Novel Biologic Agent Could be a Primary Defense Against C. Difficile

The results of a research report recently published in the Journal of Infectious Diseases may offer an alternative method for preventing the recurrence of pathogenic Clostridium difficile (C. difficile) infection (CDI), which is considered to be an urgent public health priority by the Centers for Disease Control and Prevention (CDC).¹ At present, an estimated 29,000 deaths are attributable to CDI each year in the US,² and the risk for- and severity of recurrent CDI increase with age.^3-5 Because CDI manifests with diarrhea, pseudomembranous colitis, and toxic megacolon, it requires hospitalization associated with an enormous financial burden.⁶

CDI is often a response to the use of antibiotics. Although they are ubiquitous, the benefits of these medicines are accompanied by microbial imbalances in the large intestine, referred to as antibiotic-induced dysbiosis. In such cases, the compromised bacterial environment allows for colonization and invasion by C. difficile, an anaerobic gram-positive, spore-forming, toxin-producing bacillus transmitted among humans through the orofecal route. The spores that transmit C. difficile, which are resistant to heat, acid, and antibiotics, can be found in high-levels in health care facilities, as well as in low levels in the environment and food supply. Unfortunately, this allows for both nosocomial and community transmission.²

Sahil Khanna, MBBS, an assistant professor of medicine at the Mayo Clinic in Rochester, Minnesota and the lead author on the publication, conducted a study motivated by the need for new CDI therapeutic options. Currently, the most reliable method for reestablishing an appropriate gut environment in those with CDI is fecal microbiota transplantation (FMT). Although it is associated with high rates of efficacy, FMT involves the transfer of minimally processed, uncharacterized fecal material from a healthy donor to a recipient, which can be invasive and complicated. Therefore, recent research has focused on identifying alternative approaches with comparable efficacy, improved safety, and a greater degree of convenience.

Khanna and colleagues sought to test, "...the hypothesis that spore-forming organisms would compete metabolically with C. difficile for essential nutrients and/or bile acids." To accomplish this, they used an experimental compound formulated for oral delivery in humans referred to as SER-109, which contains roughly 50 species of Firmicutes spores obtained from healthy donor stool specimens. In an explanation of the purpose and aims of the study, Khanna et al stated, "This initial study was designed to evaluate the efficacy and safety profile of SER-109 for CDI prevention in patients with recurrent infections and to measure alterations in the gut microbiota." Importantly, the healthy donor specimens were treated with ethanol to eliminate pathogens for enhanced safety.

The study enrolled 30 patients, the majority of whom were female (67%), with a median age of 66.5 years. All patients had a clinical response to antibiotic therapy for their current CDI episode immediately prior to dosing with either of two regimens. The first 15 patients received SER-109 on two consecutive days (geometric mean dose, 1.7 × 10⁹ spores). Based on encouraging results, the next 15 patients to enroll were treated for only one day with a lower fixed-dose (geometric mean dose, 1.1 × 10⁸ spores). Treatment efficacy was defined as an absence of C. difficile—positive diarrhea during an 8-week follow-up period. Additionally, Khanna et al assessed treatment-related alterations in the gut microbiomes of all patients.

Treatment with SER-109 was considered to be effective in 13 of the 15 patients from each dosing regimen group (86.7%). One patient discontinued, and three were considered to have early, self-limiting C. difficile—positive diarrhea during the study, only to have it resolve without the use of antibiotics by the end of the study. Therefore, treatment with SER-109, regardless of dosing regimen, was found to be effective in 29 of the 30 included patients (96.7%).

Adverse events considered to be treatment-related included mild diarrhea, abdominal pain, and nausea. They were noted in half of all patients, and according to Khanna, "...were mild or moderate in severity and did not differ significantly by dosing group."

As for gut microbiota remodeling, microbial diversity of a level resembling that of healthy individuals not only occurred rapidly during the study, but also exhibited durability up to 24 weeks after treatment.

In summarizing the results of their research, Khanna et al state, "Promising results from this initial study support further development of SER-109 as a novel biologic agent that restores the gut microbiome as a primary defense against potential pathogens, such as C. difficile." It is difficult to argue with this assertion based on the data; however, larger placebo-controlled studies will be necessary to confirm these preliminary results.

William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.

References

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4. Lessa FC, Gould CV, McDonald LC. Current status of Clostridium difficile infection epidemiology. Clin Infect Dis 2012;55: Suppl 2: S65-S70.
5. Zimlichman E, Henderson D, Tamir O, et al. Health care-associated infections: a meta-analysis of costs and financial impact on the US health care system. JAMA Intern Med 2013; 173: 2039-46.
6. Rupnik M. Is Clostridium difficile-associated infection a potentially zoonotic and foodborne disease? Clin Microbiol Infect 2007; 13: 457-9.