The Role of Antimicrobial Stewardship in the Treatment of C difficile
Biologics have become a novel treatment in recurrent C. difficile.
Biologics have traditionally been used to treat patients with cancer and various inflammatory diseases. More recently, biologics have emerged as a novel treatment modality in recurrent Clostridioides difficile infection (CDI). Currently, the recommended first-line treatment of CDI includes oral antibiotics vancomycin and fidaxomicin.1 However, comprehensive management of CDI cannot be achieved with antibiotics alone, as they disrupt the normal gut flora and do not target Clostridioides difficile spores. Fidaxomicin and fecal microbiota transplant (FMT) have been favored in the management and prevention of recurrent CDI due to their theorized ability to combat microbiota dysbiosis. With mounting evidence of the correlation among antibiotic use, host microbiota dysbiosis, and recurrent CDI, biologics and novel strategies may also play a key role in CDI therapy.
Bezlotoxumab (Zinplava) is a human monoclonal antibody that was approved by the United States Food and Drug Administration (FDA) in October 2016 as adjunctive therapy for the management of patients at high risk for recurrent CDI. Clostridioides difficile exerts its pathologic effects primarily through the production of enterotoxin (toxin A) and cytotoxin (toxin B).2 Bezlotoxumab functions by binding to and neutralizing the effects of toxin B. Bezlotoxumab received FDA approval based on the results of the MODIFY I and MODIFY II phase 3 clinical trials. Results of these trials showed significant reduction in the recurrence of CDI up to 12 weeks after initial resolution of symptoms with bezlotoxumab when compared with placebo (MODIFY I: 28% vs 17%, respectively, P <.001; MODIFY II: 26% vs 16%, respectively, P <.001).3 Bezlotoxumab is generally well tolerated; however, there was found to be an increased incidence of heart failure (HF) among those with underlying HF when compared with placebo.3,4
Data support the routine use of bezlotoxumab for the management of recurrent CDI. While the 2018 Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) clinical practice guidelines do not provide guidance for incorporating its use into routine practice, bezlotoxumab may be recommended in combination with fidaxomicin in a subset of patients at high risk for recurrent disease in the next iteration of the guidelines.1,5 Results from a post hoc analysis of the MODIFY trials suggested patients at highest risk of recurrence included those who were aged ≥ 65 years, had compromised immunity, severe CDI, prior CDI episode(s), and infection with ribotypes 027/078/2442,6. The greatest benefit observed with bezlotoxumab was in patients with ≥ 3 risk factors.11
Bezlotoxumab may help address the significant clinical and economic impacts seen by recurrent CDI. A 20% to 30% rate of recurrence has been shown among patients treated with antibiotics (primarily vancomycin and metronidazole) for CDI.3,7,8 Recurrent infection leads to increased length of hospital stay, prolonged antibiotic exposure, and increased morbidity and mortality.2,3 Recurrent CDI also creates significant financial costs. Approximately $8.2 billion was spent on CDI hospital stays in 2009, with a recurrent episode estimated to cost $11,146 more than an initial episode.9 On an institutional level, there is also the associated cost of infection prevention services to mitigate transmission to staff and patients. Bezlotoxumab administered as a single 10-mg/kg intravenous dose has the potential to offset these costs by preventing readmission for recurrent CDI. The average wholesale price of bezlotoxumab is estimated to be $114 per milliliter (1 gram per 40 milliliter vial).10 Not including administrative costs, insurance coverage, and unique drug pricing strategies the cost for a patient weighing 70 kg would be approximately $3192. To determine the cost-effectiveness of bezlotoxumab compared with placebo, Prabhu et al conducted a computer-based study to assess incremental cost comparisons and impact on quality-adjusted life-years (QALYs). They determined the incremental cost for receiving bezlotoxumab to be $2444 per patient.11 They also found a reduction in CDI recurrence and a 0.12 difference in QALY between the bezlotoxumab (8.45 QALY) and placebo (8.33 QALY) groups.11 Bezlotoxumab may help offset costs associated with recurrent CDI readmissions as well as enhance patients’ quality of life.
Results from additional post hoc analyses of the MODIFY trials showed no difference in recurrent CDI when bezlotoxumab was administered on days 0–2 or 3–4, or ≥ 5 days after the initiation of standard-of-care oral antibiotics (vancomycin, metronidazole, or fidaxomicin).2,12 Also, bezlotoxumab did not reduce the duration of diarrhea. Given the cost of the drug, and its use primarily to prevent recurrence, bezlotoxumab is often reserved for outpatient use. To truly carve out a niche for its use in CDI therapy, cost and efficacy comparisons between bezlotoxumab with other antibiotics and biologic strategies, such as FMT, are needed. Data suggest that treatment of CDI with fidaxomicin has a lower risk of second recurrence compared with vancomycin.7 The impact of using bezlotoxumab in patients treated with fidaxomicin would further help identify a definitive role for bezlotoxumab in CDI therapy.
As with bezlotoxumab, FMT and bacteriophage therapies have been introduced to further combat the microbiota disruption seen with traditional antibiotic treatment. FMT is recommended for patients with second or subsequent CDI who have failed appropriate antibiotic treatments.1 Guideline recommendations of 2 or more failed antibiotic treatments prior to FMT is largely based on expert opinion. Results from observational and randomized clinical trials showed treatment success rates between 77% and 94%.1 The highest success rates were observed with instillation of feces via the colon (80%-100%), and results from other studies suggested increased success with more than 2 FMT administrations.1 A small, randomized controlled trial comparing FMT with standard vancomycin 14-day treatment, with the primary end point of resolution of diarrhea without relapse after 10 weeks, was terminated early due to significant differences favoring resolution in the FMT arm.1,13 FMT is generally safe; however, there is a risk of physical complications with instillation and transmission of infection from donors. Of recent concern is the transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). COVID-19 can cause gastrointestinal symptoms, and the virus has been detected in stool.14 However, the transmission of COVID-19 infection by fecal route is unclear.16 The primary supplier of FMT, OpenBiome, suggests it is providing appropriate COVID-19 screening of all FMT donors.
Bacteriophage therapy is the use of viruses to specifically infect bacteria.15 Many bacteriophages have narrow ranges of host targets, which help prevent the dysbiosis seen with antibiotics. Furthermore, bacteriophages can potentially degrade and penetrate biofilms.15,16 Data for bacteriophage use is promising; however, identification of definitive targets for CDI are ongoing.
Antimicrobial stewardship can aid in identifying patients at risk for CDI recurrence, disease progression, and those who may benefit from biologic therapies. Although expensive compared with antibiotic treatment options, biologic therapy can provide cost savings in the long term by preventing recurrence leading to hospitalization. Antimicrobial stewardship programs can also help prevent the inappropriate use of agents like bezlotoxumab by redirecting their use to the outpatient setting. Administration of bezlotoxumab in the outpatient setting ensures the health care system will be reimbursed for the cost of the drug by third-party payers. Biologics are a novel and promising treatment option, particularly for patients with CDI refractory to antibiotic therapy. More data would assist in the incorporation of these agents into the CDI treatment algorithm in a way that is beneficial to the patient and cost-effective.
Helen Berhane, PharmD, is a PGY2 infectious diseases pharmacy resident at the University of California, Davis Medical Center in Sacramento.
Jennifer Curello, PharmD, BCIDP, is an infectious diseases clinical pharmacist at the University of California, Davis Medical Center in Sacramento.
- 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. doi:10.1093/cid/cix1085
- Alonso CD, Mahoney MV. Bezlotoxumab for the prevention of Clostridium difficile infection: a review of current evidence and safety profile. Infect Drug Resist. 2019;12:1-9. doi:10.2147/IDR.S159957
- 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
- Zinplava (bezlotoxumab) [prescribing information]. Whitehouse Station, NJ; Merck & Co, Inc: October 2016.
- Johnson, S. Focused Update on C. difficile Infection Treatment Guidelines; Fidaxomicin and Bezlotoxumab. Lecture presented at IDWeek 2020; October 23, 2020
- 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
- Cornely OA, Miller MA, Louie TJ, Crook DW, Gorbach SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis. 2012;55 Suppl 2(Suppl 2):S154-S161. doi:10.1093/cid/cis462
- Kelly CP, LaMont JT. Clostridium difficile — more difficult than ever. N Engl J Med. 2008;359(18):1932-1940. doi:10.1056/NEJMra0707500
- Dubberke ER, Schaefer E, Reske KA, Zilberberg M, Hollenbeak CS, Olsen MA. Attributable inpatient costs of recurrent Clostridium difficile infections. Infect Control Hosp Epidemiol. 2014;35(11):1400-1407. doi:10.1086/678428
- Bezlotoxumab. Lexi-Drugs. Hudson, OH: Lexicomp, 2015. http://online.lexi.com/. Updated October 24, 2020. Accessed October 26, 2020.
- Prabhu VS, Dubberke ER, Dorr MB, et al. Cost-effectiveness of Bezlotoxumab Compared With Placebo for the Prevention of Recurrent Clostridium difficile Infection. Clin Infect Dis. 2018;66(3):355-362. doi:10.1093/cid/cix809
- Birch T, Golan Y, Rizzardini G, et al. Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection. J Antimicrob Chemother. 2018;73(9):2524–2528
- van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415. doi:10.1056/NEJMoa1205037
- Gu J, Han B, Wang J. COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission. Gastroenterology. 2020;158(6):1518-1519. doi:10.1053/j.gastro.2020.02.054
- Nale JY, Spencer J, Hargreaves KR, et al. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob Agents Chemother. 2016;60(2):968-981. doi:10.1128/AAC.01774-15
- Phothichaisri W, Ounjai P, Phetruen T, et al. Characterization of Bacteriophages Infecting Clinical Isolates of Clostridium difficile. Front Microbiol. 2018;9:1701. Published 2018 Jul 31. doi:10.3389/fmicb.2018.01701