Advertisement

Experience and Outcomes at a Specialized Clostridium difficile Clinical Practice

Open AccessPublished:May 18, 2017DOI:https://doi.org/10.1016/j.mayocpiqo.2017.05.002

      Abstract

      Objective

      To report our experience with and outcomes among patients referred to a specialized Clostridium difficile clinical practice.

      Patients and Methods

      We retrospectively identified consecutive patients referred for Clostridium difficile infection (CDI) management from January 1, 2013, through May 30, 2015. Data were collected for demographic characteristics, CDI history, final diagnoses, and management.

      Results

      Overall, 211 patients (median age, 65 years; 66.4% women) were included. The most common indications for referral were recurrent CDI in 199 patients (94.3%), first CDI episode in 5 patients (2.4%), and chronic diarrhea in 7 patients (3.3%). After evaluation, the diagnoses were recurrent CDI in 127 patients (60.2%), resolved CDI in 36 patients (17.1%), first-episode CDI in 5 patients (2.4%), and non-CDI in 43 patients (20.4%). The most common non-CDI diagnoses were postinfection irritable bowel syndrome (PI-IBS) in 32 patients (15.2% overall), inflammatory bowel disease (n=3), small intestinal bacterial overgrowth (n=2), microscopic colitis (n=1), and asymptomatic C difficile colonization (n=2). Two patients had diabetic gastroparesis and food intolerances, and 1 had chronic constipation with overflow diarrhea. Of 127 patients with recurrent CDI, 30 (23.6%) received antibiotics; of these 30, 12 had antibiotic treatment failure and received fecal microbiota transplantation (FMT) for recurrent CDI. Among 97 patients (76.4%) who underwent FMT, 85 (87.6%) were cured after the first FMT, 5 were cured after the second FMT, and 7 were treated with antibiotics for FMT failure, with resolution of symptoms.

      Conclusion

      A substantial proportion of patients referred for CDI subsequently received alternative diagnoses; PI-IBS was the most common. Patients being referred for recurrent CDI should be evaluated carefully for alternative diagnoses.

      Abbreviations and Acronyms:

      CDI (Clostridium difficile infection), FMT (fecal microbiota transplantation), GI (gastrointestinal tract), IBS (irritable bowel syndrome), IRB (institutional review board), PCR (polymerase chain reaction), PI-IBS (postinfection irritable bowel syndrome)
      During the past 3 decades, the incidence of Clostridium difficile infection (CDI) has increased substantially in both hospital and community settings, and it is now the most common cause of hospital-acquired infection in the United States, with an overall cost in excess of $3.2 billion annually.
      • Miller B.A.
      • Chen L.F.
      • Sexton D.J.
      • Anderson D.J.
      Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals.
      • Lessa F.C.
      • Mu Y.
      • Bamberg W.M.
      • et al.
      Burden of Clostridium difficile infection in the United States.
      The severity and recurrence rates of CDI have increased markedly, with resulting poor outcomes.
      • Khanna S.
      • Pardi D.S.
      Clostridium difficile infection: management strategies for a difficult disease.
      • Magill S.S.
      • Edwards J.R.
      • Bamberg W.
      • et al.
      Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team
      Multistate point-prevalence survey of health care-associated infections.
      • Khanna S.
      • Baddour L.M.
      • Huskins W.C.
      • et al.
      The epidemiology of Clostridium difficile infection in children: a population-based study.
      • Khanna S.
      • Pardi D.S.
      • Aronson S.L.
      • et al.
      The epidemiology of community-acquired Clostridium difficile infection: a population-based study.
      The risk of recurrent CDI is approximately 20% to 25% after an initial episode and increases to more than 60% after 2 or more CDI episodes and with the use of additional systemic antibiotics.
      • Khanna S.
      • Pardi D.S.
      • Aronson S.L.
      • et al.
      The epidemiology of community-acquired Clostridium difficile infection: a population-based study.
      • Kelly C.P.
      • LaMont J.T.
      Clostridium difficile: more difficult than ever.
      • Khanna S.
      • Pardi D.S.
      IBD: poor outcomes after Clostridium difficile infection in IBD.
      The pathophysiology of recurrent CDI involves alteration of the gut microbiome, which is exacerbated by the use of antibiotics and which leads to further disruption of the protective intestinal microbiome and increased susceptibility to CDI. Treatment options for recurrent CDI include the use of tapered and pulsed courses of vancomycin, fidaxomicin, or rifaximin regimens. Fecal microbiota transplantation (FMT) has emerged as a safe, effective, and cost-effective treatment for recurrent and refractory CDI. It works by restoring the gut microbial diversity. Case series and observational studies have shown efficacy rates of 85% to 90%
      • Kassam Z.
      • Lee C.H.
      • Yuan Y.
      • Hunt R.H.
      Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.
      • Drekonja D.
      • Reich J.
      • Gezahegn S.
      • et al.
      Fecal microbiota transplantation for Clostridium difficile infection: a systematic review.
      • van Nood E.
      • Vrieze A.
      • Nieuwdorp M.
      • et al.
      Duodenal infusion of donor feces for recurrent Clostridium difficile.
      ; randomized controlled trials have demonstrated efficacy ranging from 50% with 1 stool enema
      • Lee C.H.
      • Steiner T.
      • Petrof E.O.
      • et al.
      Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: a randomized clinical trial.
      to more than 90% after multiple donor stool enemas or stool transplants with colonoscopy in patients with recurrent CDI.
      • Kelly C.R.
      • Khoruts A.
      • Staley C.
      • et al.
      Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial.
      Diagnosing recurrent CDI can be challenging because diagnostic test results can remain positive even after successful treatment.
      • Koo H.L.
      • Van J.N.
      • Zhao M.
      • et al.
      Real-time polymerase chain reaction detection of asymptomatic Clostridium difficile colonization and rising C. difficile-associated disease rates.
      • Gupta A.
      • Khanna S.
      Repeat Clostridium difficile testing.
      Nucleic acid amplification (polymerase chain reaction [PCR]) testing is extremely sensitive and may give false-positive results. Also, the risk of postinfection irritable bowel syndrome (PI-IBS) after resolved CDI is as high as 25%, and PI-IBS has symptoms similar to recurrent CDI.
      • Wadhwa A.
      • Al Nahhas M.F.
      • Dierkhising R.A.
      • et al.
      High risk of post-infectious irritable bowel syndrome in patients with Clostridium difficile infection.
      Patients with a diagnosis of recurrent CDI may, in fact, have functional gastrointestinal symptoms as a result of recent CDI and may have a positive stool test result due to colonization or a false-positive result, rather than true recurrent or persistent CDI. In a study of 117 patients referred with a diagnosis of recurrent CDI, 25% had an alternative cause for their diarrhea.
      • Jackson M.
      • Olefson S.
      • Machan J.T.
      • Kelly C.R.
      A high rate of alternative diagnoses in patients referred for presumed Clostridium difficile infection.
      We have demonstrated that 25% of patients with CDI have development of PI-IBS at least 6 months after their last CDI episode, which makes PI-IBS a possible cause of symptoms in patients with a history of CDI and ongoing gastrointestinal tract (GI) symptoms.
      • Wadhwa A.
      • Al Nahhas M.F.
      • Dierkhising R.A.
      • et al.
      High risk of post-infectious irritable bowel syndrome in patients with Clostridium difficile infection.
      Although FMT is not approved by the US Food and Drug Administration, several hospitals and medical centers offer it as a therapy for CDI owing to its efficacy in preventing recurrent CDI.
      • Drekonja D.
      • Reich J.
      • Gezahegn S.
      • et al.
      Fecal microbiota transplantation for Clostridium difficile infection: a systematic review.
      At our center, we established a C difficile Clinic in August 2012 to evaluate patients with recurrent CDI for FMT. This specialized clinic is designed to improve patient care and provide newer treatment options, including clinical trials and conventional FMT, for the treatment of patients with multiple recurrent episodes and refractory CDI.
      In this study, we report our experience with and outcomes in patients referred to our specialized C difficile clinical practice, including final diagnoses and management.

      Patients and Methods

      Data Collection

      The Mayo Clinic Institutional Review Board (IRB) approved prospective and retrospective data collection for this study. We first retrospectively identified all consecutive patients aged 18 years or older who were referred to our clinic for CDI management from January 1, 2013, through May 30, 2015. No patients were excluded on any basis. Data were collected and reviewed from the initial consultation and included demographic characteristics, referring diagnosis, CDI history, concurrent GI illness, final diagnoses, and management. Outcomes of interest included frequency of non-CDI diagnoses. For patients who received non-CDI diagnoses, additional information was collected regarding symptoms that might suggest alternate diagnoses and investigations to determine the exact cause of diarrhea. The PI-IBS was diagnosed on the basis of the Rome III criteria (improvement in abdominal pain with defecation or the onset of abdominal pain associated with a change in the frequency or form of the stool) and a recent history of CDI.
      • Beatty J.K.
      • Bhargava A.
      • Buret A.G.
      Post-infectious irritable bowel syndrome: mechanistic insights into chronic disturbances following enteric infection.
      Inflammatory bowel disease was diagnosed on the basis of endoscopic and histologic findings of Crohn disease or ulcerative colitis, and microscopic colitis was diagnosed on the basis of findings of normal colon on endoscopy and histologic findings consistent with lymphocytic or collagenous colitis. For patients who received FMT, the rate of prevention of future recurrent CDI was calculated.

      Patient Selection and Screening

      Patients referred to the C difficile Clinic at Mayo Clinic in Rochester, Minnesota, were evaluated for eligibility for conventional FMT and clinical trials by physicians staffing the clinic (S.K. and D.S.P.). Patients underwent a complete diagnostic evaluation to ascertain whether they truly met criteria for recurrent CDI, which included thorough history and physical examination, serologic and stool tests to rule out other causes of diarrhea, and, if needed, radiographic and endoscopic evaluation.

      Tariq R, Weatherly R, Kammer P, Pardi DS, Khanna S. Donor screening experience for fecal microbiota transplantation in patients with recurrent C. difficile infection [published online ahead of print December 14, 2016]. J Clin Gastroenterol.

      The various aspects of patient history considered while making a diagnosis of CDI and distinguishing it from other causes of diarrhea are shown in Figure 1. The diagnosis of CDI was made on the basis of the presence of watery diarrhea (≥3 watery stools/d) with a positive CDI stool test result. Eligibility criteria for FMT included patients with 3 or more CDI episodes established by a positive C difficile stool assay in the presence of diarrhea, and previous treatment with first-line therapies for CDI (metronidazole, vancomycin, or fidaxomicin), or a 6- to 8-week tapering course of vancomycin or vancomycin followed by rifaximin chaser, with a demonstrated treatment response.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      If deemed appropriate candidates for FMT, patients received education and detailed informed consent that outlined the risks and benefits of, and alternatives to, FMT before the procedure. Because FMT was a clinical procedure, IRB approval was not needed for the procedure.
      Figure thumbnail gr1
      Figure 1Diagnostic algorithm. A simplified approach for evaluation of patients to distinguish clinically between CDI recurrence and alternative causes of diarrhea. CDI = Clostridium difficile infection; FMT = fecal microbiota transplantation; IBD = inflammatory bowel disease; MC = microscopic colitis; PI-IBS = postinfection irritable bowel syndrome.

      Donor Recruitment and Screening

      In the initial stage of the program, FMT recipients identified a known stool donor, but this was later deemed an unfeasible approach.

      Tariq R, Weatherly R, Kammer P, Pardi DS, Khanna S. Donor screening experience for fecal microbiota transplantation in patients with recurrent C. difficile infection [published online ahead of print December 14, 2016]. J Clin Gastroenterol.

      First, every selected known donor had to undergo screening to determine eligibility, which created delays and high cost. Second, there were ethical issues; some patients were more comfortable using an anonymous donor, and some identified donors were found to have exclusions on preliminary testing.

      Tariq R, Weatherly R, Kammer P, Pardi DS, Khanna S. Donor screening experience for fecal microbiota transplantation in patients with recurrent C. difficile infection [published online ahead of print December 14, 2016]. J Clin Gastroenterol.

      To overcome these barriers, a standard donor pool was created. The creation of the donor pool was approved by the IRB. All donors underwent informed consent for screening before proceeding to stool donation. Donor screening (which included history and blood and stool testing) was performed with a well-defined protocol adapted from the published literature and vetted by providers within the departments of gastroenterology and infectious diseases and the Mayo Clinic Microbiome Program.
      • Bakken J.S.
      • Borody T.
      • Brandt L.J.
      • et al.
      Fecal Microbiota Transplantation Workgroup
      Treating Clostridium difficile infection with fecal microbiota transplantation.
      The donors were screened for specific exclusion criteria.

      Tariq R, Weatherly R, Kammer P, Pardi DS, Khanna S. Donor screening experience for fecal microbiota transplantation in patients with recurrent C. difficile infection [published online ahead of print December 14, 2016]. J Clin Gastroenterol.

      Recipients were then given the option to choose a known or a standard donor. In our program, most patients receive FMT via colonoscopy; a minority of patients receive FMT via retention enema or via endoscopy into the duodenum.

      Statistical Analyses

      Data were entered into JMP version 11.0 (SAS Institute Inc), which was used for statistical analyses. Demographic and clinical variables were summarized using descriptive statistics. Continuous variables are reported as median (range), and categorical variables are reported as count (percentage).

      Results

      A total of 211 patients were identified and included in the study; patients' demographic characteristics, concurrent GI illnesses, CDI history, and CDI-related medication history are presented in Table 1. The most common indication for referral was recurrent CDI (199 patients; 94.3%). The most common established GI illnesses included inflammatory bowel disease in 16 patients (7.6%), irritable bowel syndrome (IBS) in 8 patients (3.8%), and microscopic colitis in 7 patients (3.3%). None of the patients was taking concomitant systemic antibiotics along with CDI treatment at the time of consultation.
      Table 1Characteristics of Patients Referred to CDI Clinic
      CDI = Clostridium difficile infection; GI = gastrointestinal tract; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome.
      CharacteristicValue (N=211)
      Values are median (range) or No. of patients (%).
      Age (y)65 (18-93)
      Sex: women140 (66.4)
      Indication for referral
       Recurrent CDI199 (94.3)
       First episode of CDI5 (2.4)
       Nonspecific diarrhea7 (3.3)
      Most common concurrent GI illness
       IBD16 (7.6)
       IBS8 (3.8)
       Microscopic colitis7 (3.3)
      Previous CDI episodes
       05 (2.4)
       118 (8.5)
       258 (27.5)
       ≥3130 (61.6)
      CDI medications at presentation
       Vancomycin99 (46.9)
       Metronidazole10 (4.7)
       Fidaxomicin3 (1.4)
       Vancomycin and metronidazole2 (0.9)
       Loperamide1 (0.5)
      Previous CDI medications
       ≥1 course of vancomycin168 (79.6)
       ≥1 course of metronidazole149 (70.6)
       ≥1 course of fidaxomicin31 (14.7)
      a CDI = Clostridium difficile infection; GI = gastrointestinal tract; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome.
      b Values are median (range) or No. of patients (%).
      Of the 211 patients, 43 (20.4%) received a non-CDI diagnosis as a cause of their diarrhea, on the basis of clinical evaluation and diagnostic investigations (Table 2). Features consistent among most of the patients with alternative diagnoses included a history of nonresponsiveness to CDI therapy and negative CDI stool testing results. The most common alternative diagnosis was PI-IBS (32 [74.4%] of non-CDI patients; 15.2% overall) after recent CDI. Of the 32 patients with PI-IBS, 3 had positive CDI PCR test results and were considered to be CDI carriers with PI-IBS; the other 29 patients had negative CDI stool test results (Table 3). Sixteen patients had ongoing symptoms at the time of follow-up and were using symptomatic therapies, including fiber, antidiarrheals, antispasmodics, and tricyclic antidepressants; 7 of these patients had resolution of symptoms, and 9 were lost to follow-up. The median follow-up period for patients with PI-IBS was 2 years (range, 1-3 years). Among patients who received non-CDI diagnoses, 2 had multiple diagnoses, including diabetic gastroparesis, multiple food intolerances, and chronic functional diarrhea, and 1 had chronic constipation with overflow diarrhea. In addition to the 3 patients with PI-IBS and CDI colonization, 2 other patients were deemed to have asymptomatic CDI colonization owing to the absence of watery diarrhea and positive stool PCR test results.
      Table 2Final Diagnoses Among Patients Referred to CDI Clinic
      CDI = Clostridium difficile infection; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; SIBO = small intestinal bacterial overgrowth.
      DiagnosisNo. of patients (%) (N=211)
      Recurrent CDI127 (60.2)
      Resolved CDI36 (17.1)
      First episode of CDI5 (2.4)
      Non-CDI diagnosis43 (20.4)
       Postinfection IBS32 (74.4)
       IBD3 (7.0)
       SIBO2 (4.7)
       Multiple diagnoses
      Diabetic gastroparesis, multiple food intolerances, and chronic functional diarrhea.
      2 (4.7)
       Microscopic colitis1 (2.3)
       Chronic constipation with overflow diarrhea1 (2.3)
       CDI colonization2 (4.7)
      a CDI = Clostridium difficile infection; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; SIBO = small intestinal bacterial overgrowth.
      b Diabetic gastroparesis, multiple food intolerances, and chronic functional diarrhea.
      Table 3Characteristics of Patients With Postinfection Irritable Bowel Syndrome
      CDI = Clostridium difficile infection.
      CharacteristicValue (n=32)
      Values are median (range) or No. of patients (%).
      Age (y)53 (23-83)
      Sex: female21 (65.6)
      >2 Episodes of CDI21 (65.6)
      Treated with ≥1 course of vancomycin24 (75)
      Treated with ≥1 course of metronidazole20 (62.5)
      No response to CDI treatment8 (25)
      CDI positive3 (9)
      a CDI = Clostridium difficile infection.
      b Values are median (range) or No. of patients (%).
      Of the other patients, 127 (60.2%) were determined to have recurrent CDI, 36 (17.1%) had resolved CDI, and 5 (2.4%) were asymptomatic after their first episode of CDI. Table 2 presents the final diagnoses for all patients referred to the CDI clinic. Of the patients with recurrent CDI, 97 (76.4%) were treated with FMT and 30 (23.6%) had medical management, either because of patient preference or because they had not had 3 or more episodes of CDI (Figure 2). Among patients with medical management, 12 (40%) subsequently underwent FMT after failure of antibiotic treatment. Among patients who received FMT, 87.6% (n=85) were cured after the first FMT, 5 were cured after the second FMT, and 7 were treated with antibiotics for FMT failure. Of the 7 patients with FMT failure, 5 had early FMT failure (within 3 months); post-FMT antibiotic exposure was the cause of FMT failure in all patients.
      Figure thumbnail gr2
      Figure 2Outcomes among patients with recurrent CDI (n=127). CDI = Clostridium difficile infection; FMT = fecal microbiota transplantation.

      Discussion

      With an increase in the incidence of recurrent CDI, more patients are being referred for FMT owing to its high efficacy in preventing recurrent CDI.
      • Drekonja D.
      • Reich J.
      • Gezahegn S.
      • et al.
      Fecal microbiota transplantation for Clostridium difficile infection: a systematic review.
      The purpose of specialized clinics is to accept referrals and treat patients with CDI, including those not responding to traditional therapies. In the present study, we report our experience with patients referred to our specialized C difficile clinic. A substantial proportion, 20.4%, did not have recurrent CDI and ultimately received a non-CDI diagnosis. The most common alternative diagnosis was PI-IBS. Most of the patients with PI-IBS had a recent CDI episode and had negative results of CDI stool tests. A few patients with PI-IBS had a positive CDI stool test result and were considered to be CDI colonizers. These patients were treated according to their symptoms, and none was offered FMT.
      A few studies have described PI-IBS after infectious diarrhea caused by Campylobacter, Salmonella, Escherichia, and Shigella species,
      • Spiller R.C.
      • Jenkins D.
      • Thornley J.P.
      • et al.
      Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome.
      • Connor B.A.
      Sequelae of traveler's diarrhea: focus on postinfectious irritable bowel syndrome.
      • Borgaonkar M.R.
      • Ford D.C.
      • Marshall J.K.
      • Churchill E.
      • Collins S.M.
      The incidence of irritable bowel syndrome among community subjects with previous acute enteric infection.
      but the data describing PI-IBS after CDI are limited. One study described the rate of PI-IBS after CDI to be 35%, but 3 months after the initial CDI episode only 4.3% had symptoms indicative of PI-IBS.
      • Piche T.
      • Vanbiervliet G.
      • Pipau F.G.
      • et al.
      Low risk of irritable bowel syndrome after Clostridium difficile infection.
      One recent study described sequelae of CDI in a US military population and found that 14.1% of patients had development of functional gastrointestinal symptoms (eg, IBS, gastroesophageal reflux disorder, and dyspepsia), whereas only 6% among a matched unexposed population had similar symptoms.
      • Gutierrez R.L.
      • Riddle M.S.
      • Porter C.K.
      Increased risk of functional gastrointestinal sequelae after Clostridium difficile infection among active duty United States military personnel (1998-2010).
      Another recent study reported the incidence of new-onset PI-IBS 6 months or longer after an episode of CDI to be 25%.
      • Wadhwa A.
      • Al Nahhas M.F.
      • Dierkhising R.A.
      • et al.
      High risk of post-infectious irritable bowel syndrome in patients with Clostridium difficile infection.
      Finally, in a study evaluating outcomes in patients referred to their FMT center for recurrent CDI, a large percentage of the population did not have CDI but had an alternative cause of diarrhea, with IBS and PI-IBS being the most common.
      • Jackson M.
      • Olefson S.
      • Machan J.T.
      • Kelly C.R.
      A high rate of alternative diagnoses in patients referred for presumed Clostridium difficile infection.
      Our results are generally in line with these previous studies and demonstrate that PI-IBS is common after CDI.
      A careful and thorough clinical evaluation is needed to diagnose CDI. History taking should include an estimation of baseline bowel pattern and stool consistency using the Bristol stool scale, comparing it with bowel pattern and consistency during an active CDI episode, and previous response to anti-CDI therapy. The presence or absence of other symptoms such as alternating constipation or difficult defecation should be elucidated (Figure 1). In some patients, laboratory evaluation including assessment of the white blood cell count, serum creatinine and albumin levels, and upper GI endoscopy or diagnostic flexible sigmoidoscopy or colonoscopy may be helpful to rule out alternative causes of diarrhea.
      It is imperative to understand the different interpretations of stool testing for C difficile, and such testing should be performed only in the presence of symptoms suggestive of CDI. C difficile colonization and false-positive test results are common after a treated episode of CDI, with studies reporting positive CDI test results in about 63% of patients after successful treatment of a CDI episode.
      • Gerding D.N.
      • Meyer T.
      • Lee C.
      • et al.
      Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial.
      About 3% of outpatients and 4% to 29% of inpatients without infection may be colonized with C difficile.
      • Gerding D.N.
      • Meyer T.
      • Lee C.
      • et al.
      Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial.
      • Zacharioudakis I.M.
      • Zervou F.N.
      • Pliakos E.E.
      • Ziakas P.D.
      • Mylonakis E.
      Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis.
      If these patients have diarrhea at initial evaluation, it is difficult to distinguish between an alternate cause of diarrhea, such as PI-IBS, and true CDI recurrence. Several diagnostic tests are available to diagnose CDI. Enzyme immunoassay for toxin detection lacks sensitivity and, used alone, is considered insufficient for diagnosis of CDI. A 2-step algorithm using glutamate dehydrogenase antigen detection followed by enzyme immunoassay testing for toxin A or B has variable specificity (0.32-0.99).
      • Bagdasarian N.
      • Rao K.
      • Malani P.N.
      Diagnosis and treatment of Clostridium difficile in adults: a systematic review.
      The PCR test for detection of tcdB is widely used and is the preferred diagnostic test because of its high sensitivity and specificity and fast turnaround time.
      • Carroll K.C.
      Tests for the diagnosis of Clostridium difficile infection: the next generation.
      However, a limitation of PCR testing is its lack of ability to distinguish between true CDI and colonization.
      • Koo H.L.
      • Van J.N.
      • Zhao M.
      • et al.
      Real-time polymerase chain reaction detection of asymptomatic Clostridium difficile colonization and rising C. difficile-associated disease rates.
      • Gupta A.
      • Khanna S.
      Repeat Clostridium difficile testing.
      • Gerding D.N.
      • Meyer T.
      • Lee C.
      • et al.
      Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial.
      • Zacharioudakis I.M.
      • Zervou F.N.
      • Pliakos E.E.
      • Ziakas P.D.
      • Mylonakis E.
      Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis.
      A multistep algorithm using PCR for confirmation after initial testing of glutamate dehydrogenase and toxin A and B with enzyme immunoassay has good sensitivity (0.68-1.0) and specificity (0.92-1.0). This is most likely the best strategy for diagnosing CDI and may help in distinguishing true CDI from colonization.
      • Gupta A.
      • Khanna S.
      Repeat Clostridium difficile testing.
      The high rate of an alternate diagnosis in patients with presumed CDI is also associated with increased financial burden. Several studies have estimated the cost of medical care for each episode of CDI at between $2000 and $5000.
      • McFarland L.V.
      • Surawicz C.M.
      • Rubin M.
      • Fekety R.
      • Elmer G.W.
      • Greenberg R.N.
      Recurrent Clostridium difficile disease: epidemiology and clinical characteristics.
      • Kofsky P.
      • Rosen L.
      • Reed J.
      • Tolmie M.
      • Ufberg D.
      Clostridium difficile: a common and costly colitis.
      • Konijeti G.G.
      • Sauk J.
      • Shrime M.G.
      • Gupta M.
      • Ananthakrishnan A.N.
      Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis.
      Hence, an accurate diagnosis of recurrent CDI is essential to decrease the financial burden and prevent unnecessary use of anti-CDI treatments, including FMT.
      Our study highlights that all patients referred to a CDI clinic as potential candidates for FMT for presumed recurrent CDI should undergo thorough clinical evaluation, and providers should have a high degree of clinical suspicion for an alternative cause of diarrhea. This is especially true in those with atypical CDI symptoms, including absence of watery diarrhea or nonresponse to typically effective CDI treatments. In addition, it is difficult to distinguish symptomatic patients with a positive CDI stool test result due to true CDI recurrence from patients with PI-IBS with CDI colonization. Current data do not support the use of FMT as treatment, outside of research settings, for diagnoses other than recurrent CDI, especially for PI-IBS, which was the most common alternative diagnosis in our cohort.
      Our study has several limitations. Data were incomplete in certain aspects, including details regarding CDI history and management, because they were collected retrospectively. The diagnosis of PI-IBS was mostly based on clinical history, and there is no confirmatory clinical test. Our study reports a single-center experience, and the study should be replicated at other centers.
      In conclusion, a considerable proportion of patients referred to our CDI clinic subsequently received an alternative diagnosis, with PI-IBS being the most common. Clinicians should consider this diagnosis, especially in patients with symptoms refractory to CDI treatment and with ongoing symptoms but negative test results. Further prospective cohort studies with longer follow-up of patients with CDI who have PI-IBS development versus those who have symptom resolution might be helpful in understanding and exploring ways to distinguish PI-IBS from true CDI recurrence. These studies should focus on the role of gut microbiota and changes that are associated with the development of PI-IBS after CDI.

      References

        • Miller B.A.
        • Chen L.F.
        • Sexton D.J.
        • Anderson D.J.
        Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals.
        Infect Control Hosp Epidemiol. 2011; 32: 387-390
        • Lessa F.C.
        • Mu Y.
        • Bamberg W.M.
        • et al.
        Burden of Clostridium difficile infection in the United States.
        N Engl J Med. 2015; 372: 825-834
        • Khanna S.
        • Pardi D.S.
        Clostridium difficile infection: management strategies for a difficult disease.
        Therap Adv Gastroenterol. 2014; 7: 72-86
        • Magill S.S.
        • Edwards J.R.
        • Bamberg W.
        • et al.
        • Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team
        Multistate point-prevalence survey of health care-associated infections.
        N Engl J Med. 2014; 370: 1198-1208
        • Khanna S.
        • Baddour L.M.
        • Huskins W.C.
        • et al.
        The epidemiology of Clostridium difficile infection in children: a population-based study.
        Clin Infect Dis. 2013; 56: 1401-1406
        • Khanna S.
        • Pardi D.S.
        • Aronson S.L.
        • et al.
        The epidemiology of community-acquired Clostridium difficile infection: a population-based study.
        Am J Gastroenterol. 2012; 107 (Erratum in: Am J Gastroenterol. 2012;107(1):89-95): 89-95
        • Kelly C.P.
        • LaMont J.T.
        Clostridium difficile: more difficult than ever.
        N Engl J Med. 2008; 359 (Erratum in: N Engl J Med. 2010;363(16):1585): 1932-1940
        • Khanna S.
        • Pardi D.S.
        IBD: poor outcomes after Clostridium difficile infection in IBD.
        Nat Rev Gastroenterol Hepatol. 2012; 9: 307-308
        • Kassam Z.
        • Lee C.H.
        • Yuan Y.
        • Hunt R.H.
        Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.
        Am J Gastroenterol. 2013; 108: 500-508
        • Drekonja D.
        • Reich J.
        • Gezahegn S.
        • et al.
        Fecal microbiota transplantation for Clostridium difficile infection: a systematic review.
        Ann Intern Med. 2015; 162: 630-638
        • 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
        • Lee C.H.
        • Steiner T.
        • Petrof E.O.
        • 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
        • Kelly C.R.
        • Khoruts A.
        • Staley C.
        • et al.
        Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial.
        Ann Intern Med. 2016; 165: 609-616
        • Koo H.L.
        • Van J.N.
        • Zhao M.
        • et al.
        Real-time polymerase chain reaction detection of asymptomatic Clostridium difficile colonization and rising C. difficile-associated disease rates.
        Infect Control Hosp Epidemiol. 2014; 35: 667-673
        • Gupta A.
        • Khanna S.
        Repeat Clostridium difficile testing.
        JAMA. 2016; 316: 2422-2423
        • Wadhwa A.
        • Al Nahhas M.F.
        • Dierkhising R.A.
        • et al.
        High risk of post-infectious irritable bowel syndrome in patients with Clostridium difficile infection.
        Aliment Pharmacol Ther. 2016; 44: 576-582
        • Jackson M.
        • Olefson S.
        • Machan J.T.
        • Kelly C.R.
        A high rate of alternative diagnoses in patients referred for presumed Clostridium difficile infection.
        J Clin Gastroenterol. 2016; 50: 742-746
        • Beatty J.K.
        • Bhargava A.
        • Buret A.G.
        Post-infectious irritable bowel syndrome: mechanistic insights into chronic disturbances following enteric infection.
        World J Gastroenterol. 2014; 20: 3976-3985
      1. Tariq R, Weatherly R, Kammer P, Pardi DS, Khanna S. Donor screening experience for fecal microbiota transplantation in patients with recurrent C. difficile infection [published online ahead of print December 14, 2016]. J Clin Gastroenterol.

        • Surawicz C.M.
        • Brandt L.J.
        • Binion D.G.
        • et al.
        Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
        Am J Gastroenterol. 2013; 108 (quiz 499): 478-498
        • Bakken J.S.
        • Borody T.
        • Brandt L.J.
        • et al.
        • Fecal Microbiota Transplantation Workgroup
        Treating Clostridium difficile infection with fecal microbiota transplantation.
        Clin Gastroenterol Hepatol. 2011; 9: 1044-1049
        • Spiller R.C.
        • Jenkins D.
        • Thornley J.P.
        • et al.
        Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome.
        Gut. 2000; 47: 804-811
        • Connor B.A.
        Sequelae of traveler's diarrhea: focus on postinfectious irritable bowel syndrome.
        Clin Infect Dis. 2005; 41: S577-S586
        • Borgaonkar M.R.
        • Ford D.C.
        • Marshall J.K.
        • Churchill E.
        • Collins S.M.
        The incidence of irritable bowel syndrome among community subjects with previous acute enteric infection.
        Dig Dis Sci. 2006; 51: 1026-1032
        • Piche T.
        • Vanbiervliet G.
        • Pipau F.G.
        • et al.
        Low risk of irritable bowel syndrome after Clostridium difficile infection.
        Can J Gastroenterol. 2007; 21: 727-731
        • Gutierrez R.L.
        • Riddle M.S.
        • Porter C.K.
        Increased risk of functional gastrointestinal sequelae after Clostridium difficile infection among active duty United States military personnel (1998-2010).
        Gastroenterology. 2015; 149: 1408-1414
        • Gerding D.N.
        • Meyer T.
        • Lee C.
        • et al.
        Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial.
        JAMA. 2015; 313: 1719-1727
        • Zacharioudakis I.M.
        • Zervou F.N.
        • Pliakos E.E.
        • Ziakas P.D.
        • Mylonakis E.
        Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis.
        Am J Gastroenterol. 2015; 110 (quiz 391): 381-390
        • Bagdasarian N.
        • Rao K.
        • Malani P.N.
        Diagnosis and treatment of Clostridium difficile in adults: a systematic review.
        JAMA. 2015; 313: 398-408
        • Carroll K.C.
        Tests for the diagnosis of Clostridium difficile infection: the next generation.
        Anaerobe. 2011; 17: 170-174
        • McFarland L.V.
        • Surawicz C.M.
        • Rubin M.
        • Fekety R.
        • Elmer G.W.
        • Greenberg R.N.
        Recurrent Clostridium difficile disease: epidemiology and clinical characteristics.
        Infect Control Hosp Epidemiol. 1999; 20: 43-50
        • Kofsky P.
        • Rosen L.
        • Reed J.
        • Tolmie M.
        • Ufberg D.
        Clostridium difficile: a common and costly colitis.
        Dis Colon Rectum. 1991; 34: 244-248
        • Konijeti G.G.
        • Sauk J.
        • Shrime M.G.
        • Gupta M.
        • Ananthakrishnan A.N.
        Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis.
        Clin Infect Dis. 2014; 58: 1507-1514

      Linked Article

      • The Challenging Conundrum of Diagnosing and Managing Clostridium difficile Infection
        Mayo Clinic Proceedings: Innovations, Quality & Outcomes Vol. 1Issue 1
        • Preview
          Management of patients with Clostridium difficile infection (CDI) can be very difficult, especially for the approximately 25% of patients who have had recurrences, and particularly for those who have had multiple recurrences. Following recurrence, patients typically respond to a new course of antimicrobial treatment, usually with vancomycin or fidaxomicin, but often have another recurrence within a few days to months after stopping treatment. Although treatment failure to resolve symptoms is not uncommon when metronidazole is used,1 failure to resolve symptoms when treated with a new course of antimicrobial treatment with either vancomycin or fidaxomicin is an indication that a condition other than CDI may be the cause of the patient's symptoms.
        • Full-Text
        • PDF
        Open Access