Infectious Diseases, 2015; 47: 114–116
LETTER TO THE EDITOR
Faecal microbiota transplantation in Clostridium difficile infections
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SZABOLCS VIGVÁRI1, ZSUZSANNA NEMES1, ÁRON VINCZE2, JENŐ SOLT2, DÁVID SIPOS1, ZSÓFIA FEISZT1, BEÁTA KOVÁCS1, BARBARA BARTOS1 & ZOLTÁN PÉTERFI1 11st
Department of Internal Medicine, Department of Infectology and 21st Department of Internal Medicine, Department of Gastroenterology, University of Pécs, Pécs, Hungary
To the Editor, We read with interest the report by Emanuelsson et al. [1] on faecal microbiota transplantation (FMT) in which the colonic route of administration was applied. We have achieved excellent results in this condition with the use of nasoduodenal (ND) or nasogastric (NG) administration. We report here our experience in 30 cases of Clostridium difficile infection (CDI). Each of our donors was a volunteer, initially screened by means of a questionnaire to exclude potentially high-risk individuals (e.g. drug use, unprotected sexual behaviour or a history of extensive travel, illness or antibiotic intake in the past 6 months). Donated faeces were screened for parasites, enteropathogenic bacteria and C. difficile, while the serum was screened for human immunodeficiency virus (HIV)-1, HIV-2, Epstein–Barr virus (EBV), cytomegalovirus (CMV), hepatitis A, B, and C, and Treponema pallidum. Our goal was to use freshly prepared samples from donors who were relatives of the patients in each case. However, there were eight patients (26.7%) who had no living relatives, or whose illness was so severe that it was not possible to wait for the lengthy screening procedure. In these cases we made use of donors who were unknown to the patients. We used freshly prepared solutions in five cases and defrosted solutions in three cases. These samples originated from previous procedures, when the amounts of the donated faeces had made it possible to obtain extra quantities of extracts. After preparation, the solutions were frozen immediately to –20°C and stored for a maximum of 2 months at the same
temperature. In contrast with Hamilton et al. [2], no special cryoprotectant was used. The donated samples of faeces were collected and transported to our department on the day of the planned FMT. A 60 g sample was homogenized in a mortar, and suspended in 200 ml of normal saline (0.9%). The suspension was then filtered through 4 ⫻ 4 cm sheets of sterile gauze into another container, and 100 ml of the filtrate were taken in a syringe. All of the steps of the preparation were performed in a laminated flow box; sterile devices were used. Within 6 h after the collection of the faeces from the donor, the solution was infused into the patient. In general, if the condition of the patient allowed, antibiotic administration was stopped 4 days before the procedure. In serious cases this period was reduced to 1 day. In each case, thorough purging was applied on the day before the intervention, to increase the success of the procedure, by flushing away residual faeces, antibiotics, toxins, C. difficile bacteria and spores to the maximum attainable extent. The patients consumed nothing from midnight, and in the morning before the procedure they received a double dose of proton pump inhibitor (PPI) intravenously. This increases the chances of survival of the transplanted flora by reducing the gastric acid output. At 1 h before the transplantation, 20 mg of metoclopramide was administered intravenously, to prevent vomiting and to facilitate bowel movement to promote the delivery of the transplantation material to the colon. Recently published results led us to use upper gastrointestinal (GI) tract delivery methods,
Correspondence: GSz. Vigvári, 1st Department of Internal Medicine, Department of Infectology, University of Pécs, Pécs, Hungary. E-mail: szabolcs.vigvari@ gmail.com; [email protected] (Received 25 February 2014 ; accepted 17 September 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.969305
Faecal microbiota transplantation in C. difficile infections
115
Table I. Demographic and clinical characteristics of the patients.
Characteristic
Infect Dis Downloaded from informahealthcare.com by University of Calgary on 04/13/15 For personal use only.
Median age, years (range) No. of females Median no. of recurrences of CDI (range) No. of cases in which vancomycin administration was present (%) No. of cases where previous antibiotic administration was present due to an infection (not CDI) (%) No. of cases in which proton pump inhibitor was used (%) Median stool frequency/24 h (range) Median plasma leukocyte count/mm3 (range) Median serum creatinine level μmol/L (range)
FMT via ND (n ⫽ 16) 67.8 9 2.7 11
(35–88) (56.2) (1–8) (68.75)
16 (100)
76.7 8 1.75 9
(51–88) (61.5) (0–3) (69.2)
11 (84.6)
11 (68.75) 7.2 (5–15) 7900 (2900–27000) 80.75 (45–173)
including ND and NG tubes [3,4]. We performed only one lower GI tract FMT via colonoscopy, at the patient’s request. In this latter case, after appropriate preparation for colonoscopy, including purging and pre-lavage, 200 ml of the suspension was administered into the proximal colon. The patient was asked to lay on her right side for 1 h after the procedure. The positioning of ND tubes was performed under radiographic control, to ensure that the device reached the duodenum. Then 100 ml of faecal solution was installed. When NG tubes were used, they were inserted just before the procedure and 100 ml of solution was flushed in. During upper GI tract delivery, the patients were in a semi-sitting position throughout the procedure and for 1 h after it. The patients were allowed to eat 3 h after the procedure. We defined the primary cure rate as the percentage of cases in which the symptoms resolved without recurrence within 6 weeks after the FMT, and the secondary cure rate as the percentage of cases in which the symptoms resolved after a second FMT [5]. We performed FMT on a total of 30 patients, of whom 18 (60.0%) were females. The mean age was 70.1 years, with a range of 26–88 years. The average number of recurrent infections was 2.16 (range 0–8). In two cases, FMT was carried out to treat the first episode of FMT, because of the severity of the infection and the failure of preceding antibiotic treatment. In 20 cases (66.7%) the patients had severe infection at the time of the transplantation (Table I). The patient treated via the lower GI tract suffered from chronic colitis, and colonoscopy was indicated to achieve the correct diagnosis. Within 1 day after the procedure, her diarrhoea stopped, but she continued to experience bloating and abdominal cramps for several days. These symptoms were eliminated by the regular administration of simeticon and drotaverin. After 3 days, all of her complaints had disappeared and she was discharged. In the rest
FMT via NG (n ⫽ 13)
8 (61.5) 5.2 (5–10) 12000 (5600–19700) 109.12 (37–270)
FMT via colonoscope (n ⫽ 1) 26 1 (100) 2 1 (100) 1 (100) 0 15 8300 63
of the cases we decided to use upper GI tract procedures. In all of the 16 initial cases where the solution was instilled via ND tubes, the diarrhoea stopped within 24 h, as did all of the other symptoms. No recurrences occurred in this group. It should be noted that after a month the diarrhoea did resume in the case of a 70-year-old female who had had eight microbiologically proven recurrences of CDI previously. Clostridial toxins could not be detected and the bacterium could not be cultured from her stools after the FMT. Detailed gastroenterological examinations subsequently revealed a late onset of irritable bowel syndrome in this patient. The NG route of administration requires less patient preparation, clinical time and cost than the ND route. When the material was installed via NG tubes, the diarrhoea likewise stopped within 24 h in all of the cases. In 10 (76.9%) of the 13 cases, we did not experience any recurrences during 6 weeks. However, in 3 (23.1%) cases microbiologically confirmed CDI recurred. These three patients were elderly (over 75 years), with a severe underlying condition, and it is important to note that one of them had earlier been given antibiotics to treat his urinary tract infection caused by multidrug-resistant organisms. After a second transplantation, two of the three patients were cured, and thus the secondary cure rate in this subgroup was 92.3%. Overall, therefore, in our hands the overall primary cure rate of upper GI tract FMT in these subgroups was 89.6%, while the overall secondary cure rate was 96.6%. It is important to note that the recurrence rate appeared to be lower when the solution was instilled via ND tubes. Although the difference between the two subgroups was not statistically significant (p ⫽ 0.08, Fisher’s exact probability test), we consider it to be clinically important. When possible we preferred to use donors who were relatives of the patients (in 22 cases, i.e.
Infect Dis Downloaded from informahealthcare.com by University of Calgary on 04/13/15 For personal use only.
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73.3%), although we used donors who were unknown to the patients in 8 cases (26.7%). Of the three recurrences observed, two involved donors unknown to the patient. Nausea was observed in one case, but could be controlled with vitamin B6 and metoclopramide. No other side effects or reactions were detected, and therefore we cannot support the view that the ‘yuck’ factor is an important obstacle. Finally we note that in three cases we used defrosted solutions, and we experienced one recurrence with this method. All FMT procedures were carried out with the written ethical approval (permission no. 16014) of the appropriate Scientific and Ethics Committee (Egészségügyi Tudományos Tanács Tudományos és Kutatásetikai Bizottság, ETT-TUKEB), and the written informed consent of the patients.
Declaration of interest: The authors work in a university hospital, where faecal microbiota
transplantation is a treatment option for patients suffering from recurrent or severe CDI.
References [1] Emanuelsson F, Claesson BE, Ljungström L, Tvede M, Ung KA. Faecal microbiotia transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand J Infect Dis 2014;46:89–97. [2] Hamilton M, Weingarden A, Sadowsky M, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:761–7. [3] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendhal EG, Keller JJ, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407–15. [4] Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: a case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580–5. [5] Brandt L, Aroniadis O, Mellow M, Kanatzar A, Kelly C, Park T, et al. Long term follow up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:1079–87.
LETTER TO THE EDITOR
Faecal microbiota transplantation in Clostridium difficile infections
Infect Dis Downloaded from informahealthcare.com by University of Calgary on 04/13/15 For personal use only.
SZABOLCS VIGVÁRI1, ZSUZSANNA NEMES1, ÁRON VINCZE2, JENŐ SOLT2, DÁVID SIPOS1, ZSÓFIA FEISZT1, BEÁTA KOVÁCS1, BARBARA BARTOS1 & ZOLTÁN PÉTERFI1 11st
Department of Internal Medicine, Department of Infectology and 21st Department of Internal Medicine, Department of Gastroenterology, University of Pécs, Pécs, Hungary
To the Editor, We read with interest the report by Emanuelsson et al. [1] on faecal microbiota transplantation (FMT) in which the colonic route of administration was applied. We have achieved excellent results in this condition with the use of nasoduodenal (ND) or nasogastric (NG) administration. We report here our experience in 30 cases of Clostridium difficile infection (CDI). Each of our donors was a volunteer, initially screened by means of a questionnaire to exclude potentially high-risk individuals (e.g. drug use, unprotected sexual behaviour or a history of extensive travel, illness or antibiotic intake in the past 6 months). Donated faeces were screened for parasites, enteropathogenic bacteria and C. difficile, while the serum was screened for human immunodeficiency virus (HIV)-1, HIV-2, Epstein–Barr virus (EBV), cytomegalovirus (CMV), hepatitis A, B, and C, and Treponema pallidum. Our goal was to use freshly prepared samples from donors who were relatives of the patients in each case. However, there were eight patients (26.7%) who had no living relatives, or whose illness was so severe that it was not possible to wait for the lengthy screening procedure. In these cases we made use of donors who were unknown to the patients. We used freshly prepared solutions in five cases and defrosted solutions in three cases. These samples originated from previous procedures, when the amounts of the donated faeces had made it possible to obtain extra quantities of extracts. After preparation, the solutions were frozen immediately to –20°C and stored for a maximum of 2 months at the same
temperature. In contrast with Hamilton et al. [2], no special cryoprotectant was used. The donated samples of faeces were collected and transported to our department on the day of the planned FMT. A 60 g sample was homogenized in a mortar, and suspended in 200 ml of normal saline (0.9%). The suspension was then filtered through 4 ⫻ 4 cm sheets of sterile gauze into another container, and 100 ml of the filtrate were taken in a syringe. All of the steps of the preparation were performed in a laminated flow box; sterile devices were used. Within 6 h after the collection of the faeces from the donor, the solution was infused into the patient. In general, if the condition of the patient allowed, antibiotic administration was stopped 4 days before the procedure. In serious cases this period was reduced to 1 day. In each case, thorough purging was applied on the day before the intervention, to increase the success of the procedure, by flushing away residual faeces, antibiotics, toxins, C. difficile bacteria and spores to the maximum attainable extent. The patients consumed nothing from midnight, and in the morning before the procedure they received a double dose of proton pump inhibitor (PPI) intravenously. This increases the chances of survival of the transplanted flora by reducing the gastric acid output. At 1 h before the transplantation, 20 mg of metoclopramide was administered intravenously, to prevent vomiting and to facilitate bowel movement to promote the delivery of the transplantation material to the colon. Recently published results led us to use upper gastrointestinal (GI) tract delivery methods,
Correspondence: GSz. Vigvári, 1st Department of Internal Medicine, Department of Infectology, University of Pécs, Pécs, Hungary. E-mail: szabolcs.vigvari@ gmail.com; [email protected] (Received 25 February 2014 ; accepted 17 September 2014 ) ISSN 2374-4235 print/ISSN 2374-4243 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.969305
Faecal microbiota transplantation in C. difficile infections
115
Table I. Demographic and clinical characteristics of the patients.
Characteristic
Infect Dis Downloaded from informahealthcare.com by University of Calgary on 04/13/15 For personal use only.
Median age, years (range) No. of females Median no. of recurrences of CDI (range) No. of cases in which vancomycin administration was present (%) No. of cases where previous antibiotic administration was present due to an infection (not CDI) (%) No. of cases in which proton pump inhibitor was used (%) Median stool frequency/24 h (range) Median plasma leukocyte count/mm3 (range) Median serum creatinine level μmol/L (range)
FMT via ND (n ⫽ 16) 67.8 9 2.7 11
(35–88) (56.2) (1–8) (68.75)
16 (100)
76.7 8 1.75 9
(51–88) (61.5) (0–3) (69.2)
11 (84.6)
11 (68.75) 7.2 (5–15) 7900 (2900–27000) 80.75 (45–173)
including ND and NG tubes [3,4]. We performed only one lower GI tract FMT via colonoscopy, at the patient’s request. In this latter case, after appropriate preparation for colonoscopy, including purging and pre-lavage, 200 ml of the suspension was administered into the proximal colon. The patient was asked to lay on her right side for 1 h after the procedure. The positioning of ND tubes was performed under radiographic control, to ensure that the device reached the duodenum. Then 100 ml of faecal solution was installed. When NG tubes were used, they were inserted just before the procedure and 100 ml of solution was flushed in. During upper GI tract delivery, the patients were in a semi-sitting position throughout the procedure and for 1 h after it. The patients were allowed to eat 3 h after the procedure. We defined the primary cure rate as the percentage of cases in which the symptoms resolved without recurrence within 6 weeks after the FMT, and the secondary cure rate as the percentage of cases in which the symptoms resolved after a second FMT [5]. We performed FMT on a total of 30 patients, of whom 18 (60.0%) were females. The mean age was 70.1 years, with a range of 26–88 years. The average number of recurrent infections was 2.16 (range 0–8). In two cases, FMT was carried out to treat the first episode of FMT, because of the severity of the infection and the failure of preceding antibiotic treatment. In 20 cases (66.7%) the patients had severe infection at the time of the transplantation (Table I). The patient treated via the lower GI tract suffered from chronic colitis, and colonoscopy was indicated to achieve the correct diagnosis. Within 1 day after the procedure, her diarrhoea stopped, but she continued to experience bloating and abdominal cramps for several days. These symptoms were eliminated by the regular administration of simeticon and drotaverin. After 3 days, all of her complaints had disappeared and she was discharged. In the rest
FMT via NG (n ⫽ 13)
8 (61.5) 5.2 (5–10) 12000 (5600–19700) 109.12 (37–270)
FMT via colonoscope (n ⫽ 1) 26 1 (100) 2 1 (100) 1 (100) 0 15 8300 63
of the cases we decided to use upper GI tract procedures. In all of the 16 initial cases where the solution was instilled via ND tubes, the diarrhoea stopped within 24 h, as did all of the other symptoms. No recurrences occurred in this group. It should be noted that after a month the diarrhoea did resume in the case of a 70-year-old female who had had eight microbiologically proven recurrences of CDI previously. Clostridial toxins could not be detected and the bacterium could not be cultured from her stools after the FMT. Detailed gastroenterological examinations subsequently revealed a late onset of irritable bowel syndrome in this patient. The NG route of administration requires less patient preparation, clinical time and cost than the ND route. When the material was installed via NG tubes, the diarrhoea likewise stopped within 24 h in all of the cases. In 10 (76.9%) of the 13 cases, we did not experience any recurrences during 6 weeks. However, in 3 (23.1%) cases microbiologically confirmed CDI recurred. These three patients were elderly (over 75 years), with a severe underlying condition, and it is important to note that one of them had earlier been given antibiotics to treat his urinary tract infection caused by multidrug-resistant organisms. After a second transplantation, two of the three patients were cured, and thus the secondary cure rate in this subgroup was 92.3%. Overall, therefore, in our hands the overall primary cure rate of upper GI tract FMT in these subgroups was 89.6%, while the overall secondary cure rate was 96.6%. It is important to note that the recurrence rate appeared to be lower when the solution was instilled via ND tubes. Although the difference between the two subgroups was not statistically significant (p ⫽ 0.08, Fisher’s exact probability test), we consider it to be clinically important. When possible we preferred to use donors who were relatives of the patients (in 22 cases, i.e.
Infect Dis Downloaded from informahealthcare.com by University of Calgary on 04/13/15 For personal use only.
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73.3%), although we used donors who were unknown to the patients in 8 cases (26.7%). Of the three recurrences observed, two involved donors unknown to the patient. Nausea was observed in one case, but could be controlled with vitamin B6 and metoclopramide. No other side effects or reactions were detected, and therefore we cannot support the view that the ‘yuck’ factor is an important obstacle. Finally we note that in three cases we used defrosted solutions, and we experienced one recurrence with this method. All FMT procedures were carried out with the written ethical approval (permission no. 16014) of the appropriate Scientific and Ethics Committee (Egészségügyi Tudományos Tanács Tudományos és Kutatásetikai Bizottság, ETT-TUKEB), and the written informed consent of the patients.
Declaration of interest: The authors work in a university hospital, where faecal microbiota
transplantation is a treatment option for patients suffering from recurrent or severe CDI.
References [1] Emanuelsson F, Claesson BE, Ljungström L, Tvede M, Ung KA. Faecal microbiotia transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand J Infect Dis 2014;46:89–97. [2] Hamilton M, Weingarden A, Sadowsky M, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:761–7. [3] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendhal EG, Keller JJ, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407–15. [4] Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: a case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580–5. [5] Brandt L, Aroniadis O, Mellow M, Kanatzar A, Kelly C, Park T, et al. Long term follow up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:1079–87.
