Leprosy chemoprophylaxis of household contacts: A survey of Canadian infectious disease and tropical medicine specialists.

BACKGROUND: Leprosy is uncommon in Canada. However, immigration from leprosy-endemic areas has introduced the infection to a Canadian context, in which most doctors have little knowledge of the disease. Although post-exposure chemoprophylaxis (PEP) is reported to decrease leprosy transmission, no Canadian guidelines advise clinical decision making about leprosy PEP. Here, we characterize the practice patterns of Canadian infectious disease specialists with respect to leprosy PEP and screening of household contacts by yearly physical examinations. METHODS: Canadian infectious disease specialists with known experience treating leprosy were identified using university faculty lists. An online anonymous survey was distributed. Certain questions allowed more than one response. RESULTS: The survey response rate was 46.5% (20/43). Thirty-five percent responded that PEP is needed for household contacts, 40.0% responded that PEP is not needed for household contacts, and 25.0% did not know whether PEP is needed (multinomial test p = 0.79). Twenty-five percent responded that PEP should be given to all household contacts, 62.5% responded that PEP should be given to contacts of multibacillary cases, and 25.0% responded that PEP should be given to contacts who are genetically related to the index case. For specialists who prescribe PEP, 57.1% use rifampicin, ofloxacin (levofloxacin), and minocycline; 14.3% prescribe single-dose rifampicin; and 28.6% prescribe multiple doses of rifampicin (multinomial test p = 0.11). In addition, 68.4% recommend yearly screening of household contacts, whereas 31.6% do not (multinomial test p = 0.17). CONCLUSION: Consensus among Canadian infectious diseases specialists is lacking regarding leprosy PEP and screening of household contacts.

HISTORIQUE: La lèpre est peu courante au Canada. Cependant, en raison de l'immigration de régions où la lèpre est endémique, cette infection existe, mais la plupart des médecins du Canada la connaissent peu. Même s'il est établi que la chimioprophylaxie post-exposition (PPE) réduit la transmission de la lèpre, il n'existe aucune directive canadienne pour éclairer les décisions cliniques sur la PPE de la lèpre. Les chercheurs caractérisent les schémas d'exercice des infectiologues canadiens au sujet de la PPE de la lèpre et du dépistage des contacts familiaux par des examens physiques annuels des aspects dermatologiques et nerveux périphériques. MÉTHODOLOGIE: Les chercheurs ont répertorié les infectiologues canadiens qui ont une expérience démontrée du traitement de la lèpre grâce aux listes des professeurs universitaires. Ils ont distribué un sondage anonyme en ligne. Pour certaines questions, les participants pouvaient fournir plus d'une réponse. Ils pouvaient aussi sauter certaines questions. RÉSULTATS: Le taux de réponse au sondage s'élevait à 46,5 % (20 cas sur 43). De cette proportion, 35,0 % ont répondu que les contacts familiaux avaient besoin d'une PPE, 40,0 %, qu'ils n'en avaient pas besoin, et 25,0 %, qu'ils ne le savaient pas (test multinomial, p = 0,79). Sur l'ensemble des répondants, 25,0 % ont répondu que tous les contacts familiaux devraient recevoir une PPE, 62,5 %, qu'elle devait être administrée aux contacts des cas multibacillaires, et 25,0 %, aux contacts génétiquement apparentés au cas de référence. Chez les spécialistes qui prescrivent une PPE, 57,1 % utilisent de la rifampicine, de l'ofloxacine (lévofloxacine) et de la minocycline, 14,3 %, une seule dose de rifampicine, et 28,6 %, de multiples doses de rifampicine (test multinomial p = 0,11). De plus, 68,4 % recommandent le dépistage annuel des contacts familiaux, et 31,6 % ne le recommandent pas (test multinomial p = 0,17). CONCLUSION: Il n'y a pas de consensus chez les infectiologues canadiens au sujet de la PPE de la lèpre et du dépistage des contacts familiaux.

Novel approaches in the treatment of Hansen's disease (Leprosy): a case series of multidrug therapy of monthly rifampin, moxifloxacin, and minocycline (RMM) in the United States.

The World Health Organization (WHO) recommends multidrug therapy (MDT) for the treatment of paucibacillary and multibacillary forms of leprosy, also known as Hansen's disease (HD). MDT combinations of dapsone, rifampin, and clofazimine have reduced the prevalence of the disease but are not without adverse effects impacting regimen adherence. Hence, an urgent need exists to consider alternative MDT regimens with an improved safety profile that promotes treatment adherence. Herein, we described a case series of 10 patients with HD (nine patients with multibacillary leprosy and one with pure neural leprosy) treated with monthly rifampin, moxifloxacin, and minocycline (RMM). The United States National Hansen's Disease Program (NHDP) diagnosed and treated patients across US institutions. All patients received a regimen of 12-24 months of RMM. We reviewed the clinical outcomes, adherence, rate of completion, and adverse events of patients treated with monthly RMM from January 2019 to August 2022. Nine patients had multibacillary leprosy, with some having type-2 reactions. One patient had pure neural leprosy with a reversal reaction. In this case series, we identified that all patients completed the RMM regimen without treatment interruptions. None of the patients experienced any skin hyperpigmentation or any significant side effects. All patients tolerated the monthly RMM regimen with rapid improvement of skin lesions and without logistic hurdles. Based on previous clinical evidence and the results of this case series, the NHDP and other programs should consider the RMM regimen as first-line therapy.

Acute Tubular Necrosis and Thrombocytopenia Associated With Rifampin Use: Case Report and Review.

A case of rifampin-induced acute tubular necrosis requiring hemodialysis in a patient receiving thrice-weekly rifampin with daily dapsone for retreatment of relapsed Hansen's disease is reported. The patient had positive rifampin-dependent antiplatelet antibodies. Case reports of acute renal failure associated with the use of rifampin are summarized.

Treatment and Evaluation Advances in Leprosy Neuropathy.

Neuropathy and related disabilities are the major medical consequences of leprosy, which remains a global medical concern. Despite major advances in understanding the mechanisms of M. leprae entry into peripheral nerves, most aspects of the pathogenesis of leprosy neuropathy remain poorly understood. Sensory loss is characteristic of leprosy, but neuropathic pain is sometimes observed. Effective anti-microbial therapy is available, but neuropathy remains a problem especially if diagnosis and treatment are delayed. Currently there is intense interest in post-exposure prophylaxis with single-dose rifampin in endemic areas, as well as with enhanced prophylactic regimens in some situations. Some degree of nerve involvement is seen in all cases and neuritis may occur in the absence of leprosy reactions, but acute neuritis commonly accompanies both Type 1 and Type 2 leprosy reactions and may be difficult to manage. A variety of established as well as new methods for the early diagnosis and assessment of leprosy neuropathy are reviewed. Corticosteroids offer the primary treatment for neuritis and for subclinical neuropathy in leprosy, but success is limited if nerve function impairment is present at the time of diagnosis. A candidate vaccine has shown apparent benefit in preventing nerve injury in the armadillo model. The development of new therapeutics for leprosy neuropathy is greatly needed.

Emergence of Mycobacterium leprae Rifampin Resistance Evaluated by Whole-Genome Sequencing after 48 Years of Irregular Treatment.

A case of Mycobacterium leprae rifampin resistance after irregular antileprosy treatments since 1971 is reported. Whole-genome sequencing from four longitudinal samples indicated relapse due to acquired rifampin resistance and not to reinfection with another strain. A putative compensatory mutation in rpoC was also detected. Clinical improvement was achieved using an alternative therapy.

Computational saturation mutagenesis to predict structural consequences of systematic mutations in the beta subunit of RNA polymerase in Mycobacterium leprae.

Rifampin resistance in leprosy may remain undetected due to the lack of rapid and effective diagnostic tools. A quick and reliable method is essential to determine the impacts of emerging detrimental mutations in the drug targets. The functional consequences of missense mutations in the ß-subunit of RNA polymerase (RNAP) in Mycobacterium leprae (M. leprae) contribute to phenotypic resistance to rifampin in leprosy. Here, we report in-silico saturation mutagenesis of all residues in the ß-subunit of RNAP to all other 19 amino acid types (generating 21,394 mutations for 1126 residues) and predict their impacts on overall thermodynamic stability, on interactions at subunit interfaces, and on ß-subunit-RNA and rifampin affinities (only for the rifampin binding site) using state-of-the-art structure, sequence and normal mode analysis-based methods. Mutations in the conserved residues that line the active-site cleft show largely destabilizing effects, resulting in increased relative solvent accessibility and a concomitant decrease in residue-depth (the extent to which a residue is buried in the protein structure space) of the mutant residues. The mutations at residue positions S437, G459, H451, P489, K884 and H1035 are identified as extremely detrimental as they induce highly destabilizing effects on the overall protein stability, and nucleic acid and rifampin affinities. Destabilizing effects were predicted for all the clinically/experimentally identified rifampin-resistant mutations in M. leprae indicating that this model can be used as a surveillance tool to monitor emerging detrimental mutations that destabilise RNAP-rifampin interactions and confer rifampin resistance in leprosy. AUTHOR SUMMARY: The emergence of primary and secondary drug resistance to rifampin in leprosy is a growing concern and poses a threat to the leprosy control and elimination measures globally. In the absence of an effective in-vitro system to detect and monitor phenotypic resistance to rifampin in leprosy, diagnosis mainly relies on the presence of mutations in drug resistance determining regions of the rpoB gene that encodes the ß-subunit of RNAP in M. leprae. Few labs in the world perform mouse food pad propagation of M. leprae in the presence of drugs (rifampin) to determine growth patterns and confirm resistance, however the duration of these methods lasts from 8 to 12 months making them impractical for diagnosis. Understanding molecular mechanisms of drug resistance is vital to associating mutations to clinically detected drug resistance in leprosy. Here we propose an in-silico saturation mutagenesis approach to comprehensively elucidate the structural implications of any mutations that exist or that can arise in the ß-subunit of RNAP in M. leprae. Most of the predicted mutations may not occur in M. leprae due to fitness costs but the information thus generated by this approach help decipher the impacts of mutations across the structure and conversely enable identification of stable regions in the protein that are least impacted by mutations (mutation coolspots) which can be a potential choice for small molecule binding and structure guided drug discovery.

Dapsone Resistance in Leprosy Patients Originally from American Samoa, United States, 2010-2012.

Skin biopsies from US leprosy patients were tested for mutations associated with drug resistance. Dapsone resistance was found in 4 of 6 biopsies from American Samoa patients. No resistance was observed in patients from other origins. The high rate of dapsone resistance in patients from American Samoa warrants further investigation.

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)

Consensus numbering system for the rifampicin resistance-associated rpoB gene mutations in pathogenic mycobacteria.

The rpoB gene codes for the RNA polymerase ß subunit, which is the target of rifampicin, an essential drug in the treatment of tuberculosis and other mycobacterial infections. This gene is present in all bacteria, but its length and nucleotide sequence vary between bacterial species, including mycobacteria. Mutations in the rpoB gene alter the structure of this protein and cause drug resistance. To describe the resistance-associated mutations, the scientific and medical communities have been using, since 1993, a numbering system based on the Escherichia coli sequence annotation. Using E. coli reference for describing mutations in mycobacteria leads to misunderstandings, particularly with the increasing use of whole genome sequencing, which brought an alternative numbering system based on the Mycobacterium tuberculosis rpoB sequence. We propose using a consensus numbering system for the reporting of resistance mutations based on the reference genomes from the species interrogated (such as strain H37Rv for M. tuberculosis). This manuscript provides the necessary figures and tables allowing researchers, microbiologists and clinicians to easily convert other annotation systems into one common language.

Avaliação de hansenianos tratados com esquema alternativo dose única ROM (rifampicina, ofloxacina e minociclina), após sete a nove anos / Evaluation years in leprosy patients treated with single dose alternative scheme ROM (rifampin, ofloxacin, minocycline), after seven to nine

INTRODUÇÃO: Em 1997, após a realização de estudo multicêntrico, duplo cego e randomizado, em nove centros de tratamento de hanseníase na Índia, o Ministério da Saúde adotou o esquema alternativo dose única ROM para casos de lesão única, paucibacilar, sem nervo periférico afetado, índice baciloscópico negativo, em Centros de Referência da doença no Brasil. O estudo se propôs a avaliar a efetividade do esquema ROM em pacientes tratados no período de 1997 a 1999 no Serviço de Dermatologia da Santa Casa de Vitória. MÉTODOS: Foram selecionados e tratados com o esquema ROM, 54 pacientes das formas indeterminada e tuberculóide. Estes pacientes foram convocados de março a outubro de 2006 para reavaliação clínica. RESULTADOS: Vinte e nove pacientes avaliados (85,2 por cento; IC95 por cento: 70-100,4) estavam curados, cinco (14,7 por cento; IC95 por cento: 7,4-22,0) recidivaram e 20 pacientes não retornaram; porém, não havia outra notificação de reingresso ao tratamento no banco de dados da Secretaria Estadual de Saúde. CONCLUSÕES: O estudo evidenciou taxa de cura de 90,8 por cento e taxa bruta de recidiva de 9,2 por cento, após período de sete a nove anos da dose ROM. O tratamento alternativo ROM demonstrou melhor efetividade para lesão única menor que quatro centímetros e aparecimento há menos de cinco anos.

INTRODUCTION: In 1997, after obtaining a combined multi-state double-blind randomly controlled clinical trial study from nine Indian centers involved in the treatment of Hansen's Disease, the Ministry of Health adapted the single dose ROM Therapy approach in those cases involving the treatment of a single skin lesion, paucibacillary leprosy without evidence of peripheral nerve trunk involvement and indication of negative baciloscope, in the Referral Centers in Brazil. The study aimed to evaluate the effectiveness of the single dose ROM Therapy approach in those patients who were treated from the period of 1997 to 1999 in the Ambulatory Dermatologic Unit in the Hospital in Vitória, ES. METHODS: Fifty-four patients with tuberculoid and indeterminate leprosy were selected and treated with the single dose ROM Therapy approach. These patients were contacted from March 2006 up and until October 2006 for further clinical reevaluation. RESULTS: From the studies conducted, the following results were found to exist: 29 patients (85,2 percent; 95 percentCI: 70-100,4) were cured, 5 patients (14,7 percent; 95 percentCI: 7,4-22,0) relapsed, and 20 patients didn't return; however, there are no additional records of any notification of other treatment(s) in the State Department of Health's informational data banks. CONCLUSIONS: The study demonstrated a rate of cure of 90.8 percent and a rate of relapse of 9.2 percent after a period of seven to nine years using the single dose ROM Therapy approach. Additionally, this alternative treatment further demonstrated a better effectiveness for a single skin lesion smaller than four centimeters and with an appearance in less than five years.

Estudio de resistencia a la rifampicina y la dapsona en tres pacientes con recurrencia de lepra / Study of rifampin and dapsone resistance in three patients with recurring leprosy

OBJETIVO: Detectar la presencia de cepas de Mycobacterium leprae resistentes a la rifampicina y la dapsona en tres pacientes con recurrencia de lepra y sospecha clínica de resistencia antimicrobiana, mediante la aplicación de técnicas moleculares. MÉTODOS: Se realizó un estudio descriptivo retrospectivo en tres pacientes multibacilares del Sanatorio de Agua de Dios, Cundinamarca, Colombia, que habían presentado recidivas de lepra documentadas por su historia clínica, baciloscopia y biopsia. Se obtuvieron biopsias de lesiones cutáneas que se procesaron para la extracción y purificación del ADN bacilar. Se amplificaron regiones de los genes rpoB y folP1 asociadas con la resistencia antimicrobiana, mediante la reacción en cadena de la polimerasa "touch-down" y se secuenciaron los productos amplificados mediante el método de Sanger. RESULTADOS: Se detectó una mutación puntual en el nucleótido 1367 del gen rpoB en dos de las muestras estudiadas. No se encontró la mutación estudiada en el gen folP1 en ninguno de los tres pacientes. CONCLUSIONES: La mutación identificada demostró la presencia de bacilos de M. leprae resistentes a la rifampicina en dos de los tres pacientes estudiados con recurrencia de la enfermedad. No se detectó la mutación indicadora de resistencia a la dapsona en ninguno de los tres pacientes.

OBJECTIVE: To detect the presence of rifampin- and dapsone-resistant strains of Mycobacterium leprae in three patients with recurring leprosy and clinically-suspected antimicrobial resistance through molecular techniques. METHODS: A retrospective, descriptive study was conducted of three multibacillary patients at the "Agua de Dios" Sanitarium in Cundinamarca, Colombia, that presented leprosy relapses that were documented by medical history, bacilloscopy, and biopsy. Biopsies were taken of the skin lesions and the bacteria were subject to DNA extraction and purification. Regions of the rpoB and folP1 genes associated with antimicrobial resistance were amplified and subjected to touch-down polymerase chain reaction and the amplified products were sequenced using the Sanger method. RESULTS: A punctual mutation was identified in nucleotide 1367 of the rpoB gene in two of the samples studied. This mutation was not found in the folP1 gene of any of the three patients. CONCLUSIONS: The mutation identified showed strains of rifampin-resistant M. leprae in two of the three patients with recurring leprosy. Mutations that indicate dapsone-resistance were not detected in any of the three patients.

Estudo terapêutico comparando a associação de rifampicina, ofloxacina e minociclina com a associação rifampicina, clofazimina e dapsona em pacientes com hanseníase multibacilar / Therapeutic study comparing the association rifampin, ofloxacinand minocycline, with the association rifampin, clofazimine anddapsone in multibacillary leprosy patients

Foram comparados dois esquemas terapêuticos em pacientes com hanseníase multibacilar. O grupo controle com 14 pacientes recebeu o tratamento convencional.O grupo teste com 12 pacientes recebeu a associação de rifampicina 600 mg, ofloxacina 400 mg,e minociclina 100 mg, uma vez por mês, durante dois anos. Na avaliação inicial foram realizados exames clínicos, baciloscópicos e histológicos. A baciloscopia e a biópsia foram repetidas no final do primeiro e segundo ano de tratamento. As avaliações clínicas realizadas mensalmente. Todos pacientes apresentavam lesões cutâneas, que os caracterizavam como virchovianos ou peri-virchovianos. No grupo controle, o índice baciloscópico antes do tratamento variou de 2 a 4,8 e no grupo teste de 1,6 a 4,8. Histologicamente apresentavam quadro de hanseníase virchoviana ativa, exceto um paciente do grupo teste. Ao final do primeiro ano de tratamento estavam todos clinicamente melhorados,o índice baciloscópico diminuído e quadro histológico regressivo. Essa tendência se mantinha e ao final do segundo ano todos estavam clinicamente, baciloscopicamente e histologicamente ainda melhores. Análise estatística mostrou não haver diferença significante entre os grupos, sendo os esquemas equivalentes. No grupo controle todos apresentaram pigmentação cutânea devido a clofazimina. Os resultados deste estudo demonstraram que o esquema com rifampicina, ofloxacinae minociclina, teve eficácia e segurança equivalente a poliquimioterapia convencional para multibacilar. Além disso, não causa pigmentação cutânea, pode ser totalmente supervisionado, podendo ser utilizado como esquema alternativo

Two therapeutic schemes in multibacillary leprosy patients were compared. The control group with 14 patients received the conventional treatment (MDT-MB). The test group with 12 patients, received the association rifampin 600 mg, ofloxacin 400 mg and minocycline 100 mg (ROM), administrated under supervision once a month, during two years. Initial evaluations include clinical, bacilloscopic and histological exams. The bacilloscopy and the biopsy were repeated at the end of first and second year of treatment. Clinical evaluations were performed monthly. All patients presented skin lesions characteristic of the lepromatous type. In the control group, the bacterial index (BI) before treatment ranged from 2 to 4.8 and in the test group it ranged from 1.6 to 4.8. Histological picture resembled active lepromatous leprosy, except one patient from the test group. At the end of the first year of treatment all patients showed clinical improvement, decreased BI and regressive histological picture. This tendency was maintained and at a final evaluation at the end of the second year all patients showed improvement on clinical, bacilloscopic and histological evaluations. Statistical analysis showed no significant differences between the groups, therefore, the two schemes were similar. In the control group all patients presented skin pigmentation after clofazimine intake. The results demonstrated that monthly administration of ROM is as efficacious and safe as MDT-MB. Besides, it doesn’t cause skin pigmentation, it can be given under supervision and can be used as alternative scheme.