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Clostridium Difficile Research Papers

Abstract

Clostridium difficile infection (CDI) is a gastrointestinal disease believed to be causally related to perturbations to the intestinal microbiota. When standard treatment has failed, intestinal microbiota transplantation (IMT) is an alternative therapy for patients with CDI. IMT involves infusing intestinal microorganisms (in a suspension of healthy donor stool) into the intestine of a sick patient to restore the microbiota. However, protocols and reported efficacy for IMT vary. We conducted a systematic literature review of IMT treatment for recurrent CDI and pseudomembranous colitis. In 317 patients treated across 27 case series and reports, IMT was highly effective, showing disease resolution in 92% of cases. Effectiveness varied by route of instillation, relationship to stool donor, volume of IMT given, and treatment before infusion. Death and adverse events were uncommon. These findings can guide physicians interested in implementing the procedure until better designed studies are conducted to confirm best practices.

Clostridium difficile infection (CDI) is a gastrointestinal disease believed to be causally related to perturbations to the intestinal microbiota [1]. The term microbiota refers to the community of microorganisms that inhabit a particular region of the body [2]. In the human gut, there are ∼300–500 species of microorganisms (intestinal microbiota), with roughly 1012 bacterial cells per gram of stool [3]. These organisms aid in several functions, including digestion of complex carbohydrates, energy storage, immune functions, and protection against invasion by pathogens [3]. Existing evidence shows that certain classes of antimicrobials have profound effects on the intestinal microbiota [4]. The widely accepted model for C. difficile pathogenesis is that the use of broad spectrum antimicrobials alters the balance of the intestinal microbiota, allowing pathogenic strains of C. difficile to infect the intestine [1–3].

Primary episodes of CDI are treated with metronidazole or vancomycin after cessation of the antibiotic believed to be related to the infection [4], and up to 35% of patients treated experience a recurrence of symptoms after initial improvement [5, 6]. Up to 65% of these patients develop a chronic recurrent pattern of disease (recurrent CDI) [1, 5]. Recurrent CDI is typically treated using a tapered (31% recurrence rate) or pulsed (14% recurrence rate) regimen of metronidazole or vancomycin [4, 5]. Given the poor treatment outcomes for CDI, especially recurrent CDI, it is not surprising that investigation of treatment alternatives has continued over several decades [2, 4, 7–9].

One potential alternative to standard therapy is the use of indigenous intestinal microorganisms from a healthy donor (via infusion of a liquid suspension of stool) to restore the intestinal microbiota of a diseased individual. First documented in humans in 1958 [10], fecal bacteriotherapy, also called intestinal microbiota transplantation (IMT), may be a useful treatment for CDI through restoration of the intestinal microbiota [5]. IMT has not been widely adopted as a therapeutic tool probably due to concerns regarding safety and acceptability [11]. Despite these concerns, the procedure has been performed in a growing number of patients throughout the world. In addition to treating CDI, IMT has also been used to treat pseudomembranous colitis (PMC), believed to be caused by C. difficile toxins, inflammatory bowel disease and irritable bowel syndrome (IBS), 2 diseases also believed to be causally related to the intestinal microbiota [1].

IMT protocols vary with regard to the quantity of donor stool used, preparation of recipients, methods for infusion of donor stool, and measurement of outcomes. To our knowledge, 4 publications have reviewed the literature on the use of this procedure [1, 6, 12, 13], but none were systematic reviews. Additionally, we know of only 1 randomized controlled trial (RCT) currently underway to test the efficacy of IMT in the treatment of CDI [12]. To summarize the literature on the use of IMT and provide direction for future investigations of this still poorly understood intervention, we conducted a systematic review of fecal transplantation in humans as therapy for CDI and PMC.

METHODS

Search Strategy and Selection Criteria

We searched Medline, Embase, and Biosis through Ovid (up to 15 April 2011) for publications, in any language, documenting the infusion of stool from a healthy human donor, into an unhealthy human subject, as treatment for a specified medical condition (Supplementary Appendix 1, online only). Publications of any type were included if they reported original data from such a procedure for CDI or PMC treatment. Bibliographies of all identified reviews [1, 5–8, 12–16] and original research publications were hand searched for additional studies. We also searched Current Contents, Conference Papers Index, Papersfirst, and Web of Science for conference proceedings and abstracts that may not have been indexed in these 3 databases. Terms from the Ovid search were used as keywords with no limits, as shown in Supplementary Appendix 2, online only. All search strings were developed with the assistance of a qualified librarian.

Two investigators (E. G. and H. S.) independently assessed titles and abstracts for eligible publications. If eligibility could not be determined, the full article was retrieved. Publications that did not report original data on the outcome of the IMT procedure, reports describing the use of a cultured bacterial suspension rather than human feces, interviews, and reviews were excluded.

Data Abstraction and Analysis

Once eligibility was determined, 2 reviewers (E. G. and H. S.) independently abstracted data from selected publications using a standardized pretested form. Discrepancies were corrected by consensus. Data from non–English-language publications were simultaneously extracted by 2 reviewers (A. R. M. and Kerstin Tiedemann). The following information was retrieved: number of patients, patient characteristics (average age, number of men), transplantation procedures (patient preparation, choice of donor, dosage, number of infusions, route of instillation, retreatments offered if treatment failed, duration of follow-up, outcomes (death, treatment failure, resolution, relapse), and adverse events. Study period, country, and study design were also abstracted. Three investigators were emailed for unpublished data [17, 18] (Thomas Moore unpublished data). One did not respond [17], and data were no longer available from another [18]. When multiple publications reported on the same patients [18–24], we analyzed the most recent and complete data [18, 20, 24].

Data of interest were often not reported. Agreement between independent reviewers on availability of data, and data abstracted, were computed for 10 key variables using a κ statistic. Data were summarized using Stata software (version 11.0; StataCorp).

Operational Definitions

The following operational definitions were used to standardize data abstraction. A failure was defined as the continued occurrence of clinical illness during (1) the period of follow-up subsequent to transplantation but before retreatment or (2) during the period of follow-up subsequent to retreatment. Resolution was defined as either complete cessation of clinical symptoms or diagnostic confirmation of the absence of disease, during the period of follow-up after transplantation. When multiple infusions were not given as part of a retreatment for failure, they were counted as part of a single treatment. Resolution after 1 treatment was therefore counted separately from resolution after retreatment due to failure. A relapse was defined as resolution, with subsequent return of signs and symptoms during the follow-up period, and was counted only among patients with resolution. Deaths were recorded as due to the illness or not, as reported by the authors. Studies varied in the reporting of the IMT dosage given to patients. To make use of all available information related to the amount of donor stool patients were exposed to in a single infusion, stool weight was defined as the quantity (in grams) of donor stool used to make the IMT suspension, and suspension volume was defined as the volume (in milliliters) of the IMT suspension infused. Number ofinfusions was defined as the number of times donor stool was infused, not including retreatments when treatment failed.

RESULTS

Literature Review

The electronic search identified 2054 titles. All titles and abstracts were reviewed. Of the 66 reports selected for full review, 28 were excluded based on eligibility criteria [1, 4–8, 11–16, 25–40] (Figure 1). An additional 11 titles were excluded because they did not report treatment for CDI or PMC [41–44], reported data from the same subjects as more recent reports [19, 21–23], did not report data on key variables of interest [45], did not report data disaggregated by diagnosis [46], or could not be translated [47] (Figure 1).

Figure 1.

Flow diagram of study selection. aThe 27 unique publications provided 28 abstractions. CDI, Clostridium difficile infection; IMT, intestinal microbiota transplantation; PMC, pseudomembranous colitis.

Figure 1.

Flow diagram of study selection. aThe 27 unique publications provided 28 abstractions. CDI, Clostridium difficile infection; IMT, intestinal microbiota transplantation; PMC, pseudomembranous colitis.

Characteristics of Included Reports

In total, 27 unique reports were included in the analysis [10, 17, 18, 20, 24, 48–68] (Thomas Moore, unpublished data) (Table 1). One article provided 2 abstractions [50] resulting in 28 observations for analysis. Agreement among reviewers on availability of data and data abstracted was high (median κ value, 0.91 and 0.8, respectively). The majority of reports were journal articles (70%); followed by letters (15%), abstracts (12%), and unpublished data (3%). Two-thirds (67%) were case series; the remainder were case reports (data not shown). Periods of data collection spanned 1957–1958 to 2001–2011, providing data on 317 patients (Table 1) from 8 countries. The average patient age was 53 years (range, 2–95 years), and 39% of patients were male. Follow-up ranged from 36 hours to 5 years. In all studies, patients had diagnoses of recurrent or relapsing CDI (91%) or PMC (9%) (Table 1).

Table 1.

Summary of Case Series and Reports of Intestinal Microbiota Transplantation

Reference Years of data collection Diagnosis No. of patients Patients with resolution, no. (%)aAge, mean (range), y Duration of follow-up, mean (range) Stool, g/suspension volume, mL Infusions per treatment Donor relationship (no. of patients) Instillation method (no. of patients) 
Schwan et al [20] 1977–1983 CDI 1 (100.0) 67 1 y NR/450 Enema 
Tvede et al [48] NR CDI 1 (50.0) 60 (59–60) 12 mo 50/500 H (1), D (1) Enema 
Flotterod et al [49] 1982–1985 CDI 1 (100.0) 64 NR 10/NR Duodenal endoscope 
Paterson et al [50] NR CDI 1 (100.0) 39 2 y 200/200 Enema 
Paterson et al [50] NR CDI 6 (100.0) 56 (30–80) NR NR/NR NR Enema 
Lund-Tonnesen et al [18] 1995–1996 CDI 18 15 (83.3) 64 (27–89) 18 mob5–10/NR NR UR Colonoscope 
Persky et al [51] NR CDI 1 (100.0) 60 5 y NR/500 NR Colonoscope 
Borody et al [452] NR CDI/IBD 6 (100.0) NR (11–59) 8 wk 200–300/200–300 1–14 Enema 
Aas et al [53] 1994–2002 CDI 18 

Excerpt

Clostridium difficile infection (CDI) is a serious healthcare-associated infection and a growing health care problem, especially with the emergence of more virulent strains in the early 2000s. CDI is now the most common cause of nosocomial infectious diarrhea and is increasing in incidence and, in all likelihood, severity.

A comparative effectiveness review (CER) was prepared by the Minnesota Evidence-based Practice Center (EPC) on Comparative Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection (December 2011). The purpose of the CER was to provide an overarching assessment of the evidence for comparing the accuracy of diagnostic tests and the effectiveness of prevention and treatment interventions on initial and recurrent CDI-related patient outcomes in adults.

Limited high-quality evidence was available to support the diagnostic, preventive, and treatment practices for CDI carried out by providers in hospital, long-term care, and outpatient settings. Inconsistency in definitions of diarrhea, severity, resolution of symptoms, recurrence, or cure contributed to the difficulty in drawing conclusions from the evidence. There were a number of important evidence gaps identified in the CER. The objective of this Future Research Needs project was to systematically prioritize evidence gaps on prevention and treatment of CDI, and to develop a list of research questions to address the prioritized gaps. Although different diagnostic methods for toxigenic Clostridium difficile were evaluated in the CER, diagnostic methods were not included in this project primarily because polymerase chain reaction testing is rapidly becoming the standard diagnostic test for the infection.

This report is based on research conducted by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center (EPC) under contract to the Agency for healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10058-I). The findings and conclusions in this document are those of the author(s), who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help health care researchers and funders of research make well-informed decisions in designing and funding research and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of scientific judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical research and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances.

None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report.

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