How to develop a controlled human infection model for Clostridioides difficile.

IF 10.9 1区 医学 Q1 INFECTIOUS DISEASES Clinical Microbiology and Infection Pub Date : 2024-08-29 DOI:10.1016/j.cmi.2024.08.025
Annefleur D O Hensen, Maria J G T Vehreschild, Dale N Gerding, Oleg Krut, Wilbur Chen, Vincent B Young, Saul Tzipori, Philipp Solbach, Malick Mahdi Gibani, Christopher Chiu, Sigrid C J de Keersmaecker, Dileep Dasyam, Sandra Morel, Jeanne-Marie Devaster, Nicoletta Corti, Ed J Kuijper, Meta Roestenberg, Wiep Klaas Smits
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Abstract

Background: Clostridioides difficile (C. difficile) remains the leading cause of healthcare-associated diarrhoea, posing treatment challenges because of antibiotic resistance and high relapse rates. Faecal microbiota transplantation is a novel treatment strategy to prevent relapses of C. difficile infection (CDI), however, the exact components conferring colonization resistance are unknown, hampering its translation to a medicinal product. The development of novel products independent of antibiotics, which increase colonization resistance or induce protective immune mechanisms is urgently needed.

Objectives: To establish a framework for a Controlled Human Infection Model (CHIM) of C. difficile, in which healthy volunteers are exposed to toxigenic C. difficile spores, offering the possibility to test novel approaches and identify microbiota and immunological targets. Whereas experimental exposure to non-toxigenic C. difficile has been done before, a toxigenic C. difficile CHIM faces ethical, scientific, logistical, and biosafety challenges.

Sources: Specific challenges in developing a C. difficile CHIM were discussed by a group of international experts during a workshop organized by Inno4Vac, an Innovative Health Initiative-funded consortium.

Content: The experts agreed that the main challenges are: developing a clinically relevant CHIM that induces mild to moderate CDI symptoms but not severe CDI, determining the optimal C. difficile inoculum dose, and understanding the timing and duration of antibiotic pretreatment in inducing susceptibility to CDI in healthy volunteers.

Implications: Should these challenges be tackled, a C. difficile CHIM will not only provide a way forward for the testing of novel products but also offer a framework for a better understanding of the pathophysiology, pathogenesis, and immunology of C. difficile colonization and infection.

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如何开发艰难梭状芽孢杆菌控制性人体感染模型。
背景:艰难梭菌(C. difficile)仍然是医疗相关性腹泻的主要病因,其抗生素耐药性和高复发率给治疗带来了挑战。粪便微生物群移植(FMT)是一种新型治疗策略,可预防艰难梭菌感染(CDI)复发,但产生定植耐药性的确切成分尚不清楚,这阻碍了将其转化为医药产品。我们迫切需要开发出独立于抗生素的新型产品,以提高耐定植性或诱导保护性免疫机制:建立艰难梭菌受控人类感染模型(CHIM)框架,让健康志愿者暴露于毒性艰难梭菌孢子中,为测试新方法、确定微生物群和免疫学靶点提供可能性。虽然以前曾进行过接触非致毒艰难梭菌(NTCD)的实验,但致毒艰难梭菌 CHIM 面临着伦理、科学、后勤和生物安全方面的挑战:在由国际医疗卫生机构(IHI)资助的 Inno4Vac 联合企业组织的一次研讨会上,一组国际专家讨论了开发艰难梭菌 CHIM 所面临的具体挑战:专家们一致认为主要挑战在于:开发一种与临床相关的 CHIM,诱导轻度至中度 CDI 症状,但不诱导重度 CDI;确定最佳艰难梭菌接种剂量;了解抗生素预处理在诱导健康志愿者对 CDI 易感性方面的时机和持续时间:如果能解决这些难题,艰难梭菌CHIM不仅能为新型产品的测试提供前进的方向,还能为更好地了解艰难梭菌定植和感染的病理生理学、发病机理和免疫学提供一个框架。
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来源期刊
CiteScore
25.30
自引率
2.10%
发文量
441
审稿时长
2-4 weeks
期刊介绍: Clinical Microbiology and Infection (CMI) is a monthly journal published by the European Society of Clinical Microbiology and Infectious Diseases. It focuses on peer-reviewed papers covering basic and applied research in microbiology, infectious diseases, virology, parasitology, immunology, and epidemiology as they relate to therapy and diagnostics.
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