Drug resistance in leprosy: an update following 70 years of chemotherapy

Leprosy is one of the oldest infectious diseases, reported for more than 2000 years. Leprosy elimination goal as a public health problem set by the World Health Organization, aiming for a global prevalence rate < 1 patient in a population of 10,000, was achieved in 2000 mainly thanks to the worldwide use of leprosy drugs starting in the 1980s and their access at no cost for patients since 1995. However, around 200,000 new cases are still reported each year, particularly in India, Brazil, and Indonesia. As with other bacteria of medical interest, antimicrobial resistance is observed in Mycobacterium leprae strains in several parts of the world, despite multidrug therapy being the recommended standard leprosy treatment to avoid resistance selection since 1982. Therefore, identifying and monitoring resistance is necessary. We provide an overview of the historical facts that led to the current drug resistance situation, the antibiotics effective against M. leprae, their mechanisms of action and resistance, and resistance detection methods. We also discuss therapeutic management of the resistant cases, new genes with potential roles in drug resistance and bacterial adaptation, new drugs under investigation, and the risk for resistance selection with the chemoprophylaxis measures.

Ensino e pesquisa na atenção à hanseníase no estado de São Paulo / Teaching and research in leprosy care in the state of São Paulo

Ao se abrir a temática da hanseníase como um problema de saúde pública grave e atual no Brasil, uma pergunta se faz de forma incisiva: por que esse problema persiste, se ele dispõe de tratamento medicamentoso gratuito e eficaz há mais de quatro décadas?A hanseníase tem uma longa trajetória e carrega em sua história heranças dramáticas, desde aquelas pré-bíblicas até as provindas das práticas de internação compulsória, ocorrida mais recentemente.Com o avanço e o menor custo das tecnologias baseadas em biologia molecular, em 2022, foram aprovados pela CONITEC a disponibilização do teste rápido na atenção básica para casos suspeitos/contatos e o PCR para serviços de referências, auxiliando, assim, na confirmação do diagnóstico e na pesquisa de resistência medicamentosa.

Adesão à terapia farmacológica em pacientes com hanseníase / Adherence to pharmacological therapy in patients with hansen's disease / Adherencia a la terapia farmacológica en pacientes con lepra

A hanseníase é uma doença infecciosa crônica causada pelo Mycobacterium leprae, considerada um grave problema de saúde pública. A adesão à terapia farmacológica contribui para a qualidade de vida do paciente e para a interrupção da cadeia de transmissão da doença. Este trabalho objetivou analisar a adesão à poliquimioterapia em pacientes com hanseníase acompanhados em um serviço de atendimento especializado do município de Rondonópolis (MT). Trata-se de um estudo descritivo de abordagem quantitativa. Participaram da pesquisa 63 pacientes com diagnóstico de hanseníase, acompanhados no Serviço de Atendimento Especializado do Município de Rondonópolis. Para analisar a adesão, utilizou-se o teste de Morisky-Green. Foram classificados como aderentes ao tratamento 31 pacientes (49,2%) no total. As menores frequências de adesão foram observadas em mulheres, na faixa etária de 51 a 59 anos, de cor autodeclarada branca, renda familiar superior ou igual a dois salários mínimos, com até oito anos de estudo, sem companheiros e que possuíam rede de esgoto em suas residências. Observou-se diferença estatística para as variáveis sexo (p = 0,036), modo de detecção (p = 0,008) e forma clínica (p = 0,028). Os resultados indicaram baixa adesão à poliquimioterapia. Mulheres, pacientes com modo de detecção do tipo encaminhamento ou exames de coletividade, com forma clínica indeterminada, tuberculoide ou virchowiana são menos aderentes à poliquimioterapia. Os resultados indicam a necessidade de adoção de medidas que busquem promover melhor aceitação à terapia farmacológica entre os pacientes com hanseníase.

Hansen's disease, a chronic infectious disease caused by Mycobacterium leprae, is considered a major public health issue. Adherence to pharmacological therapy contributes to the patient's quality of life and to interrupting the disease transmission chain. Hence, this study analyzes adherence to multidrug therapy in patients with Hansen's disease treated at a specialized care service in Rondonópolis, Mato Grosso, Brazil. A quantitative, descriptive research was carried out with 63 patients diagnosed with Hansen's disease and treated at the Specialized Care Service of the municipality of Rondonópolis. Adherence was analyzed using the Morisky-Green test. A total of 31 (49.2%) patients were classified as adherent to treatment. The lowest frequency of adherence was observed in women, aged 51 to 59 years, white, family income ≥ 2 minimum wages, with up to eight years of schooling, without partners, and with a sewage system in their homes. Statistical difference was observed for the variables gender (p=0.036), detection mode (p=0.008), and clinical form (p=0.028). Results showed low adherence to multidrug therapy. Women, patients with referral detection or collective exams, with undetermined clinical form, tuberculoid or Lepromatous leprosy, are less adherent to polychemotherapy. The findings indicate the need to adopt measures that seek to promote better adherence to pharmacological therapy among patients with Hansen's disease.

La lepra es una enfermedad infecciosa crónica causada por Mycobacterium leprae y considerada un grave problema de salud pública. La adherencia a la terapia farmacológica contribuye a la calidad de vida del paciente y a la interrupción de la cadena de transmisión de la enfermedad. Este estudio tuvo como objetivo analizar la adherencia a la poliquimioterapia en pacientes con lepra seguidos en un servicio de atención especializado en la ciudad de Rondonópolis, en Mato Grosso (Brasil). Se trata de un estudio descriptivo, de tipo cuantitativo. Participaron en la investigación 63 pacientes diagnosticados de lepra, seguidos en el Servicio de Atención Especializado del Municipio de Rondonópolis. Para analizar la adherencia se utilizó la prueba de Morisky-Green. Un total de 31 (49,2%) pacientes fueron clasificados como adherentes al tratamiento. La menor frecuencia de adherencia se observó en mujeres, en el grupo de edad de entre 51 y 59 años, de color autodeclarado blanco, renta familiar mayor o igual a 2 salarios mínimos, con nivel de educación hasta ocho años, sin pareja y que tenían red de alcantarillado en sus hogares. Hubo diferencia estadística para la variable sexo (p = 0,036), modo de detección (p = 0,008) y forma clínica (p = 0,028). Los resultados indicaron una baja adherencia a la poliquimioterapia. Las mujeres, los pacientes con modo de detección por derivación o exámenes colectivos, con forma clínica indeterminada, tuberculoide o virchowiana fueron los menos adherentes a la poliquimioterapia. Los resultados indican la necesidad de adoptar medidas que busquen promover una mejor aceptación de la terapia farmacológica entre los pacientes con lepra.

Insuficiência renal aguda decorrente do uso intermitente de rifampicina no tratamento da hanseníase / Acute renal failure due to intermittent use of rifampicin in the treatment of leprosy

A hanseníase é uma doença infectocontagiosa crônica, causada pelo Mycobacterium leprae. Indivíduos com esta comorbidade podem ser curados graças ao tratamento com dapsona, clofazimina e rifampicina. A associação de fármacos é conhecida como poliquimioterapia e a escolha da combinação depende da classificação dos pacientes como paucibacilares ou multibacilares. A rifampicina faz parte do tratamento padrão e as anomalias renais secundárias ao seu uso são raras. No entanto, dentre elas, a mais comum é a insuficiência renal aguda. Por se tratar de um efeito colateral incomum e potencialmente fatal, é necessário que as equipes de saúde e os pacientes sejam alertados quanto à possibilidade de sua ocorrência, garantindo desta forma, detecção precoce de anormalidades e rápido manejo dos efeitos colaterais. Apresentamos caso de paciente com diagnóstico de hanseníase dimorfa em tratamento com poliquimioterapia que desenvolveu insuficiência renal aguda após a décima dose da rifampicina, sendo necessária a suspensão da mesma. (AU)

Leprosy is a chronic infectious contagious disease caused by Mycobacterium leprae. Individuals with this comorbidity can be cured thanks to treatment with dapsone, clofazimine and rifampicin. The combination of drugs is known as multidrug therapy and the choice of combination depends on the classification of patients as paucibacillary or multibacillary. Rifampicin is part of standard treatment and renal anomalies secondary to its use are rare. However, the most common of these is acute renal failure. Because it is an unusual and potentially fatal side effect, it is necessary for health teams and patients to be alerted to the possibility of their occurrence, thus ensuring early detection of abnormalities and rapid management of side effects. We present a case of a patient with a diagnosis of dimorphic leprosy in treatment with multidrug therapy who developed acute renal failure after the tenth dose of rifampicin, requiring the suspension of the same. (AU)

Seguimento farmacoterapêutico de pacientes em tratamento com talidomida em um centro especializado em hanseníase / Pharmacotherapeutic follow-up of patients treated with thalidomide at a specialized leprosy center

OBJETIVOS: Avaliar a farmacoterapia de pacientes com reação hansênica tipo 2 em tratamento com talidomida em um centro filantrópico de atendimento especializado. MÉTODOS: O estudo foi realizado no Centro Maria Imaculada de reabilitação de pacientes com hanseníase na cidade de Teresina, Piauí. Foram incluídos na pesquisa pacientes de ambos os sexos atendidos entre setembro e novembro de 2016. O Seguimento Farmacoterapêutico foi fundamentado no Método Dáder, na base eletrônica Drugdex System ­ Thomson Micromedex® ­ Interactions para análise de interações medicamentosas; na classificação de reações adversas a medicamentos de Rawlins e Thompson; e no teste de Morisky-Green para avaliar o nível de adesão terapêutica. RESULTADOS: Foram acompanhados 11 pacientes, dos quais oito eram homens. Foram identificadas três interações medicamentosas, sendo duas classificadas em risco moderado e uma em menor risco. Foram identificados 23 resultados negativos associados ao medicamento, destacando-se insegurança não quantitativa e problemas de saúde não tratados. Além disso, 22 problemas relacionados com medicamentos foram identificados, sendo o mais frequente a ocorrência de reações adversas a medicamentos. Todas as reações adversas associadas a medicamentos foram classificadas como tipo A ou previsíveis. Quanto à adesão, seis entre os nove pacientes que responderam ao teste de Morisky-Green obtiveram alto grau de adesão. A educação em saúde correspondeu à intervenção farmacêutica preponderante, sendo aplicada a todos os pacientes. CONCLUSÕES: Foram evidenciadas interações medicamentosas relevantes, resultados negativos associados ao medicamento e problemas associados a medicamentos. O grau de adesão ao tratamento com talidomida foi considerado alto. Foram necessárias intervenções farmacêuticas, sobretudo voltadas para ações de educação em saúde, o que ratifica a necessidade de acompanhamento constante desse grupo de pacientes.

AIMS: Evaluate the pharmacotherapy of patients with type 2 leprosy reaction in treatment with thalidomide in a philanthropic center of specialized care at Teresina. METHODS: The study was conducted at the Centro Maria Imaculada, for rehabilitation of patients with leprosy, in the city of Teresina, Piauí, Brazil. Patients of both sexes attended between september and november 2016 were included in the study. Pharmacotherapeutic follow-up was based on the Dáder Method, in the electronic base Drugdex System ­ Thomson Micromedex® ­ Interactions for analysis of drug interactions; in the classification of adverse drug reactions of Rawlins and Thompson; and the Morisky-Green test to evaluate the level of therapeutic adherence. RESULTS: Eleven patients were followed, of whom eight were male. Three drug interactions were identified, two of which were classified as moderate risk and one in lower risk. There were 23 negative results associated with medicines, mainly quantitative insecurity and untreated health problems. In addition, 22 drug-related problems were identified, with adverse drug reactions being the most frequent occurrence. All adverse drug reactions were classified as type A or predictable. Regarding adhesion, six patients among nine who responded to the Morisky-Green test obtained a high degree of adhesion. Health education corresponded to the preponderant pharmaceutical intervention, being applied to all patients. CONCLUSIONS: Relevant drug interactions, negative results associated with medicines, and drug-related problems were identified. Degree of adherence to thalidomide treatment was considered high. Pharmaceutical interventions were necessary, mainly focused on health education actions, which ratifies the need for constant monitoring of this group of patients.

Identification of novel chemotherapeutic strategies for metastatic uveal melanoma.

Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.

Reação reversa macular da hanseníase: relato de caso / Macular reversal reaction in leprosy: a case report

A reação reversa maculosa consiste no aparecimento abrupto de máculas hipocrômicas, ocorrendo em pacientes hansenianos dimorfos que completaram o tratamento com poliquimioterapia para hanseníase multibacilar. Em geral, surgem entre 6 a 12 meses da alta, com baciloscopia negativa e boa resposta a corticoterapia sistêmica. Ressaltamos a dificuldade em diferenciar recidiva de um episódio reacional, já que não existem critérios clínicos bem estabelecidos que possibilitem este diagnóstico, além de existirem poucos relatos em literatura. Relatamos um caso clínico com diagnóstico de reação reversa macular após período variável de alta do tratamento de hanseniase dimorfa-dimorfa. Foi feita investigação por meio de anamnese rigorosa, exame dermatológico, exame histopatológico da lesão e baciloscopia, excluindo-se os critérios de recidiva, além de analisados dados anteriores do prontuário.O paciente foi submetido a corticoterapia sistêmica,apresentando melhora das lesões. Conclui-seque a reação reversa maculosa deve ser lembrada nos diagnósticos diferenciais com hanseníase recidivada e episódios reacionais clássicos, evitando retratamentos desnecessários.

Macular reversal reaction is the abrupt onset of hypochromic lesions, occurring in borderline leprosy patients who completed treatment with multidrugtherapy for multibacillary leprosy. In general, these reactions appear 6 to 12 months after medical discharge, showing negative skin smear and good response to systemic corticosteroid therapy. We emphasize the difficulty in differentiating relapse cases from leprosy reactions, as there are no well-established clinical criteria that allow this diagnosis, and moreover there are few reports about it in the literature. We report a borderline leprosy case diagnosed with macular reversal reaction after variable period of discharge from treatment. Detailed anamnesis, dermatological and histopathological examination and bacilloscopy, analysis of previous medical records, excluding the relapse criteria, were used for the investigation. The patient was submitted to systemic corticosteroid therapy, with improvement of the lesions. It is concluded that macular reversal reaction should be considered in the differential diagnosis of relapsed leprosy and classic reactional episodes, avoiding unnecessary retreatment.

Drug repurposing: translational pharmacology, chemistry, computers and the clinic.

The process of discovering a pharmacological compound that elicits a desired clinical effect with minimal side effects is a challenge. Prior to the advent of high-performance computing and large-scale screening technologies, drug discovery was largely a serendipitous endeavor, as in the case of thalidomide for erythema nodosum leprosum or cancer drugs in general derived from flora located in far-reaching geographic locations. More recently, de novo drug discovery has become a more rationalized process where drug-target-effect hypotheses are formulated on the basis of already known compounds/protein targets and their structures. Although this approach is hypothesis-driven, the actual success has been very low, contributing to the soaring costs of research and development as well as the diminished pharmaceutical pipeline in the United States. In this review, we discuss the evolution in computational pharmacology as the next generation of successful drug discovery and implementation in the clinic where high-performance computing (HPC) is used to generate and validate drug-target-effect hypotheses completely in silico. The use of HPC would decrease development time and errors while increasing productivity prior to in vitro, animal and human testing. We highlight approaches in chemoinformatics, bioinformatics as well as network biopharmacology to illustrate potential avenues from which to design clinically efficacious drugs. We further discuss the implications of combining these approaches into an integrative methodology for high-accuracy computational predictions within the context of drug repositioning for the efficient streamlining of currently approved drugs back into clinical trials for possible new indications.

Oral drug therapy for multiple neglected tropical diseases: a systematic review.

CONTEXT: The neglected tropical diseases include 13 conditions that occur in areas of extreme poverty and are poverty promoting. The neglected tropical diseases produce a disease burden almost as great as that associated with human immunodeficiency virus/AIDS, tuberculosis, or malaria, yet are virtually unknown by health care workers in North America, because they occur almost exclusively in the poorest regions of the world. Seven of the most prevalent diseases have existing oral drug treatments. Identifying treatments that are effective against more than 1 disease could facilitate efficient and inexpensive treatment. OBJECTIVES: To systematically review the evidence for drug treatments and to increase awareness that neglected tropical diseases exist and that treatments are available. DATA SOURCES AND STUDY SELECTION: Using a MEDLINE search (1966 through June 2007), randomized controlled trials (RCTs) were reviewed that examined simultaneous treatment of 2 or more of the 7 most prevalent neglected tropical diseases using oral drug therapy. DATA SYNTHESIS: Twenty-nine RCTs were identified, of which 3 targeted 4 diseases simultaneously, 20 targeted 3 diseases, and 6 targeted 2 diseases. Trials were published between 1972 and 2005 and baseline prevalence of individual diseases varied among RCTs. Albendazole plus diethylcarbamazine significantly reduced prevalence of elephantiasis (16.7% to 5.3%), hookworm (10.3% to 1.9%), roundworm (34.5% to 2.3%), and whipworm (55.5% to 40.3%). Albendazole plus ivermectin significantly reduced prevalence of elephantiasis (12.6% to 4.6%), hookworm (7.8% to 0%), roundworm (33.5% to 6.1%), and whipworm (42.7% to 8.9%). Levamisole plus mebendazole significantly reduced prevalence of hookworm (94.0% to 71.8%), roundworm (62.0% to 1.4%), and whipworm (93.1% to 74.5%). Pyrantel-oxantel significantly reduced hookworm (93.4% to 85.2%), roundworm (22.8% to 1.4%), and whipworm (86.8% to 59.5%), while albendazole alone significantly reduced prevalence of hookworm (8.1% to 1.3%), roundworm (28.4% to 0.9%), and whipworm (51.9% to 31.9%). No RCT examined treatment of river blindness or trachoma as part of an intervention to target 2 or more neglected tropical diseases. Adverse events were generally inadequately reported. CONCLUSIONS: At least 2 of the most prevalent neglected tropical diseases can be treated simultaneously with existing oral drug treatments, facilitating effective and efficient treatment. Increasing awareness about neglected tropical diseases, their global impact, and the availability of oral drug treatments is an essential step in controlling these diseases.

Chemotherapy of leprosy.

The WHO MDT regimens have proved highly successful in preventing relapse of leprosy cases. It has indirectly lad to marked reduction in prevalence of disabilities. For PB leprosy, rifampicin 600 mg monthly and 100 mg dapsone daily for a total of 6 months therapy is required. For MB leprosy clofazimine 300 mg once monthly, supervised and 50 mg daily self administered is added. For single skin lesion the current WHO recommendation is 600 mg rifampicin + 400 mg ofloxacin + 100 mg minocycline given as a single dose for adults. Dose adjustment for children and clinical information have been discussed in a nutshell. A number of trials are going on, some are yet to be completed which do offer the prospect of perhaps simplifying therapy and improving with shorter duration.

The future incidence of leprosy: a scenario analysis

Objective: To investigate the impact of the current strategy fot the elimination of leprosy on its incidence and to assess the consequences of failure to sustain this strategy. Methods: Scenarios for assessing the impact of the elimination strategy were implemented in a coputer simulation program. The scenarios reflected the assumptions made regarding contagiousness, transmission and bacille Calmet-Guerin (BCG) vaccination. The trend in case detection rate for the main countries in which leprosy was endemic during 1985-98 was fitted, and incidence up to 2020 was projected. Findings: Owing to the gradual shortening of delays in detection up to 1998, and because of the low relapse rate that occurs with multidrug treatment MDT, incidence is predicted to decrease beyond 2000 in all scenarios. The annual decline was a few per cent higher when favourable assumptions were made about protection and coverage of BCG vaccination. Overall, the predicted annual decline in incidences ranged from 2% to 12%. Conclusions: The elimination strategy reduces transmission, but the decline amy be slow. Relaxation of control after 2005 is unjustified given the uncertainty about the rate of decline and the adverse effects of longer delays in detection. A long-term strategy for leprosy control should be adopted

Hanseníase multibacilar: índices baciloscópios e viabilidade do M. leprae após 24 doses da PQT/OMS / Multivacillar leprosy: bacilloscopic index and viability of M. leprae after 24 doses of multidrug therapy: worlld health organization (MDT/WHO)

A técnica de inoculação no coxim plantar de camundongos (técnica de Shepard) possibilita a verificação da resistência aos quimioterápicos e a viabilidade do M. Leprae. O objetivo era avaliar por meio da técnica de Shepard a viabilidade do M. leprae em material de biópsia cutânea proveniente de pacientes hansenianos multibacilares. Biópsias cutâneas e esfregaços de linfas cutâneas em 21 pacientes hansenianos multibacilares após 24 doses do esquema poliquimioterápico (PQT/OMS). A comparação dos resultados dos índices baciloscópico e morfológico entre as duas amostras demonstrou valores significativamente maiores nos índices baciloscópicos das biópsias cutâneas. A concentração do M.Leprae 12 meses após a inoculação mostrou valores inferiores ao referido como padrão de multiplicação, sugerindo que a população bacilar nas biópsias cutâneas de pacientes hansenianos multibacilares após 24 doses da PQT/OMS pode ser considerada não viável

[Lipiodol therapeutic indications from 1901 to 1930]. / Les usages therapeutiques du lipiodol, seule "huile iodee vraie", entre 1901 et 1930.

Iodine and iodide used to be very successful drugs, sometimes at massive doses. Highly iodinated oil such as lipiodol from Lafay discovered in 1901 were part of expanding the therapeutic use of iodine for various pathologies such as syphilis, cardiovascular and respiratory diseases, leprosy, goiter... The present publication reviews unpublished documents and publications from 1901 to 1930 on lipiodol to give an overview of therapeutic indications for this agent and the rationale behind it. In some areas such as asthma, iodide was still in use until the eighties. Prevention and treatment of endemic goiter is the only remaining domain for the therapeutic usage of lipiodol. It is the only reason why this product is on the WHO essential drugs list.

Tratamiento de la lepra. Nuevos esquemas

Se exponen las diferentes etapas en la terapéutica de la lepra analizando las distintas drogas. Sulfonas, Clofazimina, Rifampicina, Ofloxacina, claritromicina y Minociclina. Se comenta los diversos esquemas de multiterapia (MDT) y las últimas sugerencias de la OMS sobre el tratamiento, así como el de las leprorreaciones.

Recaídas en hanseniasis: experiencia personal / Leprosy relapses: personal experince

En un total de 451 pacientes tratados con Monoterapia con Sulfonas, se han observado 31 recaídas, 15 de ellas de forma dimorfa. El intervalo de tiempo entre inactividad y recaídas oscila entre 6 y 39 anos. En los enfermos tratados con Multiterapia se ha observado un único caso