REVIEW CME EDUCATIONAL OBJECTIVE: Readers will be aware of an effective yet little-used treatment for recurrent CREDIT Clostridium difficile infection MARKUS D. AGITO, MD ASHISH ATREJA, MD, MPH, FACP MAGED K. RIZK, MD Department of Medicine, Director, Informatics for Research, Quality Improvement Officer, Digestive Disease Akron General Medical Center, Outcomes and Quality, Assistant Professor, Institute, Cleveland Clinic; Assistant Professor, Akron, OH Division of Gastroenterology, Cleveland Clinic Lerner College of Medicine of Mount Sinai School of Medicine, Case Western Reserve University, New York, NY Cleveland, OH Fecal transplantation for recurrent C difficile infection: Ready for prime time?

■■ ABSTRACT f you had a serious disease, would you I agree to an alternative treatment that was Recurrent Clostridium difficile infection has been a major cheap, safe, and effective—but seemed dis- challenge for patients and clinicians. Recurrence of infec- gusting? Would you recommend it to patients? tion after treatment with standard is becom- Such a disease is recurrent Clostridium dif- ing more common with the emergence of more-resistant ficile infection, and such a treatment is fecal strains of C difficile. Fecal microbiota transplantation is an microbiota transplantation—instillation of alternative treatment for recurrent C difficile infection, but blenderized feces from a healthy donor (ide- ally, the patient’s spouse or “significant other”) it is not yet widely used. into the patient’s colon to restore a healthy ■■ KEY POINTS population of .1,2 The rationale behind this procedure is simple: antibiotics and other Fecal microbiota transplantation involves instilling gut factors disrupt the normal balance of the co- microbiota from a healthy donor into the diseased gut of lonic flora, allowing C difficile to proliferate, a patient who has recurrent or recalcitrant episodes of but the imbalance can be corrected by reintro- 1 diarrhea despite treatment for C difficile infec- ducing the normal flora. tion. The instillation can be done via nasogastric tube, In this article, we will review how recurrent C difficile infection occurs and the importance of endoscope, or . the in resisting colonization with this . We will also describe the protocol Donor screening is necessary to prevent transmission of used for fecal microbiota transplantation. communicable diseases to the recipient. ■■ C DIFFICILE INFECTION OFTEN RECURS Recently published studies indicate that this procedure is effective for treating recurrent C difficile infection. Ran- C difficile is the most common cause of hospi- domized clinical trials to assess its efficacy and safety are tal-acquired diarrhea and an important cause underway. of morbidity and death in hospitalized pa- tients.3,4 The cost of this infection is estimated to be more than $1.1 billion per year and its The field of microbiota therapy is rapidly progressing. incidence is rising, partly because of the emer- More physicians are learning to embrace the concept gence of more-virulent strains that make treat- of fecal microbiota transplantation, and patients are ment of recurrent infection more difficult.5,6 beginning to overcome the “yuck factor” and accept its C difficile infection is characterized by di- benefits. arrhea associated with findings suggestive of pseudomembranous colitis or, in fulminant 7 doi:10.3949/ccjm.80a.12110 cases, ileus or megacolon. Recurrent C difficile

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TABLE 1 CDC practice guidelines for treating Clostridium difficile infection

Clinical definition Supportive clinical data Recommended treatment Initial episode, White blood cell (WBC) count Metronidazole 500 mg three times per mild or moderate ≤ 15,000 cells/mL day by mouth for 10–14 days Initial episode, WBC count ≥ 15,000 cells/mL Vancomycin 125 mg four times per day severe Serum creatinine ≥ 1.5 times by mouth for 10–14 days baseline Initial episode, Severe C difficile infection com- Vancomycin 500 mg four times per day severe, complicated, plicated with hypotension, shock, by mouth or nasogastric tube, plus or fulminant ileus, or megacolon metronidazole 500 mg every 8 hours intravenously If complete ileus, consider adding rectal instillation of vancomycin First recurrence Same as for initial episode Second recurrence Vancomycin in a tapered and/or pulsed regimen

Adapted from Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemi- ology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431–455. Copyright 2010, University of Chicago Press.

infection is defined as the return of symptoms and tolevamer (a novel polymer that binds C within 8 weeks after successful treatment.7 difficile toxins).14

C difficile is C difficile produces two types of toxins. TABLE 1 summarizes the treatment regimen the most Toxin A is an enterotoxin, causing increased for C difficile infection in adults, based on clin- and fluid secretion, ical practice guidelines from the US Centers common cause while toxin B is a cytotoxin, causing intense for Disease Control and Prevention (CDC).7 of hospital- colonic . People who have a acquired poor host immune response to these toxins ■■ THE NORMAL GUT MICROBIOTA tend to develop more diarrhea and colonic in- KEEPS OUT diarrhea and an flammation.8 important cause A more virulent strain of C difficile has Immediately after birth, the sterile human gut emerged. Known as BI/NAP1/027, this strain becomes colonized by a diverse community of of morbidity is resistant to quinolones, and it also produces .15 This gut microbiota per- and death a binary toxin that has a partial gene deletion forms various functions, such as synthesizing that allows for increased production of toxins vitamin K and vitamin B complex, helping A and B in vitro.9,10 More cases of severe and digest food, maintaining the mucosal integrity recurrent C difficile infection have been asso- of the gut, and priming the mucosal immune ciated with the increasing number of people response to maintain homeostasis of commen- infected with this hypervirulent strain.9,10 sal microbiota.16 C difficile infection recurs in about 20% to However, the most important role of the 30% of cases after antibiotic treatment for it, gut microbiota is “colonization resistance” or usually within 30 days, and the risk of a sub- preventing exogenous or potentially patho- sequent episode doubles after two or more genic organisms from establishing a colony occurrences.10,11 Metronidazole (Flagyl) and within the gut.17 It involves competition for vancomycin are the primary treatments; alter- nutrients and occupation of binding sites on native treatments include fidaxomicin (Difi- the gut epithelium by indigenous flora.16 Other cid),10 rifaximin (Xifaxan),12 nitazoxanide,13 factors such as the mucosal barrier, salivation,

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MM Treating recurrent Clostridium difficile infection by restoring healthy intestinal flora

The normal healthy gut teems with bacteria, Antibiotics but most of them are benign or even beneficial in ways we are only beginning to appreciate, eg, keeping out opportunistic pathogens such as Clostridium difficile. Antibiotic therapy disrupts the normal population of bacteria, paradoxically allowing colonization by C difficile.

C difficile spores

Development of Resolution C difficile infection of symptoms

Antibiotics

Antibiotic therapy for C difficile infection suppresses active infection, but the organism can form resistant spores. In addition, Recurrence antibiotics further disrupt the normal intestinal flora. As a result, C difficile infection often recurs.

Donor fecal sample

Fecal microbiota transplantation involves instilling fecal material from a healthy donor to restore the normal C difficile spores remain intestinal flora. CCF Medical Illustrator: Beth Halasz ©2013 FIGURE 1

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swallowing, gastric acidity, desquamation of in a process known as transfaunation.24 Fecal mucosal membrane cells, intestinal motility, microbiota transplantation was first performed and secretion of antibodies also play major in humans in the late 1950s in patients with roles in colonization resistance.17 fulminant pseudomembranous colitis that did not respond to standard antibiotic therapy for ■■ ANTIBIOTICS DISRUPT THE GUT FLORA C difficile infection.25 Since then, a number of case reports and case series have described in- Physical or chemical injuries (the latter by an- stillation of donor stool via nasogastric tube,26 timicrobial or antineoplastic agents, eg) may via colonoscope,27–31 and via enema.32 Regard- disrupt the gut microbiota. In this situation, less of the protocols used, disease resolution opportunistic pathogens such as C difficile col- has been shown in 92% of cases and few ad- onize the gut mucosa, stimulate an immune verse effects have been reported, even though reaction, and release toxins that cause diar- transmission of infectious pathogens is theo- rhea and inflammation.18 C difficile will try to retically possible.33 compete for nutrients and adhesion sites until A recent multicenter long-term follow-up it dominates the intestinal tract. study34 showed that diarrhea resolved within When C difficile spores are ingested, they 90 days after fecal microbiota transplantation replicate in the gut and eventually release in 70 (91%) of 77 patients, while resolution toxins. Antibiotic therapy may eliminate C of C difficile infection after a further course difficile bacteria but not the spores; hence, C of antibiotics with or without repeating fecal difficile infection can recur after the antibiotic microbiota transplantation was seen in 76 is discontinued unless the indigenous bacteria (98%) of 77 patients.34 Some patients were can restrain C difficile from spreading.19 reported to have improvement of preexist- ing allergies, and a few patients developed ■■ HOW DOES FECAL MICROBIOTA peripheral neuropathy and autoimmune dis- TRANSPLANTATION WORK? eases such as SjÖgren syndrome, idiopathic thrombocytopenic purpura, and rheumatoid Antibiotic Fecal microbiota transplantation involves in- arthritis.33 therapy stilling processed stool that contains essential As the important role of the gut micro- intestinal bacteria (eg, Bacteroides species) biota in resisting colonization by C difficile may eliminate from a healthy screened donor into the dis- is becoming more recognized, scientists are C difficile eased of a suitable recipi- beginning to understand and explore the 1 ent (FIGURE 1). additional potential benefits of fecal micro- bacteria but The aim of this procedure is to reestablish biota transplantation on other microbiota- not its spores the normal composition of the gut flora, re- related dysfunctions.2 The Human Micro- store balance in metabolism, and stimulate biome Project is focusing on characterizing both the acquired and the humoral immune and understanding the role of the microbial responses in the intestinal mucosa after dis- components of the human genetic and meta- ruption of the normal flora.20–23 One study bolic landscape in relation to human health showed that patients who have recurrent C and disease.35 Earlier observational studies difficile infections have fewer protective mi- showed fecal microbiota transplantation croorganisms (ie, Firmicutes and Bacteriodetes) to be beneficial in inflammatory bowel dis- in their gut, but after fecal microbiota trans- ease,36,37 ,38,39 mul- plantation their microbiota was found to be tiple sclerosis,40 rheumatologic40 and autoim- similar to that of the donor, and their symp- mune diseases,41 and metabolic syndrome,42 toms promptly resolved.18 likely owing to the role of the microbiota in immunity and energy metabolism. Although ■■ STUDIES UP TO NOW these reports may provide insight into the unexplored possibilities of fecal microbiota The principle of transplanting donor stool to transplantation, further clinical investiga- treat various gastrointestinal diseases has been tions with randomized controlled trials are practiced in veterinary medicine for decades still necessary.

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■■ THE CURRENT PROTOCOL FOR TABLE 2 FECAL MICROBIOTA TRANSPLANTATION Exclusion criteria for donors As yet, there is no standardized protocol for ABSOLUTE fecal microbiota transplantation, since no completed randomized trial supporting its ef- Risk of infectious agent ficacy and safety has been published. However, Known human immunodeficiency virus (HIV), , or a group of experts in infectious disease and gas- infection troenterology have published a formal standard Known exposure to HIV or viral hepatitis within the previous 12 months 19 as summarized below. High-risk sexual behaviors practice guideline, Use of illicit drugs Tattoo or body piercing within 6 months Primary indications Incarceration or history of incarceration for fecal microbiota transplantation Known current communicable disease (eg, upper respiratory tract • Recurrent C difficile infection—at least infection) three episodes of mild to moderate C dif- Risk factors for variant Creutzfeldt–Jakob disease ficileinfection and failure of a 6- to 8-week Travel within the last 6 months to areas where diarrheal illnesses taper with vancomycin with or without an are endemic alternative antibiotic such as rifaximin or Gastrointestinal comorbidities nitazoxanide, or at least two episodes of History of inflammatory bowel disease severe C difficile infection resulting in hos- History of irritable bowel syndrome, idiopathic chronic constipation, pitalization and associated with significant or chronic diarrhea morbidity History of gastrointestinal malignancy or known polyposis • Mild to moderate C difficile infection not Factors that can or do affect the composition responding to standard therapy for at least of the intestinal microbiota 1 week Antibiotics within the preceding 3 months • Severe or fulminant C difficile colitis that Major immunosuppressive medications has not responded to standard therapy af- Systemic antineoplastic agents ter 48 hours. Additional recipient-specific considerations Recent ingestion of a substance (eg, nuts) to which the recipient Who is a likely donor? is allergic The gut microbiota is continuously replen- ished with bacteria from the environment RELATIVE in which we live, and we constantly acquire organisms from people who live in that same History of major gastrointestinal surgery (eg, gastric bypass) Metabolic syndrome environment. Hence, the preferred donor is Systemic autoimmunity, eg, multiple sclerosis, connective tissue disease someone who has intimate physical contact 33,43,44 Atopic diseases including asthma and eczema, eosinophilic disorders with the recipient. The preferred stool of the gastrointestinal tract donor (in order of preference) is a spouse or Chronic pain syndromes, eg, chronic fatigue syndrome, fibromyalgia significant partner, a family household mem- ber, or any other healthy donor.26,36 Adapted from information in Bakken J, Borody T, Brandt L, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9:1044–1049. Who should not be a donor? It is the responsibility of the physician per- forming the fecal microbiota transplantation donor’s blood and stool should be screened for to make sure that the possibility of transmit- transmissible diseases such as human immu- ting disease to the recipient is minimized. nodeficiency virus (HIV), hepatitis, , Extensive history-taking and physical ex- enteric bacteria, parasites, and C difficile. amination must never be omitted, since not The recipient has the option to be tested all diseases or conditions can be detected by for transmissible diseases such as HIV and hep- laboratory screening alone, especially if test- atitis in order to avoid future questions about ing was done during the early stage or window transmission after fecal microbiota transplan- period of a given disease.19 Nevertheless, the tation. A positive screening test must always

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TABLE 3 The upper-gastrointestinal route (naso- gastric tube, jejunal catheter, or gastroscope). Instructions for fecal microbiota transplantation The nasogastric or nasojejunal tube or gastro- Donor scope is inserted into the upper-gastrointesti- Avoid intake of substances that may cause allergies to recipient nal tract, and positioning is confirmed by radi- Report any signs and symptoms of infection ography. From 25 to 50 mL of stool suspension Take an osmotic laxative (milk of magnesia, lactulose) the night before is drawn up in a syringe and instilled into the transplantation tubing followed by flushing with 25 mL of normal saline.26 Immediately after instillation, Recipient Stop oral vancomycin and metronidazole 3 days before transplantation the tube is removed and the patient is allowed Use bowel preparation with polyethylene glycol the night before to go home and continue with his or her usual transplantation diet. Take omeprazole 20 mg on the evening before and the morning of This approach is easier to perform, costs transplantation (if by the upper-gastrointestinal route) less, and poses lower risk of intestinal perfo- Take loperamide on day of transplantation (if by the lower- ration than the colonoscopic approach. Dis- gastrointestinal route) advantages include the possibility that stool Stool preparation suspension may not reach distal areas of the Universal precautions (gown, gloves, mask, eye shield) colon, especially in patients with ileus and Collection of fresh stool sample (within 6 hours) small-bowel obstruction. There is also a high- Homogenize sample with normal saline or 4% milk in a household er risk of bacterial overgrowth in elderly pa- blender tients who have lower gastric acid levels.33 Filter with gauze pads, coffee filters, or urine stone strainers The lower-gastrointestinal route (colo- Prepare 25–50 mL of stool suspension (upper-gastrointestinal route) noscopy, retention enema). is or 250–500 mL (lower-gastrointestinal route) currently considered the first-line approach for fecal microbiota transplantation.45 After Adapted from information in Bakken J, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. giving informed consent, the patient under- Clin Gastroenterol Hepatol 2011; 9:1044–1049. goes standard colonoscopy under sedation. An initial colonoscopic examination is per- formed, and biopsy specimans are obtained if be verified with confirmatory testing.19 necessary. Approximately 20 mL of stool sus- TABLE 2 summarizes the exclusion criteria pension is drawn up in a syringe and injected and screening tests performed for donors ac- via the biopsy channel of the colonoscope cording to the practice guidelines for fecal mi- every 5 to 10 cm as the scope is withdrawn, crobiota transplantation formulated by Bak- for a total volume of 250 to 500 mL.19,27 The ken et al.19 patient should be advised to refrain from def- ecating for 30 to 45 minutes after fecal micro- Preprocedure instructions biota transplantation.46 and stool preparation This approach allows direct visualiza- The physician should orient both the donor tion of the entire colon, allowing instil- and recipient regarding “do’s and don’ts” be- lation of stool suspension in certain areas fore fecal microbiota transplantation. TABLE 3 where C difficile may predominate or hide summarizes the preprocedure instructions and (eg, in diverticuli).27,47 One disadvantage to steps for stool preparation. this route of administration is the risk of co- lon perforation, especially if the patient has Route of administration toxic colitis. The route of administration may vary de- Instillation via retention enema may be pending on the clinical situation. Upper-gas- done at home with a standard enema kit.32 trointestinal administration is performed via Disadvantages include the need for multiple nasogastric or nasojejunal tube or gastroscopy. instillations over 3 to 5 days,36 back-leakage Lower-gastrointestinal administration is per- of stool suspension causing discomfort to pa- formed via colonoscopy (the route of choice) tients, and stool suspension reaching only to or retention enema. the splenic flexure.48

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■■ Measurement of outcome one should satisfy our doubts about the effi- Fecal microbiota transplantation is considered cacy of fecal microbiota transplantation and successful if symptoms resolve and there is no hopefully pave the way for its application in relapse within 8 weeks. Testing for C difficile the near future. in asymptomatic patients is not recommended An increasing number of patients are since patients can be colonized with C diffi- learning to overcome the “yuck factor” as- cile without necessarily developing disease.19 sociated with fecal microbiota transplan- There is currently no consensus on treatment tation once they understand its safety and recommendations for patients who do not benefits.51 Moreover, the Human Microbi- respond to fecal microbiota transplantation, ome Project is attempting to identify spe- although some reports showed resolution of cific organisms in stool that may specifically diarrhea after a repeat 2-week standard course treat C difficile infection, hence eliminating of oral vancomycin26 or repeated instillation the need for whole-stool transplantation in of feces collected from new donors.49 the near future. Although fecal microbiota transplantation is still in its infancy, its low ■■ Is it ready for prime time? cost, safety, and effectiveness in treating re- current C difficile infection will likely lead Fecal microbiota transplantation has been used to the procedure becoming widely adopted primarily as an alternative treatment for recur- in mainstream clinical practice. ■ rent C difficile infection, although other indica- tions for its use are currently being identified Editor’s note: On January 16, 2013, after this and studied. This procedure is now being done article was completed, a randomized con- in several specialized centers in the United trolled trial of fecal microbiota transplanta- States and abroad, and although the protocol tion was published in the New England Journal may vary by institution, the clinical outcomes of Medicine. That trial, “Duodenal infusion of have been consistently promising. donor feces for recurrent Clostridium difficile,” The Fecal Therapy to Eliminate Associ- found: “The infusion of donor feces was sig- ated Long-standing Diarrhea (FECAL) trial, nificantly more effective for the treatment of currently underway, is the first randomized recurrent C difficile infection than the use of trial to assess the efficacy of fecal microbiota vancomycin.” The study is available online transplantation for treatment of recurrent C at http://www.nejm.org/doi/full/10.1056/NEJ- difficile infection.50 Clinical trials such as this Moa1205037 (subscription required).

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Gough E, Shaikh H, Manges AR. Systematic review of intestinal cerative colitis: patients are ready, are we? Inflamm Bowel Dis 2012; microbiota transplantation (fecal bacteriotherapy) for recurrent 18:676–684. Clostridium difficile infection. Clin Infect Dis 2011; 53:994–1002. 34. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of ADDRESS: Markus D. Agito, MD, Akron General Medical Center, 400 colonoscopic fecal microbiota transplant for recurrent Clostridium Wabash Avenue, Akron, OH 44307; e-mail [email protected].

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