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Faecal microbiota transplantation in the treatment of Clostridioides difficile infection
Journal Pre-proofs Original Article Faecal microbiota transplantation in the treatment of Clostridioides difficile infection Roman Stebel, Lenka Vojtilova, Radek Svacinka, Petr Husa PII: DOI: Reference:
S2452-2317(20)30001-4 https://doi.org/10.1016/j.humic.2020.100070 HUMIC 100070
To appear in:
Human Microbiome Journal
Received Date: Revised Date: Accepted Date:
8 December 2019 5 February 2020 13 February 2020
Please cite this article as: R. Stebel, L. Vojtilova, R. Svacinka, P. Husa, Faecal microbiota transplantation in the treatment of Clostridioides difficile infection, Human Microbiome Journal (2020), doi: https://doi.org/10.1016/ j.humic.2020.100070
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.
© 2020 Published by Elsevier Ltd.
Title: Faecal microbiota transplantation in the treatment of Clostridioides difficile infection Article type: Original article Authors: *Roman Stebel1,2, Lenka Vojtilova1,2, Radek Svacinka1,2, Petr Husa1,2 1
Faculty of Medicine, Masaryk University, Kamenice 753/5, Brno, Czech Republic
2 Department
of Infectious Diseases, University Hospital Brno, Jihlavska 20, Brno, Czech
Republic Address for correspondence: MUDr. Roman Stebel, Department of Infectious Diseases, University Hospital Brno and Faculty of Medicine, Masaryk University, Jihlavska 20, CZ-62500, Brno, Czech Republic email: [email protected] GSM: +420 777 894 574 Declarations of interest: None.
1
Faecal microbiota transplantation in the treatment of Clostridioides difficile infection
Abstract Faecal microbiota transplantation (FMT) represents a unique procedure targeted to restoring the natural diversity of the gastrointestinal microbiome and prevent recurrence of a key nosocomial disease, namely, Clostridioides difficile infection (CDI). The aim of the present study was assessing the success rate and clinical efficacy of FMT at a clinic that introduced this procedure in Czechia in 2010 and still leads in the number of transplantations performed to date. Patients enrolled in the study received primary targeted antibiotic therapy, and after the CDI episode treatment, FMT administered as a secondary prophylaxis. After the procedure, patients were followed up. The treatment was defined as successful if colitis did not recur within 8 weeks. Logistic regression analysis was used for determining the odds ratios for the individual factor variants (patient age and sex, number of previous recurrences, severity of the treated CDI episodes, presence of chronic comorbidities, performance status, initial antibiotic treatment, mode of faecal-transplant application and use of fresh or frozen stool). In the 4-year interval involved (2015–2018), 172 patients were treated using faecal microbiota transplantation. The overall success rate was 76%. Subgroup analysis identified higher age, higher Charlson Comorbidity Index reflecting the presence and severity of longterm comorbidities and higher Eastern Cooperative Oncology Group (ECOG) performance scores as risk factors for treatment failure. In the period monitored, two serious adverse events were observed: Both were rectal-wall perforations occurring during the application of enemas of stool suspension. There was no lethality. Keywords: Clostridioides difficile, faecal microbiota transplantation, gastrointestinal microbiome, intestinal dysbiosis, pseudomembranous enterocolitis
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1. Introduction Diarrhoeas associated with excessive multiplication of toxigenic Clostridioides difficile strains in the colon (C. difficile infection, CDI) represent one of the most important nosocomial diseases in developed countries. The incidence of CDI is rising globally, with the trends in severity and therapeutic failure growing as well [1]. Frequent recurrences particularly contribute to patient mortality and negatively affect patient quality of life. Approximately 20% of patients experience a relapse after the first CDI episode, while the risk of further episodes increases up to 65% [2]. According to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), FMT is recommended as a treatment option for recurrent CDI (rCDI) and can also be considered a treatment option for refractory CDI [3,4]. In Czechia, FMT was applied in clinical practice for the first time at the Department of Infectious Diseases of the University Hospital Brno in early 2010 [5]. 2. Aims of the study The aim of this prospective, observational, monocentric study was to form and describe a set of adult patients who had had CDI that was treated using FMT and assess the success rate and clinical efficacy of this treatment. Besides identifying the number of cured patients, we sought to determine whether any factors used to categorise the treated patients had a statistically significant influence on the therapy’s success rate. 3. Methods FMT was primarily indicated as a secondary prophylaxis for rCDI [6]. The faecal transplant was applied after a targeted antibiotic (ATB) therapy for colitis in patients with a history of one or more CDI recurrences. FMT was also applied in a few cases of a first CDI episode. These latter cases always involved high-risk patients, typically those receiving oncological treatment. FMT was applied outside of the period when chemotherapy, radiotherapy or biological treatment was in course. Selecting an appropriate donor was an important part of FMT preparation. Table 1 presents the factors relevant to selecting stool donors according to the Infectious Diseases Society of the Czech Medical Association guidelines [6]. Healthcare personnel were inadmissible as donors because of the risk of colon colonisation by C. difficile, as well as other multidrugresistant microorganisms [3]. The donor examination was always performed well in advance. 3
On the day of stool donation, a brief interview was held with the donor to ensure no recent health changes had occurred. Each patient and donor gave consent when FMT was planned. The research was approved by the Ethics Committee of the University Hospital Brno (104/12). All patients underwent 10 days of initial ATB therapy that was discontinued 48 hours before FMT. The drug of first choice was oral vancomycin (125 mg every 6 hours). In patients with symptoms of paralytic ileus, intravenous metronidazole (500 mg every 8 hours) was added to vancomycin. Fidaxomicin (200 mg every 12 hours) was used in individually selected patients at high risk of CDI recurrence [7]. Stool from related donors was prepared and applied immediately after acquisition. About 100 g of stool was homogenised with 200–500 ml of sterile, non-bacteriostatic crystalloid solution and filtered through several layers of gauze to remove undesirable admixtures [3]. The consistency of the suspension was adjusted individually in relation to the intended administration method. For enema administration, a thicker suspension was suitable because it would more easily adhere to the surface of the intestinal mucosa. Conversely, when administered with a nasoenteral feeding tube, a lower density was preferred to avoid blockage of the tube. The universal donor concept is based on the possibility of storing frozen stool from a thoroughly evaluated donor for a period of up to six months. Glycerol serving as a cryoprotective agent was added to the stool suspension. The final mixture was frozen at −80°C [3]. The FMT application path was selected individually. In older, polymorbid, recumbent patients, a less invasive method of FMT administration by enema was chosen. In younger, more mobile patients, administration of FMT by a nasoenteral feeding tube—introduced under endoscopic control—was preferred. Patients were prepared for FMT application into the distal duodenum by administration of a 20-mg oral dose of omeprazole to reduce stomach acidity. Those receiving a faecal-transplant enema first received a sorbitol enema to empty their bowels and oral loperamide to temporarily reduce intestinal peristalsis. After the faecal transplant, fasting was recommended to suppress the gastrocolic reflex [6]. After receiving FMT, the patients were followed up once weekly by means of personal visits or by phone. The primary response to FMT was defined as a reduction of stool count or the adjustment of stool consistency within 3 days after the procedure [8]. If there was no disease recurrence (three or more watery stools in 24 hours over 2 consecutive days and positive proof of C. difficile toxins) within 8 weeks of the procedure, the FMT was considered 4
successful [9]. For analysing the success rates by subgroups, patients were divided into categories according to the following risk factors: 1. Patient age and sex; 2. Severity of the CDI episode; 3. Number of CDI recurrences before FMT 4. Presence of chronic comorbidities and performance status of patients 5. Initial antibiotic therapy administered before FMT; 6. Mode of faecal-transplant application; and 7. Use of fresh or frozen donor stool. Unidimensional statistical testing was used for initially assessing the dependence of therapeutic success on the individual risk factors. Logistic regression using FMT failure as the dependent variable and the selected potential risk factors as the covariates was employed for further assessing the independence of the individual risk factors. The testing was done at a 0.05 level of statistical significance. 4. Results In 2015–2018, FMT was performed on 172 patients who had microbiologically confirmed CDI. The microbiological diagnosis was based on the detection of glutamate dehydrogenase (GDH) and free toxins of C. difficile in stool by enzyme immunoassay. In case of positive GDH and negativity of free toxins, real-time polymerase chain reaction (including detection of binary toxin genes and some epidemic ribotypes) was added [2]. The average patient age was 75.7 years (median: 78 years). There were 109 females and 63 males. During the monitored period, 12 patients received faecal transplants twice and 3 received them thrice, but this did not occur within an 8-week interval. Therefore, each FMT was evaluated separately. Eight patients were lost to contact during the study. The total number of FMTs analysed was 182 (Graph 1). No lethality occurred in the study set during the 8-week interval. Tables 2 and 3 present the baseline patient and procedural characteristics. Treatment failed in 44 cases, while 138 cases were free of CDI recurrence. This corresponds to an overall success rate of 76%.
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The FMT success rates were 77% in women and 75% in men, with no dependence on sex found (p = 0.582). The average age of patients without recurrence after FMT was 77.4 years (median: 77 years). The patients who experienced treatment failure had an average age of 80.1 years (median: 81 years). Testing of the results demonstrated that the success rate had an inverse relationship (Graph 2) to age that was statistically significant (p = 0.023; odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.01‒1.08). Another evaluated factor was the severity of the CDI episode, where 27 cases met the criteria for ‘severe CDI’ as defined by ESCMID [8]. A statistically significant difference in the success of FMT with ‘severe CDI’ compared with other cases was not demonstrated (p = 0.595). Neither lethality nor any serious adverse events occurred in the severe colitis group. ATLAS scores were further used to stratify the severity of the CDI. This scoring system includes assessments of age, body temperature, peripheral blood leukocyte count, serum albumin levels and concomitant ATB therapy [10]. The median ATLAS score in patients who failed FMT was 4.0. In patients without recurrence, it was 3.5. There was no statistically significant dependence (p = 0.130). The FMT-treated patients were divided into four groups: patients with one (primary) episode of CDI, one recurrence, two recurrences and three or more recurrences of CDI. The results showed a higher percentage of treatment failure in patients who had three or more recurrences (41.2%). The success rate for the groups with rCDI pooled together (without the primary episodes) was 76%. The testing of the results found no significant relationship between the success rate and the number of previous CDI recurrences (p = 0.277). Targeted ATB therapy always preceded FMT. Vancomycin was administered in 146 cases and fidaxomicin in 26 cases. Those treated with fidaxomicin had only three recurrences, representing an 88% success rate. Given the small number of patients in the fidaxomicin subgroup, the results exhibited no significant relationship between success rate and type of ATB administered prior to transplantation (p = 0.238). The result of treatment of several diseases is largely determined by the presence of chronic comorbidities. The Charlson Comorbidity Index (CCI) was calculated for all FMT-treated patients to assess the effect of comorbidity on treatment success. In the case of comorbidities, a statistically significant dependence of treatment success on CCI was demonstrated. In patients who failed treatment, CCI was significantly higher than in those who had no CDI recurrence after FMT (p = 0.004; OR: 1.35; 95% CI: 1.10–1.66). In addition to the number 6
and severity of chronic comorbidities in patients, their performance status is also of great prognostic importance. This tells us how the patient can function in everyday life. The Eastern Cooperative Oncology Group (ECOG) score was determined in all patients to assess their functional status levels [12]. In this case, a statistically significant dependence was also demonstrated. In patients with treatment failure, the ECOG score was statistically significantly higher (median: 3.0) compared with patients whose treatment was successful (p = 0.016; OR: 2.1; 95% CI: 1.15–3.82). Enema was the most frequently used mode of introducing donor stool filtrate into the patients’ intestines (121 procedures; 74% success rate). The other method used was introducing a nasoenteral feeding tube into the distal duodenum (61 cases; 80% success rate). No significant relationship was found between the mode of FMT application and success rate (p = 0.314). Frozen stool preparation was used in 41 cases, and the remaining patients were treated using freshly processed stool. In the former group, the application of thawed stool suspension yielded recurrence in 8 patients, representing an 80% success rate. In the latter group, there were 36 recurrences of colitis, which represents a 74% success rate using freshly processed stool. There was no significant relationship between success rate and the use of either fresh or frozen donor stool (p = 0.428). 5. Discussion The treatment of patients with FMT in 2015–2018 yielded results comparable to those of other international studies, as well as studies from our hospital published before 2015. The results of an earlier study in the same department demonstrated an 83.1% success rate [13]. The subgroup analysis demonstrated a statistically significant connection between the FMT success rate and patient age, the presence of long-term comorbidities and ECOG scores. Logistic regression showed a strong positive correlation between the four factors. With increasing age, the ATLAS scores, ECOG performance status and CCI increased. Similar results were recently published by the authors of a German retrospective observational study that analysed the FMT results from 35 centres [9]. The German study included patients who had histories of repeated rCDIs (a median of three recurrences prior to FMT) [9]. In the present study, FMT was applied earlier: About half the patients had a history of only a single CDI recurrence. FMT indication as early as after the second CDI attack is consistent with the procedure recommended by the Infectious Diseases 7
Society of the Czech Medical Association [6]. We think the early FMT administration in rCDI patients is because of the limited availability and cost of other secondary prophylactic procedures. The anti-toxin B monoclonal antibody bezlotoxumab is already used in many countries, but it is still not available in Czechia. Other innovative methods are under development. These include active immunisation with a toxoid vaccine, use of bacteriophages, colonisation of the intestine with non-toxic strains of C. difficile or efforts to restore homeostasis of bile acids in the intestine [7]. Generally, FMT is a safe method of treating rCDIs that is well-tolerated by patients. The most commonly reported reactions include temporary diarrhoea lasting several days after the procedure, constipation, bloating, abdominal discomfort and fever. These are insignificant, spontaneously resolving complications [14]. In this study, patients sporadically experienced these adverse reactions, which always resolved spontaneously. The literature also includes rare, severe, adverse events, including transmission of infectious diseases [15]. Another group of adverse events derives from the mode of FMT administration. Cases of regurgitation of the applied suspension followed by aspiration and the development of pneumonia have been reported with endoscopic administration of faecal transplant into the upper parts of the gastrointestinal tract [14]. Another undesirable consequence in this case may be excessive colonisation of the small intestine by faecal microbiota, so-called small intestine bacterial overgrowth (SIBO) syndrome [16]. Recently, in an effort to offer FMT to all patients who would benefit from it, there has been an evident tendency for FMT to be applied by enema. The application is simple and does not represent any burden on the patient. The disadvantage is that the enema only reaches the area of the colon’s lienal flexure, so the proximal colon sections are not sufficiently colonised by the donor microbiota [6]. Severe complications after FMT administered via rectal enema included bleeding and intestinal-wall perforation [14]. In this study, two patients developed abdominal pain, fever and clinical signs of peritoneal irritation shortly after FMT applied by enema, while enterorrhagia was observed in one of these cases. In both cases, computed tomography (CT) demonstrated rectal-wall perforation, and surgical revision of the abdominal cavity to conduct colostomy was performed. These perforations were probably due to enema application into the rectum by means of a balloon catheter. An alternative to rectal infusion of FMT could be colonoscopy application. However, the use of an endoscopic procedure alone is considered to be a significant risk against a background of inflammatory changes in the intestinal wall. A less invasive application method could be sigmoidoscopy [17]. 8
Based on the available information, FMT is considered safe from a long-term perspective. There is a theoretical risk of changing the composition of the intestinal microbiota after FMT, which can predispose the patient to developing obesity, metabolic syndrome, autoimmune diseases or cancers [14]. 6. Conclusions Colitis induced by C. difficile is currently one of the most significant diseases with causal associations to healthcare. FMT represents a safe, inexpensive therapeutic alternative to stop the apparent vicious cycle of chronically relapsing CDI by restoring the natural ecosystem of the colon. We see the future of FMT in both improving the method of application of faecal transplant (including oral administration in the form of enteric capsules) and in more targeted manipulation of intestinal microbiota, which will lead to the extension of FMT indication by a number of other diseases beyond the gastrointestinal tract.
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Acknowledgements This work was supported by the Ministry of Health, Czech Republic—Conceptual Development of Research Organisation [FNBr, 65269705]. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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References [1] Al-Jashaami LS, DuPont HL. Management of Clostridium difficile infection. Gastroenterol Hepatol 2016;12:609–16. [2] Napolitano LM, Edmiston CE. Clostridium difficile disease: diagnosis, pathogenesis, and treatment update. Surgery 2017;162:325–48. https://doi.org/10.1016/j.surg.2017.01.018. [3] Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, Satokari R, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 2017;66:569–80. https://doi.org/10.1136/gutjnl-2016-313017. [4] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407–15. https://doi.org/10.1056/NEJMoa1205037. [5] Polak P, Freibergerova M, Jurankova J, Kocourkova H, Mikesova L, Svacinka R, et al. Prvni zkusenosti s fekalni bakterioterapii v lecbe relabujici pseudomembranozni kolitidy zpusobene Clostridium difficile. Klin mikrobiol inf lek 2011;17:214–7. [6] Polivkova S, Vojtilova L, Husa P, Benes J. Doporuceny postup fekalni bakterioterapie pro lecbu rekurentni klostridiove kolitidy. Klin mikrobiol inf lek 2018;24:57–64. [7] Ooijevaar RE, van Beurden YH, Terveer EM, Goorhuis A, Bauer MP, Keller JJ, et al. Update of treatment algorithms for Clostridium difficile infection. Clin Microbiol Infect 2018;24:452–62. https://doi.org/10.1016/j.cmi.2017.12.022. [8] Debast SB, Bauer MP, Kuijper EJ, on behalf of the committee. European Society of Clinical Microbiology and Infectious Diseases. Update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20:1–26. https://doi.org/10.1111/1469-0691.12418. [9] Peri R, Aguilar RC, Tüffers K, Erhardt A, Link A, Ehlermann P, et al. The impact of technical and clinical factors on fecal microbiota transfer outcomes for the treatment of recurrent Clostridioides difficile infections in Germany. United European Gastroenterol J 2019;7:716–22. https://doi.org/10.1177/2050640619839918. [10] Miller MA, Louie T, Mullane K, Weiss K, Lentnek A, Golan Y, et al. Derivation and validation of a simple clinical bedside score (ATLAS) for Clostridium difficile infection
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which predicts response to therapy. BMC Infect Dis 2013;13(1):148. https://doi.org/10.1186/1471-2334-13-148. [11] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373–83. [12] Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–56. [13] Polak P, Freibergerova M, Husa P, Jurankova J, Svacinka R, Stebel R, et al. Fekalni bakterioterapie v lecbe rekurentni kolitidy zpusobene Clostridium difficile na Klinice infekcnich chorob Fakultni nemocnice Brno v letech 2010–2014 – prospektivni studie. Epidemiol Mikrobiol Imunol 2015;64(4):232–35. [14] Dailey FE, Turse EP, Daglilar E, Tahan V. The dirty aspects of fecal microbiota transplantation: a review of its adverse effects and complications. Curr Opin Pharmacol 2019;49:29–33. https://doi.org/10.1016/j.coph.2019.04.008. [15] Tan X, Johnson S. Fecal microbiota transplantation for C. difficile infection, just say ‘No’. Anaerobe 2019:102092. https://doi.org/10.1016/j.anaerobe.2019.102092. [16] Allegretti JR, Kassam Z, Chan WW. Small intestinal bacterial overgrowth: should screening be included in the pre-fecal microbiota transplantation evaluation? Dig Dis Sci 2018;63(1):193–7. https://doi.org/10.1007/s10620-017-4864-8. [17] Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol 2014;48(8):693– 702. https://doi.org/10.1097/MCG.0000000000000046.
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List of tables Table 1. Algorithm for evaluating stool donors Table 2. Baseline patient characteristics Table 3: Procedural characteristics of FMT List of graphs Graph 1. Study design flowchart Graph 2. Dependence of FMT success rate on patient age Abbreviations: OR: odds ratio, CI: confidence interval, CDI: Clostridioides difficile infection, ATB: antibiotic, rCDI: recurrent Clostridioides difficile infection, FMT: faecal microbiota transplantation, ESCMID: European Society of Clinical Microbiology and Infectious Diseases, GDH: glutamate dehydrogenase, CCI: Charlson Comorbidity Index, ECOG: Eastern Cooperative Oncology Group, SIBO: small intestine bacterial overgrowth, CT: computed tomography
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Table 1. Algorithm for evaluating stool donors Medical history data (stool donor questionnaire) 1) Age 18–65 years, exclusion of diarrhoea in the 3 months preceding the donation 2) Exclusion of chronic gastrointestinal tract diseases in both the donor and his/her family members: idiopathic inflammatory bowel disease, irritable bowel syndrome, cancers 3) Assessment of risk of transmitting infectious diseases: acute or chronic infections, vaccinationsa, risky sexual intercourse, piercing, body tattoo, needle stick accident, use of illegal drugs, travelling to destinations with low standards of hygiene (<6 months), blood product application (<12 months) 4) Assessment of other factors affecting the intestinal microbiota: use of immunosuppressants; chemotherapy and ATB (<3 months); chronic proton pump inhibitor use; autoimmune, metabolic, neurological and psychiatric conditions; food allergies Clinical examination 1) Evaluation of anthropometric data: body mass index < 30 kg/m2 2) Physical examination with particular focus on mouth-cavity state, presence of palpable lymph nodes, abdominal findings and rectal examination Blood tests 1) Basic biochemical and haematological examinationb: blood count, erythrocyte sedimentation, C-reactive protein, liver panel, bilirubin, creatinine, glycaemia, albumin 2) Serological tests: human immunodeficiency virus infection; syphilis; viral hepatitis B, C and E Stool tests 1) Stool cultivation for obligatory intestinal pathogens (Salmonella, Campylobacter, Shigella, Yersinia)c 2) Microscopic examination for the presence of parasites eggs 3) Immunochromatography test for detection of C. difficile antigen and free toxins
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a History b
of vaccination with a live attenuated virus, if there is a possible risk of transmission.
Abnormal laboratory test values were not an absolute contraindication to faecal donation.
The decision was always made on a case-by-case basis after thorough evaluation of all monitored criteria by the physician. c
Stool cultivation also included the detection of multi-resistant bacterial strains.
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Table 2. Baseline patient characteristics Number of patients, no.
172
Female, no. (%)
109 (63)
Age (years), median (IQR)
78 (64–92)
Less than 65 years of age, no. (%)
30 (17.5)
65‒85 years
105 (61)
More than 85 years
37 (21.5)
Proton pump inhibitors in co-medication
77 (45)
Proportion of patients with IBD
2 (1)
IQR: interquartile range, IBD: inflammatory bowel disease
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Table 3: Procedural characteristics of FMT Number of analysed FMTa, no.
182
Number of CDI recurrences before FMT, median (IQR)
1 (0‒2)
Primary episode of CDI, no. (%)
31 (17)
One recurrence
98 (53.9)
Two recurrences
36 (19.8)
Three or more recurrences
17 (9.3)
ATLAS score (value), median (IQR)
4 (1‒7)
Severe CDI episodesb, no. (%)
27 (14.8)
ECOG performance score (value), median (IQR)
3 (2‒4)
Charlson Comorbidity Index (value), median (IQR)
7 (4‒10)
Initial antibiotic therapyc, no. (%) a) Vancomycin
146 (80.2)
b) Fidoxomycin
26 (14.3)
c) Vancomycin + metronidazole
10 (5.5)
Method of FMT administration, no. (%) a) Nasoenteral feeding tube
61 (33.5)
b) Rectal enema
121 (66.5)
Frozen stool preparation, no. (%)
41 (22.5)
Family stool donors
141 (77.5)
Mild adverse events (temporary diarrhoea, constipation, bloating, abdominal
12 (6.6)
discomfort, fever), no. (%) Serious adverse events (rectal-wall perforation)
2 (1.1)
No adverse events
168 (92.3)
FMT: faecal microbiota transplantation, CDI: Clostridioides difficile infection, IQR: interquartile range, IBD: Inflammatory bowel disease, ECOG: Eastern Cooperative Oncology Group a Twelve
patients received faecal transplants twice, and 3 patients did so thrice, but not within
an 8-week interval, so every FMT was evaluated separately b Severe
CDI defined (per ESCMID guidelines) as an episode of CDI with (one or more
specific signs and symptoms of) severe colitis or a complicated course of disease, with significant systemic toxin effects and shock, resulting in the need for an intensive care unit 17
admission, colectomy or death [8] c
Targeted antibiotic therapy given prior to FMT
Roman Stebel: Conceptualization, Methodology, Formal analysis, Investigation, Writing Original Draft, Visualization Lenka Vojtilova: Conceptualization, Methodology, Investigation, Writing - Review & Editing Radek Svacinka: Conceptualization, Methodology, Investigation Petr Husa: Conceptualization, Methodology, Resources, Supervision
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Clostridioides difficile infection is one of the most frequently nosocomial diseases Faecal microbiota transplantation is safe and inexpensive therapeutic procedure Transferred donor stool can restore the natural diversity of intestinal microbiota Advanced patient age was the only significant risk factor for treatment failure
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S2452-2317(20)30001-4 https://doi.org/10.1016/j.humic.2020.100070 HUMIC 100070
To appear in:
Human Microbiome Journal
Received Date: Revised Date: Accepted Date:
8 December 2019 5 February 2020 13 February 2020
Please cite this article as: R. Stebel, L. Vojtilova, R. Svacinka, P. Husa, Faecal microbiota transplantation in the treatment of Clostridioides difficile infection, Human Microbiome Journal (2020), doi: https://doi.org/10.1016/ j.humic.2020.100070
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.
© 2020 Published by Elsevier Ltd.
Title: Faecal microbiota transplantation in the treatment of Clostridioides difficile infection Article type: Original article Authors: *Roman Stebel1,2, Lenka Vojtilova1,2, Radek Svacinka1,2, Petr Husa1,2 1
Faculty of Medicine, Masaryk University, Kamenice 753/5, Brno, Czech Republic
2 Department
of Infectious Diseases, University Hospital Brno, Jihlavska 20, Brno, Czech
Republic Address for correspondence: MUDr. Roman Stebel, Department of Infectious Diseases, University Hospital Brno and Faculty of Medicine, Masaryk University, Jihlavska 20, CZ-62500, Brno, Czech Republic email: [email protected] GSM: +420 777 894 574 Declarations of interest: None.
1
Faecal microbiota transplantation in the treatment of Clostridioides difficile infection
Abstract Faecal microbiota transplantation (FMT) represents a unique procedure targeted to restoring the natural diversity of the gastrointestinal microbiome and prevent recurrence of a key nosocomial disease, namely, Clostridioides difficile infection (CDI). The aim of the present study was assessing the success rate and clinical efficacy of FMT at a clinic that introduced this procedure in Czechia in 2010 and still leads in the number of transplantations performed to date. Patients enrolled in the study received primary targeted antibiotic therapy, and after the CDI episode treatment, FMT administered as a secondary prophylaxis. After the procedure, patients were followed up. The treatment was defined as successful if colitis did not recur within 8 weeks. Logistic regression analysis was used for determining the odds ratios for the individual factor variants (patient age and sex, number of previous recurrences, severity of the treated CDI episodes, presence of chronic comorbidities, performance status, initial antibiotic treatment, mode of faecal-transplant application and use of fresh or frozen stool). In the 4-year interval involved (2015–2018), 172 patients were treated using faecal microbiota transplantation. The overall success rate was 76%. Subgroup analysis identified higher age, higher Charlson Comorbidity Index reflecting the presence and severity of longterm comorbidities and higher Eastern Cooperative Oncology Group (ECOG) performance scores as risk factors for treatment failure. In the period monitored, two serious adverse events were observed: Both were rectal-wall perforations occurring during the application of enemas of stool suspension. There was no lethality. Keywords: Clostridioides difficile, faecal microbiota transplantation, gastrointestinal microbiome, intestinal dysbiosis, pseudomembranous enterocolitis
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1. Introduction Diarrhoeas associated with excessive multiplication of toxigenic Clostridioides difficile strains in the colon (C. difficile infection, CDI) represent one of the most important nosocomial diseases in developed countries. The incidence of CDI is rising globally, with the trends in severity and therapeutic failure growing as well [1]. Frequent recurrences particularly contribute to patient mortality and negatively affect patient quality of life. Approximately 20% of patients experience a relapse after the first CDI episode, while the risk of further episodes increases up to 65% [2]. According to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), FMT is recommended as a treatment option for recurrent CDI (rCDI) and can also be considered a treatment option for refractory CDI [3,4]. In Czechia, FMT was applied in clinical practice for the first time at the Department of Infectious Diseases of the University Hospital Brno in early 2010 [5]. 2. Aims of the study The aim of this prospective, observational, monocentric study was to form and describe a set of adult patients who had had CDI that was treated using FMT and assess the success rate and clinical efficacy of this treatment. Besides identifying the number of cured patients, we sought to determine whether any factors used to categorise the treated patients had a statistically significant influence on the therapy’s success rate. 3. Methods FMT was primarily indicated as a secondary prophylaxis for rCDI [6]. The faecal transplant was applied after a targeted antibiotic (ATB) therapy for colitis in patients with a history of one or more CDI recurrences. FMT was also applied in a few cases of a first CDI episode. These latter cases always involved high-risk patients, typically those receiving oncological treatment. FMT was applied outside of the period when chemotherapy, radiotherapy or biological treatment was in course. Selecting an appropriate donor was an important part of FMT preparation. Table 1 presents the factors relevant to selecting stool donors according to the Infectious Diseases Society of the Czech Medical Association guidelines [6]. Healthcare personnel were inadmissible as donors because of the risk of colon colonisation by C. difficile, as well as other multidrugresistant microorganisms [3]. The donor examination was always performed well in advance. 3
On the day of stool donation, a brief interview was held with the donor to ensure no recent health changes had occurred. Each patient and donor gave consent when FMT was planned. The research was approved by the Ethics Committee of the University Hospital Brno (104/12). All patients underwent 10 days of initial ATB therapy that was discontinued 48 hours before FMT. The drug of first choice was oral vancomycin (125 mg every 6 hours). In patients with symptoms of paralytic ileus, intravenous metronidazole (500 mg every 8 hours) was added to vancomycin. Fidaxomicin (200 mg every 12 hours) was used in individually selected patients at high risk of CDI recurrence [7]. Stool from related donors was prepared and applied immediately after acquisition. About 100 g of stool was homogenised with 200–500 ml of sterile, non-bacteriostatic crystalloid solution and filtered through several layers of gauze to remove undesirable admixtures [3]. The consistency of the suspension was adjusted individually in relation to the intended administration method. For enema administration, a thicker suspension was suitable because it would more easily adhere to the surface of the intestinal mucosa. Conversely, when administered with a nasoenteral feeding tube, a lower density was preferred to avoid blockage of the tube. The universal donor concept is based on the possibility of storing frozen stool from a thoroughly evaluated donor for a period of up to six months. Glycerol serving as a cryoprotective agent was added to the stool suspension. The final mixture was frozen at −80°C [3]. The FMT application path was selected individually. In older, polymorbid, recumbent patients, a less invasive method of FMT administration by enema was chosen. In younger, more mobile patients, administration of FMT by a nasoenteral feeding tube—introduced under endoscopic control—was preferred. Patients were prepared for FMT application into the distal duodenum by administration of a 20-mg oral dose of omeprazole to reduce stomach acidity. Those receiving a faecal-transplant enema first received a sorbitol enema to empty their bowels and oral loperamide to temporarily reduce intestinal peristalsis. After the faecal transplant, fasting was recommended to suppress the gastrocolic reflex [6]. After receiving FMT, the patients were followed up once weekly by means of personal visits or by phone. The primary response to FMT was defined as a reduction of stool count or the adjustment of stool consistency within 3 days after the procedure [8]. If there was no disease recurrence (three or more watery stools in 24 hours over 2 consecutive days and positive proof of C. difficile toxins) within 8 weeks of the procedure, the FMT was considered 4
successful [9]. For analysing the success rates by subgroups, patients were divided into categories according to the following risk factors: 1. Patient age and sex; 2. Severity of the CDI episode; 3. Number of CDI recurrences before FMT 4. Presence of chronic comorbidities and performance status of patients 5. Initial antibiotic therapy administered before FMT; 6. Mode of faecal-transplant application; and 7. Use of fresh or frozen donor stool. Unidimensional statistical testing was used for initially assessing the dependence of therapeutic success on the individual risk factors. Logistic regression using FMT failure as the dependent variable and the selected potential risk factors as the covariates was employed for further assessing the independence of the individual risk factors. The testing was done at a 0.05 level of statistical significance. 4. Results In 2015–2018, FMT was performed on 172 patients who had microbiologically confirmed CDI. The microbiological diagnosis was based on the detection of glutamate dehydrogenase (GDH) and free toxins of C. difficile in stool by enzyme immunoassay. In case of positive GDH and negativity of free toxins, real-time polymerase chain reaction (including detection of binary toxin genes and some epidemic ribotypes) was added [2]. The average patient age was 75.7 years (median: 78 years). There were 109 females and 63 males. During the monitored period, 12 patients received faecal transplants twice and 3 received them thrice, but this did not occur within an 8-week interval. Therefore, each FMT was evaluated separately. Eight patients were lost to contact during the study. The total number of FMTs analysed was 182 (Graph 1). No lethality occurred in the study set during the 8-week interval. Tables 2 and 3 present the baseline patient and procedural characteristics. Treatment failed in 44 cases, while 138 cases were free of CDI recurrence. This corresponds to an overall success rate of 76%.
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The FMT success rates were 77% in women and 75% in men, with no dependence on sex found (p = 0.582). The average age of patients without recurrence after FMT was 77.4 years (median: 77 years). The patients who experienced treatment failure had an average age of 80.1 years (median: 81 years). Testing of the results demonstrated that the success rate had an inverse relationship (Graph 2) to age that was statistically significant (p = 0.023; odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.01‒1.08). Another evaluated factor was the severity of the CDI episode, where 27 cases met the criteria for ‘severe CDI’ as defined by ESCMID [8]. A statistically significant difference in the success of FMT with ‘severe CDI’ compared with other cases was not demonstrated (p = 0.595). Neither lethality nor any serious adverse events occurred in the severe colitis group. ATLAS scores were further used to stratify the severity of the CDI. This scoring system includes assessments of age, body temperature, peripheral blood leukocyte count, serum albumin levels and concomitant ATB therapy [10]. The median ATLAS score in patients who failed FMT was 4.0. In patients without recurrence, it was 3.5. There was no statistically significant dependence (p = 0.130). The FMT-treated patients were divided into four groups: patients with one (primary) episode of CDI, one recurrence, two recurrences and three or more recurrences of CDI. The results showed a higher percentage of treatment failure in patients who had three or more recurrences (41.2%). The success rate for the groups with rCDI pooled together (without the primary episodes) was 76%. The testing of the results found no significant relationship between the success rate and the number of previous CDI recurrences (p = 0.277). Targeted ATB therapy always preceded FMT. Vancomycin was administered in 146 cases and fidaxomicin in 26 cases. Those treated with fidaxomicin had only three recurrences, representing an 88% success rate. Given the small number of patients in the fidaxomicin subgroup, the results exhibited no significant relationship between success rate and type of ATB administered prior to transplantation (p = 0.238). The result of treatment of several diseases is largely determined by the presence of chronic comorbidities. The Charlson Comorbidity Index (CCI) was calculated for all FMT-treated patients to assess the effect of comorbidity on treatment success. In the case of comorbidities, a statistically significant dependence of treatment success on CCI was demonstrated. In patients who failed treatment, CCI was significantly higher than in those who had no CDI recurrence after FMT (p = 0.004; OR: 1.35; 95% CI: 1.10–1.66). In addition to the number 6
and severity of chronic comorbidities in patients, their performance status is also of great prognostic importance. This tells us how the patient can function in everyday life. The Eastern Cooperative Oncology Group (ECOG) score was determined in all patients to assess their functional status levels [12]. In this case, a statistically significant dependence was also demonstrated. In patients with treatment failure, the ECOG score was statistically significantly higher (median: 3.0) compared with patients whose treatment was successful (p = 0.016; OR: 2.1; 95% CI: 1.15–3.82). Enema was the most frequently used mode of introducing donor stool filtrate into the patients’ intestines (121 procedures; 74% success rate). The other method used was introducing a nasoenteral feeding tube into the distal duodenum (61 cases; 80% success rate). No significant relationship was found between the mode of FMT application and success rate (p = 0.314). Frozen stool preparation was used in 41 cases, and the remaining patients were treated using freshly processed stool. In the former group, the application of thawed stool suspension yielded recurrence in 8 patients, representing an 80% success rate. In the latter group, there were 36 recurrences of colitis, which represents a 74% success rate using freshly processed stool. There was no significant relationship between success rate and the use of either fresh or frozen donor stool (p = 0.428). 5. Discussion The treatment of patients with FMT in 2015–2018 yielded results comparable to those of other international studies, as well as studies from our hospital published before 2015. The results of an earlier study in the same department demonstrated an 83.1% success rate [13]. The subgroup analysis demonstrated a statistically significant connection between the FMT success rate and patient age, the presence of long-term comorbidities and ECOG scores. Logistic regression showed a strong positive correlation between the four factors. With increasing age, the ATLAS scores, ECOG performance status and CCI increased. Similar results were recently published by the authors of a German retrospective observational study that analysed the FMT results from 35 centres [9]. The German study included patients who had histories of repeated rCDIs (a median of three recurrences prior to FMT) [9]. In the present study, FMT was applied earlier: About half the patients had a history of only a single CDI recurrence. FMT indication as early as after the second CDI attack is consistent with the procedure recommended by the Infectious Diseases 7
Society of the Czech Medical Association [6]. We think the early FMT administration in rCDI patients is because of the limited availability and cost of other secondary prophylactic procedures. The anti-toxin B monoclonal antibody bezlotoxumab is already used in many countries, but it is still not available in Czechia. Other innovative methods are under development. These include active immunisation with a toxoid vaccine, use of bacteriophages, colonisation of the intestine with non-toxic strains of C. difficile or efforts to restore homeostasis of bile acids in the intestine [7]. Generally, FMT is a safe method of treating rCDIs that is well-tolerated by patients. The most commonly reported reactions include temporary diarrhoea lasting several days after the procedure, constipation, bloating, abdominal discomfort and fever. These are insignificant, spontaneously resolving complications [14]. In this study, patients sporadically experienced these adverse reactions, which always resolved spontaneously. The literature also includes rare, severe, adverse events, including transmission of infectious diseases [15]. Another group of adverse events derives from the mode of FMT administration. Cases of regurgitation of the applied suspension followed by aspiration and the development of pneumonia have been reported with endoscopic administration of faecal transplant into the upper parts of the gastrointestinal tract [14]. Another undesirable consequence in this case may be excessive colonisation of the small intestine by faecal microbiota, so-called small intestine bacterial overgrowth (SIBO) syndrome [16]. Recently, in an effort to offer FMT to all patients who would benefit from it, there has been an evident tendency for FMT to be applied by enema. The application is simple and does not represent any burden on the patient. The disadvantage is that the enema only reaches the area of the colon’s lienal flexure, so the proximal colon sections are not sufficiently colonised by the donor microbiota [6]. Severe complications after FMT administered via rectal enema included bleeding and intestinal-wall perforation [14]. In this study, two patients developed abdominal pain, fever and clinical signs of peritoneal irritation shortly after FMT applied by enema, while enterorrhagia was observed in one of these cases. In both cases, computed tomography (CT) demonstrated rectal-wall perforation, and surgical revision of the abdominal cavity to conduct colostomy was performed. These perforations were probably due to enema application into the rectum by means of a balloon catheter. An alternative to rectal infusion of FMT could be colonoscopy application. However, the use of an endoscopic procedure alone is considered to be a significant risk against a background of inflammatory changes in the intestinal wall. A less invasive application method could be sigmoidoscopy [17]. 8
Based on the available information, FMT is considered safe from a long-term perspective. There is a theoretical risk of changing the composition of the intestinal microbiota after FMT, which can predispose the patient to developing obesity, metabolic syndrome, autoimmune diseases or cancers [14]. 6. Conclusions Colitis induced by C. difficile is currently one of the most significant diseases with causal associations to healthcare. FMT represents a safe, inexpensive therapeutic alternative to stop the apparent vicious cycle of chronically relapsing CDI by restoring the natural ecosystem of the colon. We see the future of FMT in both improving the method of application of faecal transplant (including oral administration in the form of enteric capsules) and in more targeted manipulation of intestinal microbiota, which will lead to the extension of FMT indication by a number of other diseases beyond the gastrointestinal tract.
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Acknowledgements This work was supported by the Ministry of Health, Czech Republic—Conceptual Development of Research Organisation [FNBr, 65269705]. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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References [1] Al-Jashaami LS, DuPont HL. Management of Clostridium difficile infection. Gastroenterol Hepatol 2016;12:609–16. [2] Napolitano LM, Edmiston CE. Clostridium difficile disease: diagnosis, pathogenesis, and treatment update. Surgery 2017;162:325–48. https://doi.org/10.1016/j.surg.2017.01.018. [3] Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, Satokari R, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 2017;66:569–80. https://doi.org/10.1136/gutjnl-2016-313017. [4] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368(5):407–15. https://doi.org/10.1056/NEJMoa1205037. [5] Polak P, Freibergerova M, Jurankova J, Kocourkova H, Mikesova L, Svacinka R, et al. Prvni zkusenosti s fekalni bakterioterapii v lecbe relabujici pseudomembranozni kolitidy zpusobene Clostridium difficile. Klin mikrobiol inf lek 2011;17:214–7. [6] Polivkova S, Vojtilova L, Husa P, Benes J. Doporuceny postup fekalni bakterioterapie pro lecbu rekurentni klostridiove kolitidy. Klin mikrobiol inf lek 2018;24:57–64. [7] Ooijevaar RE, van Beurden YH, Terveer EM, Goorhuis A, Bauer MP, Keller JJ, et al. Update of treatment algorithms for Clostridium difficile infection. Clin Microbiol Infect 2018;24:452–62. https://doi.org/10.1016/j.cmi.2017.12.022. [8] Debast SB, Bauer MP, Kuijper EJ, on behalf of the committee. European Society of Clinical Microbiology and Infectious Diseases. Update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014;20:1–26. https://doi.org/10.1111/1469-0691.12418. [9] Peri R, Aguilar RC, Tüffers K, Erhardt A, Link A, Ehlermann P, et al. The impact of technical and clinical factors on fecal microbiota transfer outcomes for the treatment of recurrent Clostridioides difficile infections in Germany. United European Gastroenterol J 2019;7:716–22. https://doi.org/10.1177/2050640619839918. [10] Miller MA, Louie T, Mullane K, Weiss K, Lentnek A, Golan Y, et al. Derivation and validation of a simple clinical bedside score (ATLAS) for Clostridium difficile infection
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which predicts response to therapy. BMC Infect Dis 2013;13(1):148. https://doi.org/10.1186/1471-2334-13-148. [11] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373–83. [12] Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–56. [13] Polak P, Freibergerova M, Husa P, Jurankova J, Svacinka R, Stebel R, et al. Fekalni bakterioterapie v lecbe rekurentni kolitidy zpusobene Clostridium difficile na Klinice infekcnich chorob Fakultni nemocnice Brno v letech 2010–2014 – prospektivni studie. Epidemiol Mikrobiol Imunol 2015;64(4):232–35. [14] Dailey FE, Turse EP, Daglilar E, Tahan V. The dirty aspects of fecal microbiota transplantation: a review of its adverse effects and complications. Curr Opin Pharmacol 2019;49:29–33. https://doi.org/10.1016/j.coph.2019.04.008. [15] Tan X, Johnson S. Fecal microbiota transplantation for C. difficile infection, just say ‘No’. Anaerobe 2019:102092. https://doi.org/10.1016/j.anaerobe.2019.102092. [16] Allegretti JR, Kassam Z, Chan WW. Small intestinal bacterial overgrowth: should screening be included in the pre-fecal microbiota transplantation evaluation? Dig Dis Sci 2018;63(1):193–7. https://doi.org/10.1007/s10620-017-4864-8. [17] Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol 2014;48(8):693– 702. https://doi.org/10.1097/MCG.0000000000000046.
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List of tables Table 1. Algorithm for evaluating stool donors Table 2. Baseline patient characteristics Table 3: Procedural characteristics of FMT List of graphs Graph 1. Study design flowchart Graph 2. Dependence of FMT success rate on patient age Abbreviations: OR: odds ratio, CI: confidence interval, CDI: Clostridioides difficile infection, ATB: antibiotic, rCDI: recurrent Clostridioides difficile infection, FMT: faecal microbiota transplantation, ESCMID: European Society of Clinical Microbiology and Infectious Diseases, GDH: glutamate dehydrogenase, CCI: Charlson Comorbidity Index, ECOG: Eastern Cooperative Oncology Group, SIBO: small intestine bacterial overgrowth, CT: computed tomography
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Table 1. Algorithm for evaluating stool donors Medical history data (stool donor questionnaire) 1) Age 18–65 years, exclusion of diarrhoea in the 3 months preceding the donation 2) Exclusion of chronic gastrointestinal tract diseases in both the donor and his/her family members: idiopathic inflammatory bowel disease, irritable bowel syndrome, cancers 3) Assessment of risk of transmitting infectious diseases: acute or chronic infections, vaccinationsa, risky sexual intercourse, piercing, body tattoo, needle stick accident, use of illegal drugs, travelling to destinations with low standards of hygiene (<6 months), blood product application (<12 months) 4) Assessment of other factors affecting the intestinal microbiota: use of immunosuppressants; chemotherapy and ATB (<3 months); chronic proton pump inhibitor use; autoimmune, metabolic, neurological and psychiatric conditions; food allergies Clinical examination 1) Evaluation of anthropometric data: body mass index < 30 kg/m2 2) Physical examination with particular focus on mouth-cavity state, presence of palpable lymph nodes, abdominal findings and rectal examination Blood tests 1) Basic biochemical and haematological examinationb: blood count, erythrocyte sedimentation, C-reactive protein, liver panel, bilirubin, creatinine, glycaemia, albumin 2) Serological tests: human immunodeficiency virus infection; syphilis; viral hepatitis B, C and E Stool tests 1) Stool cultivation for obligatory intestinal pathogens (Salmonella, Campylobacter, Shigella, Yersinia)c 2) Microscopic examination for the presence of parasites eggs 3) Immunochromatography test for detection of C. difficile antigen and free toxins
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a History b
of vaccination with a live attenuated virus, if there is a possible risk of transmission.
Abnormal laboratory test values were not an absolute contraindication to faecal donation.
The decision was always made on a case-by-case basis after thorough evaluation of all monitored criteria by the physician. c
Stool cultivation also included the detection of multi-resistant bacterial strains.
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Table 2. Baseline patient characteristics Number of patients, no.
172
Female, no. (%)
109 (63)
Age (years), median (IQR)
78 (64–92)
Less than 65 years of age, no. (%)
30 (17.5)
65‒85 years
105 (61)
More than 85 years
37 (21.5)
Proton pump inhibitors in co-medication
77 (45)
Proportion of patients with IBD
2 (1)
IQR: interquartile range, IBD: inflammatory bowel disease
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Table 3: Procedural characteristics of FMT Number of analysed FMTa, no.
182
Number of CDI recurrences before FMT, median (IQR)
1 (0‒2)
Primary episode of CDI, no. (%)
31 (17)
One recurrence
98 (53.9)
Two recurrences
36 (19.8)
Three or more recurrences
17 (9.3)
ATLAS score (value), median (IQR)
4 (1‒7)
Severe CDI episodesb, no. (%)
27 (14.8)
ECOG performance score (value), median (IQR)
3 (2‒4)
Charlson Comorbidity Index (value), median (IQR)
7 (4‒10)
Initial antibiotic therapyc, no. (%) a) Vancomycin
146 (80.2)
b) Fidoxomycin
26 (14.3)
c) Vancomycin + metronidazole
10 (5.5)
Method of FMT administration, no. (%) a) Nasoenteral feeding tube
61 (33.5)
b) Rectal enema
121 (66.5)
Frozen stool preparation, no. (%)
41 (22.5)
Family stool donors
141 (77.5)
Mild adverse events (temporary diarrhoea, constipation, bloating, abdominal
12 (6.6)
discomfort, fever), no. (%) Serious adverse events (rectal-wall perforation)
2 (1.1)
No adverse events
168 (92.3)
FMT: faecal microbiota transplantation, CDI: Clostridioides difficile infection, IQR: interquartile range, IBD: Inflammatory bowel disease, ECOG: Eastern Cooperative Oncology Group a Twelve
patients received faecal transplants twice, and 3 patients did so thrice, but not within
an 8-week interval, so every FMT was evaluated separately b Severe
CDI defined (per ESCMID guidelines) as an episode of CDI with (one or more
specific signs and symptoms of) severe colitis or a complicated course of disease, with significant systemic toxin effects and shock, resulting in the need for an intensive care unit 17
admission, colectomy or death [8] c
Targeted antibiotic therapy given prior to FMT
Roman Stebel: Conceptualization, Methodology, Formal analysis, Investigation, Writing Original Draft, Visualization Lenka Vojtilova: Conceptualization, Methodology, Investigation, Writing - Review & Editing Radek Svacinka: Conceptualization, Methodology, Investigation Petr Husa: Conceptualization, Methodology, Resources, Supervision
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Clostridioides difficile infection is one of the most frequently nosocomial diseases Faecal microbiota transplantation is safe and inexpensive therapeutic procedure Transferred donor stool can restore the natural diversity of intestinal microbiota Advanced patient age was the only significant risk factor for treatment failure
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