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47-Year-Old Man With Abdominal Pain and Diarrhea

Published:November 12, 2017DOI:https://doi.org/10.1016/j.mayocp.2017.02.023
      A 47-year-old man presented with diffuse abdominal pain and multiple watery, nonbloody, nonmelenic bowel movements of 2 days' duration. The patient stated that he had roughly 10 bowel movements daily but reported no fevers or chills.
      Over the preceding 3 months, the patient had experienced 2 episodes of Clostridium difficile infection (CDI), the most recent having occurred 7 weeks earlier. Each occurrence was treated with a 2-week course of oral vancomycin, with improvement seen after 3 days of treatment. He recovered fully between episodes and had no symptoms for 7 weeks preceding the current episode. He reported no recent antibiotic exposure, but he had been hospitalized briefly during his earlier episode of CDI.
      The patient's medical history included remote cardiac and renal transplant. His medications included tacrolimus, prednisone, clonidine, escitalopram, bupropion, oxycodone, trazodone, and simvastatin.
      The patient had normal mentation but appeared fatigued. Vital sign testing revealed a blood pressure of 105/71 mm Hg, a heart rate of 82 beats/min, a temperature of 36.6°C, and a respiratory rate of 20 breaths/min. Physical examination revealed dry mucus membranes, and skin examination revealed increased skin turgor in the supraclavicular region. His abdominal examination was notable for hyperactive bowel sounds with diffuse tenderness to palpation without rebound or guarding. Digital rectal examination revealed a scant amount of nonbloody stool.
      Laboratory studies yielded the following results (reference ranges provided parenthetically): white blood cell count (WBC), 7.1 × 109/L (3.5-10.5 × 109/L); hemoglobin, 13.5-17.5 × 109 g/dL (12.0-15.5 g/dL); platelet count, 138 × 109/L (150-450 × 109/L); creatinine, 2.6 mg/dL (0.8-1.3 mg/dL) (at his baseline); albumin, 3.1 g/dL (3.5-5.0 g/dL); and tacrolimus trough level, 6.5 ng/mL (target trough levels, 5.0-15.0 ng/mL).
      • 1.
        Based on this patient's initial presentation, which one of the following is the most appropriate next step in obtaining an underlying diagnosis?
        • a.
          C difficile culture from rectal swab
        • b.
          C difficile toxin polymerase chain reaction (PCR) stool testing
        • c.
          Tissue transglutaminase IgA antibody test
        • d.
          Upper endoscopy with duodenal biopsies
        • e.
          Colonoscopy
      In patients with acute diarrhea that requires hospitalization, stool testing for enteric pathogens should be performed. Given this patient's history of CDI, his presentation with voluminous diarrhea and abdominal pain is worrisome for recurrence. Therefore, in addition to testing for enteric pathogens, tests for CDI are required. Clostridium difficile can be obtained from a rectal swab and grown on an anaerobic culture. In the past, this test was combined with stool cytotoxicity testing with neutralization by antisera to increase sensitivity.
      • Bagdasarian N.
      • Rao K.
      • Malani P.N.
      Diagnosis and treatment of Clostridium difficile in adults: a systematic review.
      With the advent of nucleic acid amplification testing, these tests are no longer considered first-line.
      C. difficile produces toxins A and B, which are enterotoxic and cytotoxic, respectively, and cause the clinical presentation of C difficile–associated diarrhea. Rapid diagnostic tests utilizing PCR for toxins A and B are now the standard in many institutions. However, clinicians should be aware that the high sensitivity of these tests increases the false-positive rate.
      • Bagdasarian N.
      • Rao K.
      • Malani P.N.
      Diagnosis and treatment of Clostridium difficile in adults: a systematic review.
      Given that PCR testing does not differentiate between an acute infection and carrier status, health care professionals should obtain this test only in the appropriate clinical setting.
      • Gupta A.
      • Khanna S.
      Repeat Clostridium difficile testing.
      Tissue transglutaminase IgA is used as a screening test in the work-up for celiac disease. If results are positive, this test is followed by upper endoscopy with duodenal biopsies to evaluate for classic histologic changes, including crypt hyperplasia, intraepithelial leukocytosis, and flattened villi. However, celiac disease often presents with a history of chronic diarrhea, and it may be accompanied by malnutrition and vitamin deficiencies, which are not apparent in our patient.
      In CDI, colonoscopy can reveal pseudomembranes, but this finding is uncommon and has poor sensitivity for CDI. Therefore, it is not the preferred method for diagnosis because of its invasive nature and the availability of safer tests. A stool C difficile toxin PCR test result was positive in our patient. If results of CDI testing are indeterminate or the patient has no improvement with therapy for CDI, colonoscopy with biopsies is warranted to determine if inflammatory bowel disease or microscopic colitis is responsible for the patient's symptoms.
      • 2.
        Given the patient's history and these findings, which one of the following is the most appropriate treatment?
        • a.
          Oral metronidazole, 500 mg 3 times daily for 10 days
        • b.
          Oral vancomycin, 125 mg 4 times daily for 10 days
        • c.
          Oral vancomycin, 125 mg 4 times daily for 10 days, followed by a pulsed vancomycin regimen for at least 10 more days
        • d.
          Oral fidaxomicin, 200 mg twice daily for 10 days
        • e.
          Intravenous vancomycin, 1 g twice daily for 48 hours followed by a 10-day course of oral vancomycin, 125 mg 4 times daily
      The treatment of CDI is based on the severity of disease, which can be classified into 3 separate groups: mild to moderate, severe, and severe and complicated. Complicating this case is the fact that our patient has had multiple episodes of CDI, and this hospitalization was his second recurrence.
      Recurrent CDI is defined as CDI occurring within 8 weeks of the completion of therapy for a previous CDI. American College of Gastroenterology (ACG) guidelines recommend repeating a course of antibiotics for first recurrence; for patients with a second recurrence, repeating a standard course of antibiotics followed by a prolonged taper or pulsed regimen is recommended.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      Our patient is currently experiencing a second recurrence of CDI and has been treated with two 10-day courses of oral vancomycin. Although metronidazole is recommended for the initial treatment of mild to moderate disease and may be utilized in a first recurrence, it is not indicated for the second recurrence of CDI.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      Repeating another standard 10-day course of oral vancomycin is not the preferred option because the patient has already had recurrence after this regimen. Given the best available evidence, this patient should be treated with a standard oral vancomycin regimen followed by a pulsed regimen or taper for at least 10 more days.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      A typical vancomycin taper regimen starts at 125 mg orally 4 times daily and has a stepwise decrease in dosage over the course of 6 to 8 weeks.
      Fidaxomicin has been found to have noninferiority for treatment of initial CDI compared with vancomycin and to be associated with a lower risk of recurrence.
      • Louie T.J.
      • Miller M.A.
      • Mullane K.M.
      • et al.
      OPT-80-003 Clinical Study Group
      Fidaxomicin versus vancomycin for Clostridium difficile infection.
      However, this medication has not been studied prospectively in multiple recurrences, although retrospective evidence suggests that the response rate decreases after the second recurrence.

      Spiceland CM, Khanna S, Pardi DS. Outcomes with fidaxomicin therapy in Clostridium difficile infection [published online ahead of print December 22, 2016]. J Clin Gastroenterol. http://dx.doi.org/10.1097/MCG.0000000000000769.

      Further, fidaxomicin is expensive, with a standard 10-day treatment course costing $2800. Given these limitations, fidaxomicin should not be prescribed at this point in treatment.
      For CDI treatment with vancomycin, oral delivery is required. The drug is not absorbed systemically, and intravenous vancomycin is not secreted into the gut.
      The patient began an oral vancomycin regimen of 125 mg 4 times daily. Initially, the patient did note reduced diarrhea but had persistence of abdominal pain. Physical examination findings were unchanged, and results of repeated serum tests did not reveal substantial changes from admission.
      • 3.
        Given this patient's current symptoms in light of initiating treatment, which one of the following actions is most appropriate as a next step?
        • a.
          Repeat C difficile toxin PCR testing
        • b.
          Stop the vancomycin regimen and initiate a fidaxomicin regimen
        • c.
          Perform bowel decompression
        • d.
          Stop pharmacological venous thromboembolism prophylaxis, given the potential for surgical intervention
        • e.
          Continue the current vancomycin regimen
      Testing for CDI is not recommended during or shortly after a treatment course, nor is monitoring toxin presence by PCR during treatment. Toxin PCR testing does not discriminate between active infection and carrier status.
      • Bagdasarian N.
      • Rao K.
      • Malani P.N.
      Diagnosis and treatment of Clostridium difficile in adults: a systematic review.
      Thus, this test result may be positive without providing meaningful data.
      This patient's diarrhea is decreasing with current therapy. Therefore, his current regimen is effective, so switching to another medication is not appropriate.
      Complications associated with CDI include pseudomembranous colitis, ileus, and toxic megacolon, which could present with increasing abdominal distention. The initial treatment of the latter 2 complications involves bowel decompression with placement of nasogastric and rectal tubes and close monitoring of the patient's condition for potential surgical decompression if needed. Prompt surgical consultation should be obtained in all cases of complicated and severe CDI. However, our patient's clinical presentation is not consistent with complicated CDI, given his benign physical examination findings without abdominal distention and mostly normal test results.
      Withholding deep venous thrombosis prophylaxis would be inappropriate, as patients with CDI are at high risk for venous thromboembolism. The ACG guidelines recommend that patients who have CDI be given all supportive measures that any other patient would receive.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      Given the reduction in diarrhea, treatment failure is not a concern. Our patient continued with the current vancomycin regimen, and his pain resolved over the next 24 hours. He was ultimately discharged with an oral vancomycin regimen including a prolonged taper over 6 weeks.
      • 4.
        If this patient were to have another recurrence of CDI (assuming adherence to his currently prescribed prolonged vancomycin course), which one of the following interventions is most appropriate to prevent further recurrence?
        • a.
          A repeated 10-day course of oral vancomycin
        • b.
          Referral for fecal microbiota transplant (FMT)
        • c.
          Lifelong low-dose oral vancomycin therapy
        • d.
          A 10-day course of intravenous metronidazole
        • e.
          A once-daily probiotic pill
      After a first episode of CDI, the risk of recurrence ranges from 20% to 30%.
      • Khanna S.
      • Pardi D.S.
      Clostridium difficile infection: new insights into management.
      Given the patient's multiple recurrences, repeating a standard course of oral vancomycin likely would not prevent a future episode.
      Fecal microbiota transplant is indicated in patients with more than 2 recurrences of CDI, severe infection requiring 2 hospitalizations, moderate CDI while receiving recommended therapy without improvement after 1 week, or severe CDI while receiving recommended therapy without improvement after 48 hours.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      Studies have found success rates as high as 90%.
      • Kelly C.R.
      • Ihunnah C.
      • Fischer M.
      • et al.
      Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients.
      Given our patient's recurrent hospitalizations for CDI, the best therapy is FMT to achieve remission with a lower recurrence rate than repeated treatment with antibiotics.
      In patients receiving long-term systemic antimicrobials, concurrent treatment with prophylactic oral vancomycin may play a role in preventing CDI.
      • Van Hise N.W.
      • Bryant A.M.
      • Hennessey E.K.
      • Crannage A.J.
      • Khoury J.A.
      • Manian F.A.
      Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents.
      However, our patient's history requires a referral for FMT before consideration of lifelong vancomycin exposure.
      Current guidelines do not endorse sole intravenous metronidazole therapy for the treatment of recurrent CDI. In severe and complicated infections, such therapy can be combined with oral vancomycin treatment.
      A meta-analysis studying use of probiotics in the prevention of recurrent CDI did not produce a strong recommendation; therefore, current ACG guidelines do not endorse probiotic therapy for prevention of recurrent CDI.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      However, further evaluation is required because studies have found that disruption of the enteric microbiome is associated with CDI.
      • Rea M.C.
      • O'Sullivan O.
      • Shanahan F.
      • et al.
      Clostridium difficile carriage in elderly subjects and associated changes in the intestinal microbiota.
      The patient was referred for FMT, but he was hesitant to proceed and instead he continued on the vancomycin taper. Fortunately, he has not developed recurrent CDI after 6 months of follow up.
      • 5.
        Which one of the following recommendations would be most appropriate to prevent further morbidity in this patient?
        • a.
          Practice of appropriate antibiotic stewardship
        • b.
          Utilization of alcohol-based antiseptics by the patient after he uses the bathroom
        • c.
          Lowering of the tacrolimus dose to decrease the level of immunosuppression
        • d.
          Immediate utilization of antidiarrheal medications if diarrhea recurs
        • e.
          Interval testing for C difficile toxin and treatment if results are positive
      The largest risk factor for CDI is prior exposure to antibiotics. Antibiotic stewardship programs, in which health care institutions and professionals develop a program to prescribe antibiotics only with appropriate indications, have been found to significantly reduce the incidence rate of CDI.
      • Feazel L.M.
      • Malhotra A.
      • Perencevich E.N.
      • Kaboli P.
      • Diekema D.J.
      • Schweizer M.L.
      Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and meta-analysis.
      When faced with uninhabitable conditions, C difficile exists as spores, which are resistant to damage from alcohol. Adequate hand-washing with soap and water can reduce transmission of C difficile.
      • Oughton M.T.
      • Loo V.G.
      • Dendukuri N.
      • Fenn S.
      • Libman M.D.
      Hand hygiene with soap and water is superior to alcohol rub and antiseptic wipes for removal of Clostridium difficile.
      Because of his chronically immunosuppressed state, our patient always will be at a higher risk of infection compared with the general population. His trough tacrolimus dose was within the normal range. The risks, such as organ rejection, of lowering his dose to a subtherapeutic range outweigh the benefits of decreasing his immunosuppression.
      In general, use of antidiarrheals is discouraged during CDI. These medications increase the risk of complications such as ileus and toxic megacolon. However, use of these medications can play a role in therapy for mild disease that is being appropriately treated.
      • Koo H.L.
      • Koo D.C.
      • Musher D.M.
      • DuPont H.L.
      Antimotility agents for the treatment of Clostridium difficile diarrhea and colitis.
      Starting antidiarrheals before establishing a diagnosis or initiating treatment is not recommended.
      Clostridium difficile toxin testing for cure is not advised. As discussed earlier, results of PCR testing for C difficile toxin cannot be used to differentiate between colonization and active infection. Interval test results for C difficile may be positive,
      • Bagdasarian N.
      • Rao K.
      • Malani P.N.
      Diagnosis and treatment of Clostridium difficile in adults: a systematic review.
      • Gupta A.
      • Khanna S.
      Repeat Clostridium difficile testing.
      but without clear clinical signs of CDI, this approach to treatment is not appropriate.
      Antibiotic stewardship is highly recommended for our patient and in general. It is our hope that increasing awareness of the morbidity and mortality of CDI will encourage providers to carefully choose antibiotics for only the most appropriate indications.

      Discussion

      This patient receiving long-term immunosuppression had multiple recurrences of CDI. Typical presenting features of recurrent CDI include the acute onset of diarrhea and abdominal pain, with characteristic risk factors of recent hospitalization and immunosuppression.
      Guidelines from the ACG specify 3 classes of CDI, closely aligning with treatment guidelines from the Infectious Diseases Society of America and the European Society of Clinical Microbiology and Infectious Diseases.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      Mild to moderate disease includes that in patients who do not meet criteria for more severe disease. Severe disease requires an albumin level of 3 g/dL or less, as well as a WBC count of 15 × 109/L or lower or abdominal tenderness. Severe and complicated disease includes that in any patients who require admission to an intensive care unit, have signs of organ failure, are hypotensive, are febrile (temperature of 38.5°C or higher), have substantial abdominal distention or ileus, are encephalopathic, have a WBC count of 35 × 109/L or more or 2 × 109/L or less, or have serum lactate levels of 2.2 mmol/L or greater.
      Oral vancomycin or metronizadole is used in mild disease, whereas dual therapy with intravenous metronidazole and oral vancomycin is reserved for severe and complicated cases of CDI. Rectal vancomycin treatment can be used when delivery of oral vancomycin to the colon is compromised, such as in patients with ileus. Surgical intervention should be considered in all cases of severe and complicated disease, in patients with a WBC count of 50,000/μL or more, those with a lactate level of 5 mmol/L or more, or patients with no improvement after taking antibiotics for 5 days.
      Recurrence is defined as CDI occurring within 8 weeks of an appropriately treated prior episode. Physicians should also consider postinfectious irritable bowel syndrome, which affects up to 25% of patients after 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.
      The treatment for recurrent CDI entails prolonged courses of oral antibiotics or referral for FMT.
      Causes of recurrence are likely multifactorial, including impaired immune response, altered colonic microbiota, and proton pump inhibitors.
      • Khanna S.
      • Pardi D.S.
      Clostridium difficile infection: new insights into management.
      Growing evidence of altered colonic microbiota in the pathophysiology of recurrent CDI led to trials of FMT.
      • Grehan M.J.
      • Borody T.J.
      • Leis S.M.
      • Campbell J.
      • Mitchell H.
      • Wettstein A.
      Durable alteration of the colonic microbiota by the administration of donor fecal flora.
      This type of transplantation involves delivery of donor stool into the gastrointestinal (GI) tract of patients with multiple recurrences of CDI. Although no consensus has been reached on the best method for preparation or delivery,
      • Kelly C.R.
      • Kahn S.
      • Kashyap P.
      • et al.
      Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook.
      FMT to the colon via colonoscopy or enema is postulated to be more successful than FMT to the upper GI tract via esophagogastroduodenoscopy or nasogastric tube.
      • Youngster I.
      • Russell G.H.
      • Pindar C.
      • Ziv-Baran T.
      • Sauk J.
      • Hohmann E.L.
      Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection.
      Concerns for transmission of infectious agents in the stool are reduced by obtaining stool from healthy donors with normal bowel function screened for common viral, bacterial, and parasitic pathogens. Guidelines for FMT do not make special provisions for immunosuppressed patients, and research has found that FMT is safe in the immunocompromised population, with cure rates similar to those in immunocompetent patients—around 90%.
      • Kelly C.R.
      • Ihunnah C.
      • Fischer M.
      • et al.
      Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients.
      Donor stool is homogenized and diluted in normal saline, which can then be directly infused into the GI tract (via endoscopy or rectal enema) or made into capsules and swallowed.
      • Youngster I.
      • Russell G.H.
      • Pindar C.
      • Ziv-Baran T.
      • Sauk J.
      • Hohmann E.L.
      Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection.
      Patient perceptions of this treatment are positive, with 97% reporting that they would repeat the procedure, and 50% stating that they would prefer FMT to treatment with antibiotics.
      • Brandt L.J.
      • Aroniadis O.C.
      • Mellow M.
      • et al.
      Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection.
      Recurrence rates of CDI after FMT are reported to be around 10%.
      • Kelly C.R.
      • Kahn S.
      • Kashyap P.
      • et al.
      Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook.
      Most of the recurrences are seen in patients who received antibiotics after FMT for other infections.
      • Brandt L.J.
      • Aroniadis O.C.
      • Mellow M.
      • et al.
      Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection.
      Therefore, the use of prophylactic anti-CDI antibiotics and strategies to prevent antibiotic-associated microbiome shifts may be effective in preventing recurrence after FMT.
      • Van Hise N.W.
      • Bryant A.M.
      • Hennessey E.K.
      • Crannage A.J.
      • Khoury J.A.
      • Manian F.A.
      Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents.
      After FMT, judicious prescription of antibiotics should be employed. If our patient subsequently did require antibiotics, concomitant anti-CDI antibiotics should be considered.

      Conclusion

      Clostridium difficile infection remains a substantial health care problem that is associated with substantial morbidity and health care costs. Recent advances in enteric microbiome research and FMT successes are transforming our understanding of CDI. However, further studies are required to determine the long-term effects and safety of these treatments and to develop novel microbiome-based CDI treatment and prevention strategies.

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