An innovative treatment for patients with Clostridium difficile infection (CDI) which uses transplanted gut bacteria to treat the infection, is a more effective and more cost-efficient treatment than using antibiotics, a new UK study has found.
CDI is an infection of the bowel, which commonly affects people who have recently been treated in hospital, those with underlying conditions and patients over 65. Almost 30 percent of patients treated for the condition experience at least one recurrence.
A recurrence of the condition, has been associated with a higher risk of mortality and is usually treated using antibiotics.
Faecal microbial transplantation (FMT), a treatment pioneered as a licenced medicine by Professor Peter Hawkey and his team at the University of Birmingham, is a method where gut bacteria and other components in faeces are used to treat CDI.
The bacteria is taken from a screened healthy donor, processed and screened before being transplanted via a tube passed through the nose into the stomach. Treatment with FMT is associated with higher cure and lower recurrence rates than fidaxomicin or vancomycin- the two most common antibiotics used to treat recurrent CDI (rCDI).
The study, which presents the first decision model for patients with rCDI already hospitalised in the UK, analysed randomised controlled trials, observational studies and expert opinion from the UK, on patients with single or multiple rCDI.
Researchers analysed the cost of each of the four treatment options for rCDI for treatment effects, unit costs, resource and health related quality of life to identify which treatment was the most cost-effective and offered the best outcome for patients.
The study showed that both methods for administering FMT were lower in cost compared to standard treatment with antibiotics. FMT via naso-gastric tube was the least costly, with a mean cost of £8,877 per patient, while FMT via colonoscopy was £11,716 per patient.
FMT via colonoscopy was also shown to be slightly more effective than treatment via naso-gastric tube, offering patients a higher quality of life. Two other standard antibiotic treatments vancomycin and fidaxomicin were compared in the model but both these treatments were shown to be more costly and less effective than either of the FMT interventions. Moreover, Vancomycin was the most expensive and the least effective treatment.
Professor Peter Hawkey, formerly of the University of Birmingham said, “We at the University of Birmingham pioneered this treatment as the UK’s first third party FMT service. FMT is not currently a widespread treatment for this disease but by showing that it not only saves lives, but is also significantly more cost effective, we hope that this could be one of the first steps towards the treatment being accepted more widely.”
Professor Tracy Roberts, Head of the University of Birmingham’s Health Economics Unit said “As well as being more effective both in terms of cost and benefit to patients, FMT was shown to significantly reduce the amount of days patients were required to be hospitalised which could also provide longer-term cost-savings.”
Fecal microbiota transplantation (FMT) is the transfer of gut bacteria through whole stool from a healthy donor to a recipient. FMT has demonstrated high cure rates in recurrent C. difficile infection (CDI) across multiple randomized, placebo-controlled trials [1] and has now entered standard of care for multiply recurrent CDI in European and North American guidelines [2–4].
Beyond CDI, FMT is being explored in range of microbiome-mediated diseases, and has demonstrated promising results in inflammatory bowel diseases [5–10].
Despite these early successes, the underlying mechanism of FMT across all disease indications, including CDI, remains unclear. However, it is generally considered that FMT restores gut microbial community perturbations from a dysbiotic state to a healthy stable state with engraftment of donor strains, or perhaps through other donor-dependent features such as the abundance of non-bacterial components or donor clinical features [11,12].
However, not all FMT donors are alike: gut microbiota compositions vary within healthy populations in ways that could impact the findings from an FMT trial [13,14]. This critical point of microbiome variation within healthy donors is rarely considered in the development of FMT trials [15,16].
Unlike FMT trials in CDI, where selecting donors based on specific clinical or microbiome profiles does not seem to affect clinical response rates, donor selection is likely to be crucial to trial outcomes in diseases with more complex host-microbiome interplay or distinct disease-associated perturbations [14].
Most notably, in a randomized controlled trial (RCT) of FMT for ulcerative colitis (UC) using 5 donors, 78% of patients who achieved remission after FMT received stool from a single donor [17]. Thus, it is possible that without this single donor, the trial would have returned a negative result.
Given the variation in healthy donor microbiomes and donors’ potential impact on clinical efficacy, how should clinicians and investigators select their donors for a clinical trial?
To date, the typical approach for donor selection in FMT trials is to use a single healthy donor or to randomly select multiple donors from a set of screened potential donors [10,18,19].
However, in clinical indications where successful donors may be rare, such as UC, clinical trials with randomly-selected healthy donors may fail not because FMT is inappropriate for the indication, but because an ineffective donor was chosen.
An alternative approach is to expose each patient to multiple donors in order to mitigate the risk of sub-optimal donor selection. In a large RCT of FMT in UC, FMT enemas for a single patient were derived from between three and seven donors with patients receiving multiple donors throughout the 8 week course of treatment [10].
However, using multiple donors for a single patient may not be feasible or appropriate in many disease indications or clinical trial settings (e.g. single-dose FMT studies). Continuing the practice of randomly selecting donors for FMT clinical trials risks returning false negative trials, stalling the field and delaying the development of novel therapies for microbiome-mediated conditions.
Unlike traditional clinical trials which test well-defined small molecules, FMT trials test the donor microbiome, which is variable [16]. Fortunately, the emergence of large, stool banks with multiple pre-screened healthy donors captures some of this variability and makes it available for use in FMT trials.
These stool banks thus open the possibility of selecting donors rationally during the FMT clinical trial design phase, enabling clinicians to choose from among a large pool of eligible donors for donor samples which have specific desirable characteristics.
Coupled with expanded access to genome sequencing technologies and publicly available microbiome sequencing datasets, rational donor selection is feasible and presents a unique opportunity to advance the research methods of this nascent field.
In this paper, we present a framework to guide donor selection for FMT trials. The mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how donors are selected for FMT trials, and we describe different disease models which may underlie microbiome-mediated conditions (Fig 1).
We describe strategies to rationally select donors for each type of disease model, and provide examples based on previously published FMT trials and ongoing investigations. Finally, we discuss limitations of performing discovery-based retrospective research after an FMT clinical trial concludes.
To our knowledge, this is the first description of a comprehensive framework for rational donor selection in FMT trials.
In cases where the underlying model is unknown, a variety of donor selection approaches could be employed to potentially identify which disease process(es) may be involved.
https://doi.org/10.1371/journal.pone.0222881.g001
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More information: Zainab I Abdali et al. Economic evaluation of Faecal microbiota transplantation compared to antibiotics for the treatment of recurrent Clostridioides difficile infection, EClinicalMedicine (2020). DOI: 10.1016/j.eclinm.2020.100420
