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Implementing a Fecal Microbiota Transplantation Program
June 2016 - Vol. 13 No. 6 - Page #10

Clostridium difficile (C diff), an anaerobic, spore-forming, gram-positive bacterium, is responsible for a broad range of gastrointestinal illnesses. Symptoms of C diff infection (CDI) can vary widely, from mild diarrhea to, in severe infections, pseudomembranous colitis. Antimicrobial treatment for CDI includes oral vancomycin, intravenous or oral metronidazole, and a newer oral agent, fidaxomicin. Though current guidelines recommend antibiotics as first-line therapy, approximately 20% of patients will have recurrence of CDI after antibiotic treatment. Furthermore, when used to treat recurrent CDI, the efficacy of antibiotic therapy drops to approximately 60% and continues to decline after each subsequent reinfection.1

The Challenge of Treating CDI

The difficulty in treating CDI can be partly explained by its pathogenesis. It is postulated that CDI occurs in the intestinal tract due to a disruption of the normal gastrointestinal flora, typically as a result of antibiotic therapy. After extended courses of broad-spectrum antibiotics, the endogenous microbes that usually suppress C diff decline, and infection arises after C diff is able to flourish in the gastrointestinal tract. C diff also can produce toxins (toxins A and B) that damage the epithelial lining of the gastrointestinal tract. Moreover, C diff spores, which are difficult to eliminate completely, can cause reinfection if the suppressive ability of the patient’s endogenous microbes remains dysregulated.1,2

It is not uncommon for practitioners to encounter challenges when treating CDI due to the delicate balance between delivering effective antimicrobial therapy and maintaining the integrity of the gastrointestinal microbiome to prevent recurrence of infection. In addition, given the poor treatment outcomes for CDI—especially recurrent CDI—it is not surprising that alternative treatments are under investigation.3

The Role of Fecal Microbiota Transplantation

It is with these concerns in mind that fecal microbiota transplantation (FMT) has gained momentum as a treatment for CDI. The goal of FMT is to restore viable gastrointestinal flora to the colon, in order to suppress C diff and eliminate infection. With FMT, patients avoid further courses of antibiotics. Fecal material can be instilled via several methods, including enema, colonoscopy, nasogastric tube, and oral ingestion. Multiple sources for fecal material are available, encompassing related donors, anonymous donors, and nonprofit stool banks, such as OpenBiome (www.openbiome.org) and AdvancingBio (www.advancingbio.org).

Although FMT has yet to be widely adopted for CDI treatment, acceptance of the procedure as an effective, safe intervention in patients with recurrent disease is increasing.3,4 In clinical studies, FMT demonstrates a durable response and efficacy rates as high as 90%, even when used to treat recurrent CDI.3,5

Designing and Implementing a Hospital FMT Program

Baptist Hospital, a 492-bed community hospital in Pensacola, Florida, began performing FMT in September 2014, and currently is the only hospital in the area that performs the procedure. The initial motivation for developing the FMT program at our institution was the clinical data that has been published demonstrating FMT outcomes.3-7 After the FMT program was proposed by the clinical pharmacy department, it continued to gain momentum due to our practitioners’ motivation to provide the most effective therapy to our patients.

The most significant challenge to overcome when creating the FMT program was to demonstrate its financial feasibility for the institution. The cost of donor screening and colonoscopy may or may not be covered by insurance companies. Therefore, it was important to emphasize that the FMT procedure can generate cost savings by reducing the rate of hospital readmissions due to CDI recurrence.

Creating a Protocol

The next challenge in establishing the FMT program at Baptist Hospital was creating a clear, comprehensive protocol for the procedure. The protocol was developed by a multidisciplinary team, including physicians, pharmacists, procedural area personnel, and laboratory personnel. The team researched recent developments in FMT and synthesized this information into evidence-based practices. The following questions were addressed in the protocol:

  • Who will be involved in the FMT process?
  • How will potential candidates for FMT be identified?
  • What source will be used for fecal material?
  • What method will be used to perform the FMT procedure?

Roles and Responsibilities

The infectious disease physician group, gastroenterology physician group, and clinical pharmacists who lead the antimicrobial stewardship program play critical roles in the FMT program identifying patients who meet eligibility criteria to undergo FMT. The protocol defines the criteria patients must meet to be eligible for FMT consideration:

  • Three mild to moderate CDIs and have failed conventional treatments; or
  • Two severe CDIs resulting in hospitalization

After a patient is determined to be a potential FMT candidate, the gastroenterology and infectious disease physicians work in coordination to determine which patients will undergo the FMT procedure. The gastroenterology physician group plays an important function in determining which patients can safely undergo the colonoscopy necessary for fecal material to be instilled, the route of administration our organization decided upon. The gastroenterology physician group also is responsible for tracking the resolution or relapse of CDI once the procedure is completed.

Identifying a Source for Fecal Material

At the time of our FMT program implementation, fecal material banks were not widely available. This consideration, as well as the fact that donor fecal material is free (minus the cost of the screening), informed our choice to use donor fecal material for the FMT procedures, preferably from a spouse or relative as studies have shown a higher rate of CDI resolution (93%) compared to fecal donations from unrelated donors (84%).3 When choosing this option, one challenge is establishing the criteria to use to determine donor eligibility. It is important to conduct careful screening of potential donors to exclude individuals who carry a risk of generating new or worsened infection in a CDI patient.

Baptist Hospital developed a protocol that outlines who is eligible to be a fecal donor that places priority on donors who are related to the patient. The protocol defines exclusions as well, such as:

  • High-risk behaviors (eg, illicit drug use)
  • Tattoo or body piercing within the past 6 months
  • Current or known exposure to communicable disease
  • History of gastrointestinal malignancy
  • History of inflammatory bowel disease, chronic constipation, or chronic diarrhea
  • Use of immunosuppressive agents or antibiotics within the past 3 months

Additionally, the protocol includes a donor screening checklist, which must be completed before a donor can give fecal material and less than 2 weeks prior to the procedure. This checklist includes screening of both stool and blood samples for communicable diseases (eg, C diff, salmonella, HIV, hepatitis, parasitic infection).

Defining the FMT Procedure

The protocol defines the FMT procedure as follows:

  • Obtaining Consent and Cessation of Antibiotics. Patients who are cleared to undergo FMT have consent obtained and all antibiotics discontinued 1 to 3 days prior to the procedure.
  • Administration of Pre-Meds. The patient is given a bowel preparation the night before the procedure, as well as one 4 mg dose of loperamide immediately prior to FMT to aid in retention of the donated fecal material.
  • Timing from Donation to Use. Based on clinical data, we set a goal of processing and using fecal material within 6 hours of the lab receiving the specimen.8-11
  • Product Preparation. The specimen is prepared for transplantation in a level II biological safety cabinet (BSC). The product is prepared using at least 50 g of donated stool, which is blended with non-bacteriostatic saline until uniform and a volume of at least 500 mL.
  • The Procedure. The prepared solution is instilled into the patient’s colon via a colonoscope, starting from the terminal ileum. Upon completion of the colonoscopy, the patient is turned to their right side to aid in retention of the donated fecal material.

Streamlining FMT Implementation

It is essential to consider the pharmacy’s unique practice model when developing the FMT protocol and determining the pharmacist’s responsibilities in the FMT process. Consider how to use pharmacy’s unique skill set to ensure patient safety and aid in the seamless coordination of the FMT procedure. At Baptist Hospital, it seemed logical to include the FMT program as an extension of the pharmacy-led antimicrobial stewardship program. In addition, consider the facility’s practice model when weighing the pros and cons for each method of obtaining fecal material (ie, via related donor, anonymous donor, or stool bank) and for the various routes of instillation (ie, via enema, colonoscopy, nasogastric tube, or oral ingestion).

Most FMT programs will span multiple services within a hospital. Thus, coordination must be a priority, and effective communication is required when rolling out an FMT protocol to hospital staff. As discussed, the protocol should answer key questions, define the responsibilities of all disciplines involved, and include references supporting the efficacy of FMT. The inclusion of supporting references within the protocol ensures it is comprehensive and validates the FMT procedure, which is important as it is still considered experimental. Hospital-wide education should accompany the protocol; this is an area where pharmacists can provide significant value. Pharmacists can educate hospital staff and patients on the clinical data supporting the use of FMT as a treatment strategy for CDI, and also discuss the specifics of the FMT procedure.

Tracking Program Outcomes

Following the implementation of an FMT program, monitoring patient results and quantifying the benefits of the procedure are critical activities; this data can then be utilized to further improve the program and create momentum to support future pharmacy-led initiatives. To this end, pharmacy completed a retrospective research study12 to determine if our FMT procedures have resulted in a rate of CDI resolution that is consistent with the current body of literature surrounding FMT, which has identified resolution rates between 81% and 93%.6

Study Methods

Prior to data collection, the study was approved by the Institutional Review Board (IRB). The electronic medical record identified eight patients who had undergone FMT at Baptist Hospital between September 2014 and July 2015. The clinical courses of these patients were evaluated through comprehensive medical chart review; the primary end point assessed was resolution of CDI, which was defined as a termination of diarrhea with subsequent negative C diff antigen and toxin tests.

Study Patient Characteristics

Seven of the eight patients evaluated were female (87.5%) with a median age of 82 (range 61-101). Three patients (37.5%) had concomitant gastrointestinal disease, which included Crohn’s disease, diverticulitis, and a partial colectomy. Related donors where used for three of the eight patients evaluated (37.5%).

Study Results

The primary analysis found that seven of the eight patients (87.5%) had resolution of their CDI following FMT. Secondary analyses identified oral vancomycin as the most commonly prescribed antibiotic (52%; see FIGURE 112). See TABLE 112 for the results of other secondary analyses.

Study Discussion and Conclusions

Patients who have undergone FMT at Baptist Hospital have CDI resolution rates that are comparable to the currently available literature. Of the eight patients evaluated, one failed to have resolution of CDI following the FMT procedure; this patient had failed treatment with oral fidaxomicin prior to FMT being considered. Additionally, an anonymous donor supplied the fecal material for that procedure, and anonymous donation has been shown to result in slightly lower rates of CDI resolution.3 This patient later underwent a colectomy, but continued to experience CDI symptoms, and later passed away. A second patient who underwent FMT experienced resolution of their CDI, but later passed away due to cardiac complications that were presumed to be unrelated to CDI.

The study’s most significant limitation is that it is a case series with a small sample size of eight patients. In future studies, we will seek to evaluate a larger population. It also will be valuable to assess the impact of using antibiotics post-FMT to determine if this factor correlates with CDI recurrence. Additionally, we will continue to analyze the cost savings generated by the FMT program.

The results of this study support the continuation of the FMT program at Baptist Hospital, broaden the services of our established antimicrobial stewardship program, and add to the data supporting the use of FMT in CDI. Moreover, the study helped to validate the cost savings of FMT by showing that FMT patients who experienced CDI resolution avoided further costs associated with readmission.

Conclusions

An FMT program can serve as an extension of a pharmacist-led antimicrobial stewardship program, broadening the pharmacists’ scope of practice within an institution and facilitating interdisciplinary discussion regarding judicious use of antimicrobial agents. Additionally, pharmacists can play an important role in disseminating information and serving as a resource to hospital staff when initiating an FMT program.

Our pharmacy department will continue to analyze the outcomes from FMT procedures to identify opportunities for process improvement. In addition, pharmacists will disseminate FMT outcome data to hospital staff to reinforce the importance of the FMT program.

References

1. Diseases and Conditions: C. difficile infection. Mayo Clinic Web site. http://www.mayoclinic.org/diseases-conditions/c-difficile/basics/treatment/con-20029664. Accessed April 25, 2016.

2. C. difficile Infection. American College of Gastroenterology Web site. http://patients.gi.org/topics/c-difficile-infection. Accessed April 25, 2016.

3. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infectious Dis. 2011;53(10):994-1002.

4. Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Ther Adv Gastroenterol. 2012;5(6):403-420.

5. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41(9):835-843.

6. Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol. 2014;48(8):693-702.

7. Mattila E, Uusitalo-Seppala R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterol. 2012;142:490-496.

8. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003;36(5):580-585.

9. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9(12):1044-1049.

10. Kelly C, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012;46(2):145-149.

11. Landy J, Al-Hassi HO, McLaughlin SD, et al. Review article: faecal transplantation therapy for gastrointestinal disease. Aliment Pharmacol Ther. 2011;34(4): 409-415.

12. Iacobellis C, Gaudet S. Evaluating the efficacy of fecal microbiota transplantation in patients with recurrent Clostridium difficile infection. Poster presented at: 50th American Society of Health-System Pharmacy Clinical Meeting and Exhibition (ASHP); December 6-10, 2015; New Orleans, LA.


Cara Iacobellis, PharmD, is the PGY1 pharmacy practice resident at Baptist Health Care in Pensacola, Florida. She graduated from the University of Florida College of Pharmacy in 2015. Her professional interests include hematology/oncology and pediatrics.

Shelby Gaudet, PharmD, BCPS, is the clinical coordinator and clinical pharmacist in infectious disease at Baptist Health Care. She graduated from the University of Florida College of Pharmacy in 2009 and completed a residency at Baptist Health Care in 2010. Shelby serves as the infectious disease preceptor for pharmacy practice residents and as a mentor in gastroenterology for pharmacy practice residents.

Rudy J. Seelmann, PharmD, BCPS, is the director of pharmacy at Baptist Health Care.


SIDEBAR

FMT Patient Case Study

Patient 1 has a past medical history significant for colorectal cancer (treated with partial colectomy, chemotherapy, and radiation), atherosclerotic cerebrovascular disease, carotid artery disease, gout, hypertension, and hypercholesterolemia. The patient developed CDI secondary to her colorectal cancer treatment in March 2015 and was subsequently admitted. The patient was treated with metronidazole 500 mg IV Q8h, vancomycin 500 mg PO QID, and then an outpatient course of oral vancomycin. She was readmitted in April 2015 with recurrence of CDI and was treated with vancomycin 500 mg PO QID.

Following an ER visit in June 2015, the patient was referred to the infectious disease department for recurrent CDI. FMT was recommended and then performed in July 2015, when 390 mL of related (via the patient’s daughter) fecal material was instilled. Symptoms resolved after the procedure and subsequent stool cultures were toxin– and antigen-negative.

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