Journal of Clinical Gastroenterology:
Endoscopic Fecal Microbiota Transplantation: “First-Line” Treatment for Severe Clostridium difficile Infection?
Brandt, Lawrence J. MD*; Borody, Thomas Julius MD, PhD†; Campbell, Jordana BSc†
*Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY
†Centre for Digestive Diseases, Australia
Dr Lawrence J. Brandt is a member of the Advisory Board of Optimer Pharmaceuticals, Inc., however, he has no financial interest or affiliation with any institution, organization, or company relating to the study.
Jordana Campbell has no financial interest or affiliation with any institution, organization, or company relating to the study.
No support or funding, including pharmaceutical and industry support, was received for work undertaken relating to the study.
Reprints: Jordana Campbell, BSc, Centre for Digestive Diseases, Level 1/229 Great North Rd Five Dock, NSW 2046 Australia (e-mail: email@example.com).
Clostridium difficile infection (CDI) has been firmly thrust into the clinical spotlight, with the rising outbreaks of CDI in North America and Europe; emergence of the new, epidemic, hypervirulent NAP1/BI/027 strain; and markedly increased disease severity, higher colectomy rates (10.3%), and higher case-mortality rates than in decades past (34%).1–3 This strain has unique characteristics including increased production of toxin A and B, and expression of binary toxin, which contribute to these poorer outcomes.1 “Standard” treatment regimens of various antibiotics including vancomycin, metronidazole, nitazoxanide, or rifaximin, alone or in combination, fail to eradicate the infection in a proportion of patients who may go on to develop severe CDI with associated complications.4 To date, oral vancomycin and fidaxomicin are the only Food and Drug Administration-approved treatments for CDI.5 Disease recurrence is an increasing problem, with 20% to 60% of patients experiencing at least 1 recurrence within 2 to 4 weeks of completion of vancomycin treatment.6 Moreover, an increasing number of patients who require life-saving emergency colectomy experience persistent CDI postsurgery.7 There is a high and growing economic burden associated with CDI, resulting in considerable cost to patients, hospitals, national health expenditure, and insurers, with 1 report conservatively placing the cost of CDI management to the United States health care system at $1.1 billion annually.8
Published reports demonstrate that patients with CDI possess deficiencies in fecal flora composition, particularly of Bacteroides and Firmicutes, most likely as a result of earlier antibiotic usage9-11 and, in some as of yet unproven manner, these deficiencies in the microbiota facilitate colonization with C. difficile. Treatment of CDI with antibiotics fail to correct these floral deficiencies; even vancomycin is a broad-spectrum antibiotic, which targets Gram-positive anaerobic and aerobic bacteria. In contrast, fecal microbiota transplantation (FMT) is a simple, inexpensive, and highly curative method of not only eradicating the CDI but also of restoring the underlying microbiotic deficiencies.12 In this editorial, we propose that endoscopic FMT be considered among the “first-line” treatments for severe CDI.
Transplantation of enteric bacteria was first performed by Fabricius of Acquapendente (1537–1619) and has been reported for many decades in the veterinary literature as “transfaunation.”13 In the modern era, FMT has been performed since 195814 and has now reached the stage where it is arguably the most reliable and effective form of C. difficile eradication therapy.12,15–17 Its increasing use in clinical practice has been associated with minimal to no adverse effects.15,16,18 FMT can be performed by various routes including nasogastric (NG) tube, nasojejunal tube, upper tract endoscopy (EGD), colonoscopically or by retention enema, depending on which is deemed safest for the individual patient. However, because a single colonoscopic infusion of human fecal suspension is extremely efficacious,9,16,18,19 easy to perform, rapidly and safely accomplished, delivers the “healthy” bacteria directly to the site where the vast majority of C. difficile is established, and able to be carried out in both inpatient and outpatient settings, we propose this as the first-line treatment of CDI in the majority of patients. Moreover, colonoscopic infusion allows direct simultaneous inspection of the mucosa, and determination of preferential sites for infusing larger amounts of donor stool, for example, in areas of diverticulosis. Not only is the infusion “low-tech,” with delivery of the fecal suspension through the colonoscope biopsy channel directly into the terminal ileum or colon, but no additional training to colonoscopy is required17; it is also cost effective, without additional charge, at present, to the cost of colonoscopy. The high cure rate of FMT is unparalleled, with 90% to 100% of reported patients achieving cure.15–17 Perhaps the most critical point is that only FMT restores the underlying flora deficiency,9,11 changing the composition of the recipient's intestinal microbiota in a durable manner.20
Given the growing epidemic, frequent catastrophic outcomes of CDI and lack of a uniformly reliable treatment, until an effective, safe, and curative therapy is developed, we propose that endoscopic FMT should be first-line treatment of recurrent and also severe CDI. For reasons stated above, colonoscopic FMT is preferred for the vast majority of CDI patients and if carried out early may prevent development of severe CDI. The subset of patients with CDI who are candidates for first-line endoscopic FMT generally includes patients who fall within the following categories: the most well studied and least arguable groups would be patients with recurrent CDI, “hard to manage” CDI, and those with pseudomembranous colitis. Next would be patients who have comorbid and special conditions leading to more severe outcomes, for example, inflammatory bowel disease, cirrhosis, pregnancy, neoplasia, immunocompromise, corticosteroid therapy, the elderly, and perhaps postsurgical and intensive care patients with CDI. The most contentious group, but nonetheless a group that we strongly believe would benefit from endoscopic FMT, comprises patients with severe disease, characterized by severe abdominal pain and distension, fever, hemodynamic instability, leukocytosis, rising creatinine levels, falling albumin, leukemoid reaction, and computed tomographic scans that show colon wall thickening and ascites. There is a lack of extensive data to support FMT in this group although our experience with 3 patients and the 1 case report in the literature point to validation of our hypothesis that such patients with severe, even fulminant disease, may benefit from FMT, particularly if it is given early in the course of the disease.21
Although FMT can be achieved by differing routes, we recommend that the simplest method, which bypasses the need for additional training should be an endoscopic infusion. The colonoscopic method is applicable in the majority of patients with CDI and severe CDI, although in patients with significant colonic distension and a picture of toxic colitis, placement by EGD or NG tube10,15 or even a gentle rectal enema20 may be preferable. In patients who have an associated ileus, however, use of an EGD or NG tube may not allow the donated microbiota to reach the colon. In such cases, a carefully performed, prudent, colonoscopy to limited depth may be more effective. Indeed, it is not yet known what constitutes the optimal depth of insertion of donor stool. Small volume retention enemas have been effective and perhaps are appropriate for patients with toxic colitis,16 although one of the authors of this opinion study has successfully performed 3 colonoscopies with FMT on patients with severe colitis during their index presentation of CDI, with rapid response. One infusion of a homogenized stool suspension into the terminal ileum or ascending colon is generally sufficient to achieve clinical success.9,18,22
We urge that every effort should be made to use FMT to prevent colectomy, as preliminary clinical observations suggest that this therapy, although so effective in preoperative patients, generally fails to cure CDI postcolectomy. As our rationale for early endoscopic FMT is to minimize patient suffering, reduce morbidity and mortality, and save on costs, we suggest that in the already severely ill and at-risk groups for severe CDI, there should be a “hair-trigger” in the decision process to treat using FMT. Indeed, in situations where definitive demonstration of C. difficile may be missing, such as drug interference with detection, a clinical decision to progress with endoscopic FMT, nonetheless, should be strongly considered.
There are no currently available medical therapies for recurrent CDI, which rival the near 100% cure rates achieved by FMT. We believe that to persist with, or perhaps even initiate, current drug regimens for CDI given their limited and decreasing efficacy and prohibitive costs, likely will increasingly place more patients at risk of debilitating illness and potentially death. In the critically ill patient, it may be reasonable to use FMT as an adjunctive rather than definitive and sole therapy because reports in the literature suggest that in patients who have not responded to antibiotics, a single infusion of donor stool might change the balance of organisms in the intestinal microbiota to allow the antibiotics to work.21
In conclusion, we recommend that endoscopic FMT be elevated to first-line treatment of patients with deteriorating and severe CDI and its complications at the earliest possible time. FMT not only consistently eradicates CDI but also restores the underlying deficiency of fecal flora, which has been recognized as the possible mechanism for the pathogen's colonization and persistence. Whether FMT is as effective in patients with severe of fulminant CDI has not yet been proven but it is a subject worthy of study. As the risks of FMT are minimal and the potential gain in critically ill patients is great, we believe the use of FMT in this patient population is rational and clinically well grounded.
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