Changes on horizon may help lessen C. difficile burden
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The COVID-19 pandemic underscored challenges in the prevention and treatment of health care-associated infections (HAIs).
Workforce and supplies shortages, combined with higher patient censuses, contributed to an increase in HAIs in the United States in 2021 after years of declines. However, Clostridioides difficile infections showed steady improvement with a slight decrease in the standardized infection ratio (SIR) across acute-care sites, representing a 50% reduction in the SIR when compared with 2015.
C. difficile remains a major threat to patient safety, with 118,713 infections among hospitalized patients in 2021 —more than twice as many as ventilator-associated events, the next leading HAI. Listed as an urgent threat in the CDC’s 2019 report on antibiotic resistance threats in the U.S., nearly 20% to 25% of patients will experience a recurrent C. difficile infection, necessitating the need for novel prevention and treatment strategies.
Nonpharmacological strategies
Infection prevention is at the forefront of efforts to reduce all HAIs, although it is especially prominent in minimizing C. difficile transmission. Harmonizing these interventions is a tough task given the broad array of C. difficile risk factors, such as recent antibiotic exposure, immunosuppression, gastric acid suppression, advanced age and hospitalization.
Nonpharmacological prevention strategies include isolating and initiating contact precautions for suspected or confirmed C. difficile infections while ensuring proper hand-washing adherence and using dedicated patient equipment. It is crucial to create sound environmental cleaning practices and infrastructure, along with optimal testing algorithms to confirm active infection.
Some health systems have implemented universal screening to determine C. difficile colonization status in an effort to lessen nosocomial transmission in asymptomatic patients.
Incorporating clinical decision support tools to enhance diagnostic stewardship when patients are not having a high frequency of loose stools (ie, three or more daily) and/or on laxative therapy can assist in delineating infection vs. colonization and promote avoidance of retesting to confirm cure.
Adding to all nonpharmacological methods is judicious antimicrobial use, stemming from a multipronged antimicrobial stewardship approach.
Fidaxomicin vs. vancomycin
Currently, pharmacological treatment strategies for C. difficile infection are largely driven by medication costs. The Infectious Diseases Society of America, Society of Healthcare Epidemiology of America and American College of Gastroenterology recommend fidaxomicin (preferred in IDSA/SHEA guidelines) or enteral vancomycin for nonsevere and severe C. difficile infections, with high-dose enteral vancomycin and IV metronidazole reserved for fulminant disease.
Recent data support fidaxomicin — a macrolide with minimal systemic absorption and a prolonged postantibiotic effect — being associated with similar cure and lower recurrence rates compared with vancomycin. Despite lower associated recurrence rates, fidaxomicin has not been widely adapted because of prohibitive costs and inconsistent outpatient insurance coverage.
Cost analysis studies have demonstrated that high costs associated fidaxomicin acquisition may be offset by fewer recurrent episodes and hospitalizations. Given the economic burdens many health systems are facing, careful evaluation of risk factors for C. difficile recurrence will help balance fidaxomicin’s upfront costs while maximizing combined HAI efforts.
Both agents are here to stay, but the inclusion of novel preventive therapies is forging changes in overall therapy tactics.
New strategies
Several new adjunctive therapies have shown efficacy in preventing C. difficile recurrence. The oldest of the these is bezlotoxumab, a humanized IgG1 monoclonal antibody that binds to and neutralizes C. difficile toxin B.
Bezlotoxumab is administered as a one-time, weight-based dose and is eliminated via catabolism. Two phase 3 multicenter, double-blind, placebo-controlled trials — MODIFY I and II — examined the efficacy and safety of a single bezlotoxumab dose administered during 10 to 14 days of standard-of-care treatment compared with placebo. Combined study results showed a 40% relative reduction in recurrent infection with bezlotoxumab alone than with placebo, not affecting clinical cure rates.
Nearly half of patients were receiving metronidazole as standard-of-care treatment and very few received fidaxomicin, lessening generalizability to current guideline recommendations.
Bezlotoxumab should be used cautiously in those with underlying congestive heart failure because an unexplained increased risk of heart failure exacerbations was observed.
Bezlotoxumab administration tends to be deferred to the outpatient setting given associated costs and limited cost-effectiveness data.
Commercial fecal microbiota transplant products are also making headway. In December, Rebyota became the first FDA-approved microbiota-based live biotherapeutic product for recurrent C. difficile prevention. Rebyota is manufactured from human fecal matter, which is sourced from qualified donors and has been screened for transmissible pathogens. It is rectally administered in a single dose (150 mL) in adult patients within 24 to 72 hours after antibiotic treatment completion in the outpatient clinic. Most common adverse effects seen in safety trials were gas, nausea, diarrhea and abdominal bloating.
In a randomized, double-blind, placebo-controlled study, 177 patients received Rebyota and 85 received a placebo. The primary endpoint was treatment success, defined as the absence of C. difficile diarrhea for 8 weeks after completing study treatment.
The estimated rate of success in preventing recurrent C. difficile was 70.6% in the Rebyota group vs. 57.5% who received placebo. Further analyses of high-risk patients, including immunocompromised, are ongoing.
Further evaluation of Rebyota vs. bezlotoxumab is needed. Rebyota poses challenges in patients who are hospitalized for longer than 72 hours after antibiotic treatment is completed, whereas the cost and insurance coverage is difficult to elucidate presently.
In April, Vowst became the first and only FDA-approved orally administered microbiota-based therapeutic, containing purified firmicutes spores resistant to gastric acid, for recurrent C. difficile prevention as four capsules taken daily for 3 consecutive days within 2 to 4 days after completion of antibiotic treatment. In addition, patients are instructed to drink magnesium citrate (296 mL) on the day before and at least 8 hours before the first dose. The most common side effects are abdominal bloating, fatigue, constipation, chills and diarrhea.
Vowst’s effectiveness was investigated in a randomized, placebo-controlled trial of 89 patients who received Vowst and 93 patients who received a placebo. Through 8 weeks after treatment, C. difficile recurrence in the Vowst cohort was lower (12.4% vs. 39.8%). Vowst provides another option in our arsenal for combatting challenges associated with C. difficile.
Change on the horizon
More change is on the horizon to help lessen the C. difficile burden. With all HAIs, a collaborative and synchronized approach is warranted for decreasing and sustaining low HAI rates.
Although there has been a steady downtrend in C. difficile, there is great opportunity for improvement. Exciting new therapies that aid in gut microbiome restoration and show promise in prevention of C. difficile recurrence will require thorough evaluation and mindful coordination across many care settings.
The times of extended enteral vancomycin tapers for recurrent infection may be dwindling as a new synergism in C. difficile prevention and treatment is found.
References:
- CDC. Antibiotic resistance and patient safety portal – C. difficile infections. https://arpsp.cdc.gov/profile/nhsn/cdi. Accessed May 15, 2023.
- CDC. Antibiotic resistance threats in the United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Revised December 2019. Accessed May 15, 2023.
- CDC. Current HAI progress report. https://www.cdc.gov/hai/data/portal/progress-report.html. Accessed May 15, 2023.
- Collison M, et al. Infect Control Hosp Epidemiol. 2021;doi:10.1017/ice.2020.428.
- FDA approves first fecal microbiota product. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product. Published Nov. 30, 2022. Accessed May 31, 2023.
- FDA approves first orally administered fecal microbiota product for the prevention of recurrence of Clostridioides difficile infection. https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides. Published April 26, 2023. Accessed May 31, 2023.
- Johnson S, et al. Clin Infect Dis. 2021;doi:10.1093/cid/ciab549.
- Kelly CR, et al. Am J Gastroenterol. 2021;doi:10.14309/ajg.0000000000001278.
- Magill SS, et al. N Engl J Med. 2018;doiL10.1056/NEJMoa1801550.
- Rajasingham R, et al. Clin Infect Dis. 2020;doi:10.1093/cid/ciz318.
- Rebyota [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; 2023.
- Vowst [package insert]. Cambridge, MA: Seres Therapeutics, Inc.; 2023.
- Wilcox MH, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1602615.
- Zinplava [package insert]. Whitehouse Station, NJ: Merck.; 2016.
Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
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