Clinical Microbiology and Infection最新文献

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

Objectives: To establish a framework for a Controlled Human Infection Model (CHIM) for 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 (NTCD) 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 IHI-funded consortium.

Content: The experts agreed that the main challenges are: developing a clinically relevant CHIM which induces mild to moderate CDI symptoms but no severe CDI, determining optimal C. difficile inoculum dose and understanding the timing and duration of antibiotic pre-treatment in inducing susceptibility to CDI in healthy volunteers.

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

Objectives: Significant heterogeneity has been reported in cohort studies evaluating the impact of early oral antiviral treatment on preventing post-acute sequelae after COVID-19 (PASC). We evaluated the impact of early nirmatrelvir/ritonavir on risk of post-acute cardiovascular, neurological, respiratory and autoimmune diagnoses, as well as post-acute symptoms amongst older Singaporeans.

Methods: National COVID-19 registries and healthcare claims databases were utilized to construct a retrospective population-based cohort enrolling all Singaporeans aged≥60 years diagnosed with SARS-CoV-2 infection at primary care during Omicron transmission (18th March 2022-4th August 2023). The cohort was divided into nirmatrelvir/ritonavir-treated and untreated groups. Between-group differences in baseline characteristics were adjusted using overlap weighting. Risks of post-acute cardiovascular, neurological, respiratory and autoimmune diagnoses and post-acute symptoms (31-180 days) following SARS-CoV-2 infection were contrasted in treated/untreated groups using competing-risks regressions (adjusted for demographics/vaccination status/comorbidities).

Results: 188,532 older Singaporeans were included; 5.8% (10,905/188,532) received nirmatrelvir/ritonavir. No significantly decreased risk of post-acute sequelae (any sequelae: adjusted-hazards-ratio, aHR=1.06[0.94-1.19]; cardiovascular sequelae: aHR=1.01 [0.83-1.24]; neurological sequelae: aHR=1.09 [0.95-1.27]; respiratory sequelae: aHR=1.14[0.84-1.55]; autoimmune sequelae: aHR=0.76[0.53-1.09] or any post-acute symptom: aHR=0.97[0.80-1.18]) was observed up to 180 days post-infection in nirmatrelvir/ritonavir-treated individuals, versus untreated cases. Across all vaccination and age subgroups, no significantly decreased risk of any post-acute diagnosis/symptom or any cardiovascular, neurological, respiratory and autoimmune complications up to 180 days post-infection was observed.

Conclusion: Early outpatient receipt of nirmatrelvir/ritonavir did not significantly reduce risk of post-acute cardiovascular, neurological, respiratory and autoimmune sequelae or risk of post-acute symptoms in a boosted cohort of older Singaporeans.