Article

Fecal Microbiota Transplant: Treatment Options for Clostridium difficile Infection in the Intensive Care Unit

Journal of Intensive Care Medicine 1-10 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066615594344 jic.sagepub.com

Samuel Han, MD1, Sarah Shannahan, MD1, and Randall Pellish, MD1

Abstract Clostridium difficile infection (CDI) has steadily increased in incidence since the 1990s, with an associated increase in recurrence and severity, which has in turn lead to more intensive care unit (ICU) admissions. The development of recurrent CDI, in particular, has been associated with increasing patient morbidity and mortality as well as an immense financial burden on the health care system. Recently, fecal microbiota transplantation (FMT) has received much publicity as an effective means of treatment for recurrent CDI. The goal of this review is to provide evidence-based recommendations for the diagnosis and management of CDI, with a particular focus on FMT and its utilization in the ICU. Keywords fecal microbiota transplantation, refractory Clostridium difficile infection, recurrent Clostridium difficile colitis, fecal bacteriotherapy, BI/NAP1/027

Introduction Clostridium difficile is a gram-positive anaerobic spore-forming bacillus, which causes pseudomembranous colitis, diarrhea, toxic megacolon, sepsis, and death.1,2 Clostridium difficile infection (CDI) has been defined as a case of diarrhea or toxic megacolon with a positive stool assay for C difficile toxin A and/or B, pseudomembranous colitis seen on endoscopic evaluation or surgery, or pseudomembranous colitis as seen on histology. The prevalence of CDI in patients in US and Canadian hospitals has increased steadily since the mid-1990s, with data demonstrating that discharge diagnosis rates of CDI have more than doubled from 30 to 40 cases per 100 000 to 84 cases per 100 000 in 2005.3-6 In addition to the increased incidence of CDI, greater severity resulting in increased morbidity and mortality has also been observed.6-9 A recurrent case of CDI is defined as an episode that occurs 8 weeks or less after the onset of a previous episode of CDI, where symptoms had previously resolved with or without therapy.10-13 As a result of increased incidence, virulence, and recurrent CDI, the associated cost attributed to C difficile to both the patient and the health care systems has risen with estimates between US$436 million to US$3 billion in health care costs.14-16 With such disease burden, fecal microbiota transplantation (FMT) has emerged as a highly effective treatment of recurrent and/or severe CDI. Fecal microbiota transplantation has been performed since 1958 for the treatment of pseudomembranous colitis, and case studies evaluating the efficacy in treating

recurrent CDI have documented success in approximately 87% of cases.17 Fecal microbiota transplantation involves administering fecal material from a healthy individual into the gastrointestinal (GI) tract of the patient via nasogastric (NG) tubes, nasojejunal (NJ) tubes, fecal retention enemas, and by colonoscopy.18-21

Pathophysiology Clostridium difficile Toxins and the Emergence of a Hypervirulent Strain Clostridium difficile bacteria cause a toxin-medicated colitis. Virulent C difficile strains contain a pathogenicity locus, which contains regulatory genes, a porin gene, and the genes tcdA and tcdB, which encode toxin A and toxin B, respectively.22,23 These cytotoxic and proinflammatory toxins lead to the disruption of the actin cytoskeleton and impairment of tight junctions in the intestinal epithelial cells resulting in fluid accumulation, apoptosis, and cell death.24-26 1

University of Massachusetts Medical School, Worcester, MA, USA

Received July 14, 2014, and in revised form May 14, 2015. Accepted for publication May 14, 2015. Corresponding Author: Samuel Han, 55 Lake Avenue North, Worcester, MA 01655, USA. Email: [email protected]

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

2

Journal of Intensive Care Medicine

Since the mid-1990s, the rates and severity of CDI have been rising, resulting in increased complications including colectomies, intensive care unit (ICU) admissions, and deaths. This has correlated with the emergence of an epidemic strain of C difficile, known as BI/NAP1/027, which is characterized by fluoroquinolone resistance and increased toxin A and toxin B production.4,6,7,22 The BI/NAP1/027 strain has been associated with increased sporulation, as well as a third toxin known as the C difficile binary toxin, which further disrupts the cytoskeleton and is thought to contribute to virulence.9,22,27

Patient Risk Factors and Recurrent CDI Clostridium difficile infection is the major cause of antibioticinduced diarrhea and colitis.28,29 The most frequently implicated antibiotics that increase the risk of CDI include clindamycin, cephalosporins, penicillins, and fluoroquinolones.28,30 Antibiotics are thought to increase the risk of CDI by disrupting commensal gut microbiota, therefore reducing ‘‘colonization resistance’’ against C difficile. Colonization resistance provides a protective function to the host’s own indigenous gut flora, which when present in sufficient quantity and diversity limits the colonization of pathogenic bacteria.30-34 In addition to exposure to certain antibiotics, other risk factors that increase the risk of initial CDI include advanced patient age, exposure to C difficile spores through hospitalization, chemotherapy, and possibly proton pump inhibitors and histamine type 2 blockers.28, 35-37

Diagnosis Patient history is important to determine the underlying risk factors as well as past exposures to medications, specifically antibiotics. Clostridium difficile infection generally presents shortly after initiation of antibiotic therapy, although it may be delayed for several weeks after treatment.38-41 Infection most commonly manifests as mild to moderate diarrhea, defined as 3þ loose stools/d for at least 2 days. Physical examination can range depending on severity of infection. Fever, cramping, abdominal discomfort, and peripheral leukocytosis are common but found in less than 50% of patients.1,25,42 In severe cases, CDI may lead to toxic megacolon, presenting with hypotension, tachycardia, fevers, decreased bowel sounds, abdominal pain, and distention.1,25,42 Patients with evidence of severe CDI should be evaluated for ICU admission due to risk of complications including electrolytes abnormalities, bowel perforation, renal failure, septic shock, and ultimately death.6,9,42 Diagnosis of CDI consists of either laboratory testing and/or endoscopy. Laboratory testing for C difficile should only be performed on loose stools, unless ileus is suspected, in which case stool of any consistency or a rectal swab may be used.13,43-47 Repeat testing during the same episode of diarrhea is discouraged, as there is limited yield.48-50 Although the gold standard for laboratory testing is stool culture, which offers a high degree of sensitivity, most stool

cultures take a minimum of 2 days, which may be prohibitive in critical situations.51-55 Since 2009, the Food and Drug Administration (FDA) began to approve molecular platforms for direct detection of C difficile, including the BD GeneOhm Cdiff assay, the Xpert C difficile Epi assay, the Illumigene assay, and the AmpliVue C difficile assay, all of which have a sensitivity and specificity approaching 96% to 100%.56-63 Colonoscopy can assist in the diagnosis of C difficile by direct visualization of pseudomembranes, however in severe CDI, caution must be pursued with colonoscopy given the risk of perforation.64,65

Standard Treatment for CDI In patients diagnosed with CDI, the offending antibiotic agents should be discontinued, if possible, to decrease susceptibility to recurrent infection.66 Patients should be placed in isolation and strict contact precautions should be enforced to prevent further spread. According to American College of Gastroenterology and Society for Healthcare Epidemiology of America (SHEA) guidelines, initial standard therapy for mild/moderate disease starts with metronidazole 500 mg orally 3 times a day for 10 to 14 days.10,13 If patients are unable to take metronidazole or have no improvement within 5 to 7 days, the alternate regimen is oral vancomycin 125 mg 4 times a day for 10 days. No difference in outcome has been identified between metronidazole and vancomycin for mild to moderate CDI, but current guidelines favor using metronidazole as first-line treatment, with the caveat that lack of an initial response to metronidazole is associated with an increased mortality.13,67,68 See Table 1 for the approach to management of CDI.

Severe CDI Severe CDI is generally characterized as a combination of leukocytosis with a white blood cell (WBC) > 15  109/L, serum albumin < 3 g/dL, serum creatinine level >1.5 times baseline level, or abdominal tenderness. General consensus recommends initial treatment with oral vancomycin 125 mg 4 times a day for 10 to 14 days, as there appears to be no benefit for combination therapy with metronidazole and vancomycin in severe, uncomplicated CDI.10,13 All patients displaying complications of severe disease should be considered for admission to the ICU for supportive care. Severe, complicated disease includes a myriad of features suggestive of a systemic inflammatory response or sepsis including hypotension or shock, fever  38.5 C, ileus or significant abdominal distention, megacolon, mental status changes, WBC  35  109/L, serum lactate levels > 2.2 mmol/L, and other signs of end-organ damage such as renal failure or respiratory failure.10,13 Per SHEA guidelines, vancomycin can be administered by both oral and rectal (enema) routes in addition to intravenous metronidazole 500 mg every 8 hours.13 Additionally, all patients presenting with these symptoms require a surgical consultation. Currently, there is no official recommendation for the use of FMT in severe/complicated disease, and the data for the use of FMT in this setting are lacking.

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

Han et al

3

Table 1. Suggested Approaches to Treatment of Clostridium difficile Colitis. Possible Testing Modalities56-63  Preferred: molecular platforms  BD Gene Ohn C difficile assay—PCR  Xpert C difficile Epi assay  Illumigene assay—LAMP technology  AmpliVue C difficile assay  Stool culture for C. difficile (gold atandard, but takes 2 days)  2-Step method  Screening with GDH  If positive, confirm with either toxin EIA or molecular assay  EIA against toxins A and/or B  Endoscopy for direct visualization of pseudomembranes  10% to 20% of cases without pseudomembranes may require biopsy if high clinical suspicion of CDI Treatment  Identify potential triggers of CDI  Place in isolation with strict contact precautions  Consider ICU admission if WBC >15  109/L, Elevated Cre, temp >38.8, Alb < 2.5  Antibiotics  First Line & Mild-Mod: PO/IV metronidazole; if refractory PO vancomycin & Mod-Sev: PO vancomycin + IV metronidazole  Others: & Fidaxomicin & Rifaximin  Surgery  Subtotal or total colectomy  Diverting loop Ileostomy  Fecal microbiota transplantation  NG/NJ/upper endoscopy  Colonoscopy  Fecal enemas Abbreviations: PCR, polymerase chain reaction; LAMP, loop-mediated isothermal amplification; GDH, glutamate dehydrogenase; EIA, enzyme immunoassay; CDI, Clostridium difficile infection; WBC, white blood count; Cre, creatinine; temp, temperature; Alb, albumin; NG, nasogastric; NJ, nasojejunal.

Surgery Determining which patients will benefit from surgery remains a quandary as patients with severe and/or complicated CDI may be considered poor surgical candidates. Colonic perforation is an indication for emergent surgery. In patients with severe CDI and signs of sepsis, surgery should be considered if patients are not responding to antibiotic therapy. Risk factors for increased mortality in patients who undergo colectomy include need for vasopressors, lactate  5 mmol/L, mental status changes, renal failure, and mechanical ventilation. 69,70 Ideal timing for surgery is often a complex, difficult decision. Data do suggest that earlier colectomy is associated with decreased mortality.69-71 The traditional surgical approach has included either a subtotal colectomy or a total colectomy, with better results achieved with a total colectomy.72 Regardless of the surgical approach, there is a high mortality risk with rates as high as 50% ranging up to 75% in emergency colectomies.73-75 A new colon-sparing approach has been described by Neal et al,

involving a diverting loop ileostomy which found a reduced mortality rate compared to the traditional approach (50%-19%) and may present a better surgical method in these patients.76 The majority of the procedures were performed with a minimally invasive method, and most of the patients were able to regain GI continuity.76 Regardless, the high mortality rates stress the importance of identifying and considering surgery early, in addition to considering possible FMT, before a patient’s clinical status deteriorates.

Alternative Antibiotics Among alternative antibiotics, fidaxomicin has been FDA approved at a dose of 200 mg oral twice a day for 10 days of treatment. In vitro studies have shown fidaxomicin to be more effective against CDI than vancomycin.77-79 Two randomized control trials have shown fidaxomicin to be as effective as vancomycin with a decreased recurrence rate with fidaxomicin compared to vancomycin (15.4% vs 25.3%).80,81 A recent study by Penziner et al examined the use of fidaxomicin in severe CDI in an intensive care setting and found a response rate of 46%.82 While a viable alternative treatment, fidaxomicin has not been studied for efficacy in recurrent CDI and has not been compared to metronidazole. Furthermore, the high cost for a 10-day supply has raised issues of comparative cost-effectiveness. Rifaximin is another antibiotic (400-800 mg a day divided into 2 to 3 doses/d for 2 weeks) displaying effective in vitro activity against C difficile. This antibiotic is not absorbed by the GI tract nor inactivated by gastric secretions while exerting its effects only within the intestinal lumen.83,84 There have been small clinical trials testing its effects against C difficile, which have shown it to be fairly effective.85-87 A randomizedcontrolled trial found rifaximin to be as effective as vancomycin in mild to moderate CDI.88 Interestingly, a novel antibiotic protocol utilizing rifaximin after a vancomycin course had no cases of recurrent CDI.89 Supporting an adjuvant rifaximin treatment approach, an additional study in liver transplant patients displayed no recurrence of CDI when rifaximin was given after previous treatment with vancomycin and metronidazole had failed.90

The Emerging Standard for Treatment of Recurrent C difficile With FMT While metronidazole and vancomycin remain standard treatment for CDI, recurrence after antibiotics has been increasingly problematic. Recurrence rates reach 20% after a first episode and 60% after 2 or more episodes, suggesting that the use of these 2 antibiotics is not effectively curing a large proportion of patients.4,91,92 In response to this problem, FMT has emerged as a highly effective treatment and is recommended once a third recurrence has occurred.10 Over 400 patients have been documented to have received FMT for treatment of CDI, with a mean success rate of 87%.17 The majority of these patients received FMT after

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

4

Journal of Intensive Care Medicine

multiple CDI episodes. Of those patients cured with FMT, only 6.5% required more than 1 stool transplant.17

Mechanism of FMT The mechanism by which FMT works has not been fully elucidated, however evidence demonstrates that instilling feces from a healthy donor into a patient with CDI will reestablish the normal dominance of healthy bacteria and rapidly change the bacterial composition of the recipient to be more similar to that of the donor.28,30Alternatively, Weingarden et al have suggested that FMT may result in the normalization of fecal bile acids, which have progerminant and inhibitory activities, as they found that FMT corrected the disrupted metabolism of primary bile acids to secondary bile acids in patients with recurrent CDI.93

Fecal Microbiota Transplant Donor Selection and Preparation While very promising, FMT has many limiting factors, notably in donor inclusion criteria and costs of screening the stool donor. Currently, candidate donors are healthy volunteers (see Table 2), usually family members or significant others. This is not an evidence-based recommendation, but rather a protocol based on practicality.18,19,94 Donor screening is a rigorous and costly process and, while not standardized, can include screening for human immunodeficiency virus (HIV), hepatitis A virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus, Treponema pallidum, Strongyloides stercoralis, Entamoeba histolytica, stool parasites, C difficile, and other enteropathogenic bacteria.19 A recommended protocol is shown in Table 2. Institutions should develop a protocol of instructions for stool donors. Typically, the donated stool is collected within 6 hours of the procedure and filtered to remove particular matter. Hamilton et al described a process to freeze stools and thaw them later for immediate use, although this requires prior preparation.94 Alternatively, Petrof et al have prepared substitute stools, isolating 33 different colonies of bacteria from a healthy donor and successfully treated 2 patients with refractory CDI, which may further alleviate issues surrounding donor recruitment and need for expensive, multiple donor screenings.95 With strict protocols for stool donors, the nation’s first stool bank, OpenBiome, was launched at the Massachusetts Institute of Technology in 2012. OpenBiome, a nonprofit organization, supplies stool to patients for the treatment of CDI. The stool bank screens donors for infectious agents as well as for chronic conditions, and samples are frozen for long-term storage.96 As this increases access to stool for FMT, there are interesting questions regarding possible differences in frozen stool samples from anonymous donors versus fresh donated stool from related or known donors. In addition to the formation of stool banks, there is also a push for the development of encapsulated feces products that could be given in oral form.97 This could improve availability of FMT therapy as well as improve cost and reduce the risk to the patient, particularly avoiding any risk

Table 2. FMT Donor Screening Recommendations.18,19 Screening Questionnaire for Exclusion Criteria  Risk of infectious agent:  Known exposure to HIV or viral hepatitis (within the previous 12 months)  High-risk sexual behaviors including sexual contact with anyone with HIV/AIDS or hepatitis, men who have sex with men, sex for drugs, or money  Use of illicit drugs  Tattoo or body piercing within 6 months  Incarceration within previous 12 months  Known current communicable disease  Risk factors for variant Creutzfeldt-Jacob disease  Gastrointestinal comorbidities  History of inflammatory bowel disease  History of celiac disease  History of irritable bowel syndrome, idiopathic chronic constipation, or chronic diarrhea  History of gastrointestinal malignancy  Other  Antibiotic use within the preceding 90 days  Recent ingestion of a potential allergen (eg, nuts) where recipient has a known allergy to this agent  Systemic autoimmunity (eg, multiple sclerosis and connective tissue disease)  Chronic pain syndromes (eg, chronic fatigue syndrome and fibromyalgia) Donor Stool Testing  Clostridium difficile toxin B by PCR; if unavailable, then evaluations for toxins A and B by EIA  Bacterial culture for routine enteric pathogens  Fecal Giardia antigen  Fecal cryptosporidium antigen  Ova and parasites Donor Serologic Testing  HIV, types 1 and 2  HAV IgM  HBsAg, anti-HBc (both IgG and IgM), and anti-HBs  HCV Ab  RPR  EBV  CMV  HTLV 1 and 2 Abbreviations: HIV, human immunodeficiency virus, PCR, polymerase chain reaction; EIA, enzyme immunoassay; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen; anti-HBc, hepatitis B core antibody, anti-HBs, hepatitis B surface antibody; HCV, hepatitis C virus; RPR, rapid plasma reagin, EBV, EpsteinBarr virus; CMV, cytomegalovirus; HTLV, human T-lymphotropic virus; Ig, immunoglobulin; Ab, antibody.

associated with endoscopy or colonoscopy. A feasibility study by Youngster et al demonstrated the efficacy of using a frozen inoculum of unrelated stool via NG tube and colonoscopy and the follow-up study utilizing an oral, encapsulated inoculum found an initial 70% success rate, with a final response rate of 90% after retreatment in initial nonresponders.98-99

Route of FMT Administration There are currently 3 main routes of administration with FMT: (1) upper route via nasoduodenal (ND), NJ, or

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

Han et al

5

esophagogastroduodenoscopy (EGD); (2) via colonoscopy; and (3) via fecal enema to the left colon. The majority of studies report the colonoscopic approach, which is usually favored due to its ability to infuse the stool throughout the entire colon, its diagnostic ability to examine the severity of the colitis, and patient preference.100 While efficacy appears greatest with the colonoscopy approach (93%), success rates range from 81% (upper route via NG, NJ, or EGD) to 84% (via enema).19, 101-119 Very few studies have directly compared the different routes of administration, with the aforementioned study by Youngster et al finding no difference in using frozen inoculums via NG tube or colonoscopy.98 Upper endoscopy (EGD), ND, or NJ tubes can be used to access the small bowel to administer stool solution, with theoretical benefit of exposing nearly the entire GI tract to the transplanted stool.19, 101-106 A landmark randomized controlled trial by van Nood et al administered a relatively large amount of fecal solution (500 cm3) via an ND tube.19 Sixteen patients received the stool solution with 81% achieving resolution after the first infusion and 2 of the remaining 3 achieving resolution after a second infusion for a total cure rate of 94%. In comparison, the other treatment groups of vancomycin alone and vancomycin plus upper GI lavage achieved cure rates of 31% and 23%, respectively (P < .001). Additionally, patients who failed treatment with antibiotics were offered off-protocol FMT, with a resultant 15 (83%) of 18 cure rate. Some obstacles to this approach have included a theoretical risk of aspiration and low patient acceptance to undergo placement of an ND/NJ tube with stool administered into the upper GI tract.120-124 Fecal microbiota transplantation via colonoscopy has been a widely studied route of administration. While allowing for contact with the entire colon and even the terminal ileum, this route has achieved the highest reported primary cure rate.29, 107,125-134 In patients with severe colitis, specifically those admitted to the ICU, colonoscopy may present a technically challenging and riskier route including theoretical risk of colonic perforation, possibly excluding patients with the greatest need for FMT. The fecal enema route offers a simple, inexpensive, and easy method for FMT. This method has the shortest contact area of stool with the colon but still has a high average rate of success near 84%.107-119 The simplicity of this method is underscored by several reports of patients using this route at home.135,136 Recently, Dutta et al performed a novel approach of using a combination of both upper and lower endoscopies to perform FMTs in 27 patients observing not only a 100% success rate but also an associated increase in biodiversity with recolonized microbiota similar to the donor fecal microbiota.137 While more studies are needed to validate these results, this approach may prove to be the most effective method of exposing the GI tract to transplanted stool solution.

Fecal Microbiota Transplantation in the ICU Patients with severe, complicated C difficile colitis in an ICU setting present a difficult clinical decision as possible

candidates for FMT. Such patients may have recurrent CDI or be presenting with a severe initial case of CDI. Different clinical scenarios might direct choice of FMT administration route but should always be approached in a multidisciplinary manner including surgical consultation. If the patient is stable enough to endure endoscopy, FMT via EGD-placed NJ or ND tube may be the safest method, as it does not risk colonic perforation, as reported by Trubiano et al in the ICU setting.102 Weingarden et al, however, did safely utilize colonoscopy for FMT in a single patient on vasopressor and ventilator support in the ICU setting.138 In ICU patients who cannot undergo endoscopy, FMT via NG tube or rectal enema is a potential reasonable option. It remains important, however, to note that current guidelines do not recommend the use of FMT in severe and/or fulminant CDI, many of which will require surgical treatment if unresponsive to antibiotic therapy.10,13

Special Populations Exclusion criteria for FMT recipients have in the past included immunocompromised patients including those taking immunosuppressive medications, patients with decompensated liver disease, advanced HIV/AIDS, recent bone marrow transplants, and patients with low life expectancy. Despite this, Kelly et al have recently demonstrated that FMT can be effective in immunocompromised patients with few infectious related adverse events.139

Future Outlook Appropriate regulation and standardization in patient selection, donor testing, and FMT procedures is key for further studies and continued appropriate use of FMT. Knowledge gained through FMT with frozen stool specimens and encapsulated preparations could further aid in the design of synthetic stool preparations, thereby increasing availability and decreasing obstacles to those patients who have recurrent CDI. Further studies will be needed to compare routes of administration of FMT and assess the validity of FMT in ICU-level patients with severe, complicated CDI.

Conclusion Patients with recurrent and/or severe CDI requiring ICU level of care can be considered candidates for FMT but will require ongoing risk assessment to identify the ideal timing of different treatment options including repeat antibiotic courses, surgical intervention, or FMT. In the absence of stool bank specimens, the consideration of FMT for ICU patients will require early initiation of an institution’s FMT donor screening protocol as well as considering an institutional review board-approved protocol to expedite this potential, effective therapy in our sickest patients. Given the present lack of literature, more investigation is needed to understand the appropriate use of FMT, particularly versus surgical treatment, in the ICU patient population suffering from severe and/or recurrent CDI.

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

6

Journal of Intensive Care Medicine

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

15.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

16.

References

17.

1. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. 2002;346(5):334-339. 2. Marsh JW, Curry SR. Therapeutic approaches for Clostridium difficile infections. Curr Protoc Microbiol. 2013;30:9A.3.1-9. 3. Dubberke ER, Wertheimer AI. Review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30(1):57-66. 4. Kelly CP, LaMont JT. Clostridium difficile-more difficult than ever [review]. N Engl J Med. 2008;359(18):1932-1940. Erratum in: N Engl J Med. 2010;363(16):1585. 5. McDonald LC, Owings M, Jernigan JB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996 to 2003. Emerg Infect Dis. 2006;12(3):409-415. 6. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005;353(23):2442-2449. Erratum, N Engl J Med. 2006;354: 2200. 7. Pe´pin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991-2003: a changing pattern of disease severity. CMAJ. 2004;171(5):466-472. 8. Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol. 2005;26(3):273-280. 9. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353(23):2433-2441. 10. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108(4):478-499. 11. Ananthakrishnan AN. Clostridium difficile infection: epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol. 2011;8(1):17-26. 12. McDonald LC, Coignard B, Dubberke E, Song X, Horan T, Kutty PK; Ad Hoc Clostridium difficile Surveillance Working Group. Recommendations for surveillance of Clostridium difficile-associated disease. Infect Control Hosp Epidemiol. 2007;28(2):140-145. 13. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. 14. Dubberke ER, Reske KA, Olsen MA, McDonald LC, Fraser VJ. Short- and long-term attributable costs of Clostridium difficile-

18.

19.

20. 21.

22.

23.

24.

25. 26.

27.

28.

29.

30.

31.

associated disease in nonsurgical inpatients. Clin Infect Dis. 2008;46(4):497-504. O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol. 2007;28(11):1219-1227. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis. 2002;34(3):346-353. 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. Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012;46(2): 145-149. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415. Davidovics ZH, Hyams JS. Fecal transplantation: re-discovering the value of stool. Curr Opin Pediatr. 2013;25(5):618-623. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508. O’Connor JR, Johnson S, Gerding DN. Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology. 2009;136(6):1913-1924. Erratum in: Gastroenterology. 2009;137(2):743. Lyras D, O’Connor JR, Howarth PM, et al. Toxin B is essential for virulence of Clostridium difficile. Nature. 2009;458(7242): 1176-1179. Voth DE, Ballard JD. Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev. 2005;18(2): 247-263. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med. 1994;330(4):257-262. Carter GP, Rood JI, Lyras D. The role of toxin A and toxin B in Clostridium difficile-associated disease: past and present perspectives. Gut Microbes. 2010;1(1):58-64. Merrigan M, Venugopal A, Mallozzi M, et al. Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production. J Bacteriol. 2010;192(19): 4904-4911. Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009;58(6): 403-410. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. 2010;44(5):354-360. Britton RA, Young VB. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol. 2012;20(7):313-319. Vollaard EJ, Clasener HA. Colonization resistance. Antimicrob Agents Chemother. 1994;38(3):409-414.

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

Han et al

7

32. Paterson DL. ‘‘Collateral damage’’ from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis. 2004;38(suppl 4): S341-S345. 33. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis. 2008;197(3):435-438. 34. Young VB, Schmidt TM. Antibiotic-associated diarrhea accompanied by large-scale alterations in the composition of the fecal microbiota. J Clin Microbiol. 2004;42(3):1203-1206. 35. Pakyz AL, Jawahar R, Wang Q, Harpe SE. Medication risk factors associated with healthcare-associated Clostridium difficile infection: a multilevel model case-control study among 64 US academic medical centres. J Antimicrob Chemother. 2014; 69(4):1127-1131. 36. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171(1):33-38. 37. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med. 2011;365(18):1693-1703. 38. McFarland LV, Mulligan ME, Kwok RY, et al. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989;320(4):204-210. 39. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med. 2000;342(6):390-397. 40. Johnson S, Clabots CR, Linn FV, Olson MM, Peterson LR, Gerding DN. Nosocomial Clostridium difficile colonisation and disease. Lancet. 1990;336(8707):97-100. 41. Samore MH, DeGirolami PC, Tlucko A, Lichtenberg DA, Melvin ZA, Karchmer AW. Clostridium difficile colonization and diarrhea at a tertiary care hospital. Clin Infect Dis. 1994;18(2): 181-187. 42. Kyne L, Merry C, O’Connell B, Kelly A, Keane C, O’Neill D. Factors associated with prolonged symptoms and severe disease due to Clostridium difficile. Age Ageing. 1999; 28(2):107-113. 43. Gerding DN, Johnson S, Peterson LR, Mulligan ME, Silva J Jr. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995;16(8):459. 44. Sunenshine RH, McDonald LC. Clostridium difficile-associated disease: new challenges from an established pathogen. Cleve Clin J Med. 2006;73(2):187. 45. Gerding DN. Diagnosis of Clostridium difficile-associated disease: patient selection and test perfection. Am J Med. 1996; 100(5):485. 46. Katz DA, Lynch ME, Littenberg B. Clinical prediction rules to optimize cytotoxin testing for Clostridium difficile in hospitalized patients with diarrhea. Am J Med. 1996;100(5):487-495. 47. Kundrapu S, Sunkesula VC, Jury LA, Sethi AK, Donskey CJ. Utility of perirectal swab specimens for diagnosis of Clostridium difficile infection. Clin Infect Dis. 2012;55(11):1527-1530. 48. Gade R, Turett G. The utility of repeated stool toxin testing for diagnosing Clostridium difficile colitis. South Med J. 2009; 102(10):1007-1009.

49. Deshpande A, Pasupuleti V, Patel P, et al. Repeat stool testing to diagnose Clostridium difficile infection using enzyme immunoassay does not increase diagnostic yield. Clin Gastroenterol Hepatol. 2011;9(8):665. 50. Cardona DM, Rand KH. Evaluation of repeat Clostridium difficile enzyme immunoassay testing. J Clin Microbiol. 2008;46(11): 3686. 51. Laughon BE, Viscidi RP, Gdovin SL, Yolken RH, Bartlett JG. Enzyme immunoassays for detection of Clostridium difficile toxins A and B in fecal specimens. J Infect Dis. 1984;149(5): 781-788. 52. Shanholtzer CJ, Willard KE, Holter JJ, Olson MM, Gerding DN, Peterson LR. Comparison of the VIDAS Clostridium difficile toxin A immunoassay with C. difficile culture and cytotoxin and latex tests. J Clin Microbiol. 1992;30(7):1837-1840. 53. Bouza E, Munoz P, Alonso R. Clinical manifestations, treatment and control of infections caused by Clostridium difficile. Clin Microbiol Infect. 2005;11(suppl 4):57-64. 54. Kuijper EJ, van den Berg RJ, Debast S, et al. Clostridium difficile ribotype 027, toxinotype III, the Netherlands. Emerg Infect Dis. 2006;12(5):827-830. 55. Reller ME, Lema CA, Perl TM, et al. Yield of stool culture with isolate toxin testing versus a two-step algorithm including stool toxin testing for detection of toxigenic Clostridium difficile. J Clin Microbiol. 2007;45(11):3601-3605. 56. Swindells J, Brenwald N, Reading N, Oppenheim B. Evaluation of diagnostic tests for Clostridium difficile infection. J Clin Microbiol. 2010;48(2):606-608. 57. Novak-Weekley SM, Marlowe EM, Miller JM, et al. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol. 2010;48(3):889-893. 58. Whang DH, Joo SY. Evaluation of the diagnostic performance of the xpert Clostridium difficile assay and its comparison with the toxin A/B enzyme-linked fluorescent assay and in-house realtime PCR assay used for the detection of toxigenic C. difficile. J Clin Lab Anal. 2014;28(2):124-129. 59. Sharp SE, Ruden LO, Pohl JC, Hatcher PA, Jayne LM, Ivie WM. Evaluation of the C.Diff Quik Chek Complete Assay, a new glutamate dehydrogenase and A/B toxin combination lateral flow assay for use in rapid, simple diagnosis of Clostridium difficile disease. J Clin Microbiol. 2010;48(6):2082-2086. 60. Lalande V, Barrault L, Wadel S, Eckert C, Petit JC, Barbut F. Evaluation of a loop-mediated isothermal amplification assay for diagnosis of Clostridium difficile infections. J Clin Microbiol. 2011;49(7):2714-2716. 61. Noren T, Alriksson I, Andersson J, Akerlund T, Unemo M. Rapid and sensitive loop-mediated isothermal amplification (LAMP) test for Clostridium difficile diagnosis challenges cytotoxin B cell test and culture as gold standard. J Clin Microbiol. 2011;49(7): 710-711. 62. Boyanton BL Jr, Sural P, Loomis CR, et al. Loop-mediated isothermal amplification compared to real-time PCR and enzyme immunoassay for toxigenic Clostridium difficile detection. J Clin Microbiol. 2012;50(3):640-645. 63. Deak E, Miller SA, Humphries RM. Comparison of the Illumigene, Simplexa, and AmpliVue Clostridium difficile molecular

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

8

64.

65.

66.

67.

68.

69.

70.

71. 72. 73.

74.

75.

76.

77.

78.

79.

80.

81.

Journal of Intensive Care Medicine assays for diagnosis of C. difficile Infection. J Clin Microbiol. 2014;52(3):960-963. Goodhand JR, Alazawi W, Rampton DS. Systematic review: Clostridium difficile and inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33(4):428-441. Ananthakrishnan AN, Binion DG. Impact of Clostridium difficile on inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4(5):589-600. Hu Y, Katchar K, Kyne L, et al. Prospective derivation and validation of a clinical prediction rule for recurrence Clostridium difficile infection. Gastroenterology. 2009;136(4):1206-1214. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40(11):1586-1590. Markelov A, Livert D, Kohli H. Predictors of fatal outcome after colectomy for fulminant Clostridium difficile colitis: a 10-year experience. Am Surg. 2011;77(8):977-980. Byrn JC, Maun DC, Gingold DS, Baril DT, Ozao JJ, Divino CM. Predictors of mortality after colectomy for fulminant Clostridium difficile colitis. Arch Surg. 2008;143(2):150-154. Ali SO, Welch JP, Dring RJ. Early surgical intervention for fulminant pseudomembranous colitis. Am Surg. 2008;74(1):20-26. Butala P, Divino D. Surgical aspects of fulminant Clostridium difficile colitis. Am J Surg. 2010;200(1):131-135. Longo WE, Mazuski JE, Virgo KS, Lee P, Bahadursingh AN, Johnson FE. Outcome after colectomy for Clostridium difficile colitis. Dis Colon Rectum. 2004;47(10):1620-1626. Al-Abed Y, Gray E, Rothnie N. Outcomes of emergency colectomy for fulminant Clostridium difficile colitis. Surgeon. 2010; 8(6):330-333. Perera A, AKbari R, Cowher M. Colectomy for fulminant Clostridium difficile colitis: predictors of mortality. Am Surg. 2010; 76(4):418-421. Neal MD, Alverdy JC, Hall DE, Simmons RL, Zuckerbraun BS. Diverting loop ileostomy and colonic lavage: an alternative total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg. 2011;254(3): 423-427. Finegold SM, Molitoris D, Vaisanen ML, Song Y, Liu C, Bolan˜os M. In vitro activities of OPT-80 and comparator drugs against intestinal bacteria. Antimicrob Agents Chemother. 2004;48(12):4898-4902. Ackermann G, Lo¨ffler B, Adler D, Rodloff AC. In vitro activity of OPT-80 against Clostridium difficile. Antimicrob Agents Chemother. 2004;48(6):2280-2282. Karlowsky JA, Laing NM, Zhanel GG. In vitro activity of OPT-80 tested against clinical isolates of toxin-producing Clostridium difficile. Antimicrob Agents Chemother. 2008;52(11):4163-4165. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe,

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

Canada, and the USA: a double-blind, non-inferiority, randomized controlled trial. Lancet Infect Dis. 2012;12(4):281-289. Penziner S, Dubrovskaya Y, Press R, Safdar A. Fidaxomicin therapy in critically ill patients with Clostridium difficile infection. Antimicrob Agents Chemother. 2015;59(3):1776-1781. Koo HL, DuPont HL. Rifaximin: a unique gastrointestinal selective antibiotic for enteric diseases. Curr Opin Gastroenterol. 2010;26(1):17-25. Marchese A, Salerno A, Pesce ADebbia EA, Schito GC. In vitro activity of rifaximin, metronidazole and vancomycin against Clostridium difficile and the rate of selection of spontaneously resistant mutants against representative anaerobic and aerobic bacteria, including ammonia-producing species. Chemotherapy. 2000;46(4):253-266. Berman AL. Efficacy of rifaximin and vancomycin combination therapy in a patient with refractory Clostridium difficile associated diarrhea. J Clin Gastroenterol. 2007;41(10):932-933. Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44(6):846-848. Rubin DT, Sohi S, Glathar M, Thomas T, Yadron N, Surma BL. Rifaximin is effective for the treatment of Clostridium difficileassociated diarrhea: results of an open-label pilot study. Gastroenterol Res Pract. 2011;2011:106978. Pardi DS, Brennan R, Spinnell M, et al. The efficacy and safety of rifaximin vs. vancomycin in the treatment of mild to moderate C. difficile infection: a randomized double-blind active comparator trial. Gastroenterology. 2012;142(5):S-599. Garey KW, Ghantoji SS, Shah DN, et al. A randomized, doubleblind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection. J Antimicrob Chemother. 2011;66(12): 2850-2855. Neff G, Zacharias V, Kaiser TE, Gaddis A, Kemmer N. Rifaximin for the treatment of recurrent Clostridium difficile infection after liver transplantation: a case series. Liver Transpl. 2010;16(8): 960-963. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97(7):1769-1775. Khanna S, Pardi DS, Aronson SL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population based study [published correction appears in Am J Gastroenterol. 2012; 107(1):150]. Am J Gastroenterol. 2011;107(1):89-95. Weingarden AR, Chen C, Bobr A, et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. Am J Physiol Gastrointest Liver Physiol. 2014;306(4):G310-G319. Hamilton MJ, Weingarden AR, Sadowsky MJ, et al. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107(5):761-767. Petrof EO, Gloor GB, Vanner SJ, et al. Stool substitute transplant therapy for eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Microbiome. 2013;1(1):3.

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

Han et al

9

96. Smith MB, Kelly C, Alm EJ. Policy: how to regulate faecal transplants. Nature. 2014;506(7488):290-291. 97. Louie T, Cannon K, O’Grady H, Wu K, Ward L. Fecal microbiome transplantation (FMT) via oral fecal microbial capsules for recurrent Clostridium difficile infection (rCDI). IDWeek. 2013. Website. https://idsa.confex.com/idsa/2013/webprogram/ Paper41627.html 98. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, openlabel, controlled pilot study. Clin Infect Dis. 2014;58(11): 1515-1522. 99. 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(17):1772-1778. 100. Brandt LJ. American journal of gastroenterology lecture: intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol. 2013; 108(2):177-185. 101. Neemann K, Eichele DD, Smith PW, Bociek R, Akhtari M, Freifeld A. Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient. Transpl Infect Dis. 2012;14(6):E161-E165. 102. Trubiano JA, Gardiner B, Kwong JC, Ward P, Testro AG, Charles PG. Faecal microbiota transplantation for severe Clostridium difficile infection in the intensive care unit. Eur J Gastroenterol Hepatol. 2013;25(2):255-257. 103. Polak P, Freibergerova M, Jurankova J, et al. First experiences with faecal bacteriotherapy in the treatment of relapsing pseudomembranous colitis due to Clostridium difficile. Klin Mikrobiol Infekc Lek. 2011;17(6):214-217. 104. Garborg K, Waagsbø B, Stallemo A, Matre J, Sundøy A. Results of faecal donor instillation therapy for recurrent Clostridium difficile associated diarrhoea. Scand J Infect Dis. 2010;42(11-12): 857-861. 105. Nieuwdorp M, van Nood E, Speelman P, et al. Treatment of recurrent Clostridium difficile-associated diarrhoea with a suspension of donor faeces. Ned Tijdschr Geneeskd. 2008; 152(35):1927-1932. 106. Flotterod O, Hopen G. Refractory Clostridium difficile infection. Untraditional treatment for antibiotic-induced colitis. Tidsskr Nor Laegeforen. 1991;111(11):1364-1365. 107. Jorup-Ronstrom C, Hakanson A, Sandell S, et al. Fecal transplant against relapsing Clostridium difficile-associated diarrhea in 32 patients. Scand J Gastroenterol. 2012;47(5):548-552. 108. Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplant via retention enema for refractory or recurrent Clostridium difficile infection. Arch Intern Med. 2012;172(2):191-193. 109. Shahinas D, Silverman M, Sittler T, et al. Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing. MBio. 2012;3(5):e00338-12. 110. Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol. 2010;8(5):471-473.

111. You DM, Franzos MA, Holman RP. Successful treatment of fulminant Clostridium difficile infection with fecal bacteriotherapy. Ann Intern Med. 2008;148(8):632-633. 112. Jorup-Ronstrom C, Hakanson A, Persson AK, Midtvedt T, Norin E. Feces culture successful therapy in Clostridium difficile diarrhea. Lakartidningen. 2006;103(46):3603-3605. 113. Gustafsson A, Berstad A, Lund-Tønnesen S, Midtvedt T, Norin E. The effect of faecal enema on five microflora-associated characteristics in patients with antibiotic-associated diarrhoea. Scand J Gastroenterol. 1999;34(6):580-586. 114. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet. 1989; 1(8648):1156-1160. 115. Schwan A, Sjo¨lin S, Trottestam U, et al. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet. 1983;2(8354):845. 116. Bowden TA Jr, Mansberger AR Jr, Lykins LE. Pseudomembraneous enterocolitis: mechanism of restoring floral homeostasis. Am Surg. 1981;47(4):178-183. 117. Fenton S, Stephenson D, Weder C. Pseudomembranous colitis associated with antibiotic therapy—an emerging entity. Can Med Assoc J. 1974;111(10):1110-1114. 118. Collins DC. Pseudomembranous enterocolitis. Further observations on the value of donor fecal enemata as an adjunct in the treatment of pseudomembranous enterocolitis. Am J Proctol. 1960;2:389-391. 119. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854-859. 120. Rubin TA, Gessert CE, Aas J, Bakken JS. Fecal microbiome transplantation for recurrent Clostridium difficile infection: report on a case series. Anaerobe. 2013;19:22-26. 121. Russell G, Kaplan J, Ferraro M, Michelow IC. Fecal bacteriotherapy for relapsing Clostridium difficile infection in a child: a proposed treatment protocol. Pediatrics. 2010;126(1):e239-e242. 122. MacConnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM. 2009;102(11):781-784. 123. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003;36(5): 580-585. 124. Lund-Tønnesen S, Berstad A, Schreiner A, Midtvedt T. Clostridium difficile-associated diarrhoea treated with homologous faeces. Tidsskr Nor Laegeforen. 1998;118(7):1027-1030. 125. Mattila E, Uusitalo-Seppala R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology. 2012; 142(3):490-496. 126. Nagy GG, Varvolgyi C, Paragh G. Successful treatment of life threatening, treatment resistant Clostridium difficile infection associated pseudomembranous colitis with faecal transplantation. Orv Hetil. 2012;153(52):2077-2083. 127. Kahn SA, Young S, Rubin DT. Colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection in a child. Am J Gastroenterol. 2012;107(12):1930-1931.

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015

10

Journal of Intensive Care Medicine

128. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107(7): 1079-1087. 129. Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107(5):761-767. 130. Gallegos-Orozco JF, Paskvan-Gawryletz CD, Gurudu SR, et al. Successful colonoscopic fecal transplant for severe acute Clostridium difficile pseudomembranous colitis. Rev Gastroenterol Mex. 2012;77(1):40-42. 131. Hellemans R, Naegels S, Holvoet J. Fecal transplantation for recurrent Clostridium difficile colitis, an underused treatment modality. Acta Gastroenterol Belg. 2009;72(2):269-270. 132. Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol. 2000; 95(11):3283-3285. 133. Harkonen N. Recurrent pseudomembranous colitis treated with the donor feces. Duodecim. 1996;112(19):1803-1804.

134. Paterson DL, Iredell J, Whitby M. Putting back the bugs: bacterial treatment relieves chronic diarrhoea. Med J Aust. 1994; 160(4):232-233. 135. Swaminath A. The power of poop: patients getting ahead of their doctors using self-administered fecal transplants. Am J Gastroenterol. 2014;109(5):777-778. 136. Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol. 2010;8(5):471-473. 137. Dutta SK, Girotra M, Garg S, et al. Efficacy of combined jejunal and colonic fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2014; 12(9):1572-156. 138. Weingarden AR, Hamilton MJ, Sadowsky MJ, Khoruts A. Resolution of severe Clostridium difficile infection following sequential fecal microbiota transplantation. J Clin Gastroenterol. 2013;47(8):735-737. 139. Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109(7): 1065-1071.

Downloaded from jic.sagepub.com at UNIVERSITE DE MONTREAL on July 11, 2015