Contemporary Strategies for Reducing the Risk of Recurrent C difficile Infection

Princy N. Kumar, MD, FIDSA, MACP

Professor of Medicine and Microbiology
Division of Infectious Diseases and Travel Medicine
Senior Associate Dean of Students
Georgetown University School of Medicine
Washington, DC

Princy N. Kumar, MD, MACP, has disclosed that she has received funds for research support from Merck and Seres Therapeutics.

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Released: December 14, 2018

Clostridioides difficile (formerly Clostridium difficile) is the most common cause of infectious diarrhea in hospitalized patients and has maintained a largely steady prevalence despite overall healthcare-associated infections decreasing from 2011 to 2015. Approximately 25% of patients who develop an initial C difficile infection (CDI) will experience recurrent CDI, with approximately 40% of those experiencing a second recurrence. In this commentary, I discuss my approaches to reducing recurrence of CDI.

Prior to CDI
Several general strategies may be implemented in healthcare settings to reduce the risk of CDI. The 2017 IDSA-SHEA guidelines recommend that hospitalized patients with CDI be placed in a private room to prevent infection of other patients. In addition, healthcare personnel should use gloves and gowns whenever they come in contact with infected patients. Appropriate hand hygiene—which includes washing hands with soap and water and not just alcohol foam—is also essential.

Antibiotic use can lead to disturbed colonic microbiota, increasing the risk of C difficile colonization. The 2017 IDSA-SHEA guidelines recommend appropriate antimicrobial stewardship as a preventive measure to reduce CDI risk.

The use of probiotics for prevention of CDI is debated, and the 2017 IDSA-SHEA guidelines state that there are currently insufficient data to recommend probiotics for primary prevention of CDI. However, several large meta-analyses have suggested that probiotic use may reduce the risk of CDI in those at high risk for infection.

Choice of Initial Therapy for CDI
For patients with a nonsevere or severe initial CDI, the 2017 IDSA-SHEA guidelines recommend treatment with either vancomycin or fidaxomicin. In a double-blind phase III trial in which 629 patients with CDI were randomized to receive fidaxomicin or vancomycin, fidaxomicin treatment was associated with a significant decrease in initial CDI recurrence vs vancomycin treatment (recurrence rates of 15.4% vs 25.3%, respectively; P = .005) It should be noted, however, that this decrease was seen mainly in patients with non–North American Pulsed Field type 1 (NAP1) strains. Testing for C difficile strains is not available in many laboratories, suggesting that additional strategies may be needed in everyday practice to further aid in the prevention of recurrence.

Targeted Agents for Prevention of CDI
In October 2016, the FDA approved bezlotoxumab—a human monoclonal antibody that binds C difficile toxin B—to reduce CDI recurrence in patients who are receiving antibacterial treatment for CDI and are at high risk for recurrence. The approval of bezlotoxumab was based on 2 randomized, double-blind phase III trials: MODIFY I and MODIFY II. A combined 2655 adults with primary or recurrent CDI received oral standard-of-care antibiotics and were randomized to receive a single infusion of actoxumab (an investigational monoclonal antibody to toxin A) plus bezlotoxumab, bezlotoxumab alone, or placebo.

The rate of recurrent infection was significantly lower in both of the groups that received bezlotoxumab vs placebo (actoxumab plus bezlotoxumab: 15%; bezlotoxumab alone: 17%; placebo: 27%; both study groups P < .001 vs placebo). The rate of sustained cure—defined as initial cure without recurrent infection in 12 weeks—was 58% with actoxumab plus bezlotoxumab, 64% with bezlotoxumab, and 54% with placebo. The rate and pattern of adverse events was similar across these groups.

Of importance, a post hoc analysis assessed bezlotoxumab efficacy in participants with factors placing them at increased risk for recurrent CDI (older than 65 years of age, history of CDI, immunocompromise, severe CDI, ribotype 027/078/244). This analysis reported that, as might be expected, recurrence of CDI increased with the number of risk factors; among individuals with 0 risk factors, the recurrence rate was 20.9%; with 1 risk factor, 31.3%; with 2 risk factors, 41.1%; and with ≥ 3 risk factors, 46.1%. Bezlotoxumab significantly reduced the rate of recurrent CDI among those with risk factors (1 risk factor, recurrence rate of 17.1%; 2 risk factors, 26.9%; and ≥ 3 risk factors, 21.2%). Moreover, bezlotoxumab also reduced the rate of subsequent fecal microbial transplantations and CDI-associated 30-day readmissions in participants with ≥ 1 risk factor for recurrent CDI. These data illustrate the benefit of adding bezlotoxumab to antibacterial therapy for preventing CDI recurrence. Patients with 1-2 CDI risk factors can benefit from bezlotoxumab along with standard-of-care antibiotics, but patients with ≥ 3 risk factors may gain the greatest benefit.

Emerging Strategies
There are several areas of study into effective prevention of CDI. One of the most interesting involves the administration of nontoxigenic C difficile spores. In a recent phase II study, 173 patients who had been successfully treated for initial or recurrent CDI were randomized to receive an oral liquid formulation of nontoxigenic C difficile spores or placebo. CDI recurrence (within 6 weeks) was observed in 30% of patients receiving placebo vs 11% of patients receiving spores (odds ratio: 0.28; P = .006), suggesting the potential efficacy of this approach.

Another strategy involves restoration of the intestinal microbiota. In a recent phase IIB trial, 120 patients who had been treated for recurrent CDI were randomized to 1 of 2 doses of enema with RBX2660 (a suspension of intestinal microbes) or placebo. CDI recurrence (within 8 weeks) was significantly reduced with 1 of the doses of RBX2660 vs placebo; this strategy is now being assessed for CDI prevention in a phase III trial.

Your Thoughts
What strategies do you employ to reduce CDI recurrence? Please answer the polling question on your screen and share your thoughts in the comments box.

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