Microbiota-Based Therapeutic May Reduce Clostridioides Difficile Infection Recurrence

A new report suggests microbiota-based therapeutics could help prevent drug-resistant infections and lead to lasting alterations in patients’ gut microbiota.

This study, published in Genome Medicine, could potentially offer the first effective strategy of preventing or decreasing colonization by antibiotic-resistant bacteria.

The authors noted that antibiotic resistance continues to be a pressing problem globally, as antibiotic overuse has sparked increases in antibiotic-resistant organisms (AROs) and antibiotic-resistant genes (ARGs) in individuals and in the environment.

“Even when appropriately delivered, antibiotics disrupt the commensal gut microbiota, select for antibiotic resistance, and decrease colonization resistance to AROs and opportunistic pathogens,” they wrote.

The use of antibiotics can make a person more susceptible to Clostridioides difficile infection, while at the same time, the primary treatment for C diff infection, vancomycin or metronidazole, can disrupt the microbiome and increase a patient’s risk for recurrent infection, the authors said.

In hopes of addressing the problem, the authors constructed a study of RBX2660, a microbiota-based investigational therapeutic consisting of a liquid formulation of donor microbiota screened for pathogens. They wanted to understand how the treatment affects the gut microbiota and resistome, as well as whether such changes might impact multidrug-resistant organisms in patients with recurrent C diff infection.

The trial involved 11 health care centers and 29 patients with recurrent CDI. Stool samples were collected from each patient, and then each patient was given either 1 dose (n = 16) or 2 doses (n = 13) of RBX2660. After 6 months, a second sample was taken and analyzed using 16S rRNA gene sequencing, whole metagenome shotgun sequencing, and selective and differential bacterial culturing followed by isolate genome sequencing.

The analysis showed that the microbiota restoration treatment succeeded in reducing both ARO and ARG carriage. C diff recurrence varied among the patients and correlated with the convergence of patient microbiota to the donor microbiota, the investigators said.

Twelve patients did not see a recurrence of C diff infection after receiving 1 dose. The other 17 had recurrences between days 7 and 60. Those patients then received a second dose of RBX2660 and/or antibiotics.

“These data demonstrate that in successful first treatments, the overall patient microbiota profile shifts quickly to resemble the donors after the study treatment,” the authors wrote. “However, convergence is never absolute for these patients during the length of the study…”

The authors wrote that the abundance of antibiotic-resistant Enterobacteriaceae fell dramatically in the 2 months following administration of the therapy and fecal ARG carriage decreased “in direct relationship to the degree to which donor microbiota engrafted.”

A subsequent study is warranted, they said, in which results in patients with the intervention can be compared with a placebo group. The current study was open label without a control arm.

Dubberke and colleagues concluded that their study suggests microbial therapeutics can be an effective tool to alter patients’ gut community composition.

“The abundance of ARGs and AROs can potentially be lastingly reduced with this method,” they wrote, “making it a promising tool in combating the global threat of antibiotic resistance.”

Reference

Langdon A, Schwartz DJ, Bulow C, et al. Microbiota restoration reduces antibiotic-resistant bacteria gut colonization in patients with recurrent Clostridioides difficile infection from the open-label PUNCH CD study. Genome Med. Published online February 16, 2021. doi:10.1186/s13073-021-00843-9