Subhajit Nan, Amity University, Kolkata
Clostridioides Difficile is a bacterium responsible for causing severe diarrhea and inflammation of the colon (colitis). Though guidelines for infection control measures are firmly in place, Clostridioides Difficile Infection or CDI remains the chief cause of diarrhea associated with healthcare. Since the burden associated with CDI is high, both from the health and economic point of view, there is an urgent need for new and novel strategies to keep the CDI at bay in susceptible patients and prevent their spread and development.
Active and Passive Immunization Strategy
Considerable work has been carried out in the field of active immunization and vaccine development, yet no vaccine is currently available. Discouraging results were reported from a recently concluded 3rd phase trial of a toxoid vaccine. Clinical development of the vaccine candidate was halted. Simultaneously, a toxin-based vaccine is currently in its 3rd phase trials and is being conducted in adults aged above 50 years, who are most susceptible to Clostridioides Difficile (CDI) infection. The results of the 3rd phase trials are yet to be released.
Regarding passive immunization, a human monoclonal antibody against C. difficile toxin B, named bezlotoxumab, was recently developed and approved for the prevention of recurring CDI in combination with antibiotics for treatment of CDI. While the efficacy of bezlotoxumab for primary prevention of CDI has not yet been verified, it would be expensive. Passive immunity would not be a cost-effective strategy for treating primary infection of CDI because though the protection is immediate, it is short-lived.
Microbiota Specific Treatment Strategy
Fecal microbiota transplantation (FMT), live biotherapeutic products (LBPs), and probiotics have been suggested as methods to restore microorganisms present in the human gut, thereby inhibiting the colonization of dangerous pathogenic bacteria. FMT transfers a whole set of intestinal microbiotas in bulk, while LBPs are less diverse, containing a lesser number of different species of bacteria. Conventional probiotics, too, contain very few bacteria.
Now, a novel strategy for the prevention of CDI is the administration of poorly absorbed beta-lactamase enzymes simultaneously while providing antibiotics to degrade these in the esophagus. Ribaxamase is the first oral class A serine enzyme designed to protect the bacterium in the colon from the effects of common intravenous beta-lactam antibiotics. The clinical production and development of ribaxamase are ongoing.
Challenges in Mass Immunisation
As mentioned above, there is no vaccine for CDI as of now. The recent failure of one of the vaccine candidates means that there is further room for improvement and research. Non-toxin antigens should be considered as a viable alternative formulation for potential vaccines, which target and prevent the colonization and sporulation of the C. difficile bacteria. An effective vaccine needs to produce an immune response with a considerable duration of protection in elderly and immunocompromised patients who are at particularly high risk for CDI because the bacteria target mainly the elderly people, in whom immune senescence can cause impaired recognition of antigens.
The other challenge is implementing a viable and cost-effective vaccination program. Passive immunization strategies could be implemented for secondary treatment of recurring CDI in high-risk patients. Bezlotoxumab has only been recently introduced, and it has not yet been incorporated into international guidelines. In patients with a history of heart-related issues, it should only be used when the benefit outweighs the potential risk. The use of bezlotoxumab is limited, although it could prove cost-effective in an appropriately selected population.
Conclusion
In conclusion, we can say that there are no effective prophylactic options for primary prevention of CDI that allow for widespread use, as of now. Conventional probiotics have not yet clearly proven to be an effective strategy for primary prevention of CDI, and antibiotics should not be routinely administered as prophylaxis of CDI because of its side effects. FMT has proven to be very effective for the prevention of secondary or recurring CDI. Bezlotoxumab does protect recurring CDI, although more research and testing are necessary. Secondary treatment of CDI with antibiotics can only be considered after a thorough evaluation by doctors in very selected high-risk patients susceptible to recurring CDI. In future studies, we anticipate increased use of therapies that target the specific pathogen, improvements in the administration of FMT, development of improved multi-strain probiotics, and selective antibiotics.
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References:
1. Reigadas E, van Prehn J, Falcone M, Fitzpatrick F, Vehreschild MJGT, Bouza E, Kuijper E, How to: prophylactic interventions for prevention of Clostridioides difficile infection, Clinical Microbiology and Infection, https://doi.org/10.1016/j.cmi.2021.06.037.
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