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Assessing the efficacy of faecal microbiota transplant in recurrent C. difficile infection

Faecal microbiota transplant

Faecal microbiota transplant (FMT) is the transplant or infusion of faecal suspension from a healthy individual into the GI tract of another affected individual. In essence, it is a direct and radical way of recolonising the gut of an individual with an established healthy microbiome.

Our GI tract contains over a trillion bacterial cells, outnumbering our human cells at a ratio of 10:1.4

History of FMT

The theory of recolonising the gut is not a new one. In the animal kingdom, the instinctive behaviour of coprophagy, the ingestion of faeces, is common practice and is believed to diversify animal gut microbiomes and protect against pathogenic bacteria.5,6,7

Documentation of faecal material being used as a therapeutic agent dates back to the 4th Century in Chinese medicine where dried, fermented and fresh samples were used to treat various illnesses.8 And in Europe during the 1600s, a book was written by German physician Christian Paullini, outlining the virtues of faecal material as a therapeutic agent.

The first record of a faecal transplant in modern medicine was carried out in 1958 by Eiseman et al, a group of surgeons who were faced with patients with fulminant pseudomembranous colitis and faecal infusion enemas were given to four patients, with total resolution of symptoms. Eiseman et al postulated further clinical applications for this procedure9 but this was halted due to the advent of the discovery and approval of vancomycin.10

To date, over 550 faecal transplants have been recorded in the literature worldwide.1

Clostridium difficile

Clostridium difficile is a spore-forming anaerobe that is the leading cause of nosocomial or iatrogenic diarrhoea in the industrialised world.11 C. difficile is a native to our distal colon and is carried by approximately 3 per cent of the population. However, its overgrowth is held in check by commensal gut bacteria — when the gut flora have been eliminated or disrupted by antibiotic use, C. difficile flourishes.

Antibiotics such as fluoroquinolones, broad-spectrum cephalosporins and clindamycin are the most common offending agents but CDI can occur with any antibiotic. It is an extremely virulent bacterium due to its sporulation efficiency and genetic diversity. Transmission of C. difficile infection (CDI) is via the faecal-oral route and spores can survive on surfaces for months. While the incidence of CDI has been decreasing in the past number of years in hospitals, there is an increasing trend of community-acquired CDI and the emergence of CDI in previously-considered low-risk groups such as children, peripartum women and persons with no previous antibiotic exposure.15

The cost, both human and financial, of CDI is huge. The mortality of CDI is reported at 22 per cent overall and it is directly responsible for death in 2 per cent of cases and a contributor to death in 7 per cent of cases.12

The financial cost on our already-stretched healthcare system is enormous. CDI lengthens hospital stay by a median of seven days and the average cost of a patient per episode of an acquired CDI ranges from €4,067 to €9,276.13 In the US, CDI is estimated to cost $3 billion (€2.65 billion) per annum.14

Irish data surrounding CDI shows an Irish weighted mean incidence of 7.3 cases per 10,000 patient days; this figure is higher than the European average.14

The recurrence rate for CDI is approximately 20 per cent after initial treatment and patients who experience one recurrence have a 40 per cent risk of another recurrence.16,17,18

How does FMT work against C. difficile?

The aim of FMT is to induce a stable and diverse community of gut micro-organisms, the goal of which is to replace the disrupted microbiome that occurs in CDI.

A number of hypotheses exist to explain the methods by which the gut microbiome counteracts CDI.

Firstly, the classic mechanism of ecology is that no two species can occupy the same niche in an ecosystem at the same time.19 This microbiome can aggregate and result in a synergistic biofilm that produces bacteriocins.

These antimicrobial peptides inhibit the growth of certain species of bacteria, and so are a narrow-spectrum antimicrobial in their own right. One such bacteriocin produced by Bacillus thuringiensis against C. difficile is called thuricin CD and is currently undergoing clinical trials. Interestingly, thuricin CD selectively kills C. difficile while leaving dominant bacterial populations intact.20

The microbiome can alter the life-cycle of C. difficile indirectly by using the host. Many colonic bacteria can alter the life-cycle of C. difficile by the metabolism of bile acids. Primary bile acids lead to an environment that is favourable to C. difficile population but when colonic bacteria deconjugate bile acids to secondary bile acids, the gut environment becomes inhospitable to CDI and so is protective.21 The commensal bacteria in our guts can also trigger and modulate immune reactions to pathogenic bacteria and much research has been done on the toll-like receptor (TLR) signalling in the gut.22

Regardless of the mechanism of action of FMT, the data speaks for itself. The primary cure rate of FMT when used in recurrent C. difficile is over 90 per cent and the secondary cure rate is 98 per cent.23,24,25 In a recent open-label RCT comparing FMT against antibiotic therapy alone, FMT showed far superior outcomes and as a result, the study had to be terminated prematurely. In this study, recurrence rates of 62 per cent were seen post vancomycin therapy and only 6 per cent recurrence seen post FMT.26

Challenges of FMT

There are many challenges that face the utilisation and progress of FMT. The first challenge is the natural aversion that we, as humans, have against the ingestion or infusion of faeces. Both the preparation and administration of the faecal transplant is a struggle for patients and staff alike.

This natural aversion lends itself to further challenges with donor recruitment, especially in cases where a family member or partner donor cannot be used or is not available. This then leads to an over-reliance on family members volunteering their stool, however a biobank of donor microbiomes is now available in the US and may overcome these issues.

A more modern challenge of FMT is the increasing information that is accessible to patients regarding FMT for the treatment of recurrent C. difficile but also many other GI disease processes. Many websites and forums are dedicated to the utilisation of FMT at home and advise on DIY kits that can be used to infuse faeces without prior screening or medical consultation. As a result, desperate patients will seek this treatment and physicians will need to be prepared to answer their queries.

In a qualitative study of patients with ulcerative colitis,27 the majority of patients welcomed this treatment and also expressed their eagerness that this treatment become readily available.

One of the greatest challenges is the unknown risk associated with FMT. When transferring bodily fluids, there is always a risk that an unknown infection could be transmitted and have a hugely detrimental effect on the patient’s health. We are also unaware of the long-term sequelae of FMT. Recent research in the field has found that disrupted microbiomes are associated with many human diseases,28 for example type 2 diabetes, obesity, metabolic syndrome and IBD. While it is unknown whether these disruptions are causal or consequential, an FMT in a very young patient could potentially expose them to a new disease process.

FMT in the future

The future on FMT depends heavily on the advent of stardardisation of protocols, including route of administration. In our case, we chose naso-jejunal tube due to the fragility of the patient, however administration via colonoscopy and enemas are also options to consider.

The route of administration dictates the number of FMTs needed to achieve cure, and so further confounds results. A step to further clarify the role of FMT in C. difficile infection would be guidelines on who should receive FMT and where FMT fits into the treatment paradigm of this infection.

A step towards this standardisation was published in JAMA in 2014,29 whereby FMT was administered as frozen slurry, encapsulated and administered orally over two days. The results of this study showed similar outcomes to infusion FMT but its relevance for the future of FMT is promising. This study could lead to the establishment of a stool bank, whereby all donor faeces are frozen and so can be encapsulated and shipped to centres where they are needed. Not only does this make FMT more accessible to patients, but it is also a non-invasive technique for altering the microbiome.

Stool-based therapeutics are currently being researched30 and trialled in many centres around the world and the challenges we face today are likely to be rapidly addressed. Similarly, a better understanding of the mechanism underlying successful FMT will lead to the development of novel therapeutic molecules, subverting any need for actual faecal transplant in the future. However for the time being, FMT remains a viable and useful clinical option for severe, recurrent C. difficile-related illness.

Conclusions

In the past 60 years, since the discovery and ubiquitous use of antibiotics, both in medicine and in the food industry, our gut microbiomes have been changing and adapting to the constant offensive of these therapies. As a result, many human diseases have been found to show a dysbiosis in gut microbiomes and could be a clue to the pathogenesis of many GI and non-GI illnesses. The scope for research in this field with FMT and these established pathologies is an exciting prospect and could yield many discoveries yet to come.

Case report

NL, an 81-year-old lady, was brought in by ambulance and admitted to Tallaght Hospital in July 2014 following the second episode of four days of watery diarrhoea associated with abdominal cramps, foul-smelling faeces and faecal incontinence. Past medical history was significant for multiple comorbidities such as type 2 diabetes, CKD stage III, COPD and diverticular disease.

She had previously been admitted in July 2014 for C. difficile-positive diarrhoea and most notably had a nine-week admission in April 2014 for pneumococcal sepsis, culminating in two ICU admissions.

The patient was haemodynamically stable and so her care was centered on fluid resuscitation, electrolyte correction and infection control measures. Investigations yielded leukocytosis, an acute kidney injury with creatinine at 190μmol/l and disruption to electrolytes. Stool samples were C. difficile toxin-positive and treatment with oral vancomycin was commenced.

The patient continued to have diarrhoea and vancomycin pulsed and tapering regimens were used, to no effect. Four weeks after admission, the diarrhoea continued and the antibiotic fidaxomicin was used, again with no effect.

At this juncture, the patient weighed 35kg (having lost 10kg over seven weeks) and had suffered multiple falls at night due to nocturnal diarrhoeal symptoms. Her clinical condition was declining and without further antibiotic regimens to use, we began the process of a work-up for faecal microbiota transplant (FMT).

We looked to our colleagues internationally and studied multiple protocols, including recent NICE recommendations,1 for both the ward and the laboratory.2,3 We devised a local protocol using an MDT approach including microbiology, nursing staff and infection control.

Informed consent from both the recipient and the donor was sought and completed prior to FMT.

The donor

The donor was a member of the patient’s family who did not live with the patient. Donor screening involved questions regarding general health (medications, recent antibiotic use and autoimmune disorders ruled out), serum testing for hepatitis B and C, HIV, syphilis, and TB and three consecutive stool samples for culture and sensitivities, ova and parasite screening and C. difficile toxin.

The recipient

A date was set for the FMT to take place and the patient was commenced on a one-week course of vancomycin 500mg BD, the last dose of which was to stop 24 hours prior to the procedure. The day prior to the procedure, an NJ tube was inserted by a specialist nurse and bowel preparation was given to remove the existing microbial populations in order to replace them.

The transplant

The donor submitted the faeces to the laboratory on the day of the transplant and the stool was processed within six hours of defecation. Approximately 200g of fresh stool was mixed with 0.9 per cent saline and sieved through gauze to remove particulate matter. The slurry was then placed in 100ml syringes to be administered by hand; 150ml was administered on the ward, at a rate of 1.5ml/minute and so the transplant itself took one hour and 40 minutes and the NJ tube was flushed, once finished, and removed two hours post-FMT.

The results

Within 48 hours of the infusion, our patient went from opening her bowels seven-to-10 times per day to once daily.

One week post-FMT, our patient was discharged from our care to a convalescent facility.

One month post transplant, our patient was reviewed in the Gastroenterology Outpatients Department. She had gained 4kg since her discharge and reported regular, once-daily bowel motions, with no recurrence of her diarrhoeal symptoms.

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