre o estresse oxidativo, em hansenianos da forma multibacilar sob tratamento / Effectiveness of vitamin E on oxidative stress in patients with leprosy, multibacillary form of under treatment

INTRODUÇÃO: A hanseníase é uma doença infecto contagiosa crônica, causada pelo Mycobacterium leprae, enão foi exterminada no Brasil, que atualmente, ocupa o segundo lugar em número absoluto de casos, perdendoapenas para a Índia. A doença hanseníase não provoca estresse oxidativo, e sim a terapêutica utilizada. Diversos trabalhos evidenciam a redução do estresse oxidativo, em diferentes patologias, pelo uso da vitamina E. Na hanseníase, no entanto, a literatura é escassa a respeito desse efeito OBJETIVO: O objetivo deste estudo foi verificar a redução, pela vitamina E, do estresse oxidativo causado pelo uso da dapsona, clofazimina e rifampicina no tratamento pacientes hansenianos, da forma multibacilar. CASUÍSTICA E MÉTODO: Foi avaliada a presença prévia de estresse oxidativo em 32 pacientes hansenianos, da forma multibacilar, por meio de exames de sangue e, posteriormente, os pacientes foram divididos em 2 grupos, aleatoriamente, com 16 pacientes em cada grupo,denominados: grupos “com vitamina E” e “controle”. Os pacientes do grupo “com vitamina E” fizeram uso de800 UI/dia, por via oral, de vitamina E e o grupo “controle” não fez uso de suplemento vitamínico. Decorridos30, 60 e 90 dias de tratamento suplementar, foram coletadasamostras de sangue dos 2 grupos para determinar a concentração de metahemoglobina e presença de corpos de Heinz. RESULTADOS: Os resultados foram submetidos ao testeestatístico Qui-quadrado (χ2). Não foi encontrada diferença entre os 2 grupos.CONCLUSÃO: Conclui-se que a vitamina E na dose e duração de tratamentos utilizados, não confere efeitoprotetor contra o estresse oxidativo causado pela dapsona, clofazimina e rifampicina utilizada pelos pacientesportadores de hanseníase da forma multibacilar.

INTRODUCTION: Leprosy is a chronic contagious infectious disease caused by Mycobacterium leprae, and has not been wiped out in Brazil, which currently ranks second in the absolute number of cases, second only to India. The disease is not leprosy causes oxidative stress, but the therapy used. Several studies show the reductionof oxidative stress in different pathology, the use of vitamin E. In leprosy, however, the literature is scarce about this effect. OBJECTIVE: The aim of this study was the reduction by vitamin E, oxidative stress caused by the use of dapsone, rifampicin and clofazimine for treating leprosy patients, the multibacillary form.PATIENTS AND METHODS: We reviewed the previous presence of oxidative stress in 32 leprosy patients, themultibacillary form, through blood tests and then the patients were divided into two groups randomly, with 16 patients in each group, namely: groups with vitamin E “and” control “. Patients in the group with vitamin E “made use of 800 IU / day orally, vitamin E and” control “group did not use vitamin supplement. After 30, 60 and 90 days of treatment, blood samples were collected from two groups to determine the concentration of methemoglobin and the presence of Heinz bodies.RESULTS: The results were subjected to statistical test Chi-square (χ2). No difference was found between thetwo groups. CONCLUSION: We conclude that vitamin E dose and durationof treatments, does not confer a protective effect against oxidative stress caused by dapsone, rifampicinand clofazimine used by patients with multibacillary leprosy.

Agranulocytosis induced by multidrug therapy in leprosy treatment: a case report

Multidrug therapy (WHO/MDT) in multibacillary leprosy consists of treatment with rifampicin, dapsone andclofazimine. However, adverse effects can cause the patient to abandon treatment. We report on a patient whopresented agranulocytosis and hemolytic anemia associated with this treatment regime. We also examined theimportance of laboratory exams for diagnosis and follow-up of the patient, and for early detection of adverse effects, with a view to improving adhesion to treatment and contributing to the eradication of Hansen’s disease as a public health issue.

Clofazimine induced enteropathy--a case highlighting the importance of drug induced disease in differential diagnosis.

A patient on treatment for multibacillary leprosy for the past three years, presented with episodes of abdominal pain. Since the patient improved with conservative management, clofazimine induced enteropathy was considered as a remote possibility. A review of the mucosal biopsies showed macrophages with crystal-storing spaces consistent with clofazimine deposition in the duodenum. This case highlights the need to consider and investigate drug-induced disease as part of the differential diagnosis.

Reactions and their management.

The uneventful response to chemotherapy in leprosy is marked by clinically disturbing episodes encountered in 20-30% of patients and these phenomena are called "reactions". Generally they are classified as reversal reaction (type-1) and erythema nodosum leprosum (type-2). The cutaneous menifestations are: (1) Type-2 reactions in LL, BL types constituting erythema nodosum leprosum, erythema multiforme, erythema necroticans, subcutaneous nodules, lepromatous exacerbation. (2) Type-1 reactions in borderline and tuberculoid leprosy. The other manifestations include: Acute neuritis, lymphadenitis, arthritis, oedema of the hands and feet, ocular lesions, etc. Sequelae of reactions are: Paralytic deformities, non-paralytic deformities, extensive scarring and renal damage. A simple guideline to identify the risk-prone cases has been narrated. Prednisolone in standard dosage schedule as recommended by WHO is now being widely used in control programmes.

Efeitos adversos da poliquimioterapia em pacientes com hanseníase: um levantamento de cinco anos em um Centro de Saúde da Universidade Federal de Uberlândia / Adverse effects of multidrug therapy in leprosy patients: a five-year survey at a Health Center of the Federal University of Uberlândia

A implementaçäo da poliquimioterapia (PQT/OMS) - composta pelas drogas dapsona, clofazimina e rifampicina - possibilitou a cura da hanseníase, porém näo foram priorizados o manejo dos efeitos adversos pelas equipes de saúde. Objetivando determinar a magnitude dos efeitos adversos da poliquimioterapia para hanseníase e relacioná-los como possível causa de näo adesividade do paciente ao tratamento, revisou-se prontuários de 187 pacientes tratados com PQT, de 1995 a 2000, no Centro de Saúde Escola (CSE) -UFU, com registro de efeitos colaterais em 71 pacientes (37,9 por cento). Dentre os 113 efeitos adversos, 80 (70,7 por cento) relacionaram-se à dapsona, 7 (6,2 por cento) à rifampicina, 26 (20,5 por cento) à clofazimina. Esses efeitos levaram à mudança de esquema terapêutico em 28 (14,9 por cento) dos 187 pacientes ou 39,4 por cento dos 71 com efeitos adversos. Discute-se a importância de considerar os efeitos adversos da PQT na capacitaçäo das equipes de saúde para maior adesäo do paciente ao tratamento, colaborando para eliminar a hanseníase como problema de saúde pública

Efeitos adversos da poliquimioterapia em pacientes com hanseníase: um levantamento de cinco anos em um Centro de Saúde da Universidade Federal de Uberlândia / Adverse effects of multidrug therapy in leprosy patients: a five-year survey at a Health Center of the Federal University of Uberlandia

The introduction of multidrug therapy (WHO/MDT)-composed by the drugs dapsone, clofazimine and rifampicin has enabled the cure of Hansen's disease, however, the adverse effects of these drugs were not given priority by the health team. Aiming to determine MDT's adverse effects' magnitude and relate them to the non-adhesion of patients to the treatment, a study of 187 charts of patients treated with MDT from January of 1995 to May 2000, was carried out at a Health Center of the Federal University of Uberlandia. Side effects were recorded in 71 patients' charts. Among the 113 side effects found, 80 (70.7 per cent) were related to dapsone, 7 (6.2 per cent) were caused by rifampicin and 26 (20.5 per cent) were attributed to clofazimine. These effects induced 28 (14.9 per cent), patients to change the therapeutic scheme, representing 39.4 per cent from the 71 patients with adverse effects. Throughout this study, the importance is discussed of considering MDT's adverse effects when training the health team to heighten the patient's adhesion to the treatment and thereby collaborating to eliminate Hansen's disease as a public health problem.

Hepatic and haematological adverse reactions associated with the use of multidrug therapy in leprosy--a five year retrospective study.

This study analyses retrospectively some of the risks associated with the use of WHO-multidrug therapy (MDT) in Sri Lanka. Case records of 3,333 new cases of leprosy attending the Central Leprosy Clinic in Colombo during 1991-1995, were analysed for adverse drug reactions involving the liver and blood. There were 81 reports of suspected hepatic or haematological adverse reactions associated with the use of MDT, of which 39 were classified as haemolytic anaemia, 25 as toxic hepatitis, 2 as methaemoglobinaemia and 15 as anaemia. Dapsone, was incriminated in the majority of adverse reactions (72%). Adverse drug reactions were more common in female than male subjects (55% vs 45%; P < 0.5), but there was no significant differences between the age groups. Majority of adverse reactions was seen within the first three months of initiation of MDT. This study in no way undermines the benefits of MDT but highlights the risks and suggests measures to minimize these risks.

Pioderma gangrenoso: a propósito de un caso controlado con bajas dosis de clofazimina / Pyoderma gangrenosum: report of a case controlled with low dose of clofazimine

Se presenta una paciente de 49 años con pioderma gangrenoso atendida en el Hospital Regional Ushuaia entre 1991 y 1996. Presentó lesiones que comenzaron como nódulos en miembros inferiores y evolucionaron a úlceras necróticas, mostrando distintos cuadros histopatológicos como expresión de una misma enfermedad, sin manifestaciones sistémicas. Fue tratada con clofazimina a bajas dosis con resultado favorable, sin efectos colaterales y sin concurrencia a la fecha

Dermatosis cenicienta: experiencia del Departamento de Dermatología del Hospital Gea González de la ciudad de México / Ashy dermatosis: the experience of the Department of Dermatology, Gea Gonzalez Hospital, Mexico city

La dermatosis cenicienta es un padecimiento inflamatorio de la piel que, en su fase tardía, muestra manchas hiperpigmentadas de color gris-parduzco ("cenicientas") muy características. Es un padecimiento que tiende a la cronicidad y cursa de manera asintomática; se le observa predominantemente en población mestiza de Latinoamérica. La mayoría de los enfermos responden bien al tratamiento con 50 mg/día de clofazimina durante varios meses. Estudios recientes sugieren que se trata de un padecimiento de base inmunológica

Hiperpigmentación cutáneo-mucosa en pacientes HIV positivos / Muco-cutaneous hyperpigmentation in HIV patients

Las alteraciones en la pigmentación cutáneo-mucosa en los pacientes infectados por el virus HIV pueden ser frecuentes, pero su etiología está aún en discusión. Se analizó el seguimiento dermatológico desde 1988 hasta 1995 de 320 casos infectados por el virus del HIV, donde 61 eran mujeres y 259 varones, cuyas edades promedio fueron de 26,6 años en los primeros y 22,2 en los segundos. Del total de casos (320), se observó hiperpigmentación cutáneo-mucosa difusa en el 16,32 por ciento de los casos e hiperpigmentación de mucosa y semimucosa oral exclusivamente en 2 mujeres (0,77 por ciento) y 12 varones (4,18 por ciento). En nuestra experiencia, la hiperpigmentación se comportó como un marcador de mal pronóstico, dado que en menos de 6 meses de su aparición, los pacientes presentaron complicaciones más severas que los llevaron a la muerte

Intercorrências pelas drogas utilizadas nos esquemas poliquimioterápicos em hanseníase / Intercurrence by drugs used in combination drug therapy schedules in leprosy

Os autores apresentam as intercorrências clínicas atribuídas as drogas utilizadas nos esquemas poliquimioterápicos padronizados pela Organizaçao Mundial da Saúde para o tratamento da Hanseníase. O estudo abrange a esperiência adquirida em 8 anos comum total de 98O pacientes sendo 496 (50 por cento) alocados no esquema para paucibacilares 484 (49,3 por cento) e para multibacilares. Foram observadas intercorrências atribuídas as drogas utilizadas - Rifampicina, Dapsona e Clofazimina, em 18 (l,8 por cento) dos casos. Entre os paucibacilares os efeitos colaterais ocorreram em 10 (2 por cento) e entre os multibacilares em 8 pacientes (l,6 por cento). Em todos os casos o esquema padrao foi adaptado permitindo a continuidade do tratamento.

Impregnaçäo sui generis conjuntivo-escleral por clofazimina em um paciente portador de hanseníase / Impregnation sui generis of the conjunctiva and sclera by clofazimine in a carrier Hansen's disease

Os autores apresentam o caso de um paciente de 40 anos de idade, portador de hanseníase forma virchoniana que recebeu, por via oral, durante 9 anos, clofazimina, numa dose total de 324 gramas. Apresentou intensa pigmentaçäo na conjuntiva e esclera por este medicamento. A biomicroscopia observavam-se com facilidade cristais policromáticos na conjuntiva e esclera de ombos os olhos. O estudo destes cristais também foi possível à microscopia óptica de fragmento da conjuntiva a fresco. O caso é discutido com os achados na literatura e os autores chamam a atençäo para os diagnóticos diferenciais