Fecal microbiota transplantation:
a new standard treatment option for
Clostridium difficile infection Expert Rev. Anti Infect. Ther. 11(5), 447–449 (2013)
Thomas J Borody
Author for correspondence: Centre for Digestive Diseases, Sydney, NSW 2046, Australia Tel.: +61 297 134 011
Fax: +61 297 121 675 thomas.borody@cdd.com.au
“...the most rational therapy for Clostridium difficile infection in patients with a relapsing or refractory pattern of infection is the restoration of antibiotic-damaged microbiota...”
Lawrence J Brandt
Albert Einstein College of Medicine, Bronx, NY 10461, USA
and
Gastroenterology, Montefiore Medical Center, Bronx,
NY 10467, USA
The last 20 years have seen a progressive increase in the global incidence and sever- ity of Clostridium difficile infection (CDI), particularly in North America and Europe. This increase has been accompanied by the identification and increased prevalence of new, hypervirulent toxigenic strains such as NAP1/BI/027 [1], which in the USA alone is responsible for worsened outcomes and a mortality reaching some 300 deaths per day from 3 million new cases annu- ally [2]. It is within the context of the CDI epidemic that fecal microbiota transplanta- tion (FMT) has gained acceptance as the most effective therapy for CDI [3].
This editorial makes the case that the most rational therapy for CDI in patients with a relapsing or refractory pattern of infection is the restoration of anti- biotic-damaged microbiota rather than pharmacologic therapy.
CDI pathogenesis
Risk factors for developing CDI include advanced age, proton-pump inhibitor therapy, serious underlying diseases, for example, inflammatory bowel disease and cirrhosis, and contact with infected
patients, staff and surfaces, for example, during extended hospitalization or insti- tutionalization in a nursing home [4]. The key factor remains recurrent use of Antibiotics , especially broad-spectrum agents.
Antibiotic use over the past 60 years has led to significant inadvertent damage to the human enteric microbiome, an extraor- dinarily complex composition of highly concentrated and diverse microorganisms that serves as a major defense against gas- trointestinal infections. In relapsing CDI, distinct abnormalities have been noted in the microfloral composition, including the reduction or absence of members of Bacteroidetes and Firmicutes phyla [5,6]. Loss of normal gastrointestinal microbiota volume and diversity appears to be the root cause of CDI.
Current therapies for CDI
First-line therapy for CDI is traditionally either oral metronidazole or vancomycin for 10–14 days. After relapse, a longer tapered or pulsed course of vancomycin is often employed. Alternative Antibiotics include fidaxomicin, rifaximin, nitazoxa- nide, tigecycline, teicoplanin and the ansamycins. A recent (pre-fidaxomycin) Cochrane review and meta-analysis found no single Antibiotic that was clearly supe- rior to others in the treatment of CDI, although teicoplanin and vancomycin were among the best [7]. Other treatment
Sudarshan
Paramsothy
St Vincent’s Hospital Clinical School, Darlinghurst,
NSW 2010, Australia
Gaurav Agrawal
Centre for Digestive Diseases, Sydney, NSW 2046, Australia
“ Antibiotic use over the past 60 years has led to significant inadvertent damage to the human enteric microbiome...”
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Keywords: Antibiotics • Clostridium difficile • fecal • microbiota • probiotics • transplantation 10.1586/ERI.13.26 © 2013 Expert Reviews Ltd ISSN 1478-7210 447
Editorial
Editorial
Borody, Brandt, Paramsothy & Agrawal
“The term Fecal Microbiota Transplantation implies use of the full spectrum of human colonic microbiota and is associated with numerous advantages over other forms of microbiota therapy.”
options that have been explored include antibiotic enema with vancomycin, along with adjunctive use of intravenous monoclonal antibodies against C. difficile toxins A and B.
Rationale for use of FMT versus pharmacologic therapies
While anti-C. difficile antibiotics theoretically target clostridial species, in relapsing CDI they often fail to eradicate the organ- ism because of the presence of resistant spores. Such treatment is counter-intuitive, as antibiotics are utilized to treat a disease that largely results from antibiotic-induced disruption of gut micro- biota and therefore, in a sense, maintain the condition of which they are the cause.
Even with narrow-spectrum agents, such as fidaxomicin, anti- biotics are not selective enough to specifically target C. difficile and they invariably damage the microbiota further. Approximately 20% of patients experience a second bout of CDI after initial anti- biotic therapy, presumably due to spores that reinitiate infection. Approximately 40% of these ‘second infection’ patients develop recurrent CDI despite repeated antibiotic therapy, and 65–80% of such recurrent CDI patients fail antibiotic therapy for their third C. difficile infection. For patients who experience ≥three CDIs, there is essentially no hope that antibiotics will prevent fur- ther recurrence. CDI recurs or persists when the underlying gut microbiota deficiency has not been properly replenished. Hence, antibiotics are an inappropriate therapy for CDI, particularly for relapsing C. difficile infection that results from persistent intestinal dysbiosis and the inability to eradicate spore forms.
The human colonic microbiota contains over 3.3 million non-redundant genes, with each individual harboring around 160 species with up to 1150 prevalent bacterial species in the entire cohort, as studied by Qin et al. [8]. Reintroduction of such a rich flora by FMT restores diversity and colonization resistance in recurrent CDI, thereby enabling recovery of normal bowel function and eradication of CDI.
There is now a wealth of noncontrolled data from a variety of centers and one randomized controlled study that highlights the efficacy of FMT for recurrent CDI. A single FMT administration cures the majority of patients, while the remainder are successfully treated with a second infusion. A recent New England Journal of Medicine paper, which reports the first randomized controlled trial of FMT, demonstrated the superiority of microbiota transplanta- tion over traditional antibiotic therapy [3]. FMT had a success rate of 81% following a single nasoduodenal infusion and 94% following a second infusion, whereas vancomycin 500 mg four- times daily for 2 weeks ,with or without bowel lavage, resulted in only a 23–31% success rate. Regulatory authorities stopped the
trial early following interim analysis and a judgment that it was unethical to continue to deny patients FMT. This trial provides the highest-level evidence of superiority of FMT over optimal antibiotic therapy and has also brought FMT further into the general medical spotlight and public arena.
A recent review of over 300 FMT cases administered via colono- scopy or retention enema revealed mean cure rates that were consistently approximately 91% [9,10]. The route of FMT adminis- tration seems quite influential, with one infusion via upper GI tract endoscopy or nasogastric/duodenal tube resulting in a 76–79% cure [10] and a single colonoscopic infusion affording a cure rate of over 90% [11]. Hence, FMT, particularly transcolonoscopically, is the appropriate therapy for relapsing CDI [12].
Rationale for the use of complete microbiota FMT versus probiotics or limited cultured FMT
The term FMT implies use of the full spectrum of human colonic microbiota and is associated with numerous advantages over other forms of microbiota therapy. Probiotics are perceived to correct intestinal microbiota compositional imbalance and have been investigated as a treatment option for CDI. Available probiotics have limitations because they are generally not anaerobes, repre- sent only few strains, do not implant and are not standardized. The human gastrointestinal microbiome, meanwhile, is largely anaerobic, highly complex and specific deficiencies that require replacement are difficult to measure. The fact that FMT replaces all microbiota groups means that even though the missing/defi- cient microbiota components in a recipient may be unknown, FMT can deliver lacking components by providing a complete human intestinal microbiota. Additionally, the ‘wild-types’ from donor microbiota in FMT durably implant in the recipient [13] in contrast to cultured probiotics. Cultured probiotics progres- sively change during the process of ‘passaging’, when bacteria are successively recultured. They subsequently lose their capability to implant and to inhibit pathogen growth, as exemplified by the anti-CDI Lactobacillus GG [14], which progressively lost anti-CDI activity. Thus, FMT results in sustained correction of intestinal dysbiosis and protects against future recurrent CDI infection, whereas cultured probiotics do not.
Cultured, ‘mini’ versions of the complete human gut micro- biota have been developed in the hope of avoiding treatment with material of fecal origin, and these preparations have succeeded in treating CDI in a handful of human cases [5,15]. In fact, there is a multitude of potential human microbiota components that could be grouped and developed into ‘mini’ versions of the full flora that could still eradicate CDI. However, difficulty in maintaining identical bacterial characteristics and function in the long term after prolonged serial passaging during the manufacturing process prevents such a product from retaining its original efficacy, and such cell cultures continue to smell like their fecal origin [16].
Microbiota-based therapies are now being explored as a treat- ment option for numerous other medical conditions besides CDI, including inflammatory bowel disease, irritable bowel syndrome, autism, metabolic syndrome and other disorders [17]. Until the specific defects of the gastrointestinal microbiome in
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these various conditions are clearly defined, the use of a complete human intestinal microbiota will remain a better approach to exploring the therapeutic potential for FMT in these non-CDI disorders.
Ongoing issues & the future of FMT
In spite of growing interest in FMT, many questions and chal- lenges remain. The exact features of what makes a ‘good donor’ are not well understood. Currently, donor selection is limited to healthy individuals with no comorbidities who have passed an infectious screening for transmissible diseases and do not have obvious factors that will affect intestinal composition, such as recent antibiotic therapy [18]. One could define a ‘good donor’ as an individual whose colonic microbiota can reverse a specific microbiota-related condition. The actual microbiological charac- teristics that define a ‘good donor’ are unknown at present, owing to the complexity of the gastrointestinal microbiome, and are not identifiable by standard laboratory techniques. Furthermore, a good donor for one disease may not be a good donor for another. Advances in metagenomics along with further targeted research may answer some of these questions in the future.
Recent advances suggest that an FMT floral product can be produced by repeated filtering, washing, freezing and even freeze- drying feces – and yet still deliver a clinical result equivalent to that of fresh crude fecal homogenate when treating CDI [19], and implanting healthy microbiota components into the recipient [20] while removing the fecal odor. In the future, lyophilized full spectrum human donor microbiota may be available in capsule formulation to treat CDI (even initial episodes) and perhaps be used routinely after antibiotic usage to prevent gut flora damage.
Financial & competing interests disclosure
TJ Borody has a pecuniary interest in the Center for Digestive Diseases, where Fecal Microbiota Transplantation is a treatment option for patients, and he has filed patents in this field. LJ Brandt is a member of the Speakers’ Bureau of Optimer Pharmaceuticals, Inc.; however, he has no financial interest or affiliation with any institution, organization, or company relating to the manuscript. The authors have no other relevant affiliations or finan- cial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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