Experts Review C Diff Treatment Options for Special Patient Populations, Future Treatments in Development

During a presentation at the American Society of Health-System Pharmacists 2021 Midyear conference, the panelists reviewed current treatments for Clostridioides difficile infection (CDI) and how they can be applied to special patient populations, as well as what treatments can be expected in the future.

According to the panelists, fidaxomicin may be preferred over vancomycin for patients with primary non-severe CDI, as well as in certain other patients with CDI. Additionally, bezlotoxumab reduces the risk of recurrence in high-risk patients with CDI.

Fidaxomicin is a narrow spectrum, macrocyclic antibiotic which inhibits RNA polymerase and spore formation; it has been compared to vancomycin in 4 clinical trials. Efficacy endpoints in these trials include clinical cure (defined as a resolution of diarrhea and no need for further CDI antibiotic therapy at day 12), CDI recurrence, and sustained clinical response (defined as clinical cure without CDI recurrence).

“What you’ll notice is that the rates [of clinical cure at day 12] are very similar between the 2 groups, with no statistical differences,” said Travis Carlson, PharmD, BCIDP, assistant professor at High Point University, during the presentation. “However, if you look at the rate of CDI recurrence between the 2 groups, you’ll notice that in 3 of these 4 clinical trials, recurrence rate in those that received fidaxomicin was significantly lower than in the vancomycin arm, with absolute rate reductions between 10% and about 14%, corresponding to numbers needed to treat between 8 and 11.”

In terms of which patients should receive fidaxomicin over vancomycin, the panelists recommend that patients with primary non-severe CDI should always receive fidaxomicin, while those with severe CDI or their first recurrence would probably benefit from fidaxomicin. They found it was currently unclear whether patients with their second CDI recurrence or hospitalized patients under the age of 65 years should receive fidaxomicin.

Carlson then reviewed bezlotoxumab, a fully human monoclonal antibody that neutralizes C. difficile toxin B. The drug is being studied as an adjunctive treatment along with standard-of-care antibiotic therapy.

Two studies reviewed the use of bezlotoxumab in combination with an antibiotic: MODIFY I and MODIFY II. Both trials had CDI recurrence as their primary outcome, with efficacy endpoints including clinical cure (defined as no diarrhea for 2 consecutive days following 16 days or fewer of CDI antibiotic therapy), CDI recurrence, and sustained clinical response.

Examining the results of these 2 trials, the American College of Gastroenterology (ACG) and the Infectious Diseases Society of America along with the Society for Healthcare Epidemiology of America (IDSA/SHEA) came to different conclusions on who should receive bezlotoxumab. The ACG guidelines suggest that bezlotoxumab can be considered in patients aged 65 years or older with 1 or more risk factors, including previous CDI episode within the past 6 months, severe CDI, or immunocompromised status. On the other hand, IDSA/SHEA recommended bezlotoxumab for patients with a previous CDI episode within the last 6 months, and can be considered in patients with primary CDI and 1 or more risk factors, including an age of 65 years or older, severe CDI, and immunocompromised status.

“Even though both guideline committees were considering these same data, you might be asking yourself, ‘why did they come to different conclusions?’” Carlson said. “Perhaps the ACG felt that age really was that important of a risk factor, and so they felt that you have to be aged greater than 65 and have 1 additional risk factor.”

The panel also discussed future treatments in development for CDI. Ridinilazole and MGB‐BP‐3 are both novel oral antibiotics taken twice daily; ridinilazole has finished recruiting for a phase 3 trial, whereas MGB‐BP‐3 has completed phase 2a. Additional twice-daily oral antibiotics in development include ibezapolstat, a DNA polymerase 3C inhibitor recruiting for a phase 2b trial, and CRS3123, a type 1 methionyl‐tRNA synthetase inhibitor currently recruiting for a phase 2 trial. Finally, the intravenous protein synthesis inhibitor DNV3837, delivered in 1.5 mg/kg over 6 hours each day for 10 days, is currently recruiting for phase 2 trials.

“[DNV3837] is a pro-drug administered intravenously,” Carlson said. “The downside is, it’s administered as a continuous infusion over 6 hours each day for 10 days. But assuming that it makes it through phase 2 and phase 3 clinical trials, it will be the first FDA-approved IV antibiotic used to treat C. diff infection.”

REFERENCE

Carlson T, Alonso C. Applying the guidelines on recurrent Clostridioides difficile infection in special patient populations. Presented at: ASHP Midyear 2021. Accessed December 6, 2021.