REVIEW
10.1111/1469-0691.12795
Faecal microbiota transplantation: from practice to legislation before considering industrialization J.-C. Lagier1,2 1) URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Aix Marseille Universite and 2) Assistance Publique H^opitaux de Marseille, CHU Nord, P^ole Infectieux, Institut Hospitalo-Universitaire Mediterranee Infection, Marseille, France
Abstract Recurrent Clostridium difficile infections constitute an important medical concern. Evidence has been provided showing that faecal microbiota transplantation is a more efficient treatment than antibiotics. Serious side effects are unusual, and acceptability is not an obstacle. Nevertheless, protocols are heterogeneous with respect to the selection of donors and the methodology used for the faecal transplantation. Regulations by both the Food and Drug Administration and the French authorities consider stool samples to be drugs, and suggest strict supervision in clinical trials. Donor screening by questionnaire or by blood and stool analysis, which is essential in eliminating pathogens or viruses before transplantation, is similar in different countries, with a few exceptions. The traceability of the faecal transplant and long-term follow-up of the patients in clinical trials are issues that may be difficult to organize. The use of frozen microbiota facilitates transplantation, and the nasogastric route seems to be at least as effective as other invasive methods and avoids the risk of anaesthesia. Synthetic microbiota is an approach that selects a mixture of bacteria, thereby eliminating the risk of transmissible disease; however, this approach is not yet evidence-based. The use of pills, which is currently being tested in clinical trials, will certainly be the starting point for the extensive use and wide industrialization of faecal microbiota transplantation. Keywords: Clostridium difficile, faecal microbiota transplant, industrialization, pills, regulation Article published online: 1 October 2014 Clin Microbiol Infect 2014; 20: 1112–1118
Corresponding author: Dr J.-C. Lagier, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte de Medecine, Aix-Marseille Universite, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France E-mail: [email protected]
Introduction Clostridium difficile infection (CDI) is the primary cause of healthcare-associated diarrhoea, with worldwide outbreaks caused by diverse ribotypes [1,2]. The mortality rate ranges from 5% to more than 40%, depending on the strains and clinical status of the host [1,3–6]. For example, the Centers for Disease Control and Prevention estimated that CDI causes 14 000 deaths annually in the USA. Despite antibiotic treatment with metronidazole, vancomycin, or fidaxomicin, the relapse rate is still up to 35% [7]. Faecal microbiota transplantation (FMT) was first proposed empirically in 1958 as a method of treating CDIs [8], and cases series using FMT as a treatment for recurrent infections were reported [9]. FMT has recently been shown to be clearly superior to antibiotics in
a randomized clinical study [10]. Indeed, in 2013, Van Nood et al. [10] demonstrated better efficacy of FMT than of the conventional treatment with vancomycin in patients with recurrent CDI. Among the 16 patients treated with faeces infusion, none had severe adverse events. Most of the patients had their diarrhoea resolved within 3 h after infusion, and 19% had constipation. Recently, the European Society of Clinical Microbiology and Infectious Diseases strongly recommended the use of FMT in patients with several relapses [11]. The cost-effectiveness of FMT colonoscopy for the management of recurrent CDI was recently demonstrated to be superior to that of the usual antibiotics [12]. Additionally, a recent study demonstrated the efficiency of FMT in recurrent CDI, even in strongly immunocompromised patients, who had initially represented a limited indication [13]. Finally, some scientists
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have proposed the use of FMT in other clinical conditions, such as inflammatory bowel diseases, although the results are less encouraging than those obtained for recurrent CDIs [14–16]. Consequently, this alternative and efficient treatment needs regulation and standardization (Fig. 1). However, no consensus exists regarding health safety, legislative aspects, donor screening, and the administration route. We herein provide a review regarding these aspects, which will require standardization before the probable wide-scale industrialization because of the promising number of indications.
Regulation Aspects Health authorities have been alerted to the absence of faecal transplant status and regulations, given the accumulating evidence showing the effectiveness of such treatments [10]. In France and the USA, authorities have considered FMT to be a drug, in contrast to the UK, Denmark, and The Netherlands. We can also observed the difficulties of authorities, shared between the high pressure from patients and clinical doctors performing FMT, and the necessary regulations [17]. Indeed, in the USA, the US Food and Drug Administration (FDA) stated in the autumn of 2012 that human faeces
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constituted a drug (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/Vaccines/UCM361393.pdf) [18]. This had the unintended consequence of putting faeces used for FMT under the jurisdiction of hospital pharmacies, requiring storage of the faecal product in the pharmacy [18]. In addition, a timeconsuming investigational new drug (IND) status was first proposed for the conduct of studies in humans [19]. The objectives were to improve the safety of and standardize the use of FMT [17]. The FDA noted that the efficacy and safety profiles of this intervention had not yet been fully evaluated in controlled clinical trials, and organized a public workshop to provide a forum for the exchange of experiences among the medical and scientific community about the regulatory issues associated with FMT. After this public meeting and several opinions of different authorities, 6 weeks later, the FDA’s guidance documents stated that this protocol including an IND status was suggested or recommended but not required [17,19]. Indeed, the FDA proposed a compassionate exception to allow the many people suffering from CDI to benefit from the use of FMT. The FDA recommended that the treating physician obtain adequate informed consent from the patient or his or her legally authorized representative for the use of FMT. Informed consent should include, at a minimum, a
2500 2000 1500 1000
N° of citations
Review of 317 cases Gough et al. [9]
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1958
First report Eiseman et al. [8]
0
2006 2007 2008 2009 2010 2011 2012 2013 2014
First randomized study in reccurent CDI Van Nood et al. [10]
??
Food and Drug Administration recommendations, USA [17] ANSM recommendations, France [20]
NICE recommendations, United Kingdom [21]
FIG. 1. Scientific and regulatory key events from 1858 to 2014 in faecal microbiota transplantation. We found an increasing number of citations by using the ISI web of knowledge and ‘fecal microbiota transplantation’ as the keyword. CDI, Clostridium difficile infection. ª2014 The Author Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1112–1118
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statement that the use of FMT products to treat CDI is investigational and a discussion of its potential risks. The FDA proposed this on an interim basis while the agency develops appropriate policies for the use of FMT as an IND. In France, in March 2014, the National Security Drugs Agency (Agence Nationale pour la Securite du Medicament) also considered FMT to be a drug (http://ansm.sante.fr/var/ ansm_site/storage/original/application/5e5e010183037901942 75ded0e02353c.pdf). In the absence of market authorization, the National French Agency recommended that FMT must have the same legislative framework as experimental drugs or magisterial preparations. Indeed, the preparation was under the responsibility of the hospital pharmacist. The authorities strongly recommended supervising the use of FMT in clinical trials, but left open the possibility of clinicians performing FMT with compliance with stringent recommendations [20]. They also recommended stringent screening of the donors, asking the clinicians to determine the reasons for non-compliance with the protocol. Finally, in the UK, in March 2014, the UK National Institute for Health and Care Excellence (IPG 485) deemed FMT to be a safe and effective treatment for recurrent CDI (http://www.nice.org.uk/guidance/IPG485) [21]. Overall, to date, most countries have proposed strict requirements to limit the practice of FMT for recurrent CDI. Nonetheless, differences regarding the ‘drug’ or ‘tissue’ status remain. For example, the FDA defines drugs as ‘articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease’ [17]. Faecal microbiota is a variable and complex ecosystem composed of a mixture of microorganisms, metabolites, and human cells [17,19,22]. As has been the case for semen, which is a tissue product, and blood, which has its own rules, a special status for FMT may be useful, because it is very difficult to characterize faecal samples according to the rigorous standards applied to conventional drugs. We must find the balance between stringent rules to protect human health and rules that are too restrictive, and that may lead patients to consider unregulated and expensive proposals that are available on the Internet or, worse, home-made protocols that are available on YouTube [17].
How do we Preserve the Health and Safety of Patients Treated with FMT? The recruitment and screening of donors is a lengthy process that is essential to ensure the health and safety of patients.
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patients, who have a high risk of developing CDI, pregnant women, and patients treated with antibiotics for reasons other than for CDI on the day of inclusion. Nevertheless, a recent study that included human immunodeficiency virus (HIV) patients, solid organ transplant patients and patients with immunosuppressive therapy for inflammatory bowel disease obtained an overall cure rate of 89%, without related infectious complications, in these high-risk patients. These results should significantly and rapidly affect the current recommendations [13,23]. Donor screening
Clinical examination. For example, the National French Agency proposes a two-step selection process. The first visit consists of a pre-inclusion screening with questioning, a clinical examination, and a biological examination. Donors younger than 18 years with a history of Salmonella Typhi infection, chronic diseases or long-term treatment (without precision), diarrhoea within the past 3 months, or overseas travel within the past 3 months, and donors who had been hospitalized, or whose family members had been hospitalized, within the past 12 months, were systematically excluded. In addition, the French authorities recommend avoiding donors who are aged >65 years or have a body mass index of >30, donors treated with antibiotics within the past 3 months, or donors with a familial history of autoimmune diseases, inflammatory bowel diseases, or colorectal neoplasms. The second visit for consideration consists of a supplementary questionnaire to detect criteria for non-inclusion that may have occurred since the inclusion visit (e.g. diarrhoea, travel, human blood exposure, and sexual exposure to risk) [20]. Biological screening: faecal samples
Van Nood recommended performing both bacteriological and parasitological evaluations and testing for the presence of C. difficile (toxin ELISA and culture) [10]. The French authorities proposed extremely detailed recommendations that included the detection of a comprehensive list of pathogens: C. difficile, Listeria monocytogenes, Vibrio cholerae, Vibrio parahaemolyticus, Salmonella species, Shigella species, adenoviruses, astroviruses, caliciviruses, picornaviruses, rotavirus, and hepatitis A and E viruses. Regarding parasitic infections, they recommended testing for the presence of Strongyloides stercoralis, Cryptosporidium species, Cyclospora species, Entamoeaba histolytica, Giardia intestinalis, Isospora species and microsporidia. The National French Agency also strongly recommends testing for the carriage of extended-spectrum b-lactamase-producing enterobacteria in the donors [20,24].
Patient selection
Most of the clinical studies and the authority recommendations that have been suggested to date exclude immunocompromised
Biological screening: blood samples. Van Nood [10] proposed testing for active infections caused by cytomegalovirus,
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Epstein–Barr virus, hepatitis A virus, hepatitis B virus, HIV-1, HIV-2, human T-lymphotropic virus types I and II, Treponema pallidum, E. histolytica, and S. stercoralis. In addition, the French authorities recommend testing for Toxoplasma gondii and Trichinella species [20].
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Ethics and acceptability
The strong evidence for the efficacy of FMT in the treatment of recurrent CDI leads to the question, ‘Is it ethical to not be able to propose FMT to all patients suffering from recurrent CDI?’ rather than the question, ‘Is it ethical to propose FMT for the treatment of recurrent CDI?’ Brandt et al. [27] demonstrated that 73% of patients treated with FMT would undergo the treatment again, and that 53% would prefer FMT as the initial therapy in instances of recurrent CDI. Zipursky et al. assessed patients’ perceptions regarding the management of CDI by proposing diverse scenarios. After patients had been informed of the cure rate percentages for various treatments, most of the patients chose FMT for treatment, but they did not know the nature of the treatment. Only 16 individuals changed their choices when the authors explained what FMT actually was [7]. The authors noted that the acceptability was higher when the clinician recommended this alternative. Finally, the media’s attraction to a treatment regimen that is easy to sensationalize has increased its acceptability [17].
Adverse outcome follow-up
Smits et al. [15], who have a large amount of experience with FMT, reported no serious side effects. Van Nood [10] reported diarrhoea or abdominal pain, which disappeared a few hours after the procedure. In a recent study by Kelly et al. [13], one patient died of aspiration during sedation for FMT administered via a colonoscopy. Overall, transient abdominal discomfort, diarrhoea, constipation and bloating have been the most frequently described side effects. Nevertheless, very few long-term follow-up data are available in the literature [17]. Additionally, the theoretical risk that FMT could modify the microbiota of the patients and make them susceptible to chronic conditions such as obesity or autoimmune disorders [17] encourages the establishment of mandatory registries to protect against infectious diseases and to track adverse events, including long-term adverse events, as required by the FDA and the French authorities [17,20]. Considering the efficacy of FMT for the treatment of recurrent CDI performed in a large number of patients [25,26], the benefit/risk ratio is clearly in favour of this procedure (Table 1).
How do we Facilitate FMT and Consider Industrialization? Frozen faeces and faecal banks
The main limitation of transplantation with fresh faeces was overcome by the use of frozen faeces; this avoids the need to maintain an available pool of donors, and allows for the establishment of a bank of preprocessed material that is rapidly usable [28]. In 2012, Hamilton et al. [29] proposed moving from patient-identified individual donors to standard volunteer donors, and recently Youngster et al. [28] demonstrated that transplantation with frozen faeces was effective. Faecal banks have been established, such as OpenBiome, a company based in Cambridge, which is a non-profit organization that was
How do we Choose the Donor? To the best of our knowledge, there is no scientific argument to recommend anonymous donation rather than directed donation. Similarly, transplants with pooled faecal material are comparable with transplants from unique donors in both their safety and efficacy.
TABLE 1. Summary of the benefit/risk ratio of faecal transplantation for the treatment of recurrent Clostridium difficile infection and inflammatory bowel diseases Type of study and indication
No. of patients
Benefit
Risk
Recurrent C. difficile infection
–
–
–
Randomized study using the duodenal route
16
81% cure after one infusion, 93% overall
Review Review
536 317
87% resolution of diarrhoea 92% resolution of diarrhoea
No severe adverse event Diarrhoea (94%) Constipation (19%) No severe adverse event One upper gastrointestinal haemorrhage
Inflammatory bowel disease Review
26
76% reduction of symptoms
One activation of Crohn’s disease
Outstanding safety questions
Reference
Long-term adverse event Risk of anaesthesia depends on the route of administration –
–
– –
Cammarota et al. [25] Gough et al. [9]
Long-term outcome
Anderson et al. [26]
Van Nood et al. [10]
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funded in 2012 to provide faecal transplants for different hospitals (OpenBiome 2014, http://www.openbiome.org/). The samples were homogenized, and frozen for long-term storage [17]. Usually, the faecal solution is poured through a clean metal sieve in order to remove the food-derived debris [10]. Nevertheless, the FDA recently decided to allow FMT only when the source of faeces is known to either the physician or the patient [30], consequently creating difficulties for organizations such as OpenBiome in the USA [30]. In addition, two teaching hospitals, including the Massachusetts General Hospital in Boston and the Emory University Hospital in Atlanta, developed their own faecal banks for their patients [17] following the FDA recommendations. Route of administration
Retention enema was the only route available until 1989 [31]. Since then, alternative methods using colonoscopy, duodenal tubes or nasogastric tubes have been established [28,31]. Recently, despite difficulties in comparing protocols, owing to unavailable data and differences regarding the quantity of the transplant, a review concluded that an enema or the colonoscopy route were probably the most effective protocols. The only randomized clinical trial demonstrating the efficiency of FMT in recurrent CDI used the duodenal route with gastroscopy [10]. Finally, a recent study comparing colonoscopic administration and nasogastric tube administration demonstrated better efficacy of the upper route [29]. This mode of administration remains the easiest and the least invasive, thereby avoiding the risk inherent in general anaesthesia. Synthetic microbiota
Knowledge regarding the gut microbiota composition has been increased by the use of next-generation sequencing, which has led researchers to suggest links between diseases and the bacterial community at the genus or species level [31–34]. The next step could be using this association to improve human health by designing an ideal microbiota [17]. Preliminary studies have been designed in mice or in patients with CDI [35]. For example, Jorup-Ronstrom et al. [36] used subcultured human donor microbiota, obtaining a success rate of 69%, and Petrof et al. [37] used 33 isolates of bacterial species cultured from the human gut of one donor to demonstrate efficacy in two patients with infections caused by the virulent ribotype O78. The cocktail was composed of Lactobacillus species, Escherichia coli, Raoultella species, Bifidobacterium species, Clostridium species, and other anaerobic bacterial species. Different companies in the USA have already tested synthetic approaches [17]. The advantages of synthetic microbiota include avoiding the risks of pathogens and viruses
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that are inherent to the use of stool samples, and the reproducibility of manufacture, which facilitates industrialization [35]. Nonetheless, treatments with synthetic communities will not be available for many years. Currently, to the best of our knowledge, except case series, there is no evidence of comparable efficiency, than transplantation using stool samples. In addition, caution should be recommended because we know the differences in the composition of the gut microbiota depends of the tools used to explore the microbiota [38,39]. Pills
FMT, which allows for the recovery of the gut microbiota [40] to cure recurrent CDI, is a method that remains limited to a few hospital centres. To the best of our knowledge, no human clinical studies have been published to date regarding the use of lyophilized, encapsulated and enteric-coated capsules for oral administration. Nevertheless, clinical trials with stool-derived pills are ongoing (http://clinicaltrials.gov/show/NCT 01914731; http://www.idweek.org/pr-2013-cdiff/) [30,41,42]. The development of pills containing microbiota, based on the model of Saccharomyces boulardii pills, which have been used for >80 years [43], is likely to accelerate. Ultimately, it is conceivable that, after any use of antibiotics in patients aged >65 years, oral FMT will become a routine procedure to ecologically conserve the gut microbiota.
Conclusion The efficacy of FMT has now been strongly demonstrated in recurrent CDI [10]. Other indications, such as the decontamination of patient carriers of extended-spectrum b-lactamase producers, could be proposed to expand the field of interest for industry [44]. Over six clinical trials studying FMT in inflammatory bowel diseases have also been registered [17]. The standardization of the stringent screening of donors and follow-up will increase the health and safety of the patients. Currently, recent data recommending the nasogastric route and the use of frozen faeces should be applied to facilitate manipulations and to avoid the risk of anaesthesia [29]. Finally, in the near future, the use of pills with a possibly standardized microbiota will be the final step before widening the indications and acceptability of FMT.
Transparency Declaration The author declares no conflict of interest.
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44. Singh R, Van Nood E, Nieuwdorp M et al. Donor faeces infusion for eradication of extended-spectrum b-lactamase-producing Escherichia coli in a patient with end-stage renal disease. Clin Microbiol Infect 2014; doi: 10.1111/1469-0691.12683.
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10.1111/1469-0691.12795
Faecal microbiota transplantation: from practice to legislation before considering industrialization J.-C. Lagier1,2 1) URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Aix Marseille Universite and 2) Assistance Publique H^opitaux de Marseille, CHU Nord, P^ole Infectieux, Institut Hospitalo-Universitaire Mediterranee Infection, Marseille, France
Abstract Recurrent Clostridium difficile infections constitute an important medical concern. Evidence has been provided showing that faecal microbiota transplantation is a more efficient treatment than antibiotics. Serious side effects are unusual, and acceptability is not an obstacle. Nevertheless, protocols are heterogeneous with respect to the selection of donors and the methodology used for the faecal transplantation. Regulations by both the Food and Drug Administration and the French authorities consider stool samples to be drugs, and suggest strict supervision in clinical trials. Donor screening by questionnaire or by blood and stool analysis, which is essential in eliminating pathogens or viruses before transplantation, is similar in different countries, with a few exceptions. The traceability of the faecal transplant and long-term follow-up of the patients in clinical trials are issues that may be difficult to organize. The use of frozen microbiota facilitates transplantation, and the nasogastric route seems to be at least as effective as other invasive methods and avoids the risk of anaesthesia. Synthetic microbiota is an approach that selects a mixture of bacteria, thereby eliminating the risk of transmissible disease; however, this approach is not yet evidence-based. The use of pills, which is currently being tested in clinical trials, will certainly be the starting point for the extensive use and wide industrialization of faecal microbiota transplantation. Keywords: Clostridium difficile, faecal microbiota transplant, industrialization, pills, regulation Article published online: 1 October 2014 Clin Microbiol Infect 2014; 20: 1112–1118
Corresponding author: Dr J.-C. Lagier, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Faculte de Medecine, Aix-Marseille Universite, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France E-mail: [email protected]
Introduction Clostridium difficile infection (CDI) is the primary cause of healthcare-associated diarrhoea, with worldwide outbreaks caused by diverse ribotypes [1,2]. The mortality rate ranges from 5% to more than 40%, depending on the strains and clinical status of the host [1,3–6]. For example, the Centers for Disease Control and Prevention estimated that CDI causes 14 000 deaths annually in the USA. Despite antibiotic treatment with metronidazole, vancomycin, or fidaxomicin, the relapse rate is still up to 35% [7]. Faecal microbiota transplantation (FMT) was first proposed empirically in 1958 as a method of treating CDIs [8], and cases series using FMT as a treatment for recurrent infections were reported [9]. FMT has recently been shown to be clearly superior to antibiotics in
a randomized clinical study [10]. Indeed, in 2013, Van Nood et al. [10] demonstrated better efficacy of FMT than of the conventional treatment with vancomycin in patients with recurrent CDI. Among the 16 patients treated with faeces infusion, none had severe adverse events. Most of the patients had their diarrhoea resolved within 3 h after infusion, and 19% had constipation. Recently, the European Society of Clinical Microbiology and Infectious Diseases strongly recommended the use of FMT in patients with several relapses [11]. The cost-effectiveness of FMT colonoscopy for the management of recurrent CDI was recently demonstrated to be superior to that of the usual antibiotics [12]. Additionally, a recent study demonstrated the efficiency of FMT in recurrent CDI, even in strongly immunocompromised patients, who had initially represented a limited indication [13]. Finally, some scientists
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have proposed the use of FMT in other clinical conditions, such as inflammatory bowel diseases, although the results are less encouraging than those obtained for recurrent CDIs [14–16]. Consequently, this alternative and efficient treatment needs regulation and standardization (Fig. 1). However, no consensus exists regarding health safety, legislative aspects, donor screening, and the administration route. We herein provide a review regarding these aspects, which will require standardization before the probable wide-scale industrialization because of the promising number of indications.
Regulation Aspects Health authorities have been alerted to the absence of faecal transplant status and regulations, given the accumulating evidence showing the effectiveness of such treatments [10]. In France and the USA, authorities have considered FMT to be a drug, in contrast to the UK, Denmark, and The Netherlands. We can also observed the difficulties of authorities, shared between the high pressure from patients and clinical doctors performing FMT, and the necessary regulations [17]. Indeed, in the USA, the US Food and Drug Administration (FDA) stated in the autumn of 2012 that human faeces
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constituted a drug (http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/Vaccines/UCM361393.pdf) [18]. This had the unintended consequence of putting faeces used for FMT under the jurisdiction of hospital pharmacies, requiring storage of the faecal product in the pharmacy [18]. In addition, a timeconsuming investigational new drug (IND) status was first proposed for the conduct of studies in humans [19]. The objectives were to improve the safety of and standardize the use of FMT [17]. The FDA noted that the efficacy and safety profiles of this intervention had not yet been fully evaluated in controlled clinical trials, and organized a public workshop to provide a forum for the exchange of experiences among the medical and scientific community about the regulatory issues associated with FMT. After this public meeting and several opinions of different authorities, 6 weeks later, the FDA’s guidance documents stated that this protocol including an IND status was suggested or recommended but not required [17,19]. Indeed, the FDA proposed a compassionate exception to allow the many people suffering from CDI to benefit from the use of FMT. The FDA recommended that the treating physician obtain adequate informed consent from the patient or his or her legally authorized representative for the use of FMT. Informed consent should include, at a minimum, a
2500 2000 1500 1000
N° of citations
Review of 317 cases Gough et al. [9]
500
1958
First report Eiseman et al. [8]
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2006 2007 2008 2009 2010 2011 2012 2013 2014
First randomized study in reccurent CDI Van Nood et al. [10]
??
Food and Drug Administration recommendations, USA [17] ANSM recommendations, France [20]
NICE recommendations, United Kingdom [21]
FIG. 1. Scientific and regulatory key events from 1858 to 2014 in faecal microbiota transplantation. We found an increasing number of citations by using the ISI web of knowledge and ‘fecal microbiota transplantation’ as the keyword. CDI, Clostridium difficile infection. ª2014 The Author Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20, 1112–1118
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statement that the use of FMT products to treat CDI is investigational and a discussion of its potential risks. The FDA proposed this on an interim basis while the agency develops appropriate policies for the use of FMT as an IND. In France, in March 2014, the National Security Drugs Agency (Agence Nationale pour la Securite du Medicament) also considered FMT to be a drug (http://ansm.sante.fr/var/ ansm_site/storage/original/application/5e5e010183037901942 75ded0e02353c.pdf). In the absence of market authorization, the National French Agency recommended that FMT must have the same legislative framework as experimental drugs or magisterial preparations. Indeed, the preparation was under the responsibility of the hospital pharmacist. The authorities strongly recommended supervising the use of FMT in clinical trials, but left open the possibility of clinicians performing FMT with compliance with stringent recommendations [20]. They also recommended stringent screening of the donors, asking the clinicians to determine the reasons for non-compliance with the protocol. Finally, in the UK, in March 2014, the UK National Institute for Health and Care Excellence (IPG 485) deemed FMT to be a safe and effective treatment for recurrent CDI (http://www.nice.org.uk/guidance/IPG485) [21]. Overall, to date, most countries have proposed strict requirements to limit the practice of FMT for recurrent CDI. Nonetheless, differences regarding the ‘drug’ or ‘tissue’ status remain. For example, the FDA defines drugs as ‘articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease’ [17]. Faecal microbiota is a variable and complex ecosystem composed of a mixture of microorganisms, metabolites, and human cells [17,19,22]. As has been the case for semen, which is a tissue product, and blood, which has its own rules, a special status for FMT may be useful, because it is very difficult to characterize faecal samples according to the rigorous standards applied to conventional drugs. We must find the balance between stringent rules to protect human health and rules that are too restrictive, and that may lead patients to consider unregulated and expensive proposals that are available on the Internet or, worse, home-made protocols that are available on YouTube [17].
How do we Preserve the Health and Safety of Patients Treated with FMT? The recruitment and screening of donors is a lengthy process that is essential to ensure the health and safety of patients.
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patients, who have a high risk of developing CDI, pregnant women, and patients treated with antibiotics for reasons other than for CDI on the day of inclusion. Nevertheless, a recent study that included human immunodeficiency virus (HIV) patients, solid organ transplant patients and patients with immunosuppressive therapy for inflammatory bowel disease obtained an overall cure rate of 89%, without related infectious complications, in these high-risk patients. These results should significantly and rapidly affect the current recommendations [13,23]. Donor screening
Clinical examination. For example, the National French Agency proposes a two-step selection process. The first visit consists of a pre-inclusion screening with questioning, a clinical examination, and a biological examination. Donors younger than 18 years with a history of Salmonella Typhi infection, chronic diseases or long-term treatment (without precision), diarrhoea within the past 3 months, or overseas travel within the past 3 months, and donors who had been hospitalized, or whose family members had been hospitalized, within the past 12 months, were systematically excluded. In addition, the French authorities recommend avoiding donors who are aged >65 years or have a body mass index of >30, donors treated with antibiotics within the past 3 months, or donors with a familial history of autoimmune diseases, inflammatory bowel diseases, or colorectal neoplasms. The second visit for consideration consists of a supplementary questionnaire to detect criteria for non-inclusion that may have occurred since the inclusion visit (e.g. diarrhoea, travel, human blood exposure, and sexual exposure to risk) [20]. Biological screening: faecal samples
Van Nood recommended performing both bacteriological and parasitological evaluations and testing for the presence of C. difficile (toxin ELISA and culture) [10]. The French authorities proposed extremely detailed recommendations that included the detection of a comprehensive list of pathogens: C. difficile, Listeria monocytogenes, Vibrio cholerae, Vibrio parahaemolyticus, Salmonella species, Shigella species, adenoviruses, astroviruses, caliciviruses, picornaviruses, rotavirus, and hepatitis A and E viruses. Regarding parasitic infections, they recommended testing for the presence of Strongyloides stercoralis, Cryptosporidium species, Cyclospora species, Entamoeaba histolytica, Giardia intestinalis, Isospora species and microsporidia. The National French Agency also strongly recommends testing for the carriage of extended-spectrum b-lactamase-producing enterobacteria in the donors [20,24].
Patient selection
Most of the clinical studies and the authority recommendations that have been suggested to date exclude immunocompromised
Biological screening: blood samples. Van Nood [10] proposed testing for active infections caused by cytomegalovirus,
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Epstein–Barr virus, hepatitis A virus, hepatitis B virus, HIV-1, HIV-2, human T-lymphotropic virus types I and II, Treponema pallidum, E. histolytica, and S. stercoralis. In addition, the French authorities recommend testing for Toxoplasma gondii and Trichinella species [20].
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Ethics and acceptability
The strong evidence for the efficacy of FMT in the treatment of recurrent CDI leads to the question, ‘Is it ethical to not be able to propose FMT to all patients suffering from recurrent CDI?’ rather than the question, ‘Is it ethical to propose FMT for the treatment of recurrent CDI?’ Brandt et al. [27] demonstrated that 73% of patients treated with FMT would undergo the treatment again, and that 53% would prefer FMT as the initial therapy in instances of recurrent CDI. Zipursky et al. assessed patients’ perceptions regarding the management of CDI by proposing diverse scenarios. After patients had been informed of the cure rate percentages for various treatments, most of the patients chose FMT for treatment, but they did not know the nature of the treatment. Only 16 individuals changed their choices when the authors explained what FMT actually was [7]. The authors noted that the acceptability was higher when the clinician recommended this alternative. Finally, the media’s attraction to a treatment regimen that is easy to sensationalize has increased its acceptability [17].
Adverse outcome follow-up
Smits et al. [15], who have a large amount of experience with FMT, reported no serious side effects. Van Nood [10] reported diarrhoea or abdominal pain, which disappeared a few hours after the procedure. In a recent study by Kelly et al. [13], one patient died of aspiration during sedation for FMT administered via a colonoscopy. Overall, transient abdominal discomfort, diarrhoea, constipation and bloating have been the most frequently described side effects. Nevertheless, very few long-term follow-up data are available in the literature [17]. Additionally, the theoretical risk that FMT could modify the microbiota of the patients and make them susceptible to chronic conditions such as obesity or autoimmune disorders [17] encourages the establishment of mandatory registries to protect against infectious diseases and to track adverse events, including long-term adverse events, as required by the FDA and the French authorities [17,20]. Considering the efficacy of FMT for the treatment of recurrent CDI performed in a large number of patients [25,26], the benefit/risk ratio is clearly in favour of this procedure (Table 1).
How do we Facilitate FMT and Consider Industrialization? Frozen faeces and faecal banks
The main limitation of transplantation with fresh faeces was overcome by the use of frozen faeces; this avoids the need to maintain an available pool of donors, and allows for the establishment of a bank of preprocessed material that is rapidly usable [28]. In 2012, Hamilton et al. [29] proposed moving from patient-identified individual donors to standard volunteer donors, and recently Youngster et al. [28] demonstrated that transplantation with frozen faeces was effective. Faecal banks have been established, such as OpenBiome, a company based in Cambridge, which is a non-profit organization that was
How do we Choose the Donor? To the best of our knowledge, there is no scientific argument to recommend anonymous donation rather than directed donation. Similarly, transplants with pooled faecal material are comparable with transplants from unique donors in both their safety and efficacy.
TABLE 1. Summary of the benefit/risk ratio of faecal transplantation for the treatment of recurrent Clostridium difficile infection and inflammatory bowel diseases Type of study and indication
No. of patients
Benefit
Risk
Recurrent C. difficile infection
–
–
–
Randomized study using the duodenal route
16
81% cure after one infusion, 93% overall
Review Review
536 317
87% resolution of diarrhoea 92% resolution of diarrhoea
No severe adverse event Diarrhoea (94%) Constipation (19%) No severe adverse event One upper gastrointestinal haemorrhage
Inflammatory bowel disease Review
26
76% reduction of symptoms
One activation of Crohn’s disease
Outstanding safety questions
Reference
Long-term adverse event Risk of anaesthesia depends on the route of administration –
–
– –
Cammarota et al. [25] Gough et al. [9]
Long-term outcome
Anderson et al. [26]
Van Nood et al. [10]
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funded in 2012 to provide faecal transplants for different hospitals (OpenBiome 2014, http://www.openbiome.org/). The samples were homogenized, and frozen for long-term storage [17]. Usually, the faecal solution is poured through a clean metal sieve in order to remove the food-derived debris [10]. Nevertheless, the FDA recently decided to allow FMT only when the source of faeces is known to either the physician or the patient [30], consequently creating difficulties for organizations such as OpenBiome in the USA [30]. In addition, two teaching hospitals, including the Massachusetts General Hospital in Boston and the Emory University Hospital in Atlanta, developed their own faecal banks for their patients [17] following the FDA recommendations. Route of administration
Retention enema was the only route available until 1989 [31]. Since then, alternative methods using colonoscopy, duodenal tubes or nasogastric tubes have been established [28,31]. Recently, despite difficulties in comparing protocols, owing to unavailable data and differences regarding the quantity of the transplant, a review concluded that an enema or the colonoscopy route were probably the most effective protocols. The only randomized clinical trial demonstrating the efficiency of FMT in recurrent CDI used the duodenal route with gastroscopy [10]. Finally, a recent study comparing colonoscopic administration and nasogastric tube administration demonstrated better efficacy of the upper route [29]. This mode of administration remains the easiest and the least invasive, thereby avoiding the risk inherent in general anaesthesia. Synthetic microbiota
Knowledge regarding the gut microbiota composition has been increased by the use of next-generation sequencing, which has led researchers to suggest links between diseases and the bacterial community at the genus or species level [31–34]. The next step could be using this association to improve human health by designing an ideal microbiota [17]. Preliminary studies have been designed in mice or in patients with CDI [35]. For example, Jorup-Ronstrom et al. [36] used subcultured human donor microbiota, obtaining a success rate of 69%, and Petrof et al. [37] used 33 isolates of bacterial species cultured from the human gut of one donor to demonstrate efficacy in two patients with infections caused by the virulent ribotype O78. The cocktail was composed of Lactobacillus species, Escherichia coli, Raoultella species, Bifidobacterium species, Clostridium species, and other anaerobic bacterial species. Different companies in the USA have already tested synthetic approaches [17]. The advantages of synthetic microbiota include avoiding the risks of pathogens and viruses
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that are inherent to the use of stool samples, and the reproducibility of manufacture, which facilitates industrialization [35]. Nonetheless, treatments with synthetic communities will not be available for many years. Currently, to the best of our knowledge, except case series, there is no evidence of comparable efficiency, than transplantation using stool samples. In addition, caution should be recommended because we know the differences in the composition of the gut microbiota depends of the tools used to explore the microbiota [38,39]. Pills
FMT, which allows for the recovery of the gut microbiota [40] to cure recurrent CDI, is a method that remains limited to a few hospital centres. To the best of our knowledge, no human clinical studies have been published to date regarding the use of lyophilized, encapsulated and enteric-coated capsules for oral administration. Nevertheless, clinical trials with stool-derived pills are ongoing (http://clinicaltrials.gov/show/NCT 01914731; http://www.idweek.org/pr-2013-cdiff/) [30,41,42]. The development of pills containing microbiota, based on the model of Saccharomyces boulardii pills, which have been used for >80 years [43], is likely to accelerate. Ultimately, it is conceivable that, after any use of antibiotics in patients aged >65 years, oral FMT will become a routine procedure to ecologically conserve the gut microbiota.
Conclusion The efficacy of FMT has now been strongly demonstrated in recurrent CDI [10]. Other indications, such as the decontamination of patient carriers of extended-spectrum b-lactamase producers, could be proposed to expand the field of interest for industry [44]. Over six clinical trials studying FMT in inflammatory bowel diseases have also been registered [17]. The standardization of the stringent screening of donors and follow-up will increase the health and safety of the patients. Currently, recent data recommending the nasogastric route and the use of frozen faeces should be applied to facilitate manipulations and to avoid the risk of anaesthesia [29]. Finally, in the near future, the use of pills with a possibly standardized microbiota will be the final step before widening the indications and acceptability of FMT.
Transparency Declaration The author declares no conflict of interest.
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44. Singh R, Van Nood E, Nieuwdorp M et al. Donor faeces infusion for eradication of extended-spectrum b-lactamase-producing Escherichia coli in a patient with end-stage renal disease. Clin Microbiol Infect 2014; doi: 10.1111/1469-0691.12683.
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