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Fecal microbiota transplant for C. difficile infection: Just say yes
Journal Pre-proof Fecal microbiota transplant for C. difficile infection: Just say yes Giovanni Cammarota, Antonella Gallo, Stefano Bibbò PII:
S1075-9964(19)30181-7
DOI:
https://doi.org/10.1016/j.anaerobe.2019.102109
Reference:
YANAE 102109
To appear in:
Anaerobe
Received Date: 13 April 2019 Revised Date:
9 October 2019
Accepted Date: 11 October 2019
Please cite this article as: Cammarota G, Gallo A, Bibbò S, Fecal microbiota transplant for C. difficile infection: Just say yes, Anaerobe (2019), doi: https://doi.org/10.1016/j.anaerobe.2019.102109. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
1
FECAL MICROBIOTA TRANSPLANT FOR C. DIFFICILE INFECTION: JUST SAY YES
2
Giovanni Cammarota1,2, Antonella Gallo3, Stefano Bibbò4
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
1. Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli, 8, 00168 Roma, Italy. [email protected]. 2. Università Cattolica del Sacro Cuore, 00168 Roma, Italy. [email protected]. 3. Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli, 8, 00168 Roma, Italy. [email protected] 4. Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli, 8, 00168 Roma, Italy. [email protected].
18 19 20 21
Correspondence
22
Tel/fax numbers: +39 06 30155948/+39 06 35502775;0
23
e-mail address: [email protected]
24 25 26
Prof. Giovanni Cammarota; Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 – Rome, Italy.
1
ABSTRACT
2
The burden of Clostridium difficile associated diarrhea is a worrying clinical issue worldwide,
3
mainly as regarding the high incidence of recurrences after standard antibiotic therapy and the risk
4
for more severe clinical manifestations. For this reason, new and more effective therapies are
5
needed for the treatment of recurrent episodes. Fecal microbiota transplantation seems to be a valid
6
tool considering the mechanism of action and the growing number of studies that demonstrate its
7
clinical efficacy.
8 9 10 11 12 13 14 15 16 17 18 19 20 21
1
MAIN TEXT
2
Clostridium difficile infection (CDI) represents a burdensome clinical issue, associated with a
3
significant morbidity and mortality worldwide (1). CDI is caused by the abnormal proliferation of
4
C. difficile, a Gram-positive anaerobic spore-forming bacillus that is a pathobiont in the human gut.
5
Indeed some subjects are carriers of the bacterium but do not develop the symptoms of the infection
6
and more specifically we can refer to CDI only in the presence of gastrointestinal symptoms(2). The
7
disease is characterized by a wide spectrum of severity, ranging from mild to severe diarrhea;
8
furthermore some patients may develop the pseudomembranous colitis (PMC) that may progress to
9
toxic megacolon, sepsis, and death(3). The heterogeneous clinical picture of CDI depends by
10
several factors such as older age (over 80% of CDI deaths occur in people over 65 years) (4) or the
11
presence of comorbidities, however the main pathogenic factor is the disruption of gut microbiota
12
that is caused by protracted and combined antimicrobial therapies (5-6).
13
CDI represents a relevant cause of antibiotic-associated diarrhea (1). Its epidemiology is evolving in
14
the last years, since the emergence of hyper virulent strains, the high risk of recurrence after
15
standard antibiotic therapy and the increased incidence also in community setting (7).
16
In the United States the incidence of CDI among hospitalized adults patients nearly doubled
17
between 2001 and 2010 (1). However, it has been reported that, since 2009, CDI incidence showed
18
a slightly decline, mainly in hospital setting (7) and in European countries (4). This is mostly linked
19
to an increased awareness about the high social and economical impact of these diseases, thus
20
leading to implementation to prevention strategies, improvement of surveillance and infection
21
control measures. At this regards, rigorous antibiotic stewardship programs, as suggested by Lawes
22
et al (8), may represent a successful strategy to reduced growth of highly resistant ribotypes and
23
positively impact on total CDI incidence.
24
CDI has a relevant impact on healthcare costs, causing an expenditures by approximately 5.4 billion
25
annually in the United States (9-10),
mainly linked to prolonged hospitalization and re-
1
hospitalization. But the economic and clinical burden becomes more relevant for episodes of
2
recurrent CDI, that may cost three times more than an episode of primary CDI (11).
3
The standard treatment for the first occurrence of CDI was represented by metronidazole or
4
vancomycin administration (12). However the rate of recurrence after standard antibiotic therapy is
5
rapidly increasing in the latest years, indeed about 10-20% of patients with CDI experienced a
6
recurrence and after the first recurrence this percentage may increase to 40-50% for further episodes
7
(13). In the United States, from 2001 to 2012, the annual incidence of CDI and recurrent CDI
8
(rCDI) increased respectively by 42.7% and 188.8% (14), showing that recurrent CDI has
9
disproportionately increased in western countries compared to the absolute number of CDI, since
10
the outbreak of a pathogen more virulent and resistant to standard therapies.
11
These alarming epidemiological data have prompted the scientific community to develop new and
12
more effective therapies to treat rCDI, among these fecal microbiota transplantation (FMT) has
13
been largely shown to be effective in the treatment of rCDI (15).
14
FMT is a simple procedure that consists in the infusion of feces from a healthy donor into the
15
gastrointestinal tract of a recipient (16). FMT is a new old tool, in fact it has been anecdotally used
16
by more than two thousand years, but only in recent years the researchers have understood the
17
clinical importance of this method through an evidence-based approach (16-26). Figure 1 shows the
18
most relevant findings reported by RCTs during these years and the consequent statements of
19
scientific societies in supporting role of FMT (figure 1).
20
The first randomized control trial that investigated the role of FMT for recurrent CDI was
21
performed by van Nood el al in 2013 (17). They demonstrated that a single FMT delivered by
22
nasoduodenal route was superior to standard therapy with oral vancomycin (overall cure rate of
23
94% for FMT vs 31% for vancomycin) (17).
1
FMT represents a successful strategy in rCDI, the secret of success can be identified into the
2
mechanism of action because it is a restorative treatment of gut microbiota, unlike to the antibiotic
3
therapy that represents a disruptive treatment. Indeed, the administration of FMT to patients with
4
rCDI results in prompt and sustained donor-like normalization of microbial community structure
5
and of the gut microbiota metabolic activity. In particular, specific members of the fecal microbiota
6
transferred can either directly or indirectly interfere with the proliferation of CD within the gut (27).
7
FMT also play a relevant metabolic role. It is known, in fact, that the amount of secondary bile
8
acids and short-chain fatty acids (SCFAs) was increased by FMT, associated with a consequent
9
generation of inhibitory compounds to germination of C. difficile spore (28).
10
During these last years, a great heterogeneity regarding FMT procedure was reported among the
11
different studies. The donor selection, the route of administration (by colonoscopy, naso-duodenal
12
tube, capsules, or enemas) and the number of fecal infusions and the type of delivery material
13
(fresh or frozen material) can vary widely (15-16, 24-26). However, despite the efforts to ensure
14
standardization definitive FMT protocols have not yet been designed. To date, there is still no clear
15
evidence supporting the superiority of one protocol over another one for the treatment of rCDI (29-
16
30).
17
Tarig et al recently performed a systematic meta-analysis on 31 clinical trials of FMT for CDI from
18
January 1978 to March 2017 (30), showing that FMT was associated with lower cure rates in
19
randomized trials than in open-label and in observational studies. As regarding routes of delivery,
20
colonoscopy and oral route resulted more effective than enema for stool delivery (30).
21
Moreover, Ianiro and al, have recently compared the efficacy of different FMT protocols, analyzing
22
fifteen studies (1150 subjects). Efficacy rates of FMT achieved by all types of protocols were 93%
23
overall. Colonoscopy appear to be superior to all other routes of administration; furthermore this
24
study demonstrated that multiple infusions compared to single infusion increased efficacy rates in
25
more severe cases (93% vs 76%) (15).
1
These positive clinical evidences have encouraged the scientific societies to include the FMT
2
among the recommended treatments for rCDI. Already in 2014, the European Society of Clinical
3
Microbiology and Infectious Disease (ECSMID) strongly recommended FMT after a second
4
recurrence of CDI (21), while the American College of Gastroenterology (ACG) suggested that
5
FMT should be considered in the case of third recurrence after a pulsed vancomycin regimen (20).
6
More recently the European Consensus Conference held in Rome stated that FMT is recommended
7
as a treatment option for rCDI and should be also considered for refractory CDI (29), moreover in
8
2018 the Infectious Disease Society of America (IDSA) recommended it after the second CDI
9
recurrence (12).
10
Beyond its validated role in rCDI, new evidences suggest that FMT may represent a promising
11
treatment also for severe CDI refractory to antibiotics (29,31). Hocquart et al (31) also showed in a
12
retrospective cohort study that FMT significantly improved survival in patients with severe CDI in
13
respect to medical treatment alone (31). Based on these results, the authors also suggested the use of
14
FMT as a first-line treatment for severe CDI, although further studies are still necessary to
15
consolidate this evidence (31).
16
Unfortunately, FMT is not without side effects or adverse effects. The most common side effects
17
include self-limiting gastrointestinal symptoms (bloating, abdominal pain, flatulence, diarrhea, and
18
constipation), which arise immediately after the procedure and are self-limited in a few days (29).
19
Adverse events, such as aspiration pneumonia or vomiting was mainly reported if FMT is delivered
20
via upper GI tract, moreover were reported cases of bacterial translocation mostly in
21
immunocomprised patients; to date long-term safety data are still lacking.
22
The prevention of adverse events related to the infusion of fecal material represent a challenge for
23
physicians. At this regards, donor selection represents a crucial step both for doctors and patients.
24
FMT has been initially performed using a patient-selected donor model (e.g. spouse, sibling), who
25
had to submit to an extensive screening. This model may create a significant delay between
1
screening for treatment and delivery of therapy, while probably reassuring patients about selection
2
of donor within its own family. However, in the last years, there is a progressive implementation of
3
stool banks, able to offer improved safety, since the rigorous screening protocols, and reduced costs,
4
with fecal material rigorously stored and then used for clinical administration as needed.
5
In 2016, Kelly et al. performed a double-blind, randomized, controlled trial on 46 patients with
6
rCDI, showing that FMT with donor stool (heterologous) resulted as safe as FMT with patient’s
7
own stool (autologous), in terms of occurrences of adverse and serious adverse events, and of new
8
medical conditions in the 6 months after FMT. Moreover, heterologous FMT resulted more
9
efficacious (91% of patients achieved clinical cure) than autologous FMT (63% of patients) (32).
10
In conclusion, we can consider several good reasons to say “yes” to FMT in rCDI. Worrying
11
epidemiological data, such as the clinical burden of CDI and more important the burden of CDI
12
recurrence after treatment, make new therapeutic approaches necessary. So FMT appears to be a
13
lifeline, it is supported by a scientific rationale, by a relevant strength of literature evidences and
14
also by statement of international society guidelines. Finally, cost-effectiveness analysis identified
15
FMT as the preferred treatment option for recurrent CDI, with best results obtained using early
16
colonoscopy route (33). In view of the strength of clinical results and favorable cost-effectiveness
17
analysis, we hope that FMT is no longer considered merely as an unfortunate, temporary bridge
18
therapy until drug companies come up with simpler and undoubtedly more expensive alternatives,
19
but it may expand more widely in clinical practice.
20
21
1
2
Figure 1. The modern history of Fecal Microbiota Transplantation for the treatment of Clostridium
3
difficile infection
4
5
1 2
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Leffler DA, Lamont JT. Clostridium difficile infection. The New England journal of
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6. Bibbo S, Lopetuso LR, Ianiro G, Di Rienzo T, Gasbarrini A, Cammarota G. Role of microbiota
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7. Desai K, Gupta SB, Dubberke ER, et al. Epidemiological and economic burden of Clostridium
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McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical
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Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the
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Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of
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America (SHEA). Clinical infectious diseases. 2018;66(7):e1-e48.
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Clostridium difficile Infection in the United States: A Cohort Study. Annals of internal medicine.
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Ma GK, Brensinger CM, Wu Q, Lewis JD. Increasing Incidence of Multiply Recurrent
Ianiro G, Maida M, Burisch J, Simonelli C, Hold G, Ventimiglia M, et al. Efficacy of
Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, et al. Update on Fecal
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17. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal
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infusion of donor feces for recurrent Clostridium difficile. The New England journal of medicine.
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Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of
Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium
Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al.
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Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. The
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American journal of gastroenterology. 2013;108(4):478-98; quiz 99.
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Infectious Disease. European Society of Clinical Microbiology and Infectious Diseases: update of
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the treatment guidance document for Clostridium difficile infection. Clinical microbiology and
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infection. 2014;20 Suppl 2:1-26.
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frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. Jama.
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2014;312(17):1772-8.
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23.
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Gasbarrini A. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs.
21
vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther.
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2015 May;41(9):835-43.
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Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent
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Clostridium difficile Infection: A Randomized Clinical Trial. Jama. 2016;315(2):142-9.
Debast SB, Bauer MP, Kuijper EJ, European Society of Clinical Microbiology and
Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized,
Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, Sanguinetti M,
Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, et al. Frozen vs Fresh
1
25.
Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of Oral Capsule- vs
2
Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile
3
Infection: A Randomized Clinical Trial. Jama. 2017;318(20):1985-93.
4
26.
5
Randomised clinical trial: faecal microbiota transplantation by colonoscopy plus vancomycin for
6
the treatment of severe refractory Clostridium difficile infection-single versus multiple infusions.
7
Alimentary pharmacology & therapeutics. 2018;48(2):152-9.
8
27.
9
Clostridium difficile colonization resistance. Trends in microbiology. 2012;20(7):313-9.
Ianiro G, Masucci L, Quaranta G, Simonelli C, Lopetuso LR, Sanguinetti M, et al.
Britton RA, Young VB. Interaction between the intestinal microbiota and host in
10
28. Weingarden AR, Vaughn BP Intestinal microbiota, fecal microbiota transplantation, and
11
inflammatory bowel disease.Gut Microbes. 2017;8(3):238-252.
12
29.
13
consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66(4):569-
14
80.
15
30. Tariq R, Pardi DS, Bartlett MG, et al. Low Cure Rates in Controlled Trials of Fecal Microbiota
16
Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-
17
analysis. Clin Infect Dis. 2019 Apr 8;68(8):1351-1358.
18
31. Hocquart M, Lagier JC, Cassir N, et al.Early Fecal Microbiota Transplantation Improves
19
Survival in Severe Clostridium difficile Infections. Clin Infect Dis. 2018 Feb 10;66(5):645-650
20
32. Kelly CR, Khoruts A, Staley C, et al. Effect of Fecal Microbiota Transplantation on Recurrence
21
in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med. 2016
22
Nov 1;165(9):609-616.
23
33. Heimann SM, Cruz Aguilar MR, Mellinghof S, Vehreschild M. Economic burden and cost-
24
effective management of Clostridium difficile infections. Medecine et maladies infectieuses.
25
2018;48(1):23-9.
26
Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, Satokari R, et al. European
1958: First reported application of FMT for pseudomembr anous colitis18
1958
2013: A systematic review and meta-analysis on FMT for CDI showed that it achieved clinical resolution in 245 out of 273 (89%) reported patients19
2013
2013: FMT included in American guidelines for the management of rCDI20
2014: Feasibility study on oral, capsulized, frozen FMT for relapsing C. difficile infection22 2013: RCT. Efficacy of FMT via nasoduodenal tube in treating rCDI when compared with standard antibiotic therapy17
2015: RCT. FMT via colonoscopy vs pulsed vancomycin23
2014
2014: FMT recommended by the European Society of Clinical Microbiology and Infectious Diseases for the treatment of rCDI21
2016: RCT: Frozen vs fresh FMT and clinical resolution of diarrhea in patients with rCDI24
2016
2017: European European Consensus Conference: FMT is recommended as a treatment option for rCDI and should be also considered for refractory CDI 29
2017: RCT. Oral capsule– vs colonoscopydelivered FMT on rCDI26
2017
2018
2018: IDSA and SHEA guidelines: FMT strongly recommended for rCDI.12
2018:FMT may represent a promising treatment also for severe refractory CDI29
HIGHLIGHTS -The occurrence of severe and recurrent cases of clostridium difficile-associated colitis is an important challenge for health systems -FMT has proven to be very effective compared to standard antibiotic therapies, particularly in severe and recurrent cases -Side effects are usually mild and self-limiting, serious adverse effects are rare and limited to the most fragile patients -Further studies are needed to optimize the procedure, a better selection of donors could reduce the occurrence of adverse events
S1075-9964(19)30181-7
DOI:
https://doi.org/10.1016/j.anaerobe.2019.102109
Reference:
YANAE 102109
To appear in:
Anaerobe
Received Date: 13 April 2019 Revised Date:
9 October 2019
Accepted Date: 11 October 2019
Please cite this article as: Cammarota G, Gallo A, Bibbò S, Fecal microbiota transplant for C. difficile infection: Just say yes, Anaerobe (2019), doi: https://doi.org/10.1016/j.anaerobe.2019.102109. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
1
FECAL MICROBIOTA TRANSPLANT FOR C. DIFFICILE INFECTION: JUST SAY YES
2
Giovanni Cammarota1,2, Antonella Gallo3, Stefano Bibbò4
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
1. Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli, 8, 00168 Roma, Italy. [email protected]. 2. Università Cattolica del Sacro Cuore, 00168 Roma, Italy. [email protected]. 3. Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli, 8, 00168 Roma, Italy. [email protected] 4. Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli, 8, 00168 Roma, Italy. [email protected].
18 19 20 21
Correspondence
22
Tel/fax numbers: +39 06 30155948/+39 06 35502775;0
23
e-mail address: [email protected]
24 25 26
Prof. Giovanni Cammarota; Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 – Rome, Italy.
1
ABSTRACT
2
The burden of Clostridium difficile associated diarrhea is a worrying clinical issue worldwide,
3
mainly as regarding the high incidence of recurrences after standard antibiotic therapy and the risk
4
for more severe clinical manifestations. For this reason, new and more effective therapies are
5
needed for the treatment of recurrent episodes. Fecal microbiota transplantation seems to be a valid
6
tool considering the mechanism of action and the growing number of studies that demonstrate its
7
clinical efficacy.
8 9 10 11 12 13 14 15 16 17 18 19 20 21
1
MAIN TEXT
2
Clostridium difficile infection (CDI) represents a burdensome clinical issue, associated with a
3
significant morbidity and mortality worldwide (1). CDI is caused by the abnormal proliferation of
4
C. difficile, a Gram-positive anaerobic spore-forming bacillus that is a pathobiont in the human gut.
5
Indeed some subjects are carriers of the bacterium but do not develop the symptoms of the infection
6
and more specifically we can refer to CDI only in the presence of gastrointestinal symptoms(2). The
7
disease is characterized by a wide spectrum of severity, ranging from mild to severe diarrhea;
8
furthermore some patients may develop the pseudomembranous colitis (PMC) that may progress to
9
toxic megacolon, sepsis, and death(3). The heterogeneous clinical picture of CDI depends by
10
several factors such as older age (over 80% of CDI deaths occur in people over 65 years) (4) or the
11
presence of comorbidities, however the main pathogenic factor is the disruption of gut microbiota
12
that is caused by protracted and combined antimicrobial therapies (5-6).
13
CDI represents a relevant cause of antibiotic-associated diarrhea (1). Its epidemiology is evolving in
14
the last years, since the emergence of hyper virulent strains, the high risk of recurrence after
15
standard antibiotic therapy and the increased incidence also in community setting (7).
16
In the United States the incidence of CDI among hospitalized adults patients nearly doubled
17
between 2001 and 2010 (1). However, it has been reported that, since 2009, CDI incidence showed
18
a slightly decline, mainly in hospital setting (7) and in European countries (4). This is mostly linked
19
to an increased awareness about the high social and economical impact of these diseases, thus
20
leading to implementation to prevention strategies, improvement of surveillance and infection
21
control measures. At this regards, rigorous antibiotic stewardship programs, as suggested by Lawes
22
et al (8), may represent a successful strategy to reduced growth of highly resistant ribotypes and
23
positively impact on total CDI incidence.
24
CDI has a relevant impact on healthcare costs, causing an expenditures by approximately 5.4 billion
25
annually in the United States (9-10),
mainly linked to prolonged hospitalization and re-
1
hospitalization. But the economic and clinical burden becomes more relevant for episodes of
2
recurrent CDI, that may cost three times more than an episode of primary CDI (11).
3
The standard treatment for the first occurrence of CDI was represented by metronidazole or
4
vancomycin administration (12). However the rate of recurrence after standard antibiotic therapy is
5
rapidly increasing in the latest years, indeed about 10-20% of patients with CDI experienced a
6
recurrence and after the first recurrence this percentage may increase to 40-50% for further episodes
7
(13). In the United States, from 2001 to 2012, the annual incidence of CDI and recurrent CDI
8
(rCDI) increased respectively by 42.7% and 188.8% (14), showing that recurrent CDI has
9
disproportionately increased in western countries compared to the absolute number of CDI, since
10
the outbreak of a pathogen more virulent and resistant to standard therapies.
11
These alarming epidemiological data have prompted the scientific community to develop new and
12
more effective therapies to treat rCDI, among these fecal microbiota transplantation (FMT) has
13
been largely shown to be effective in the treatment of rCDI (15).
14
FMT is a simple procedure that consists in the infusion of feces from a healthy donor into the
15
gastrointestinal tract of a recipient (16). FMT is a new old tool, in fact it has been anecdotally used
16
by more than two thousand years, but only in recent years the researchers have understood the
17
clinical importance of this method through an evidence-based approach (16-26). Figure 1 shows the
18
most relevant findings reported by RCTs during these years and the consequent statements of
19
scientific societies in supporting role of FMT (figure 1).
20
The first randomized control trial that investigated the role of FMT for recurrent CDI was
21
performed by van Nood el al in 2013 (17). They demonstrated that a single FMT delivered by
22
nasoduodenal route was superior to standard therapy with oral vancomycin (overall cure rate of
23
94% for FMT vs 31% for vancomycin) (17).
1
FMT represents a successful strategy in rCDI, the secret of success can be identified into the
2
mechanism of action because it is a restorative treatment of gut microbiota, unlike to the antibiotic
3
therapy that represents a disruptive treatment. Indeed, the administration of FMT to patients with
4
rCDI results in prompt and sustained donor-like normalization of microbial community structure
5
and of the gut microbiota metabolic activity. In particular, specific members of the fecal microbiota
6
transferred can either directly or indirectly interfere with the proliferation of CD within the gut (27).
7
FMT also play a relevant metabolic role. It is known, in fact, that the amount of secondary bile
8
acids and short-chain fatty acids (SCFAs) was increased by FMT, associated with a consequent
9
generation of inhibitory compounds to germination of C. difficile spore (28).
10
During these last years, a great heterogeneity regarding FMT procedure was reported among the
11
different studies. The donor selection, the route of administration (by colonoscopy, naso-duodenal
12
tube, capsules, or enemas) and the number of fecal infusions and the type of delivery material
13
(fresh or frozen material) can vary widely (15-16, 24-26). However, despite the efforts to ensure
14
standardization definitive FMT protocols have not yet been designed. To date, there is still no clear
15
evidence supporting the superiority of one protocol over another one for the treatment of rCDI (29-
16
30).
17
Tarig et al recently performed a systematic meta-analysis on 31 clinical trials of FMT for CDI from
18
January 1978 to March 2017 (30), showing that FMT was associated with lower cure rates in
19
randomized trials than in open-label and in observational studies. As regarding routes of delivery,
20
colonoscopy and oral route resulted more effective than enema for stool delivery (30).
21
Moreover, Ianiro and al, have recently compared the efficacy of different FMT protocols, analyzing
22
fifteen studies (1150 subjects). Efficacy rates of FMT achieved by all types of protocols were 93%
23
overall. Colonoscopy appear to be superior to all other routes of administration; furthermore this
24
study demonstrated that multiple infusions compared to single infusion increased efficacy rates in
25
more severe cases (93% vs 76%) (15).
1
These positive clinical evidences have encouraged the scientific societies to include the FMT
2
among the recommended treatments for rCDI. Already in 2014, the European Society of Clinical
3
Microbiology and Infectious Disease (ECSMID) strongly recommended FMT after a second
4
recurrence of CDI (21), while the American College of Gastroenterology (ACG) suggested that
5
FMT should be considered in the case of third recurrence after a pulsed vancomycin regimen (20).
6
More recently the European Consensus Conference held in Rome stated that FMT is recommended
7
as a treatment option for rCDI and should be also considered for refractory CDI (29), moreover in
8
2018 the Infectious Disease Society of America (IDSA) recommended it after the second CDI
9
recurrence (12).
10
Beyond its validated role in rCDI, new evidences suggest that FMT may represent a promising
11
treatment also for severe CDI refractory to antibiotics (29,31). Hocquart et al (31) also showed in a
12
retrospective cohort study that FMT significantly improved survival in patients with severe CDI in
13
respect to medical treatment alone (31). Based on these results, the authors also suggested the use of
14
FMT as a first-line treatment for severe CDI, although further studies are still necessary to
15
consolidate this evidence (31).
16
Unfortunately, FMT is not without side effects or adverse effects. The most common side effects
17
include self-limiting gastrointestinal symptoms (bloating, abdominal pain, flatulence, diarrhea, and
18
constipation), which arise immediately after the procedure and are self-limited in a few days (29).
19
Adverse events, such as aspiration pneumonia or vomiting was mainly reported if FMT is delivered
20
via upper GI tract, moreover were reported cases of bacterial translocation mostly in
21
immunocomprised patients; to date long-term safety data are still lacking.
22
The prevention of adverse events related to the infusion of fecal material represent a challenge for
23
physicians. At this regards, donor selection represents a crucial step both for doctors and patients.
24
FMT has been initially performed using a patient-selected donor model (e.g. spouse, sibling), who
25
had to submit to an extensive screening. This model may create a significant delay between
1
screening for treatment and delivery of therapy, while probably reassuring patients about selection
2
of donor within its own family. However, in the last years, there is a progressive implementation of
3
stool banks, able to offer improved safety, since the rigorous screening protocols, and reduced costs,
4
with fecal material rigorously stored and then used for clinical administration as needed.
5
In 2016, Kelly et al. performed a double-blind, randomized, controlled trial on 46 patients with
6
rCDI, showing that FMT with donor stool (heterologous) resulted as safe as FMT with patient’s
7
own stool (autologous), in terms of occurrences of adverse and serious adverse events, and of new
8
medical conditions in the 6 months after FMT. Moreover, heterologous FMT resulted more
9
efficacious (91% of patients achieved clinical cure) than autologous FMT (63% of patients) (32).
10
In conclusion, we can consider several good reasons to say “yes” to FMT in rCDI. Worrying
11
epidemiological data, such as the clinical burden of CDI and more important the burden of CDI
12
recurrence after treatment, make new therapeutic approaches necessary. So FMT appears to be a
13
lifeline, it is supported by a scientific rationale, by a relevant strength of literature evidences and
14
also by statement of international society guidelines. Finally, cost-effectiveness analysis identified
15
FMT as the preferred treatment option for recurrent CDI, with best results obtained using early
16
colonoscopy route (33). In view of the strength of clinical results and favorable cost-effectiveness
17
analysis, we hope that FMT is no longer considered merely as an unfortunate, temporary bridge
18
therapy until drug companies come up with simpler and undoubtedly more expensive alternatives,
19
but it may expand more widely in clinical practice.
20
21
1
2
Figure 1. The modern history of Fecal Microbiota Transplantation for the treatment of Clostridium
3
difficile infection
4
5
1 2
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Survival in Severe Clostridium difficile Infections. Clin Infect Dis. 2018 Feb 10;66(5):645-650
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Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, Satokari R, et al. European
1958: First reported application of FMT for pseudomembr anous colitis18
1958
2013: A systematic review and meta-analysis on FMT for CDI showed that it achieved clinical resolution in 245 out of 273 (89%) reported patients19
2013
2013: FMT included in American guidelines for the management of rCDI20
2014: Feasibility study on oral, capsulized, frozen FMT for relapsing C. difficile infection22 2013: RCT. Efficacy of FMT via nasoduodenal tube in treating rCDI when compared with standard antibiotic therapy17
2015: RCT. FMT via colonoscopy vs pulsed vancomycin23
2014
2014: FMT recommended by the European Society of Clinical Microbiology and Infectious Diseases for the treatment of rCDI21
2016: RCT: Frozen vs fresh FMT and clinical resolution of diarrhea in patients with rCDI24
2016
2017: European European Consensus Conference: FMT is recommended as a treatment option for rCDI and should be also considered for refractory CDI 29
2017: RCT. Oral capsule– vs colonoscopydelivered FMT on rCDI26
2017
2018
2018: IDSA and SHEA guidelines: FMT strongly recommended for rCDI.12
2018:FMT may represent a promising treatment also for severe refractory CDI29
HIGHLIGHTS -The occurrence of severe and recurrent cases of clostridium difficile-associated colitis is an important challenge for health systems -FMT has proven to be very effective compared to standard antibiotic therapies, particularly in severe and recurrent cases -Side effects are usually mild and self-limiting, serious adverse effects are rare and limited to the most fragile patients -Further studies are needed to optimize the procedure, a better selection of donors could reduce the occurrence of adverse events