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Faecal microbiota transplantation for Clostridium difficile infection: a multicentre study of non-responders

Roshan Razik*, Majdi Osman*, Alexandra Lieberman, Jessica R Allegretti and Zain Kassam
Med J Aust 2017; 207 (4): 159-160. || doi: 10.5694/mja16.01452
Published online: 21 August 2017

Faecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrent Clostridium difficile infection (rCDI), but 10–30% of patients do not respond to treatment.1,2 Data on this patient phenotype are scarce; in this article we describe a cohort of 135 patients in the United States who did not respond to FMT.

We assessed consecutively collected prospective case report forms for patients who did not respond to FMT for rCDI, completed by physicians during August 2014 – November 2015 and submitted to a not-for-profit stool bank (OpenBiome, http://www.openbiome.org/).3 Demographic, clinical, and treatment characteristics were evaluated. Non-response to FMT was defined by clinical symptoms and laboratory confirmation or endoscopic evaluation, according to standard of care. Clinicians who reported non-response were asked to complete a detailed non-response form.

Outcomes for 1845 FMT treatments during the study period were reported; the efficacy rate was 84.0%. Among the 295 non-responders, 135 non-response forms (46% response rate) were received from 74 health care facilities in 27 US states and the Netherlands. Most of these 135 non-responders were women (70%) and Caucasian (79%); the mean age was 65.9 years; 23 patients (17%) had previously undergone FMT. Of ten patients who received FMT by nasogastric tube, two had not received pre-procedure proton pump inhibitors (PPI). At least 19% of patients did not clean high-touch surface areas at home, such as toilets; only 30% of non-responders were clinically assessed for post-infectious irritable bowel syndrome (IBS) (Box).

Three novel observations are particularly important for practice. First, some physicians who performed FMT by nasogastric tube did not provide pre-therapy PPIs. Acid suppression is recommended for protecting the microbiota from gastric acid when delivered above the pre-pyloric sphincter; not doing so may significantly affect the efficacy of treatment.1,4

Second, 19% of non-responders did not decontaminate toilets from CDI spores after FMT. As molecular typing studies indicate that 10–50% of rCDIs are caused by re-infection,2 our results suggest that counselling patients about cleaning high-touch surfaces may be useful; however, more evidence about the benefits of home decontamination is required.

Finally, only 30% of patients were assessed for post-infectious IBS, a common aetiology of loose stool after CDI. Concerns about the accuracy of rCDI diagnosis in patients referred for FMT have been reported.5 There is no gold standard test for distinguishing these entities; differentiating rCDI from post-infectious IBS with underlying colonisation detected by polymerase chain reaction is particularly challenging.

Our study included the largest cohort of FMT treatment non-responders reported to date. We publish our findings with caution, given the uncontrolled design of our study and the potential for selection bias. However, this large multicentre study offers insights into the heterogeneity of the current state of FMT practice. Given the broad adoption of FMT, guidelines are required for improving education, developing criteria for assessing non-response to FMT, and guiding the informed consent process, so that clear advice about risks, benefits and alternatives can be provided, including the risk of non-response.

Box – Demographic and clinical characteristics of 135 United States patients who did not respond to faecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI)

Characteristic

 


Age at time of FMT (years), mean (SD)

65.9 (17.9)

Sex (men)

41 (30%)

Ethnic background

 

 Caucasian

107 (79%)

 Black or African American

11 (8%)

 Hispanic or Latino

6 (4%)

 Other

3 (2%)

 Not reported

8 (6%)

Long term care resident

19 (14%)

History of inflammatory bowel disease

17 (13%)

History of irritable bowel syndrome

18 (13%)

Medications at time of FMT

 

 Proton pump inhibitors

53 (39%)

 Immunosuppressive agents

33 (24%)

 Laxatives

3 (2%)

 Anti-motility agents

26 (19%)

Horn index (of disease severity)

 

 1 (mild)

7 (5%)

 2 (moderate)

62 (46%)

 3 (severe)

45 (33%)

 4 (extremely severe)

7 (5%)

 Not reported

14 (10%)

Received antibiotics prior to CDI diagnosis

81 (60%)

Health care-associated CDI

34 (25%)

Initial CDI diagnosis method*

 

 Toxin A or B

42 (31%)

 Polymerase chain reaction

89 (66%)

 Anaerobic culture/other

2 (2%)

 Not reported

12 (9%)

CDI treatment prior to FMT*

 

 Vancomycin

84 (62%)

 Metronidazole

59 (44%)

 Fidaxomicin

2 (2%)

CDI type*

 

 Refractory CDI

48 (37%)

 Recurrent CDI

101 (77%)

Average number of recurrences, mean (SD)

3.0 (1.9)

Inpatient admission to hospital

79 (61%)

NAP-1 strain of C. difficile

9 (7%)

FMT delivery modality

 

 Colonoscopy

81 (60%)

 Enema

10 (7%)

 Flexible sigmoidoscopy

2 (2%)

 Oesophagogastroduodenoscopy

15 (11%)

 Nasogastric tube

10 (7%)

 Nasoduodenal tube

2 (2%)

 Other

11 (8%)

 Not reported

4 (3%)

Colonoscopy preparation

95 (74%)

 Proton pump inhibitor prior to nasogastric tube

8 (80%)

Frozen FMT thaw methods

 

 Water bath

73 (56%)

 Room temperature

40 (30%)

Time between FMT and non-response (days), mean (SD)

15.3 (12.8)

Patient decontaminated toilets at home

 

 Yes

51 (38%)

 No

26 (19%)

 Not reported

58 (43%)

Assessed for post-infectious irritable bowel syndrome

41 (30%)


NAP-1 = North American pulsed-field gel electrophoresis type 1; SD = standard deviation. * Physicians could select more than one option. † Colonoscopy preparation is applied outside colonoscopy because of its potential role in spore clearance.

Received 20 December 2016, accepted 1 May 2017

  • Roshan Razik*1
  • Majdi Osman*2
  • Alexandra Lieberman3
  • Jessica R Allegretti4
  • Zain Kassam2,5

  • 1 University of Calgary, Calgary, AB, Canada
  • 2 OpenBiome, Somerville, MA, USA
  • 3 George Washington University School of Medicine and Health Sciences, Washington, DC, USA
  • 4 Brigham and Women's Hospital, Boston, MA, USA
  • 5 Massachusetts Institute of Technology, Cambridge, MA, USA

Correspondence: zain@openbiome.org

*Equal first authors


Acknowledgements: 

We thank Nancy Dubois (OpenBiome and Boston College, Boston, MA) for her technical assistance, and the Neil and Anna Rasmussen Family Foundation (Concord, MA) and the Anna Maria and Stephen Kellen Foundation (New York City, NY) for their financial support of OpenBiome.

Competing interests:

Majdi Osman, Alexandra Lieberman and Zain Kassam are employed at OpenBiome, a not-for-profit stool bank that provides clinicians with preparations for faecal microbiota transplantation and supports research into the human microbiome and its role in medicine. Zain Kassam is a research consultant and shareholder at Finch Therapeutics; Jessica Allegretti is a special advisor to OpenBiome and research consultant at Finch Therapeutics.

  • 1. 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.
  • 2. 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: 142-149.
  • 3. Smith M, Kassam Z, Edelstein C, et al. OpenBiome remains open to serve the medical community. Nat Biotechnol 2014; 32: 867.
  • 4. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9: 1044-1049.
  • 5. Jackson M, Olefson S, Machan JT, Kelly CR. A high rate of alternative diagnoses in patients referred for presumed Clostridium difficile infection. J Clin Gastroenterol 2016; 50: 742-746.

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