Clostridium difficile infection (CDI) is the leading cause of nosocomial diarrhoea and causes substantial morbidity and mortality. Efforts to reduce the impact of CDI have succeeded in reducing rates through antibiotic stewardship, improved diagnostic testing and optimisation of infection control measures. Further reductions in CDI could be achieved through a better understanding of what makes patients susceptible to CDI. Such knowledge would support interventions targeting patients most at risk and help develop treatments to reduce susceptibility. The aim of this thesis was to further our understanding of patient susceptibility to CDI by investigation of three specific areas. The first study investigated the role of the probiotic Lactobacillus casei DN114001 in preventing antibiotic associated diarrhoea (AAD), including CDI, as part of a large multicentre, double-blind, randomised placebo-controlled trial. Probiotics are live microorganisms that may help restore antibiotic disruption to the host microflora and prevent C. difficile colonisation. The final results were not available at the time of writing this thesis and therefore a descriptive analysis of the first 650 blinded cases is provided. This is the largest probiotic study ever conducted and will contribute significantly to the existing literature in the field. The humoral immune response has been implicated in determining outcome in CDI. Previous studies have focused on recurrence of CDI and toxin A (TcdA), which was originally thought to be the most important virulence factor in CDI. However, recent studies have suggested toxin B (TcdB) may be essential for CDI pathogenesis. Therefore, the second study tested the hypothesis that antibodies to TcdB determine patient susceptibility in CDI. A case-control laboratory based study was conducted using a novel antibody ELISA and antibody responses to both toxins were assessed in two cohorts recruited in Brighton, UK and Michigan, USA. Lower antibody levels to TcdB, but not TcdA, were found in cases of acute CDI compared to controls. These novel findings are in contrast to previous studies and confirm the importance of TcdB in CDI pathogenesis. In addition, the antibody response to TcdB could be used as a surrogate marker for the efficacy of novel therapeutic agents. The third study sought to identify risk factors predicting recurrence of CDI. A longitudinal cohort study of 248 patients with confirmed CDI was conducted that confirmed the previously observed relationship between concomitant antibiotic treatment and risk of recurrence. The study also identified a novel risk factor namely that treatment on a cohort ward was associated with recurrence of CDI. This is likely to be a result of reinfection of patients who remain susceptible to CDI after treatment. This is the first study to demonstrate an association between cohorting of patients and recurrence of CDI and raises important questions about current infection control policies in hospitals. Efforts to combat CDI have focused on reducing exposure of patients to infection. The data presented here contribute to a rapidly emerging understanding that patient susceptibility is a crucial factor in determining risk of infection, risk of severe disease and risk of recurrence following treatment. In the near future interventions targeting susceptibility including probiotics, specific antibiotics such as fidaxomicin and immunotherapies such as vaccines may all have a role to play in combatting this devastating disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:607633 |
| Date | January 2013 |
| Creators | Islam, Jasmin |
| Publisher | University of Brighton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://research.brighton.ac.uk/en/studentTheses/059dba8c-ad37-4d2a-9f0e-13b94f843e0e |
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