Leprosy Mailing List – July 20, 2019
Ref.: (LML) Confronting multiple-drug resistant (MDR) bacilli
From: Joel Almeida, London and Mumbai
Dear Pieter & colleagues,
Multiple-drug resistant (MDR) bacilli have been found in over 40% of MDT-treated patients showing recurrent disease, and in over 20% of those they infect.(1) This study in a Brazilian settlement was the first total-population survey of drug-resistance anywhere, during the MDT era. It shows that drug-resistant mutants are selected during even MDT. These mutant bacilli may die out in treated patients with adequate innate immunity. However, they can be spread unknowingly by persons with genetically determined anergy who suffer recurrence of disease. MDR bacilli and recurrence of disease interact dangerously in endemic hot spots. An investigation of all people in that settlement revealed that as many as 1282/10000 persons had shown signs of disease.(2) If MDR bacilli continue spreading, they could wipe out our past gains.
Anti-microbial drug resistance is one of the few health threats ever to have received a resolution from both the World Health Assembly (WHA) and the UN General Assembly. It is highlighted also in the Sustainable Development Goals (para 26). Many disease control programmes, including TB, neglected the design of effective measures against drug-resistance until the problem got out of hand. All this underlines the importance of mobilising the best brains, resources and efforts speedily to devise and implement effective measures against MDR bacilli in Hansen's Disease (HD).
Fortunately, the world seems poised for a step change in effective action against HD. There are positive signals from the highest political levels in India and Brazil. The Goodwill Ambassador has been busy mobilising commitment at all levels. Such growing commitment provides a necessary foundation for effective measures.
The World Health Assembly resolution included the following measures to contain the threat of drug-resistance:
A. Reduce the incidence rate of disease.
B. Optimise the use of anti-microbial drugs.
C. Invest in R&D for new drugs, vaccines and diagnostics.
A. Reducing the incidence rate of disease
Shandong province interrupted transmission by preventing recurrence of disease among LL patients after the usual duration of MDT. New cases in Shandong declined by 20%/year. This decline continued relentlessly until near-zero transmission. We can strive to match this success. Monthly post-MDT chemoprophylaxis using three bactericidal drugs can be given to all LL patients in endemic areas.(3) This is also a key part of competent case management for LL patients, helping to protect them against recurrent disease and further nerve damage. Monthly doses of three bactericidal drugs in combination are likely to match or exceed the efficacy of the prolonged anti-microbial protection used in Shandong. We can keep tweaking and improving the intervention, but it seems important to start. Given the threat from MDR bacilli, delay would be dangerous.
B. Optimising the use of anti-microbial drugs
Bactericidal drugs such as rifampicin, if used singly, rapidly select drug-resistant mutants. Therefore, bactericidal drugs are best combined with other bactericidal drugs of roughly equivalent anti-microbial efficacy. Given the measured anti-microbial effect of rifampicin in mouse footpad tests, a single dose in an undiagnosed person with sub-clinical LL infection is likely to result in a 10-fold increase in the frequency of rifampicin-resistant mutant bacilli. This is best avoided because persons with untreated LL disease can shed tens of millions of viable bacilli per day. Selecting drug-resistant mutant bacilli in such persons unnecessarily increases the risk of an eventual epidemic of MDR bacilli. That catastrophe is best avoided.
C. R&D for new tools
The pipeline of new anti-mycobacterial drugs and vaccines has depended largely on TB research, which is more generously funded than HD research. Many TB drugs and vaccines have an effect against HD. We can make the most of drugs and vaccines available in the TB pipeline, alongside any other promising HD candidates. Candidate TB drugs or novel combinations of effective HD drugs can usefully be tested in the mouse footpad model for HD, as was done as recently as 2016.(3) Controlled clinical trials of mycobacterial vaccines against TB in HD-endemic areas enable us to gauge the effect on the subsequent incidence rate of HD too. It would be helpful also to have easily usable diagnostics in HD (alongside skin smears) to help distinguish between persons with sub-clinical LL disease, who can spread highly concentrated viable bacilli, and persons with a relatively effective immune response who mostly remain non-infectious. These are examples. The list can be expanded.
The frequency of MDR bacill in that Brazilian population (1) foreshadows what could happen elsewhere. This supports the case for boosted investment in R&D.
D. Inviting in new faces
We could be more pro-active in inviting the brightest talent to participate in HD work. Brazilian colleagues have been doing this with some success, as was evident at the 2018 congress of the Brazilian Hansenology Society. New faces bring fresh eyes to the challenges. This can help enlarge our horizons, improve our interventions, and boost our chances of success. Even the most optimistic among us recognise that our efforts are more like a marathon than a sprint.
What's in it for them? The chance to help wipe out a dreaded disease, while showing respect, competence, compassion and affection to some of the most vulnerable and ostracised people on earth. Most of the young professionals I spoke to in Brazil cited the inspiring example of senior colleagues as a decisive attracting factor. We need not hesitate to present the option and invitation. As the website of the Indian programme says, quoting Mahatma Gandhi, our work is "not merely medical relief. It is transforming the frustration of life into the joy of dedication, personal ambition into selfless service." That can appeal to many.
Conclusions
We have a limited window of opportunity to interrupt transmission before MDR bacilli overtake us. We can seize the opportunity by providing monthly post-MDT chemoprophylaxis to all LL patients in endemic areas. This is also a key part of competent case management for LL patients. With prompt action, we can hope to match Shandong's achievement of a 20% / year decline in incidence rate, ending in near-zero transmission.
Joel Almeida
Translations
ब्राजील की एक बस्ती के नए शोध के अनुसार, एमडीटी के बाद आवर्ती रोग वाले 40% रोगियों में मल्टीड्रग प्रतिरोधी (एमडीआर) बेसिली होता है। एमडीआर बैसिली 20% से अधिक नव निदान रोगियों में होता है जो बार-बार होने वाले रोगियों से संक्रमित थे। एमडीआर बेसिली हमारे पिछले सभी लाभ को उलट सकता है। अब शून्य संचरण जल्दी प्राप्त करना बहुत महत्वपूर्ण है।
हम प्रत्येक एलएल रोगी को एमडीटी के बाद मासिक केमोप्रोफिलैक्सिस देकर शांडोंग प्रांत की तरह प्रति वर्ष 20% की गिरावट प्राप्त कर सकते हैं। एलएल रोगियों को आवर्तक बीमारी और अधिक तंत्रिका क्षति से बचाने के लिए एमडीटी के बाद मासिक केमोप्रोफिलैक्सिस की आवश्यकता होती है। मासिक रूप से दी जाने वाली 3 जीवाणुनाशक दवाएं 100% प्रभावी होने की संभावना है।
रिफैम्पिसिन की एक खुराक से दवा प्रतिरोधी बेसिली की एकाग्रता दस गुना बढ़ जाती है। इसलिए केवल संयोजन में जीवाणुनाशक दवाओं का उपयोग करना आवश्यक है।
हम नए उपकरणों के लिए R & D में भी निवेश कर सकते हैं।
De acordo com nova pesquisa de um assentamento brasileiro, após a MDT, até 40% dos pacientes com doença recorrente têm bacilos resistentes a múltiplas drogas (MDR). Os bacilos MDR ocorrem em mais de 20% dos pacientes recém-diagnosticados que foram infectados por pacientes com doença recorrente. Os bacilos MDR podem reverter todos os nossos ganhos passados. Agora é muito importante alcançar a transmissão zero rapidamente.
Podemos alcançar um declínio de 20% ao ano, como na província de Shandong, dando quimioprofilaxia mensal pós-MDT a todos os pacientes com LL. A quimioprofilaxia mensal pós-MDT é necessária para proteger os pacientes com LL de doenças recorrentes e danos adicionais nos nervos. 3 medicamentos bactericidas administrados mensalmente são provavelmente 100% eficazes.
Uma dose única de rifampicina aumenta a concentração de bacilos resistentes à rifampicina em dez vezes. É por isso que é necessário usar drogas bactericidas somente em combinação.
Também podemos investir em pesquisa e desenvolvimento para novas ferramentas.
Selon de nouvelles recherches effectuées dans une colonie brésilienne, après la PCT, jusqu'à 40% des patients présentant une maladie récurrente sont porteurs du bacille polychimiorésistant (MDR). Les bacilles MDR surviennent chez plus de 20% des patients nouvellement diagnostiqués et infectés par des patients présentant une maladie récurrente. Les bacilles MDR peuvent inverser tous nos acquis passés. À présent, il est très important de parvenir rapidement à une transmission zéro.
Nous pouvons atteindre un déclin de 20% par an, comme dans la province du Shandong, en administrant une chimioprophylaxie post-PCT mensuelle à tous les patients LL des zones d'endémie. Une chimioprophylaxie mensuelle post-PCT est nécessaire pour protéger les patients LL contre les maladies récurrentes et les lésions nerveuses. Trois médicaments bactéricides administrés mensuellement ont probablement une efficacité de 100%.
Une seule dose de rifampicine multiplie par dix la concentration de bacilles résistants à la rifampicine. C'est pourquoi il est nécessaire d'utiliser des médicaments bactéricides en combinaison uniquement.
Nous pouvons également investir dans la R & D pour de nouveaux outils.
De acuerdo con una nueva investigación de un asentamiento brasileño, después del MDT, hasta el 40% de los pacientes con enfermedad recurrente tienen los bacilos resistentes a múltiples fármacos (MDR). Los bacilos de MDR ocurren en más del 20% de los pacientes recién diagnosticados que fueron infectados por pacientes con enfermedad recurrente. Los bacilos MDR pueden revertir todas nuestras ganancias pasadas. Ahora es muy importante lograr una transmisión cero rápidamente.
Podemos lograr una disminución del 20% por año como la provincia de Shandong al administrar quimioprofilaxis post-MDT mensual a todos los pacientes con LL en áreas endémicas. Se necesita una quimioprofilaxis post-MDT mensual para proteger a los pacientes con LL de una enfermedad recurrente y más daño a los nervios. 3 medicamentos bactericidas administrados mensualmente son probablemente 100% efectivos.
Una dosis única de rifampicina aumenta la concentración de bacilos resistentes a la rifampicina diez veces. Por eso es necesario usar medicamentos bactericidas en combinación solamente.
También podemos invertir en I + D para nuevas herramientas.
References
1. Rosa PS, D'Espindula HRS, Melo ACL et al. Emergence and transmission of drug/multidrug-resistant Mycobacterium leprae in a former leprosy colony in the Brazilian Amazon. Clinical Infectious Diseases. 1 July 2019, ciz570, https://doi.org/10.1093/cid/ciz570
2. Lázaro FP, Werneck RI, Mackert CC et al. A major gene controls leprosy susceptibility in a hyperendemic isolated population from north of Brazil.J Infect Dis. 2010 May 15;201(10):1598-605. doi: 10.1086/652007
3. Drug costs & impact of post-MDT chemoprophylaxis for LL patients. LML 9 July 2019
4. Arumugam S, Joseph P, Ponnaiya J et al. Murine Model to Identify Short Duration Alternative Chemotherapy for Leprosy. Indian Journal of Leprosy 2016, 88 (3): 159-76
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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