Optimising Vancomycin Dosing for C. difficile Infection (OVID-CDI)

The bacterium Clostridium difficile causes an infection in the bowel/guts of patients which results in diarrhoea. Symptoms can range from mild to severe with >10 episodes of diarrhoea per day, and can be life-threatening. C. difficile only causes an infection in guts where the normal balance of good bacteria has been disturbed, usually by taking drugs (antibiotics) for other bacterial infections. Often, patients with C. difficile infection (CDI) are elderly and frail, particularly as these people are the most likely to have received many antibiotics. Because CDI is a bacterial infection, the treatments involve taking even more antibiotics, which can further damage the good bacteria in the gut. Patients can then develop another CDI infection, known as recurrent CDI, which increases the chance of hospital readmission and dying. Currently, the most commonly used and recommended treatment option is an antibiotic called vancomycin. Another option, called fidaxomicin does not reduce the populations of good bacteria as much as vancomycin, and therefore leads to fewer cases of recurrent CDI, but it is much more expensive and so is not used as often.
The amount of vancomycin we use to treat CDI was decided a long time ago, but not following any specific trials/experiments to find out the best amount to use. Some data available in papers suggest that the C. difficile bacteria can be killed by amounts far lower than those that we currently use. It is possible, therefore, that we can give a much smaller amount of vancomycin, still treat the infection effectively, but not damage the good bacteria as much. This would theoretically lead to fewer recurrent CDI cases, which is better for patients and the NHS. Less vancomycin would also mean that CDI treatments would be cheaper for the NHS and in other countries.
In Leeds, we have developed laboratory models of the gut that mimic the populations of normal good gut bacteria (sourced from poo samples from healthy volunteers). This means we can see how drugs affect the good bacteria in our guts, without having to test patients. We would like to use these gut models to see if lower amounts of vancomycin can still treat the CDI infection, while not damaging the good gut bacteria so much. We will also be able to check whether lower amounts of vancomycin can lead to less CDI recurrence because of this. In order to decide the amounts of vancomycin to use, we will review all of the current published knowledge on vancomycin and then combine this information with carefully designed laboratory experiments. These experiments will determine the lowest amounts of vancomycin that will kill the C. difficile bacteria, and will help us determine the best doses to test in the gut models.
We plan to engage with patients, the public, healthcare professionals and industry representatives by holding two educational events; one at study kick off and one at the end of the study. By developing visual interpretations of the study aims and outcomes, we hope to ensure that they can be easily understood by all who attend. These one page information leaflets can also be distributed via our connections with various patient engagement organisations, such as the C. Diff Foundation. The University of Leeds also hosts an annual public engagement event called Be Curious, which we will attend and present our study findings. Study results will be presented to the international scientific community at conferences and via publication in open access journals.
The ultimate aim of this project is to identify a better, affordable vancomycin treatment that may be beneficial to patients, and so can be tested in a future clinical trial.

C. difficile infection (CDI) is a major cause of nosocomial diarrhoea, with recurrent disease (rCDI) occurring in ~25% of cases. CDI arises as a result of antimicrobial-mediated gut dysbiosis, which is exacerbated by antibiotics directed at C. difficile, leading to this high rCDI rate. CDI treatments are limited to metronidazole (MET), vancomycin (VAN) and fidaxomicin (FDX), but, as MET efficacy is inferior, guidelines favour VAN and FDX. FDX is associated with lower rCDI risk, due to its narrow spectrum and relative sparing of gut microbiota (unlike current VAN), but is expensive, meaning VAN remains the main therapeutic option. The standard dosage of oral VAN (125 mg qds) achieves high faecal concentrations (>1000mg/kg), yet its MIC for almost all C. difficile isolates is <2mg/L. VAN killing kinetic data suggest limited additional benefit beyond 2xMIC. So, it is possible that a substantially reduced VAN dosage could still be effective at inhibiting C. difficile, while markedly reducing impact on the microbiota, potentially reducing rCDI rates. While FDX and newer CDI antimicrobials have undergone dosage-ranging studies, VAN has not. The significant expertise in clinically-reflective CDI gut models at Leeds allows us to perform in vitro studies to evaluate the effects of new, reduced VAN dosages/schedules on C. difficile, gut microbiota, resistance selection/development and rCDI risk. We will perform in vitro killing kinetic studies on prevalent C. difficile ribotypes and representatives of key gut microbial populations. These will inform a series of gut models testing dose/frequency/duration, each with rCDI risk, to optimise a CDI VAN dosage regimen. This will be compared with FDX, & extended dosage FDX, current alternatives to standard VAN therapy for CDI. We will co-develop a clinical trial alongside this grant to test the optimised VAN regimen beyond this application.