Resistance Mechanisms, Host Interactions Remain Elusive for Clostridioides difficile Research

Although there has been an influx of research for the treatment of Clostridioides difficile (C. difficile) in the past few years, there remain significant knowledge gaps in C. difficile that still need to be addressed. Investigators of a review published in Virulence said that understanding virulence factors, resistance mechanisms, and host interactions can help establish the development of novel therapeutics for the infection.

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C. difficile is the cause of antibiotic-associated diarrhea. According to the investigators, treatment is complex because antibiotics are a major risk factor but the main source of treatment, whereas C. difficile is usually resistant to antibiotics.

Transmission of the infection is typically achieved through spore and contaminated surfaces. The spore is resistant to oxygen, ultraviolet rays, desiccation, heat, many disinfectants, and antibiotics, which make it particularly challenging to decontaminate health care facilities and other environments.

The investigators of the review discussed the transmission of the disease via the spore; however, they noted that because this has been an area of intense research, the review only touches on the molecular basis of sporulation. They added that sporulation is sensitive to environmental pH, so they can survive in low pH conditions in the gut microbiome. However, the study authors said that “much of the complex process of sporulation regulation remains to be elucidated.”

Once the spore is induced, the germination process is rapid, with vegetative cells undergoing the first round of cell division anywhere between 90 and 180 minutes, according to the study investigators.

The process of recurrent infection comes from the spore, which was previously thought to be solely due to the resistance of the spore to antibiotics. In recent studies, spores have been found to enter the intestinal epithelial cells, indicating an unexpected mechanism for C. difficile infections.

As for virulence factors, the clinical presentation of C. difficile includes various toxins and surface proteins, according to the authors of the review. The toxins are internalized in the gut, which contribute to cell death and loss of intestinal barrier function. The symptoms are affected by the host immune response, typically involving acute intestinal inflammatory responses and neutrophil infiltration.

Investigators of the review also discussed the 2 primary challenges to antibiotic resistance: the extensive resistance reducing treatment options and treatment options being limited through the adaption and flexibility of the C. difficile genome. Metronidazole, fidaxomicin, and vancomycin have been standard-of-care treatments for C. difficile until recently. Metronidazole has been used for mild-to moderate infections, vancomycin was for severe and severe-complicated disease before migrating to replace metronidazole, and fidaxomicin was a narrow-spectrum antibiotic. Fidaxomicin has been overlooked due to higher cost, according to the study.

However, investigators added that new research has been paving the way for novel antimicrobials and alternative therapeutics. The study authors noted that problems with antibiotics are associated with broad-spectrum antibiotics. New therapeutics are focused on targeted or narrower spectrum to reduce the risk of recurrence. These treatments have included fecal microbial transplantation (FMT), phage therapy, and narrow-spectrum antimicrobials, according to the review authors.

Although FMT has grown in popularity, concerns linger due to the lack of standardization and reports of adverse events (AEs). FMT has been used as a monotherapy or a combination therapy with antibiotics.

For phage therapy, investigators noted that it is able to evolve with the infection, as opposed to static antimicrobial agents. Limitations include that the host inflammatory responses to phage have occurred in in vivo models, though phage treatment has been regarded as safe, with smaller human trials not showing significant AEs.

For antibody therapies, recent therapeutics include fidaxomicin, which was approved in 2011 by the FDA, followed by bezlotoxumab, which was approved in 2016. Bezlotoxumab also has shown minimal AEs during clinical trials while reducing the rate of recurrence and demonstrating the ability to block extraintestinal organ damage. Limitations include the cost of the drug, which is estimated to exceed $6000 per patient.

Although there has been increased interest and investment into novel small molecule antimicrobials, is has been found difficult to develop treatments that are sufficient and superior to vancomycin and fidaxomicin. Currently, ridinilazole is the only anti-C. difficile antibiotic in phase 3, which has shown a sustained 66.7% clinical response rate compared to 42.4% for vancomycin.

These new and novel therapeutics show promise for the future of treating C. difficile, however, it is important to remember that the infection continues to adapt to therapeutic treatment so further investigation on virulence factors and resistance mechanisms are needed.

Reference

Buddle JE, Fagan RP. Pathogenicity and virulence of Clostridioides difficile. Virulence. 2023;14(1):2150452. doi:10.1080/21505594.2022.2150452