Clostridioides difficile-associated disease - Emerging treatments

Investigational live biotherapeutic products

There are two donor-derived live biotherapeutic products approved in the US for the treatment of recurrent infection. Other products are also in development. These products are cultivated in a laboratory rather than being donor-derived. VE303 is a live biotherapeutic product that includes 8 strains of commensal Clostridia. A phase 2 randomised controlled trial found that high-dose VE303 reduced recurrence of C difficile infection compared with placebo.[138] The Food and Drug Administration (FDA) has granted fast track designation to VE303 for the prevention of recurrent C difficile infection. Other investigational products are also in development (e.g., NTCD-M3, ADS024, MET-2, SER-262).[69][134]

Biological agents

LMN-201 is a first-in-class, investigational, oral monoclonal antibody cocktail that combines four therapeutic proteins which act together to neutralise both the C difficile bacteria (by destroying the cell wall) and its associated toxins. A phase 1 trial has been completed.[139] A phase 2/3 trial to assess LMN-201 for the prevention of C difficile infection is in progress.[140] The FDA has granted fast track designation to LMN-201 for the prevention of C difficile infection. Other biological agents (e.g., IM-01) are also in development.[69]

Small molecules

Ridinilazole is a novel antibacterial agent with a highly-targeted spectrum of activity that has the ability to spare normal gut microbiota. It has completed phase II testing and shows potential in the treatment of initial C difficile infection, but further research is required.[141] Other small molecules (e.g., ibezapolstat) are also in development.[69]

Ribaxamase

Ribaxamase is being studied for the prevention of C difficile infection. It is an orally administered beta-lactamase designed to be given with intravenous beta-lactam antibiotics, which are associated with a high risk of C difficile infection due to their biliary excretion into the gastrointestinal tract. Ribaxamase acts by degrading excess antibiotics in the upper gastrointestinal tract before they disrupt the gut microbiome and lead to C difficile infection. A randomised, double-blind, placebo-controlled phase 2b trial found that ribaxamase reduced the incidence of C difficile infection in patients treated with ceftriaxone for lower respiratory infections compared with placebo.[142]

Teicoplanin

A semi-synthetic glycopeptide antibiotic. One Cochrane review found that sustained symptomatic cure was improved with teicoplanin compared with vancomycin; however, the quality of evidence for its use is low, and it is not available in the US.[84]

Resins

Cholestyramine and colestipol bind C difficile toxin and have been used in recurrent disease with or without vancomycin. These medications also bind vancomycin, and they have not been well studied.[21] Monotherapy with these luminal toxin-binding agents has been found to be inferior to standard therapy with metronidazole and vancomycin.[143]