Frontiers in antibiotic alternatives for Clostridioides difficile infection

Abstract

Clostridioides difficile ( C. difficile ) is a gram-positive, anaerobic spore-forming bacterium and a major cause of antibiotic-associated diarrhea. Humans are naturally resistant to C. difficile infection (CDI) owing to the protection provided by healthy gut microbiota. When the gut microbiota is disturbed, C. difficile can colonize, produce toxins, and manifest clinical symptoms, ranging from asymptomatic diarrhea and colitis to death. Despite the steady-if not rising-prevalence of CDI, it will certainly become more problematic in a world of antibiotic overuse and the post-antibiotic era. C. difficile is naturally resistant to most of the currently used antibiotics as it uses multiple resistance mechanisms. Therefore, current CDI treatment regimens are extremely limited to only a few antibiotics, which include vancomycin, fidaxomicin, and metronidazole. Therefore, one of the main challenges experienced by the scientific community is the development of alternative approaches to control and treat CDI. In this Frontier article, we collectively summarize recent advances in alternative treatment approaches for CDI. Over the past few years, several studies have reported on natural product-derived compounds, drug repurposing, high-throughput library screening, phage therapy, and fecal microbiota transplantation. We also include an update on vaccine development, pre- and pro-biotics for CDI, and toxin antidote approaches. These measures tackle CDI at every stage of disease pathology via multiple mechanisms. We also discuss the gaps and concerns in these developments. The next epidemic of CDI is not a matter of if but a matter of when. Therefore, being well-equipped with a collection of alternative therapeutics is necessary and should be prioritized.

Comparison of fidaxomicin, metronidazole and vancomycin for initial episode and recurrence of Clostridioides difficile infection - An observational cohort study

“…Antimicrobial resistance is a serious public health problem, recognized by the World Health Organization (WHO), which is associated with severe socio-economic consequences [ 30 ]. For this reason, new therapeutic strategies, such as new small molecules, natural products, antitoxin monoclonal antibodies, bacteriophages or fecal microbiota transplantation, are urgently needed [ 31 ]. One of the most promising small molecules tested is ridinilazole, which is a likely narrow-spectrum antibiotic associated with minor changes in gut microbiota in patients with CDI [ 32 ].…”

A Novel Treatment Approach to Treatment-Resistant, Recurrent <i>Clostridium difficile</i>

“…Sufficiently low bacterial and spore loads allow for successful fecal microbial transplants, as the transplanted, healthy colonic gut flora will exist in high enough titers to prevail over the relatively lowered C. difficile bacterial titers. Fecal microbial transplants then restore the normal gut microbiome composition, thus rendering C. difficile growth incapable of producing clinically significant disease [5] .…”

“…In patients suffering from C. difficile colitis, 15–30% experience recurrence after antibiotics courses, with rates in the USA increasing in recent years [3, 5]. While fecal microbial transplants are widely used in refractory cases, there is limited data on real-world practices as well as guidance on optimal timing of the procedure.…”

The metabolic impact of bacterial infection in the gut

“…The damage caused to the gut would liberate nutrients required for the bacterium to grow and thereby compromise repair pathways. Treatment of C. difficile infection involves restoring the host microbiota using probiotics or faecal microbiota transplant or targeting C. difficile with antibiotics such as vancomycin or antibodies to C. difficile toxin B [140].…”