Updated C. Difficile Infection Guidelines Incorporate New Trials

Clostridioides difficile is a gram-positive, spore-forming, toxin-producing anaerobic bacterium that causes antibiotic-associated diarrhea.^1,2

C.difficile infection (CDI) may occur when the human intestinal tract is disrupted by broad-spectrum antibiotics.1,2 Certain antibiotic agents, such as clindamycin, fluoroquinolones, and some cephalosporins, are known to have the highest risk of causing antibiotic-associated diarrhea.³ Depending on the host, the infection can range from being asymptomatic to life-threatening C. difficile colitis.1,2 Untreated CDI can lead to serious complications, including death, perforations of the colon, pseudomembranous colitis, sepsis, and toxic megacolon.⁴

The Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America began updating the clinical practice guidelines for the management of C. difficile in early 2019 to incorporate new randomized control trials that compared C. difficile agents. This update contains 3 new recommendations for the treatment of CDI and is strictly limited to adults, while the previous guidelines were for both adult and pediatric populations.⁵

The 2017 guidelines were fidaxomicin- and vancomycin-centered, with recurrent episodes guided by what therapy was selected for the initial episode of CDI. For initial CDI episodes that are severe or not, fidaxomicin 200 mg by mouth twice daily for 10 days is preferred, while initial fulminant episodes remain unchanged from the 2017 guidelines, with oral metronidazole and oral vancomycin the preferred agents. For the first recurrent episode, fidaxomicin is the treatment of choice. Subsequent recurrences can be treated with fidaxomicin, oral vancomycin in a tapered and pulsed regimen or fecal microbiota transplantation as a last-line option, as there are 3 safety alerts published by the FDA, including the transmission of E. coli, SARS-CoV-2, and multi-drug resistant organisms.^6-8

Fidaxomicin is an oral macrolide antibiotic agent that the FDA approved for the use of CDI in May 2011. Compared with vancomycin, the initial clinical responses are similar for both agents. However, fidaxomicin was associated with lower recurrence of CDI in clinical studies (OR of 0.47 (95% confidence interval (CI), 0.37 - 0.60, I2 = 0).⁹ The reduction in recurrence rates of C.difficile infection may lead to fewer hospital visits and collectively minimize CDI costs. A cost-effectiveness study by Kelly R et al assessed the use of fidaxomicin versus vancomycin as first-line therapy in the treatment of C.difficile associated diarrhea. This analysis suggested that the total treatment cost of using fidaxomicin was $14,442 versus $14,179 per patient with vancomycin in the general population. Fidaxomicin use could lead to total hospital cost savings of $616 per patient in patients with cancer and $312 per patient in patients with concomitant antibiotic use. On the other hand, vancomycin use resulted in hospital cost savings of $243 in the elderly and $371 in patients with renal impairment. The study results suggested a potential cost benefit with fidaxomicin in patients with cancer and those needing concomitant antibiotic use. However, vancomycin had potential cost savings in elderly patients and those with renal impairment.¹⁰ The study concluded that fidaxomicin was shown to have similar total costs compared with oral vancomycin.10 The study was funded by Merck and Co, the same pharmaceutical company that makes fidaxomicin.

Fidaxomicin and oral vancomycin both have minimal systemic absorptions. Therefore, serious adverse effects (AEs) are rare.^11,12

According to the FDA package insert, the most commonly reported AEs when using fidaxomicin in clinical trials are abdominal pain, anemia, gastrointestinal hemorrhage, nausea, neutropenia, and vomiting.¹²

Postmarking reported hypersensitivity reactions, such as angioedema, dyspnea, pruritis, and rash.¹² Oral vancomycin’s most commonly reported AEs in clinical trials are abdominal pain, hypokalemia, and nausea.¹¹ Because of its minimal systemic absorption, the risk for nephrotoxicity and ototoxicity is significantly reduced. Postmarking reported symptoms, such as dyspnea, hypotension, pruritis, and wheezing, which are consistent with anaphylactoid reactions. They can persist from minutes to several hours, normally resolving within 20 minutes.¹¹

The guideline recommendations are summarized in the Table.⁵

Table. New C.difficile Infection Treatment Guidelines5

CDI indicates C.difficile infection; IV, intravenously; sCr, serum creatinine; and WBC, white blood cells.

^a An example of a tapered/pulsed vancomycin regimen is 125 mg by mouth 4 times daily for 10 to 14 days, 3 times daily for 7 days, once daily for 7 days, and then every 2 to 3 days for 2 to 8 weeks.

^b Bezlotoxumab may also be considered for patients considered high risk for CDI recurrence (age > 65 years, immunocompromised, and severe CDI on presentation). Bezlotoxumab should be reserved for use in patients with congestive heart failure when the benefit outweighs the risk, because of an increased risk of heart failure and mortality in the 12 weeks following the infusion. Do not combine bezlotoxumab and fidaxomicin.

----------------------------------------------------------------------------------

Alyson Houle and Hien Nguyen are PharmD candidates at the Massachusetts College of Pharmacy and Health Sciences in Boston.

Zaid Jalil is a PharmD candidate at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts.

Tiffany Russo, PharmD, is an antimicrobial stewardship pharmacist at the University of Toledo in Ohio.

-----------------------------------------------------------------------------------

References

1. Lamont JT, Kelly CP, Bakken JS. Clostridioides difficile infection in adults: clinical manifestations and diagnosis. UpToDate. Updated September 9, 2021. Accessed November 11, 2021. https://www.uptodate.com/contents/clostridioides-difficile-infection-in-adults-clinical-manifestations-and-diagnosis
2. Schroeder MS. Clostridium difficile--associated diarrhea. Am Fam Physician. 2005;71(5):921-928.
3. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated clostridium difficile infection. Antimicrob Agents Chemother. 2013;57(5):2326–2632.doi:10.1128/AAC.02176-12
4. C. diff (Clostridioides difficile). CDC. Updated July 12, 2021. Accessed December 27, 2021. https://www.cdc.gov/cdiff/index.html
5. 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. doi:10.1093/cid/ciab549
6. Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms. FDA. June 13, 2019. Accessed December 27, 2021. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse
7. Safety alert regarding use of fecal microbiota for transplantation and additional safety protections pertaining to SARS-CoV-2 and COVID-19. FDA. March 23, 2020. Accessed December 27, 2021. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/safety-alert-regarding-use-fecal-microbiota-transplantation-and-additional-safety-protections
8. Fecal microbiota for transplantation: safety alert – risk of serious adverse events likely due to transmission of pathogenic organisms. FDA. Updated April 7, 2020. Accessed December 27, 2021. https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission
9. Al Momani LA, Abughanimeh O, Boonpheng B, Gabriel JG, Young M. Fidaxomicin vs vancomycin for the treatment of a first episode of clostridium difficile Infection: a meta-analysis and systematic review. Cureus. 2018;10(6):e2778. doi:10.7759/cureus.2778
10. Reveles KR, Backo JL, Corvino FA, Zivkovic M, Broderick KC. Fidaxomicin versus vancomycin as a first-line treatment for clostridium difficile–associated diarrhea in specific patient populations: a pharmacoeconomic evaluation. Pharmacotherapy. 2017;37(12):1489-1497. doi:10.1002/phar.2049
11. Firvanq. Prescribing information. CutisPharma. 2018. Accessed December 27, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208910s000lbl.pdf
12. Dificid.Prescribing information. Merck Sharp & Dohme Corp. 2020. Accessed December 27, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213138lbl.pdf