"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."

Review article
peer-reviewed

## Cost-Effectiveness of Fecal Microbiota Transplantation in the Treatment of Recurrent Clostridium Difficile Infection: A Literature Review

### Abstract

Clostridium difficile (C. difficile) is a common cause of antibiotic-­associated diarrhea (AAD), being responsible for 15­-25% of all AAD cases. The purpose of this literature review is to determine the cost-effectiveness of fecal microbiota transplantation (FMT) and how it compares in this regard to the standard treatments of choice for recurrent C. difficile infection (CDI). The review of the literature along with the evaluation of three comparative cost effective analyses yielded findings consistent with the view that FMT is the most cost-effective option in treating recurrent CDI. There are some (but considerably less) data indicating that FMT may be a cost effective strategy in treating initial CDI, as well. The superior cost-effectiveness of FMT as compared to the preferred standards of treatment for recurrent CDI suggest FMT use should become more integrated in routine clinical practice. Increased utilization of FMTs would allow for better control of this increasingly problematic disease as well as lower costs associated with its management.

### Introduction & Background

Clostridium difficile [C. difficile] is a common cause of antibiotic-associated diarrhea [AAD], accounting for up to 25% of all AAD cases. This anaerobic Gram-positive bacillus forms exotoxins [toxin A and toxin B] and spores, which are found in the feces of infected patients [1]. Transmission of C. difficile occurs through contact with surfaces contaminated with feces. The patients at greatest risk for infection are the elderly [≥ 65 years old], especially those receiving care in hospitals or nursing homes [2]. The most significant risk factor, however, is a history of recent antibiotic exposure. The most frequently implicated antibiotics include clindamycin, fluoroquinolones, penicillins, and cephalosporins. The C. difficile infections [CDIs] arise most commonly in patients on prolonged antibiotic regimens as this destroys the normal flora of the gut [2-3]. The C. difficile then grows in place of the normal gut flora, producing the aforementioned toxins which damage the intestines and cause disease.

The disease caused by uncontrolled CDI ranges from mild diarrhea to pseudomembranous colitis with potentially fatal sequelae such as bowel perforation, toxic megacolon, and sepsis [1]. Furthermore, CDIs have been known to recur in 20-35% of patients treated for initial CDI and in up to 65% in patients treated for recurrent CDI [rCDI] using conventional treatment strategies [3-5].

### Review

Healthcare costs in the United States have become one of the most pressing economic concerns of the 21st century. Currently, it is estimated that the United States spends about 18% of the GDP on healthcare, leading the world in healthcare spending [35]. However, even with this increase in spending, the United States lags behind in life expectancy at birth and life expectancy at 65- 79 years. The life expectancy at birth in the United States is the lowest out of the top 18 countries in terms of healthcare spending [35]. Better and more cost effective management is of paramount concern for the healthcare industry as a whole; in depth, studies of both outcomes and cost effectiveness of new treatment options for establishing diagnoses like the case of FMT for recurrent CDI must be performed in order to more effectively manage patients and reduce the healthcare burden.

In our analysis of different studies of the cost effectiveness of fecal microbiota transplantation for the treatment of recurrent CDI, FMT has been associated with both better outcomes and as a more cost effective treatment.

While examining outcomes for recurrent CDI treatment using vancomycin and FMT [24-25], two studies have shown that both FMT by colonoscopy and FMT by duodenal infusion have resulted in significantly higher cure rates for patients with recurrent infection. By colonoscopy, the cure rates of infection were 90% for FMT vs. 26% for vancomycin in a 39 patient sample from July 2013 to June 2014 [25]. In a different study of rCDI treatment using a duodenal infusion of FMT, the cure rates of infection were 94% for FMT, 31% for Vancomycin, and 23% for Vancomycin + bowel lavage in a study of 42 patients from April 2008 to January 2010 [24]. Both studies were statistically significant (P < .0001 and P < .001 respectively) and showed that FMT could be a viable alternative to vancomycin treatment.

However, even with the viability of FMT as a treatment for rCDI, its cost effectiveness is paramount to the discussion as rCDI is associated with long and costly hospital stays [3]. Three separate studies involving the cost effectiveness of FMT demonstrated its advantages over traditional vancomycin treatment [31-32, 34].

The first study (represented in Table 3) analyzed costs, quality adjusted life years (QALY) and cost/QALY, all of which favored FMT vs. traditional vancomycin treatment (cost/QALY: $6,896.69 vs.$16,119.15) [31]. This demonstrated that not only is the procedure generally considered cheaper, it is also associated with better outcomes, and when combining both factors, FMT demonstrated far superior cost effectiveness. This study did demonstrate some limitations, however, the author’s own words a “lack of existing studies examining FMT from which to gather inputs” shows that more studies must be conducted in order to gather more accurate data regarding the true cost benefit of FMT [31].

Another study (represented in Table 4) also analyzing costs, QALY and costs/QALY demonstrated a similar result, showing that FMT was more cost effective than the current practice for all age groups 18 years or older [32]. For all age groups, cost/QALY of FMT vs. current practice (metronidazole and Vancomycin) was $21,430.40 vs.$27,391.97. This study concluded that FMT is associated with lower costs and the authors endorsed FMT as the dominant treatment strategy for treating recurrent CDI.

Lastly, we examined a study that used an incremental cost effectiveness ratio (ICER) to evaluate the cost effectiveness of multiple different treatment modalities for rCDI. These included metronidazole, Vancomycin, fidaxomicin and FMT [34]. Although the results do show that FMT by colonoscopy is the most cost effective treatment when all four treatments are compared, the study also showed that vancomycin was more cost effective if FMT is performed by duodenal infusion, enema, or when FMT is unavailable. This leads to some limitations in treatment, as FMT colonoscopy may not always be a viable option for the treatment.

Some limitations and stipulations must be applied to both our study and the current state of research into FMT. Our study was limited by the current amount of data on FMT and focused on cost-benefit analyses, which have a number of significant drawbacks. In some cases, cost-benefit analyses may not take into account all relevant health outcomes and variations in treatment across a diverse population with geography and access to care. As this is the case of the studies currently available for FMT, these studies are models of health-outcomes and cost and are not randomized controlled trials. The authors of the studies in this research do believe that the benefits of their models outweigh the disadvantages of these studies with regards to their inherent limitations.

Furthermore, because FMT is a developing treatment procedure, new evidence could come to light that is more compelling than preliminary results discussed here. A new randomized controlled trial sponsored by the North Shore University HealthSystem analyzing outcomes for FMT versus antimicrobial treatment for rCDI was verified on March 2016 and is currently undergoing recruitment [36]. This study and other randomized controlled trials (RCTs) in the future could help reveal some of the details regarding specific outcomes for FMT, which could then be incorporated into older and newer studies examining the cost-benefit ratio of FMT vs. standard treatment. Overall, because of the current state of research, we feel as if our current analysis of FMT reveals new insight into the possibility for FMT to become the mainstay of treatment for rCDI, based on both outcomes and cost-benefit, but new research must be conducted in order to determine how substantial that benefit may be.

Though more compelling evidence may arise, FMT has already demonstrated greater efficacy with comparable or even lower costs than the conventional agents which comprise our current standards of care for recurrent CDI. Furthermore, in contrast to the limitations on patient acceptance predicted by the researchers, recent findings indicate that the vast majority of patients would be willing to receive FMT despite its inherently unappealing nature, especially if it were endorsed by a physician [17, 36-37]. The barrier though maybe an endorsement from a physician. For instance, it has been postulated that physicians, curiously enough, have been less willing to accept FMT as a therapeutic modality than their patients [38]. Ongoing and future research can address the limitations in the previous studies, particularly those stemming from a lack of sufficient data. This underscores the need for more multisite, adequately powered, high-quality studies comparing the costs and benefits of viable treatment modalities for recurrent C. difficile [39].

### Conclusions

At present, FMT is not a first line option in the treatment of adults with CDI. In fact, it is generally not a second or third line option either. Thus, FMT use is essentially restricted to treatment of CDI in individuals who have relapsed despite the first, second and third line therapy. Moreover, many facilities do not offer FMT as an intervention altogether. With this review, given the apparent readiness of patients to accept this as a treatment, there is evidently favorable cost effectiveness profile against a backdrop of rising healthcare costs and the increasing incidence and morbidity associated with this disease, it would be rational to expect a more widespread adoption of FMT in the treatment of rCDI than that which is currently observed. It stands to reason, then, that barriers to adoption unrelated to cost, efficacy or patient perception exist. In order to better characterize and ultimately address these concerns, further exploration of the impediments to broader FMT utilization is warranted. Since negative attitudes towards FMT among physicians would certainly hinder FMT integration in routine clinical practice, it may be worthwhile to study this subject in greater detail. Alternatively, it is plausible that logistical constraints, lack of awareness, and/or uncertainty regarding the route of administration are to be blamed. Even more generally, however, the epidemiologic and financial data suggest there is a need for continued generation and judicious review of evidence-based research on both preventative and novel interventions, FMT and otherwise, that may enable us to contain and combat this growing epidemic more effectively and efficiently.

### References

1. Frequently Asked Questions about Clostridium difficile for Healthcare Providers. Centers for disease control and prevention. 2010, Accessed: September 29: https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html.
2. Lamont JT: Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology. Uptodate. Waltham, M.A (ed): UpToDate, 2014.
3. Rao K, Safdar N: Fecal microbiota transplantation for the treatment of Clostridium difficile infection. J Hosp Med. 2016, 11:56–61. 10.1002/jhm.2449
4. Marsh JW, Arora R, Schlackman JL, et al.: Association of relapse of Clostridium difficile disease with BI/NAP1/027. J Clin Microbiol. 2012, 50:4078–4082. 10.1128/JCM.02291-12
5. Clostridium difficile Infection Information for Patients. Centers for Disease Control and Prevention. Accessed, 2015.
6. Liubakka A, Vaughn BP: Clostridium difficile infection and fecal microbiota transplant. AACN Adv Crit Care. 2016, 27:324–337. 10.4037/aacnacc2016703
7. Lee CH, Steiner T, Petrof EO, et al.: Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: A randomized clinical trial. JAMA. 2016, 315:142-149. 10.1001/jama.2015.18098
8. Bagdasarian N, Rao K, Malani PN: Diagnosis and treatment of clostridium difficile in adults: A systematic review. JAMA. 2015, 313:398-408. 10.1001/jama.2014.17103
9. Austin M, Mellow M, Tierney WM: Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection.. Am J Med. 2104, 127:479–483. 10.1016/j.amjmed.2014.02.017
10. Dupont HL: Diagnosis and management of Clostridium difficile infection. Clin Gastroenterol Hepatol . Texas; 2013. 11:1216-1223. 10.1016/j.cgh.2013.03.016
11. Hedge DD, Strain JD, Heins JR, et al.: New advances in the treatment of Clostridium difficile infection (CDI). Ther Clin Risk Manag. 2008, 4:949–964. 10.2147/TCRM.S3145
12. Cocanour CS: Best strategies in recurrent or persistent Clostridium difficile infection. Surg Infect . 2011, 12:235–239. 10.1089/sur.2010.080
13. Bowman KA, Broussard EK, Surawicz CM: Fecal microbiota transplantation: Current clinical efficacy and future prospects. Clin Exp Gastroenterol. 2015, 8:285–291. 10.2147/CEG.S61305
14. Paasche S: Fecal microbiota transplantation: An innovative approach to treating Clostridium difficile disease. JAAPA. 2013 , 26:46-9.
15. Oldfield EC IV, Oldfield EC III, Johnson DA: Clinical update for the diagnosis and treatment of Clostridium difficile infection. World J Gastrointest Pharmacol Ther. 2014, 5:1-26. 10.4292/wjgpt.v5.i1.1
16. Kling J: Fecal transplant cost effective for recurrent C difficile. 2013,
17. Merlo G, Graves N, Brain D, et al.: Economic evaluation of fecal microbiota transplantation for the treatment of recurrent Clostridium difficile infection in Australia. Gastroenterol Hepatol. 2016, 31:1927–1932. 10.1111/jgh.13402
18. Teasley DG, Olson MM, Gebhard R, et al.: Prospective randomized trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhea and colitis. Lancet. 1983, 322:1043–1046. 10.1016/S0140-6736(83)91036-X
19. Hassoun A: Clostridium difficile-associated disease. Epocrates® Online Accessed. San; 2016.
20. Surawicz CM, Brandt LJ, Binion DG, et al.: Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013. 108:478-498 . 10.1038/ajg.2013.4
21. Musher DM, Aslam S, Logan N, et al.: Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005, 40:1586–1590. 10.1086/430311
22. Pepin J, Alary ME, Valiquette L, et al.: Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. 2005, 40:1591–1597. 10.1086/430315
23. Khanna S, Pardi DS: Clostridium difficile infection: : New insights into management. Mayo Clin Proc. 2012, 87:1106–1117. 10.1016/j.mayocp.2012.07.016
24. van Nood E, Vrieze A, Nieuwdorp M, et al.: Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013, 368:407–415. 10.1056/NEJMoa1205037
25. Cammarota G, Masucci L, Ianiro G, et al.: Randomized clinical trial: Faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015, 41:835–843. 10.1111/apt.13144
26. Prieto L, Sacristán Je A: Problems and solutions in calculating quality-adjusted life years (QALYs). Health Qual Life Outcomes. 2003, 1:80. 10.1186/1477-7525-1-80
27. Owens DK: Interpretation of cost-effectiveness analyses. J Gen Intern Med. 1998, 13:716–717. 10.1046/j.1525-1497.1998.00211.x
28. Glick HA, Polsky D: Lecture 1: Cost-benefit and cost-effectiveness analysis: The University of Pennsylvania, Leonard Davis Institute of Health Economics. Davis, Economics; 2015.
29. Torres Edejer TT, Baltussen R, Adam T, et al.: WHO Guide to cost-effectiveness analysis. World Health Organization . Geneva; 2003.
30. Marseille E, Larson B, Kazi DS, et al.: Thresholds for the cost-effectiveness of interventions: alternative approaches. Bull World Health Organ. 2015, 93:118–124. 10.2471/BLT.14.138206
31. Varier RU, Biltaji E, Smith KJ, et al.: Cost-effectiveness analysis of fecal microbiota transplantation for recurrent Clostridium difficile infection. Infect Control Hosp Epidemiol. 2015, 36:438-444. 10.1017/ice.2014.80
32. Zowall H, Brewer C, Deutsch A: Cost-effectiveness of fecal microbiota transplant in treating Clostridium difficile infection in Canada. Value. 2014, –17.
33. Gyrd-Hansen D: Concepts of efficiency in health care. Encyclopedia of Health Economics. Elsevier; 267–271.
34. Konijeti GG, Sauk J, Shrime MG, et al.: Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: A decision analysis. Clin Infect Dis. 2014, 58:1507–1514. 10.1093/cid/ciu128
35. Louise BR: The science of making better decisions about health: cost­effectiveness and cost­benefit analysis. Econstor. 2014, Accessed: September 30: https://www.econstor.eu/handle/10419/123823.
36. Zipursky JS, Sidorsky TI, Freedman CA, et al.: Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis. 2012, 55:1652–1658. 10.1093/cid/cis809
37. Bell EA: Pharmacotherapy of C. difficile-associated disease. Healio. Thorofare (ed): 2007.
38. Moossavi S, Salimzadeh H, Katoonizadeh A, et al.: Physicians knowledge and attitude towards fecal microbiota transplant in Iran. Middle East J Dig Dis. 2015, 7:155–160.
39. O'Horo JC, Jindai K, Kunzer B, et al.: Treatment of recurrent Clostridium difficile infection: A systematic review. Infection. 2014, 42:43-59. 10.1007/s15010-013-0496-x
Review article
peer-reviewed

### Author Information

###### Ethics Statement and Conflict of Interest Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Review article
peer-reviewed

5.4