Clostridioides difficile infection is the most common cause of diarrhoea acquired in acute health-care settings. Hospital-acquired C difficile infection increases health-care costs by four times over matched hospitalisation, an added annual cost of US$1 billion in the US and CA$100 million in Canada.1, 2 Within 8 weeks of finishing treatment for C difficile infection, 20–30% of patients will have C difficile infection recurrence with vancomycin or metronidazole. Risk of recurrence increases with each subsequent episode, approaching 60% after a third episode.3, 4, 5, 6 Furthermore, incidence of multiply recurrent C difficile infection is increasing disproportionately to incidence of C difficile infection. Between 2001 and 2012, the incidence of C difficile infection increased by 46%, whereas the incidence of recurrent C difficile infection increased by 189%.7 Although C difficile itself might be suppressed by vancomycin, patients with recurrent C difficile infection continue to experience fatigue, anorexia, weight loss, and reduced quality of life.8 Managing recurrent C difficile infection is a major clinical challenge, because there are few therapeutic options. The result is increased health-care use, costs, and patient suffering.
Research in context
Evidence before this study
We searched MEDLINE for articles published between database inception and Sept 19, 2020, in English with search terms including “Clostridium difficile” or “Clostridiodes difficile”, combined with “fecal microbiota transplant*”, “fecal transplant*”, “microbiome therapeutic*”, “microbial therapeutic*”, “microbiota therapeutic*”, or “microbial ecosystem therapeutic*”. This search yielded 574 results. Randomised controlled trials to date have focused on faecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection. Resolution of recurrent C difficile infection in randomised trials was lower (about 76%) than in open-label studies (about 83%). FMT is not without its clinical challenges, however, because it is undefined, variable, and requires dedicated stool donors with substantial screening of donors for known pathogens. Even with stringent donor selection, when screening and quarantine of donor material between two screening points is correctly done, there is still potential to transmit disease, including antibiotic-resistant organisms and emerging pathogens, such as SARS-CoV-2.
From our literature review, live biotherapeutic products that are under development include stool specimens treated with ethanol (SER-109), microbiota suspension manufactured using standardised processes (RBX2660), and sterile filtrate from donor stool. These products have shown possible effectiveness for recurrent C difficile infection in small phase 1 or 2 trials including 5–40 patients.
Microbial Ecosystem Therapeutic 2 (MET-2) consists of a proprietary consortium of 40 bacterial species derived from the stool of a screened, healthy donor. Strains were highly purified and combined as lyophilised material in capsules for oral delivery. This product does not require further stool donors.
Added value of this study
We assessed the safety, tolerability, and activity of MET-2 in the treatment of recurrent C difficile in a phase 1, single-group trial. This treatment was not associated with any serious adverse events, and 18 (95%) of 19 participants achieved clinical resolution of recurrent C difficile infection. Alpha diversity metrics increased in these patients, and abundances of taxa associated with MET-2 were shown to increase, indicating potential incorporation of MET-2 taxa into patient microbiomes. These findings are similar to those from FMT treatment. This study is also one of the few to assess C difficile ribotypes and toxinotypes throughout its 130-day study period. Patients were infected with a variety of ribotypes and toxinotypes, and ribotype switching occurred in two patients during follow-up. Recurrent C difficile infection resolution was not necessarily associated with clearance of C difficile.
Implications of all the available evidence
There is an unmet need for an effective and safe treatment for recurrent C difficile infection that does not require donor stool, which MET-2 might fulfil. Larger clinical trials are needed to validate these promising results.
Faecal microbiota transplantation (FMT) seems to be the most effective and cost-effective treatment for prevention of recurrent C difficile infection.9, 10 The first randomised trial11 of FMT compared FMT by nasogastric tube with vancomycin and found that a single FMT treatment was 81% efficacious compared with 31% for vancomycin. Further randomised trials showed that FMT is highly efficacious through various delivery routes (colonoscopy 91%,12 enema 85%,13 and oral capsules 96%14) and in various formulations (fresh 100% and frozen-and-thawed 85%).13 Lyophilised FMT capsules have similar efficacy to fresh or frozen FMT (80–90%).15
The short-term safety profile of FMT is favourable, but potential exists for transmission of disease, despite donor screening. In the USA, eight cases of transmission of serious infections through FMT have occurred: two cases of extended spectrum β-lactamase-producing Escherichia coli, two cases of enteropathogenic E coli, and four cases of Shiga toxin-producing E coli. Three patients died in association with these transmissions, prompting warnings from the US Food & Drug Administration (FDA).16, 17, 18, 19, 20 Emergence of novel pathogens (eg, SARS-CoV-2) poses an additional safety hazard, and donor screening protocols must be constantly updated to reflect continually evolving threats. Although these eight cases of transmission could have been prevented with more thorough donor screening, a defined microbiome-derived therapy would mitigate these risks and improve safety.
Petrof and colleagues21 developed a defined microbial consortium (RePOOPulate or Microbial Ecosystem Therapeutic 1 [MET-1]), comprised of 33 bacterial strains derived from stool of a healthy donor. This formulation (100 ml; 3·5 × 109 colony forming units/mL), delivered by colonoscopy, prevented recurrence in two patients with recurrent C difficile infection and demonstrated the feasibility of MET-1 as an alternative to FMT. The latest iteration, MET-2, comprises strains of 40 bacterial species, lyophilised and encapsulated for oral administration. This study was done to determine the safety, activity, and tolerability of MET-2 in recurrent C difficile infection patients.