New treatment approaches for Clostridioides difficile infections: alternatives to antibiotics and fecal microbiota transplantation

Abstract

Clostridioides difficile causes a range of debilitating intestinal symptoms that may be fatal. It is particularly problematic as a hospital-acquired infection, causing significant costs to the health care system. Antibiotics, such as vancomycin and fidaxomicin, are still the drugs of choice for C. difficile infections, but their effectiveness is limited, and microbial interventions are emerging as a new treatment option. This paper focuses on alternative treatment approaches, which are currently in various stages of development and can be divided into four therapeutic strategies. Direct killing of C. difficile (i) includes beside established antibiotics, less studied bacteriophages, and their derivatives, such as endolysins and tailocins. Restoration of microbiota composition and function (ii) is achieved with fecal microbiota transplantation, which has recently been approved, with standardized defined microbial mixtures, and with probiotics, which have been administered with moderate success. Prevention of deleterious effects of antibiotics on microbiota is achieved with agents for the neutralization of antibiotics that act in the gut and are nearing regulatory approval. Neutralization of C. difficile toxins (iii) which are crucial virulence factors is achieved with antibodies/antibody fragments or alternative binding proteins. Of these, the monoclonal antibody bezlotoxumab is already in clinical use. Immunomodulation (iv) can help eliminate or prevent C. difficile infection by interfering with cytokine signaling. Small-molecule agents without bacteriolytic activity are usually selected by drug repurposing and can act via a variety of mechanisms. The multiple treatment options described in this article provide optimism for the future treatment of C. difficile infection.

Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

“…Toxin-based therapies not only help in treating the infection but also promote the preservation of the host's microbiota. Additionally, vaccination against toxins offers protection against CDI by activating the immune system to defend against the development of the infection [23,76,229].…”

“…Despite its clinical use, bezlotoxumab has limitations because it is unable to interfere with the interaction between TcdB and FZD1,2,7 and PVRL3 receptors [74,233]. Furthermore, due to mutations in the TcdB epitopes of hypervirulent C. difficile strains, bezlotoxumab's neutralizing activity may be restricted [23].…”

“…Unlike bezlotoxumab, it cannot simultaneously bind both epitopes, resulting in less impact on toxin conformation. Additionally, other regions influencing TcdA entry into cells and a variety of toxin strains may impact neutralization potency for both actoxumab and bezlotoxumab [23].…”