Tackling Clostridioides difficile (CD): current evidences and future directions in the treatment of CD infections

Clostridioides difficile (C. difficile) is a Gram-positive, anaerobic, spore-forming bacterium, responsible for hospital-acquired diarrhea worldwide, accounting for 12% of all healthcare-associated infections.¹ C. difficile infection (CDI) has been linked to over 200,000 cases of illness in hospitalized patients and over 20,000 deaths annually in US,² and around 124,000 cases and 3700 deaths annually in Europe.³ Moreover, recent data suggest a rise in community-acquired cases.⁴ Furthermore, diagnostic and treatment guidelines for CDI are not always properly adhered, resulting in suboptimal care and outcomes.⁴

C. difficile spreads primarily through the fecal-oral route, with spores capable of germinating and releasing toxins that lead to symptoms ranging from mild colitis to severe complications, including death.¹ Despite appropriate treatment, recurrent CDI frequently occurs due to the persistence of C. difficile spores, which can germinate and multiply, particularly when there is microbiota disruption.⁵ Older, frailty adults are at the highest risk, with high recurrence rates and mortality rates that can reach 13.5%.¹

Traditional CDI therapies include antibiotics such as vancomycin and metronidazole, though these have limited effectiveness in preventing CDI recurrence. Since 2013, fecal microbiota transplantation (FMT) has been shown to be effective in treating recurrent CDI,⁶ and since 2017, fidaxomicin, along with vancomycin, has been recommended as first-line treatment for initial CDI episodes whereas FMT has been reserved for cases of multiple recurrence.⁷

In this issue of The Lancet Regional Health—Europe, the systematic review and network meta-analysis conducted by Bednárik and colleagues compared various treatment options to identify the most effective CDI treatment, considering both recurrent and non-recurrent cases and including the FMT.⁸ This network meta-analysis found that FMT had the highest cure rate overall (P-score: 0.9927), especially in recurrent CDI cases (P-score: 0.9836). In recurrent CDI, fidaxomicin (P-score: 0.6734) was found to be more effective than vancomycin (P-score: 0.3677) and tolevamer (P-score: 0.0365). Of note, tolevamer (a toxin-binding polymer) development was halted 15 years ago, because in two phase III studies comparing tolevamer to standard anti-C. difficile therapy, tolevamer was found to be inferior to both comparators.⁹

In the study by Bednárik and colleagues, ridinilazole, fidaxomicin, FMT, and nitazoxanide showed similar efficacy for non-recurrent CDI. Fidaxomicin and ridinilazole were also more effective in preventing recurrence than vancomycin or metronidazole.⁸

This study⁸ evidences several pivotal issues pertaining to the current management of CDI. Firstly, the authors highlighted significant variations in the definition of CDI recurrence across the included trials, which could impact the consistency of treatment outcomes. This emphasises the need for future initiatives to establish standardised definitions and management approaches to CDI on a global scale.

Secondly, FMT demonstrated superiority in terms of cure rate compared to the other treatments for CDI.⁸ Based on these findings, FMT was identified as the most effective treatment for recurrent CDI cases. Moreover, it can be postulated that in the near future FMT could emerge as a prominent therapeutic option even for initial CDI cases. The ongoing FMT trials addressing non-recurrent CDI cases will provide further insights.¹⁰

So far, FMT gained considerable acceptance in clinical practice, but it is not free from problems. Its implementation is complicated by logistical issues such as donor screening, stool processing, and patient monitoring for adverse effects. Nevertheless, FMT is currently regarded as the standard of care for patients with a third or more episode of CDI and is being increasingly performed in clinical centres across Europe.^7,10

Among the FMT limitations, the composition of stool preparations remains poorly characterised, with a significant proportion of genes and metabolites in faecal samples poorly understood.^5,6,10 Recently, live biotherapeutic products derived from stool samples have been approved as alternatives to prevent CDI recurrence following antibiotic treatment for recurrent CDI.⁵ The ease of use of oral live biotherapeutic products is a significant advantage. The efficacy of these products in restoring the gastrointestinal microbiome is particularly important during the critical window of vulnerability, when the risk of recurrence of CDI is highest.⁵

Finally, Bednárik and colleagues analyzed the effectiveness of probiotics, including Lactobacillus, Saccharomyces and a mixed group with both of them, and found no significant benefits in the prevention of CDI, even though in a pairwise meta-analysis Lactobacillus was significantly better than placebo.⁸

Thus considering, FMT and live biotherapeutic products derived from stool samples inaugurate a new era of care for patients with recurrent CDI.⁵ In the near future, the management of recurrent CDI may potentially be achieved through a two-stage approach, comprising initial treatment with anti-C. difficile antibiotics and subsequently, microbiome-targeted interventions including FMT or live biotherapeutic products to address the underlying pathophysiology of microbiome dysbiosis, preventing C. difficile spore germination and CDI recurrence.⁵

Contributors

GG and NP equally conceptualised the manuscript and prepared the original draft and writing-reviewing and editing.

Declaration of interests

In the last two years, NP received payment or honoraria for lectures and presentations and speakers bureau from Takeda, MSD, Pfizer, Valneva, Shionogi, Q-linea. GG declares no conflicts of interest.