The Pre-brief
- Clostridioides difficile is a gram-positive anaerobic bacillus that produces spores as well as exotoxins, toxin A and toxin B.
- Clostridioides difficile infection (CDI) accounts for 15-25% of all antibiotic-associated diarrhea and is one of the most common healthcare-associated infections in the United States.
- In 2017, there were an estimated 223,900 cases in hospitalized patients and 12,800 deaths in the United States.
- CDI is defined by the presence of symptoms and either a stool test positive for C. difficile toxins or colonoscopic findings demonstrating characteristic pseudomembranous colitis.
- Hallmark clinical symptoms include watery diarrhea, fever, loss of appetite, nausea, and abdominal pain.
- If left untreated, CDI may progress to pseudomembranous colitis, toxic megacolon, bowel perforation, sepsis, and death.
- Risk factors for CDI include antibiotic exposure (especially with fluoroquinolones, third or fourth-generation cephalosporins, clindamycin, and carbapenems), gastrointestinal surgery, prolonged stays in healthcare settings, immunocompromised states or illness, and advanced age.
- Inappropriate antibiotic prescribing is a major target of antimicrobial stewardship interventions to reduce the risk of CDI development.
- It is estimated that greater than 50% of hospitalized patients are prescribed antibiotics during a hospital stay, and 30-50% of antibiotic use in hospitalized patients is unnecessary or incorrect.
Guideline updates
Recently, the 2021 focused update on the management of CDI was published by the Infectious Disease Society of America (IDSA) and the Society of Healthcare Epidemiology of America (SHEA).
What’s different in this new guideline compared to the 2017 update? For starters, the pathogen was renamed from Clostridium to Clostridioides difficile. And if that isn’t enough syllables, wait until we discuss fidaxomicin and bezlotoxumab!
Fidaxomicin
Fidaxomicin is a narrow-spectrum, macrolide antibiotic that has minimal systemic absorption or activity against normal bowel flora. Phase III clinical trials demonstrated that fidaxomicin was non-inferior to oral vancomycin to achieve clinical response in the management of initial CDI. However, fidaxomicin was shown to reduce recurrent CDI infections compared to oral vancomycin. Ultimately, it received FDA approval for CDI in 2011, but the steep cost led many clinicians to continue prescribing the tried-but-true, oral vancomycin. The 2017 IDSA and SHEA CDI guidelines ultimately recommended either oral vancomycin or fidaxomicin for management of initial CDI.
However, an updated pooled analysis included in the 2021 guideline indicates that fidaxomicin increased CDI sustained response 4 weeks after the end of therapy for initial CDI compared to standard oral vancomycin (RR 1.16, 95% CI 1.09-1.24), although there was a comparable clinical cure (RR 1.00, 95% CI 0.96-1.04) and failure to show a reduction in mortality (RR 0.90, 95% CI 0.66-1.23). Similar findings were seen in patients with recurrent CDI based on a pooled analysis from 3 studies. Fidaxomicin resulted in increased sustained response 30 days after end of therapy compared to vancomycin (RR 1.27, 95% CI 1.05-1.54), but there was no significant difference in sustained response at 90 days, CDI clinical cure, and all-cause mortality. Interestingly, sustained response with fidaxomicin at 30 days was higher in patients having 2 or more prior recurrences (RR 2.0, 95% CI 0.88-4.54) than with 1 prior recurrence (RR 1.23, 95% CI 1.01-1.49) compared to vancomycin. Therefore, the 2021 CDI-focused update now prefers fidaxomicin when resources are available over other treatment options. However, the guidelines do acknowledge oral vancomycin is still an acceptable alternative.
While the cost of a fidaxomicin treatment regimen remains high (~$245/tablet, total cost of 10-day treatment ~$4900), it’s important to compare it to oral vancomycin. While hospitals would historically compound oral vancomycin solution from the IV product to keep cost low (total treatment cost <$5), the commercially available oral vancomycin capsules (~$100/capsule, total treatment cost ~$4000) would need to be prescribed at discharge. Due to the high cost of oral vancomycin, discharge planning would often be complicated by insurance coverage and prior authorizations. Given the recent literature supporting use of fidaxomicin over oral vancomycin for CDI, many insurance companies have opted to cover this preferred treatment which is an important aspect of discharge planning.
Bezlotoxumab
Bezlotoxumab is a humanized monoclonal antibody against C. difficile toxin B. With a half-life of 18 days, adequate antibody concentrations remain 3 months after a single infusion. In 2016, bezlotoxumab received FDA approval for prevention of recurrent CDI in high-risk adults when given with standard antimicrobial therapy.
Analysis of pooled data from two phase III clinical trials demonstrated that bezlotoxumab reduced CDI recurrence after initial clinical cure at 12 weeks (RR 0.62, 95% CI 0.51-0.75) and evidence) and CDI-associated readmission at 30 days (RR 0.46, 95% CI 0.29-0.71), although it did not reduce mortality compared to placebo. The effect of bezlotoxumab was evaluated in patients with risk factors for recurrent CDI including age ≥65 years, history of CDI, immunocompromised state, severe CDI, and infection with hypervirulent strain. Overall, recurrent CDI increased based on the number of risk factors. However, bezlotoxumab resulted in significant reductions in recurrent CDI rates in patients with ≥3 risk factors (RR -24.8%, 95% CI -39.1% to -9.3%), 2 risk factors (RR -14.2%, 95% CI -24.0% to -4.1%), or 1 risk factor (RR -14.2%, 95% CI -21.9% to -6.4%), compared to patients without risk factors (RR -2.1%, 95% CI -11.1 to 6.9%).
Importantly, bezlotoxumab may increase the risk of death in patients with heart failure and should not be routinely used in this population.
The Debrief
- CDI accounts for significant morbidity and mortality as it is one of the most common healthcare-associated infections in the United States.
- Antimicrobial stewardship initiatives aimed at reducing inappropriate antimicrobial prescribing play an important role in reducing the risk of CDI.
- While oral vancomycin therapy has been a mainstay of CDI treatment for years, fidaxomicin has been shown to reduce recurrent CDI infections compared to oral vancomycin.
- Updated guidelines place preference on the use of fidaxomicin over vancomycin for treatment of CDI.
- While cost was historically a barrier to use with fidaxomicin, many insurance companies have expanded coverage due to the recent literature and guideline updates.
- Bezlotoxumab when given as adjunctive therapy to standard antimicrobial treatment significantly reduces the risk of recurrent CDI in high-risk patients and should be considered for those with prior CDI within 6 months.
References
- Information for healthcare professionals about C. diff. Centers for Disease Control and Prevention. Accessed 25 October 2021: https://www.cdc.gov/cdiff/clinicians/index.html
- Johnson S, Lavergne V, Skinner AM, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021; 73(5):e1029-e1044.
- McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018; 66(7):e1-e48.
