- Email: [email protected]
Faecal microbiota transplantation for recurrent Clostridium difficile infection and beyond: risks and regulation
Journal of Hospital Infection 92 (2016) 115e116 Available online at www.sciencedirect.com
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Editorial
Faecal microbiota transplantation for recurrent Clostridium difficile infection and beyond: risks and regulation Up to 25% of patients with Clostridium difficile infection (CDI) will suffer a recurrence within three months of the initial episode.1e3 Recurrence is associated with considerable morbidity and mortality and results in significant financial costs for payors. Between 50% and 75% of patients with a first recurrence require a further admission to hospital.4 Furthermore, recurrences are associated with a longer length of hospital stay than first episodes.5 Although treatment with fidaxomicin appears to significantly reduce the risk of recurrence compared to treatment with oral vancomycin or metronidazole, a proportion of patients fails standard therapy and suffers multiple relapses or reinfections.1,2,6 Cycles of infection become almost inevitable for some extensively antibioticexposed patients, so the use of a non-antimicrobial therapy with the intention of restoring a normal microbial gut ecology is a rational and attractive approach. Manipulation of the gut microflora via faecal microbiota transplant (FMT) has been shown to be highly effective in treating recurrent CDI. In these most difficult cases, the reported cumulative success rate of FMT is w90%.7e9 Such is the success of FMT that it is no longer considered as an alternative last-ditch therapy. Rather, it is establishing mainstream acceptance as a highly effective, although poorly understood, treatment. Although the notion of using donor faeces to reconstitute a patient’s colonic microflora is not new, there has been a recent increase in attention in its use as demonstrated by the deluge of recent publications. Of the 10,000 publications on FMT, faecal bacteriotherapy, or faecal enemas, >25% have been published in the last five years. Thanks to an assortment of reports in the lay press, patients have begun seeking to obtain FMT for many applications, including conditions where the role of the microbiota in causing disease is less well defined. However, wholesale adoption of FMT has been tempered by a number of important obstacles. First, there has been a lack of well-controlled randomized trials to support its use. The situation has improved with several randomized studies now reported in the literature and more are expected.7,10e12 Second, the concept is aesthetically unappealing both to patients and clinicians, resulting in a reluctance to offer it among the uninitiated.13,14 Third, it presents certain logistical challenges in terms of selecting and screening of donors as well
as obtaining and processing material. This issue is exacerbated by the lack of consensus about exactly how to do this. Both of these problems are being overcome by the availability of material through frozen stool banks.15 Frozen stool appears to be as effective as fresh stool and can be kept for up to six months, allowing its use on demand.11,16e18 Additionally, less invasive methods of FMT administration are being implemented by investigators, including the use of orally administered capsules. This may be preferred by patients, may result in favourable cost-effectiveness, and probably results in fewer procedureassociated adverse events.17,19 The issue of safety brings us to the fourth barrier which has limited use of FMT and which is addressed in the review by Baxter and Colville.20 Adverse events can be divided into short term and long term; however, the long-term risks are mostly theoretical since the majority of published studies are retrospective case series or systematic reviews and report very limited long-term safety data. Evidently, the technique of administration of FMT can result in a range of adverse events; for example, colonoscopic perforation, gastrointestinal bleeding, aspiration pneumonia associated with anaesthesia, and other drug-associated side-effects. The potential for transmission of infection is one of the other major safety fears, however extensive donor screening; but testing mitigates this potential problem and usually only a fraction of donors ‘make the grade’.15,21 Although long-term risks may be underappreciated, the available data suggest that adverse events are infrequent and usually both minor and self-limiting. Interestingly, safety concerns seem to be more of a preoccupation of regulatory authorities than of clinicians. In a survey of UK-based infectious diseases, microbiology and gastroenterology physicians, only 12.1% of respondents had safety concerns that would limit their use of FMT; of greater concern was the feasibility and practicality of the procedure with 57.4% of respondents citing that this would inhibit their use.22 Lack of a defined, standardized product and methods of obtaining that product are compounded by ambiguity around the regulatory framework for approval of FMT. A proper, proportionately regulated product that has a proven safety record is urgently needed to meet the growing demand for this treatment. It seems sensible to move towards using material that is well defined and quality controlled, and several companies are developing these.23,24 Ultimately human-derived products may be completely eliminated in favour of a standardized bioengineered cocktail of cultured bacteria.25 In the interim, practitioners should actively monitor adverse events and collaborate to work towards an agreed protocol that
http://dx.doi.org/10.1016/j.jhin.2015.12.004 0195-6701/ª 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
116
Editorial / Journal of Hospital Infection 92 (2016) 115e116
standardizes screening, preparation, and storage of material. An international registry and consensus guidelines may help with these aims. In the UK the Healthcare Infection Society has set up a working group to produce a set of guidelines that we hope will address some of these problems.
References 1. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422e431. 2. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281e289. 3. Vardakas KZ, Polyzos KA, Patouni K, et al. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents 2012;40:1e8. 4. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 2012;55(Suppl. 2):S88e92. 5. Le Monniet A, Duburq A, Zahar J-R, et al. Hospital cost of Clostridium difficile infection including the contribution of recurrences in French acute-care hospitals. J Hosp Infect 2015;91:117e122. 6. Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis 2015 Dec 12. http://dx.doi.org/10.1007/s10096-015-2538-z [Epub ahead of print]. 7. Van Nood E, Vrieze A, Niewdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407e415. 8. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA 2015;313:398e408. 9. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med 2015;162:630e638. 10. Cammarota G, Masucci GI, Bibbo S, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41:835e843. 11. Youngster I, Russell GH, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis 2014;58:1515e1522. 12. Kelly CR. A multicenter, randomized, placebo-controlled, doubleblind study to evaluate the efficacy and safety of fecal microbiota transplantation in patients with recurrent Clostridium difficile infection. Abstract O44, American College of Gastroenterology Scientific Meeting, October 16th‒21st, 2015, Hawaii, USA. 13. Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis 2012;55:1652e1658.
14. Paramsothy S, Walsh AJ, Borody T, et al. Gastroenterologist perceptions of faecal microbiota transplantation. World J Gastroenterol 2015;21:10907e10914. 15. Costello SP, Tucker EC, La Brooy J, Schoeman MN, Andrews JM. Establishing a fecal microbiota transplant service for the treatment of Clostridium difficile infection. Clin Infect Dis 2015 Nov 30. http://dx.doi.org/10.1093/cid/civ994. pii: civ994 [Epub ahead of print]. 16. Costello SP, Conlon MA, Vuaran MS, Roberts-Thomson IC, Andrews JM. Faecal microbiota transplant for recurrent Clostridium difficile infection using long-term frozen stool is effective: clinical efficacy and bacterial viability data. Aliment Pharmacol Therapeut 2015;42:1011e1018. 17. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312:1772e1778. 18. Hamilton MJ, Weingarden AJ, Sadowski MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:761e767. 19. Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, Honig G. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis 2015;15:191. 20. Baxter M, Colville A. Adverse events in faecal microbiota transplant: a review of the literature. J Hosp Infect 2016;92:117e127. 21. Parmasothy S, Borody TJ, Lin E, et al. Donor recruitment for fecal microbiota transplantation. Inflamm Bowel Dis 2015;21: 1600e1606. 22. Porter RJ, Fogg C. Faecal microbiota transplantation for Clostridium difficile infection in the United Kingdom. Clin Microbiol Infect 2015;21:578e582. 23. Orenstein R, Dubberke E, Hardi R, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis 2015. http://dx.doi.org/10.1093/cid/civ938 [Epub ahead of print]. 24. Brandt LJ. Fecal microbiota transplant: respice, adspice, prospice. J Clin Gastroenterol 2015;49:S65eS68. 25. Petroff EO, Gloor GB, Vanner SJ. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013;1:3.
S.D. Goldenberg* Centre for Clinical Infection and Diagnostics Research, King’s College, London, and Guy’s & St Thomas’ NHS Foundation Trust, London, UK * Address: St Thomas’ Hospital, 5th Floor North Wing, Westminster Bridge Road, London SE1 7EH, UK. Tel.: þ44 (0)20 7188 8515. E-mail address: [email protected] (S.D. Goldenberg). Available online 21 December 2015
Journal of Hospital Infection journal homepage: www.elsevierhealth.com/journals/jhin
Editorial
Faecal microbiota transplantation for recurrent Clostridium difficile infection and beyond: risks and regulation Up to 25% of patients with Clostridium difficile infection (CDI) will suffer a recurrence within three months of the initial episode.1e3 Recurrence is associated with considerable morbidity and mortality and results in significant financial costs for payors. Between 50% and 75% of patients with a first recurrence require a further admission to hospital.4 Furthermore, recurrences are associated with a longer length of hospital stay than first episodes.5 Although treatment with fidaxomicin appears to significantly reduce the risk of recurrence compared to treatment with oral vancomycin or metronidazole, a proportion of patients fails standard therapy and suffers multiple relapses or reinfections.1,2,6 Cycles of infection become almost inevitable for some extensively antibioticexposed patients, so the use of a non-antimicrobial therapy with the intention of restoring a normal microbial gut ecology is a rational and attractive approach. Manipulation of the gut microflora via faecal microbiota transplant (FMT) has been shown to be highly effective in treating recurrent CDI. In these most difficult cases, the reported cumulative success rate of FMT is w90%.7e9 Such is the success of FMT that it is no longer considered as an alternative last-ditch therapy. Rather, it is establishing mainstream acceptance as a highly effective, although poorly understood, treatment. Although the notion of using donor faeces to reconstitute a patient’s colonic microflora is not new, there has been a recent increase in attention in its use as demonstrated by the deluge of recent publications. Of the 10,000 publications on FMT, faecal bacteriotherapy, or faecal enemas, >25% have been published in the last five years. Thanks to an assortment of reports in the lay press, patients have begun seeking to obtain FMT for many applications, including conditions where the role of the microbiota in causing disease is less well defined. However, wholesale adoption of FMT has been tempered by a number of important obstacles. First, there has been a lack of well-controlled randomized trials to support its use. The situation has improved with several randomized studies now reported in the literature and more are expected.7,10e12 Second, the concept is aesthetically unappealing both to patients and clinicians, resulting in a reluctance to offer it among the uninitiated.13,14 Third, it presents certain logistical challenges in terms of selecting and screening of donors as well
as obtaining and processing material. This issue is exacerbated by the lack of consensus about exactly how to do this. Both of these problems are being overcome by the availability of material through frozen stool banks.15 Frozen stool appears to be as effective as fresh stool and can be kept for up to six months, allowing its use on demand.11,16e18 Additionally, less invasive methods of FMT administration are being implemented by investigators, including the use of orally administered capsules. This may be preferred by patients, may result in favourable cost-effectiveness, and probably results in fewer procedureassociated adverse events.17,19 The issue of safety brings us to the fourth barrier which has limited use of FMT and which is addressed in the review by Baxter and Colville.20 Adverse events can be divided into short term and long term; however, the long-term risks are mostly theoretical since the majority of published studies are retrospective case series or systematic reviews and report very limited long-term safety data. Evidently, the technique of administration of FMT can result in a range of adverse events; for example, colonoscopic perforation, gastrointestinal bleeding, aspiration pneumonia associated with anaesthesia, and other drug-associated side-effects. The potential for transmission of infection is one of the other major safety fears, however extensive donor screening; but testing mitigates this potential problem and usually only a fraction of donors ‘make the grade’.15,21 Although long-term risks may be underappreciated, the available data suggest that adverse events are infrequent and usually both minor and self-limiting. Interestingly, safety concerns seem to be more of a preoccupation of regulatory authorities than of clinicians. In a survey of UK-based infectious diseases, microbiology and gastroenterology physicians, only 12.1% of respondents had safety concerns that would limit their use of FMT; of greater concern was the feasibility and practicality of the procedure with 57.4% of respondents citing that this would inhibit their use.22 Lack of a defined, standardized product and methods of obtaining that product are compounded by ambiguity around the regulatory framework for approval of FMT. A proper, proportionately regulated product that has a proven safety record is urgently needed to meet the growing demand for this treatment. It seems sensible to move towards using material that is well defined and quality controlled, and several companies are developing these.23,24 Ultimately human-derived products may be completely eliminated in favour of a standardized bioengineered cocktail of cultured bacteria.25 In the interim, practitioners should actively monitor adverse events and collaborate to work towards an agreed protocol that
http://dx.doi.org/10.1016/j.jhin.2015.12.004 0195-6701/ª 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
116
Editorial / Journal of Hospital Infection 92 (2016) 115e116
standardizes screening, preparation, and storage of material. An international registry and consensus guidelines may help with these aims. In the UK the Healthcare Infection Society has set up a working group to produce a set of guidelines that we hope will address some of these problems.
References 1. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422e431. 2. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281e289. 3. Vardakas KZ, Polyzos KA, Patouni K, et al. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents 2012;40:1e8. 4. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis 2012;55(Suppl. 2):S88e92. 5. Le Monniet A, Duburq A, Zahar J-R, et al. Hospital cost of Clostridium difficile infection including the contribution of recurrences in French acute-care hospitals. J Hosp Infect 2015;91:117e122. 6. Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis 2015 Dec 12. http://dx.doi.org/10.1007/s10096-015-2538-z [Epub ahead of print]. 7. Van Nood E, Vrieze A, Niewdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407e415. 8. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA 2015;313:398e408. 9. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection: a systematic review. Ann Intern Med 2015;162:630e638. 10. Cammarota G, Masucci GI, Bibbo S, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther 2015;41:835e843. 11. Youngster I, Russell GH, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis 2014;58:1515e1522. 12. Kelly CR. A multicenter, randomized, placebo-controlled, doubleblind study to evaluate the efficacy and safety of fecal microbiota transplantation in patients with recurrent Clostridium difficile infection. Abstract O44, American College of Gastroenterology Scientific Meeting, October 16th‒21st, 2015, Hawaii, USA. 13. Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis 2012;55:1652e1658.
14. Paramsothy S, Walsh AJ, Borody T, et al. Gastroenterologist perceptions of faecal microbiota transplantation. World J Gastroenterol 2015;21:10907e10914. 15. Costello SP, Tucker EC, La Brooy J, Schoeman MN, Andrews JM. Establishing a fecal microbiota transplant service for the treatment of Clostridium difficile infection. Clin Infect Dis 2015 Nov 30. http://dx.doi.org/10.1093/cid/civ994. pii: civ994 [Epub ahead of print]. 16. Costello SP, Conlon MA, Vuaran MS, Roberts-Thomson IC, Andrews JM. Faecal microbiota transplant for recurrent Clostridium difficile infection using long-term frozen stool is effective: clinical efficacy and bacterial viability data. Aliment Pharmacol Therapeut 2015;42:1011e1018. 17. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 2014;312:1772e1778. 18. Hamilton MJ, Weingarden AJ, Sadowski MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012;107:761e767. 19. Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, Honig G. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis 2015;15:191. 20. Baxter M, Colville A. Adverse events in faecal microbiota transplant: a review of the literature. J Hosp Infect 2016;92:117e127. 21. Parmasothy S, Borody TJ, Lin E, et al. Donor recruitment for fecal microbiota transplantation. Inflamm Bowel Dis 2015;21: 1600e1606. 22. Porter RJ, Fogg C. Faecal microbiota transplantation for Clostridium difficile infection in the United Kingdom. Clin Microbiol Infect 2015;21:578e582. 23. Orenstein R, Dubberke E, Hardi R, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis 2015. http://dx.doi.org/10.1093/cid/civ938 [Epub ahead of print]. 24. Brandt LJ. Fecal microbiota transplant: respice, adspice, prospice. J Clin Gastroenterol 2015;49:S65eS68. 25. Petroff EO, Gloor GB, Vanner SJ. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome 2013;1:3.
S.D. Goldenberg* Centre for Clinical Infection and Diagnostics Research, King’s College, London, and Guy’s & St Thomas’ NHS Foundation Trust, London, UK * Address: St Thomas’ Hospital, 5th Floor North Wing, Westminster Bridge Road, London SE1 7EH, UK. Tel.: þ44 (0)20 7188 8515. E-mail address: [email protected] (S.D. Goldenberg). Available online 21 December 2015