Expert Perspectives on Advances in the Management of Clostrioides difficile: Bezlotoxumab and Unmet Needs

When used in conjunction with antibiotic therapy, bezlotoxumab (Zinplava) has shown promising efficacy in reducing recurrence of Clostridioides difficile infection (CDI) in patients who are at high risk for recurrence, but the high cost of the therapy limits widespread use in clinical practice, according to infectious disease experts who participated in a Contagion® Peer Exchange panel moderated by Peter L. Salgo, MD. Teena Chopra, MD, MPH, concluded the panel with an overview of the need for microbiome- and metabolome-sparing treatments for recurrent CDI.

C difficile Treatment: Bezlotoxumab

Bezlotoxumab, an intravenously administered human monoclonal antibody that binds to C difficile toxin B, was approved as an adjunct to antibacterial drug treatment for patients at least 18 years of age who are at high risk for recurrent CDI.1 This approval was supported by data from the MODIFY I and II trials (NCT01241552 and NCT01513239, respectively), which showed that the rate of recurrent CDI was significantly lower with bezlotoxumab than it was with placebo (MODIFY I: 17% vs 28%; adjusted difference, –10.1 percentage points; 95% CI, –15.9 to –4.3; P < .001. MODIFY II: 16% vs 26%; adjusted difference, –9.9 percentage points; 95% CI, –15.5 to –4.3; P < .001).2 Bezlotoxumab plus actoxumab, a human monoclonal antibody targeting C difficile toxin A, was also associated with lower rates of recurrent CDI than placebo (MODIFY I: 16% vs 28%; adjusted difference, –11.6 percentage points; 95% CI, –17.4 to –5.9; P < .001. MODIFY II: 15% vs 26%; adjusted difference, −10.7 percentage points; 95% CI, –16.4 to –5.1; P < .001), but the addition of actoxumab did not improve efficacy over bezlotoxumab alone.2

“[Bezlotoxumab’s] sole purpose is to reduce the recurrence rate,” said Dale N. Gerding, MD.

Gerding was the first author on a post hoc analysis of participants in the MODIFY I and II trials, which analyzed the efficacy of bezlotoxumab in patients with risk factors for recurrent CDI, including aged 65 years or older, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244.3

“The target [of this study] was to determine which patient is most likely to respond to the use of bezlotoxumab in terms of having a significant reduction in recurrence,” said Gerding.

Among the participants who received placebo and achieved an initial clinical cure, more than 30% of participants within each of the prespecified risk groups had recurrent CDI during the 12-week follow-up period, and the proportion of patients who had a recurrence increased with an increasing number of risk factors (from 20.9% among patients with no risk factors to 46.1% among patients with 3 or more risk factors).3 Bezlotoxumab was associated with lower rates of recurrent CDI than placebo for all of the prespecified groups, with a statistically significant difference in all except the ribotype 027/078/244 subgroup (aged 65 years or older, 19.3% vs 39.4%; history of CDI, 31.6% vs 49.5%; immunocompromised status, 19.0% vs 36.0%; severe CDI, 15.9% vs 31.5%; ribotype 027/078/244, 28.2% vs 41.1%).3 Furthermore, treatment with bezlotoxumab reduced rate of recurrent CDI among patients with at least 1 risk factor (relative reductions 45.3%, −34.5%, and −53.9% for patients with 1, 2, and 3 or more risk factors, respectively).3 Of the patients with no risk factors, the proportion with recurrent CDI was similar between the bezlotoxumab and placebo groups (18.8% and 20.9%, respectively).3

“The significant takeaway is that if patients did not have any of these risk factors…they did not appear to benefit from bezlotoxumab in terms of lowering [the recurrence rate] any further,” said Gerding. “We now know that if patients have any of these risk factors, and particularly if they have multiple risk factors, that [they] have a high risk for recurrence, and the likelihood is very high that they’re going to respond to bezlotoxumab.”

Joseph Reilly, PharmD, added that reductions in recurrence for patients at high risk for recurrence are clinically significant, but cost continues to be a major barrier to widespread uptake. “This is another treatment option that seems to significantly decrease recurrences, which we should certainly be concerned about; it decreases the recurrences in patients who had CDI. Similar to fidaxomicin, the number needed to treat in MODIFY I and II was about 10…but if we target certain patients, like patients over the age of 65 years or those that had a prior history of CDI in that study, that number dropped to about 6. It’s an impactful treatment option. Cost seems to be a barrier for using this drug.”

Thomas Lodise, PharmD, PhD, added that whether bezlotoxumab should be used with fidaxomicin, another high-cost drug, remains an unanswered question because the combination may be cost-prohibitive. Data from the MODIFY I and II trials showing that only 4% of participants received fidaxomicin2 strongly suggests that cost is a key barrier to access, according to Lodise. Lodise added that most of the data on fidaxomicin and bezlotoxumab are from patients who have had only a single recurrence, and whether these data can be extrapolated to patients with multiple recurrences is currently unclear, especially because such a small proportion of patients in the MODIFY trials used fidaxomicin with bezlotoxumab. “How do you support the argument for using 2 [premium-]priced agents [when] only 50 people received fidaxomicin in the MODIFY trials?” he said.

Preventing/Treating C difficile Unmet Needs

At the conclusion of the panel, Teena Chopra, MD, MPH, said that the lack of effective treatment options for recurrent CDI remains a big gap in the research. “C difficile remains an urgent threat to public health in general, and we want newer treatments that are targeted toward the microbiome and are microbiome-sparing,” she said. She also stressed the importance of colonization sparing in the microbiome when treating recurrent CDI and how the newer therapies such as fecal transplantation are generally better in that respect than conventional treatments. “Newer therapies that are sparing the microbiome are definitely much better,” she said. “We want to make sure that we have a lot of diversity in our gut microbiome, and this diversity decreases as we age.”

Chopra added that the diversity in the gut microbiome is low in patients with recurrent CDI and may reach “a point of no return” in which the microbiome is unable to overcome the colonization, and additional therapies are urgently needed for this subset of patients.

The metabolome is also thought to be affected by CDI, according to Chopra. One study of a mouse model of CDI showed that carbohydrates and amino acids, particularly proline and the branched-chain amino acids, decrease throughout colonization and infection, and C diff gene expression was consistent with the utilization of these nutrients.4 Another study showed that had a significant effect on the metabolic environment in the guts of mice pretreated with cefoperazone or streptomycin, and metagenome-enabled metatranscriptomics showed that infected animals had reductions in transcripts for genes associated with carbon and energy acquisition (which suggests that the niches were occupied by C difficile), with the largest changes observed in the least abundant species.5 According to the study authors, the results suggest that C difficile promotes persistent infection by restructuring the nutrient-niche landscape.5 Chopra concluded that the changes in the gut metabolome that occur with recurrent CDI is an area that needs further research.

Moderator

Peter L. Salgo, MD
Columbia University Irving Medical Center
New York, New York

Panelists

Teena Chopra, MD, MPH
Wayne State University School of Medicine
Detroit, Michigan

Paul Feuerstadt, MD
Yale New Haven Hospital
New Haven, Connecticut

Dale N. Gerding, MD
Edward Hines Jr Veterans Affairs Hospital
Chicago, Illinois

Thomas Lodise, PharmD, PhD
Albany College of Pharmacy and Health Sciences
Albany, New York

Joseph Reilly, PharmD
AtlantiCare Regional Medical Center
Galloway, New Jersey

References

^{1. Zinplava. Prescribing information. Merck Sharp & Dohme Corp. Updated October 2016. Accessed August 8, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761046s000lbl.pdf}

^{2. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317. doi:10.1056/NEJMoa1602615}

^{3. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence. Clin Infect Dis. 2018;67(5):649-656. doi:10.1093/cid/ciy171}

^{4. Fletcher JR, Erwin S, Lanzas C, Theriot CM. Shifts in the gut metabolome and Clostridium difficile transcriptome throughout colonization and infection in a mouse model. mSphere. 2018;3(2):e00089-18. doi:10.1128/mSphere.00089-18}

^{5. Jenior ML, Leslie JL, Young VB, Schloss PD. Clostridium difficile alters the structure and metabolism of distinct cecal microbiomes during initial infection to promote sustained colonization. mSphere. 2018;3(3):e00261-18. doi:10.1128/mSphere.00261-18}