Managing Clostridium Difficile: An Old Bug With

932 The Red Section see related editorial on page x Managing Clostridium Difficile: An Old Bug With New Tricks Stephen M. Vindigni, MD, MPH 1,2 and Christina M. Surawicz, MD 1 Am J Gastroenterol (2018) 113:932 935. https://doi.org/10.1038/s41395-018-0059-y Introduction Epidemics of Clostridium difficile infection (CDI) in the US, Canada, and Europe began around the year 2000 with the emergence of a hypervirulent strain with sicker patients who are more likely to require emergent colectomy or die. Previously, CDI was seen mostly in older hospitalized patients on broad-spectrum antibiotics, but now we see more CDI in immune suppressed patients, especially following solid organ or bone marrow transplant and in inflammatory bowel disease (IBD) patients. Furthermore, there are more community-acquired cases, even in healthy people, peripartum women and some without prior antibiotic exposure. Still, the highest rates and highest mortality are in the elderly, especially over age 75. C. difficile, but it does not detect toxin. The main downside of these tests is that they will be positive in carriers, which will lead to over diagnosis [2]. Approximately 5 15% of healthy adults are carriers of C. difficile and rates are even higher in those in hospitals or long-term care facilities. Some experts are now recommending 2-step diagnostic testing in which a highly sensitive test like PCR, when positive, is followed by a more specific test, like the EIA, to minimize false positives [3]. Only diarrheal stools should be sent for testing and there is no role for repeat stool testing. Stool tests like PCR may remain positive for a prolonged period after successful therapy so testing for cure is not recommended. Bottom line: there is no perfect diagnostic test so find out what your lab is doing, understand the limitations and remember the importance of clinical correlation. Clinical presentation, diagnosis, and treatment Clinical presentation Watery diarrhea and crampy abdominal pain are the most common symptoms, but there can be bloody stools in those with concomitant IBD or severe colitis. However, there may be no diarrhea and only abdominal distension and pain with severe disease, such as pseudomembranous colitis (Fig. 1) or an associated ileus. The spectrum of severity is classified as mild to moderate, severe, or severe/complicated disease (Table 1) [1]. In addition to diarrhea and abdominal distension, laboratory indicators of severe disease are leukocytosis, hypoalbuminemia, and elevated serum creatinine. Response to therapy is determined by following diarrhea, abdominal exam, and these laboratory parameters. Diagnostic tests Laboratory diagnosis of CDI can be confusing and there currently is no perfect diagnostic test. The rapid enzyme immunoassays (EIA) for toxin A and/or B that detect the presence of toxin have relatively low sensitivity (80 90%), so using them alone may miss some cases. Many laboratories now use a nucleic acid amplification test (NAAT), such as polymerase chain reaction (PCR) that detects the gene for toxin B; this is highly sensitive for detecting Treatment of first episodes Following treatment guidelines is associated with better patient outcomes, especially in sicker patients; specific regimens are in Table 2 [1]. In patients with mild to moderate CDI, a 10-day course of oral metronidazole is the recommended first line drug in the ACG guidelines. Fidaxomicin is an option, but is much more expensive. Expert opinion recommends oral vancomycin as first line therapy in IBD patients, even for mild disease [4]. Oral vancomycin is the best initial therapy for those with severe disease. Patients with severe/complicated CDI (also referred to as refractory or fulminant) should be started on oral vancomycin, as well as intravenous metronidazole with consideration of adding vancomycin enemas, especially if there is an ileus. If these severely ill patients are not improving with maximal medical therapy, one should consider surgery to remove or bypass the colon. Surgical options include subtotal colectomy or a loop ileostomy. The loop ileostomy leaves the colon in place so that a vancomycin solution can be lavaged into the downstream colon until it heals with later reversal of the ileostomy [1, 5]. Surgery is the standard of care for these ill patients not responding to maximal medical therapy, but an emerging alternative especially for patients too sick for surgery is fecal microbiota transplantation (FMT), which is putting 1 Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA. 2 Alaska Native Tribal Health Consortium, Alaska Native Medical Center, Anchorage, Alaska, USA. Correspondence: S.M.V. (email: smvindigni@anthc.org) Published online 24 April 2018 The American Journal of Gastroenterology Volume 113 July 2018 www.nature.com/ajg

The Red Section 933 Table 2 Recommended treatment regimens by CDI severity Fig. 1 Pseudomembranous colitis. The yellow plaques are the pseudomembranes, composed of inflammatory cells, fibrin, and debris Table 1 Definitions of severity of CDI Severity of CDI Mild-moderate Severe Severe and complicated Clinical presentation Watery diarrhea Absence of below findings (e.g., albumin <3 g/dl, significant leukocytosis, fever, evidence of end-organ damage) Albumin <3 g/dl and WBC >15,000 cells/mm 3 or abdominal tenderness Severe disease and any of the following attributable to CDI: Intensive care unit admission Mental status changes Hypotension with or without need for pressors Significant leukocytosis >35,000 cells/mm 3 Significant leukopenia <2000 cells/mm 3 Hypoalbuminemia Elevated serum lactate (>2.2 mmol/l) Fever >38.5 C Abdominal distention ± ileus Evidence of end-organ damage, including pulmonary or renal dysfunction stool from a healthy person into the diseased colon. A series of 57 cases of severe or severe/complicated CDI treated at one center by serial FMT administration showed overall efficacy of 91% and a 3-month survival of 78% [6, 7]. Proceeding with FMT can be a difficult decision in such patients; if being considered, we recommend using these authors protocol given their extensive experience. Treatment of CDI in IBD patients These patients are sicker than patients with either IBD or CDI alone; they also may be harder to evaluate, as the symptoms of CDI severity Mild-moderate CDI Severe CDI Severe and complicated CDI Recommended regimens 1. Metronidazole 500 mg PO TID 10 days 2. For IBD patients, vancomycin 125 mg PO QID 10 days Vancomycin 125 mg PO QID 10 days Vancomycin 250 500 mg PO QID and metronidazole 500 mg IV Q8 hours Additional considerations Discontinue intercurrent antibiotics, if possible. If no improvement with metronidazole after 5 7 days, change to vancomycin Fidaxomicin equivalent to vancomycin with fewer recurrences but role unclear given its high cost If no improvement, increase dose to 250 500mg PO QID For patients with ileus, add vancomycin 500 mg enema QID If not responding to maximal medical therapy, consider surgery to remove or bypass colon (standard of care) or FMT (role emerging). both diseases are similar. Any IBD patient, especially with colonic disease, experiencing a flare or not responding to therapy should be tested for C. difficile. As mentioned, vancomycin is recommended as first line therapy, even in mild cases. Experts also recommend not starting or escalating immune suppressing therapies for at least 2 3 days after starting CDI therapy while assessing response to therapy [4]. If colonoscopy is part of the evaluation, IBD patients may not form the classic pseudomembranes seen in many severe CDI cases. We have a low threshold for consulting an IBD expert when patients do not improve. Recurrent CDI (RCDI) Recurrent CDI is defined as recurrence of diarrhea (with a positive stool test) after successful response to therapy. Symptoms usually recur within 2 weeks of completing the anti-cdi therapy, but can occur up to 3 months later, especially in IBD patients. The major risk factors for recurrence are older age, more severe disease and having had a prior recurrence. Antibiotics For the first recurrence, one can use metronidazole, fidaxomicin, or vancomycin, unless it is severe in which case vancomycin is suggested. In a prior study of RCDI, pulsing and/or tapering vancomycin was associated with fewer recurrences [8], so we recommend this for the second recurrence. A simple pulse/ taper regimen is oral vancomycin 125 mg four times a day for 10 days followed by 125 mg daily pulsed every 3 days for 10 doses (Table 3). Others recommend a prolonged course of vancomycin for 4 6 weeks. 2018 The American College of Gastroenterology The American Journal of Gastroenterology

934 The Red Section Fecal microbiota transplantation In the patient with multiple recurrences, no current therapy is as effective as FMT with an overall 80 90% cure rate. In those who fail to achieve cure after FMT, repeating with another donor is often effective. Patients with IBD should be counseled that FMT might cause IBD to flare in a subset of patients [9, 10]. It is important to ensure the patient really has CDI recurrence and not diarrhea due to something else. For example, post-infectious irritable bowel syndrome (PI-IBS) with mild to moderate diarrhea is common after CDI and a positive stool test may indicate carriage of C. difficile rather than active infection. Often we will give a trial of vancomycin since this treats only CDI. If the patient does not get better and disease is not severe, they probably are carriers with PI-IBS or have another cause of diarrhea and FMT will not be helpful. Conversely, rapid and clear response to vancomycin would suggest that the etiology is indeed C. difficile. The FDA has stated that practitioners may use FMT for C. difficile not responding to standard therapy. Two excellent guides to FMT have been published [11, 12]. Sources of stool include patient-identified individuals, established donor pools at your individual institution, or from an established, reliable stool bank. All donors must be screened for gastrointestinal symptoms and other diseases and have blood and stool tested for pathogens. Fresh and frozen stool seem to be equally effective [13], as are oral capsules [14]. Stool can be delivered by nasoenteric tube, enema or colonoscopy. Colonoscopy allows for visualization of the colon, but enemas may be a better option in very ill or frail patients (Table 4). Rarely, multiple FMTs fail. This is more common in elderly patients who need frequent courses of antibiotics; long-term suppressive vancomycin therapy with low-dose vancomycin (125 mg daily) is effective. A dilute bleach solution in a spray bottle (9:1 water to bleach) is recommended to clean the environment at home, particularly high-touch surfaces, and can help prevent reinfection. Table 3 Management of recurrent C. difficile infection Definition of RCDI First recurrence CDI episode within 12 weeks of prior episode (severity may vary) Can be treated with metronidazole, vancomycin, or fidaxomicin Second recurrence Consider vancomycin 125 mg PO QID 10 days followed by additional pulsed vancomycin 125 mg daily every 3 days 10 doses or a longer, 4 6 week, course of vancomycin. Third recurrence Consider fecal microbiota transplantation if appropriate; Long-term suppressive vancomycin is an alternative in those with limited life expectancy Prevention of future episodes of RCDI Patients who need antibiotics again are at increased risk for RCDI. A narrow spectrum antibiotic is recommended, if appropriate. The role of probiotics is confusing since meta-analyses indicate they may decrease CDI, but these are evaluating many different probiotics, so one does not know which one to choose. There is good evidence that Saccharomyces boulardii and Lactobacillus GG prevent antibiotic-associated diarrhea, but not that they prevent CDI. An inexpensive option is drinking kefir (a yogurtlike drink), although efficacy is only anecdotal. Vancomycin co- administered with antibiotics to prevent future recurrences may be useful in the patient with many co-morbidities who has had RCDI and is at high risk of recurrence [15]. Bezlotoxumab is an intravenously administered monoclonal antibody to C. difficile toxin B that is FDA approved as an adjunct to antibiotics to prevent RCDI in those at high risk of recurrence. Table 4 Fecal microbiota transplantation for recurrent CDI: advantages and disadvantages by route Route of administration Advantages Disadvantages Nasoenteric No sedation required Patient discomfort with tube placement Oral capsules of frozen stool Enema Colonoscopy Less invasive Can be administered in office No sedation required Less invasive than colonoscopy Can be administered in non-endoscopy settings, including office or home No sedation required Easier to repeat, if failure of initial application May be more effective than the upper route Ability to evaluate colonic mucosa and obtain biopsies Risk of aspiration lower route Inability to evaluate colonic mucosa Cannot be used for patients with dysphagia or inability to swallow pills lower route colonoscopic route Transplanted stool generally does not reach beyond descending colon Generally requires sedation More expensive More invasive Standard risks of colonoscopy (e.g., patient discomfort, bleeding, and perforation) The American Journal of Gastroenterology Volume 113 July 2018 www.nature.com/ajg

The Red Section 935 Table 5 CDI therapies in the pipeline Treatment of CDI Antibiotics Treatment of RCDI Microbe-based therapies Prevention of CDI Enzymes Vaccines In trials, the number needed to treat to prevent one recurrence was 10 [16]. At this time, we do not know the best use for this expensive new therapy. What is in the pipeline? There are several products in development. For treatment, ridinilazode is a narrow spectrum antibiotic to treat CDI with a presumed benefit of preserving beneficial gut microbes; cadazolid recently failed to show efficacy. For prevention of CDI, there are three vaccines in development and an enzyme that degrades betalactam antibiotics in the gut. There are several microbial-based products in trials to treat RCDI, preventing further recurrences (Table 5). Take home points: Ridinilazode RBX2660: a live, human-derived microbiota suspension delivered by enema. In phase 2 trials, it was more effective than placebo in preventing further recurrences. SER 109: oral capsules of spores. It is currently in phase 3 trials even though a phase 2 trial failed to show efficacy. Analysis of the phase 2 trial indicated many subjects in the study might not have had RCDI. SYN-004: an oral enzyme (ribaxamase) that degrades beta-lactam antibiotics in the gastrointestinal tract is currently in trials. There are currently three vaccines in development. 1. Understand the C. difficile testing at your institution, recognizing there is no perfect diagnostic test. The EIA toxin assays are only 80 90% sensitive, so may miss cases. Gene based tests, like PCR, are very sensitive and may lead to over diagnosis. 2. Determine the severity of disease and treat according to guidelines, especially in sicker patients. 3. FMT is very effective for patients with multiple recurrences of CDI who recur after a vancomycin taper/pulse or prolonged regimen. There is limited long-term safety data, but in the short term, complications are uncommon. It is important to select the right patients, to acknowledge there may be unknown long-term risks, and to use established, published methods. Disclaimer The findings and conclusions in this editorial are those of the authors and do not necessarily reflect the views of the University of Washington or the Alaska Native Tribal Health Consortium. Conflict of interest Guarantor of the article: Christina Surawicz. Specific author contributions: S.M.V. and C.M.S. wrote text sections and edited them together. Financial support: None. Potential competing interests: None. References 1. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478 98. 2. Polage CR, Gyorke CE, Kennedy MA, et al. Overdiagnosis of Clostridium difficile infection in the molecular test era. JAMA Intern Med. 2015;175:1792 801. 3. Crobach MJ, Planche T, Eckert C, et al. European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2016;22(Suppl 4):S63 81. 4. Khanna S, Shin A, Kelly CP. Management of Clostridium difficile infection in Inflammatory Bowel Disease: expert review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol. 2017;15:166 74. 5. Neal MD, Alverdy JC, Hall DE, et al. Diverting loop ileostomy and colonic lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg. 2011;254:423 7. discussion 427-9 6. Fischer M, Sipe B, Cheng YW, et al. Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: a promising treatment approach. Gut Microbes. 2017;8:289 302. 7. Fischer M, Sipe BW, Rogers NA, et al. Faecal microbiota transplantation plus selected use of vancomycin for severe-complicated Clostridium difficile infection: description of a protocol with high success rate. Aliment Pharmacol Ther. 2015;42:470 6. 8. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97:1769 75. 9. Fischer M, Kao D, Kelly C, et al. Fecal microbiota transplantation is safe and efficacious for recurrent or refractory Clostridium difficile infection in patients with Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016;22:2402 9. 10. Khoruts A, Rank KM, Newman KM, et al. Inflammatory Bowel Disease affects the outcome of fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2016;14:1433 8. 11. Kelly CR, Kahn S, Kashyap P, et al. Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook. Gastroenterology. 2015;149:223 37. 12. Allegretti JR, Kassam Z, Osman M, et al. The 5D framework: a clinical primer for fecal microbiota transplantation to treat Clostridium difficile infection. Gastrointest Endosc. 2018;87:18 29. 13. 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 9. 14. Kao D, Roach B, Silva M, et al. Effect of oral capsule- vs colonoscopydelivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial. JAMA. 2017;318:1985 93. 15. Carignan A, Poulin S, Martin P, et al. Efficacy of secondary prophylaxis with vancomycin for preventing recurrent Clostridium difficile infections. Am J Gastroenterol. 2016;111:1834 40. 16. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile Infection. 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GASTROENTEROLOGY ARTICLE OF THE WEEK September 27, 2018 Vindigni SM, Surawicz CM. Managing Clostridium Difficile: An old bug with new tricks. Am J Gastroenterol 2018;113:932 935 1. For patients who have had C. diff and require additional antibiotic therapy, measures that may reduce risk of recurrence include a. Use of probiotics b. Use of bezlotoxumab c. Add vancomycin to the antibiotic regimen d. Drink Kefir e. Add fidaxomicin to the antibiotic regimen True or False 2. After initiation of vancomycin for C. diff in a patient with IBD, escalation or initiation of immunosuppressive therapy should be delayed by 2 3 days 3. Persistent diarrhea with positive C. diff testing does not always indicate relapsing C. diff 4. Follow up C. difficile testing should be done after therapy to confirm eradication in all patients 5. Intravenous metronidazole + oral vancomycin with or without vancomycin enemas is recommended for patients with severe or complicated C. diff infection. 6. PCR test for toxin B have a high sensitivity for detecting C. difficile, but does not differentiate between carriers are people with C. difficile infection 7. Vancomycin is the recommended first line therapy for all patients with C. difficile infection 8. Vancomycin should be used for C. difficile infection in IBD only if the patient has moderate to severe symptoms