Indy Rutks

Fecal Microbiota Transplantation for Clostridium difficile Infection: A Systematic Review

Key Summary Points Fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) is increasingly used, primarily for recurrent CDI but also for refractory CDI and treatment of the initial CDI episode. Although 35 studies of FMT for CDI were identified, only 2 were randomized, controlled trials (RCTs), with only 1 RCT having a non-FMT comparator group. Among the 36 patients who received FMT for recurrent CDI in the 2 RCTs, 27 (75%) had resolution of symptoms without recurrence. Among the 480 patients in 21 case-series studies who received FMT for recurrent CDI, 85% had resolution of symptoms without recurrence. Few studies reported on FMT for refractory CDI or for treatment of the initial CDI episode; among these, success rates were highly variable. Since its discovery as the cause of pseudomembranous colitis in 1978 (1, 2), Clostridium difficile has become an increasingly important pathogen. Initially largely confined to patients with health care exposure, C. difficile infection (CDI) now also affects persons with no or limited contact with the health care system (3). In 2013, the Centers for Disease Control and Prevention placed C. difficile into the top threat category (urgent) in its threat report on antimicrobial resistance (4). The high rate of recurrence15% to 30% of patients after their initial CDI episode and increasing thereafteris a major challenge (5, 6). Several treatment or recurrence episodes may result in repeated hospitalizations, clinic visits, deconditioning, malnourishment, and fecal incontinence. Antimicrobial treatment of recurrent disease yields success rates between 30% and 80%, depending on the number of recurrences and the agent and treatment duration selected (58). These suboptimal response rates have spurred investigation of additional treatment options, including fecal microbiota transplantation (FMT). Severe colonic microbiome (normal colonic bacteria) alterations are characteristic of CDI. Restoring the microbiome has been proposed to prevent recurrence, and probiotics are the most widely used intervention. However, probiotic microorganisms are less diverse than those of the organisms that characterize the colonic microbiome in healthy persons (9). Fecal microbiota transplantation is increasingly used as a treatment of recurrent CDI on the basis of the idea that importing the colonic microbiome of a healthy person is a simple method of reconstituting the normal colonic flora. Most FMT cases in the medical literature are from noncontrolled case-series studies (10). Reported success rates of up to 100% and the publication of a randomized, controlled trial (RCT) comparing FMT with antimicrobial treatment (11) have increased interest in FMT, even as regulations have evolved. The U.S. Food and Drug Administration currently requires an investigational new drug application for human studies of FMT but not for clinical use in treating CDI. The first reported use of FMT (delivered via enema) in medical literature was a small case-series study of hospitalized patients. Since then, various reports have described performing the procedure outside of the hospital, including at home by means of self-administered enema (12). Timing and frequency of FMT has also varied; most are administered in a single session, whereas others have relied on serial administration over several days. Several guidelines and reviews are available to help providers select appropriate patients for FMT, guide the selection and screening of stool donors, and choose from among the delivery methods (1315). The 2 most recent guidelines differ about the strength of evidence supporting FMTa European guideline stated that FMT is strongly recommended (A-I) after a second recurrence of CDI (13), whereas a guideline from the American College of Gastroenterology offered a more cautious recommendation, stating that if there is a third recurrence after a pulsed vancomycin regimen, fecal microbiota transplant (FMT) should be considered. (Conditional recommendation, moderate-quality evidence) (14). We did a systematic review of the evidence about the effectiveness of FMT for recurrent, refractory, and initial CDI and looked for evidence that effectiveness varied by method of transplantation. We also assessed harms of FMT and procedure acceptability. This report is derived from work done for a larger U.S. Department of Veterans Affairs Evidence-based Synthesis Program review. Methods Search Strategy We searched MEDLINE for articles published in English from 1980 to January 2015 that enrolled human participants and described FMT for known or suspected CDI (Appendix Table). We also searched the Cochrane Library and ClinialTrials.gov through January 2015. Our search included studies of any design, although we excluded case reports unless they reported harms. Additional articles, including some predating our search period or using nonstandard descriptors for CDI or FMT, were identified from hand-searching reference lists of existing systematic reviews and included studies as well as from suggestions by a technical expert panel. Appendix Table. Search Strategy Study Selection and Definitions Titles, abstracts, and articles were independently reviewed by 2 investigators, and disagreements were resolved by discussion and involvement of a third investigator, if needed. We considered initial CDI to be the first occurrence of CDI in a particular patient, recurrent CDI to be an episode occurring after previous treatment and favorable response for at least 1 previous episode, and refractory CDI to be an episode that did not respond to antimicrobial treatment. Data Abstraction and Quality Assessment Study characteristics, patient characteristics, and outcomes data were abstracted from included articles. Because all but 2 of the included studies were case-series studies, we did not formally assess quality but rather noted that conventional methods for rating strength of evidence would classify even well-conducted and reported case-series studies as high risk of bias (16). Therefore, strength of evidence would typically be considered insufficient or low. For the 2 RCTs, quality was assessed on the following criteria: allocation concealment, blinding, analysis approach, and description of withdrawalsa modification of the Cochrane approach to determining risk of bias (17). Our key outcomes included resolution of symptoms (primary outcome), time to resolution of symptoms, recurrence, all-cause mortality, and adverse events. We report results after a single administration of FMT or, in the case of studies that specified serial administration of FMT on successive days, a single prespecified series of administrations. In several studies, patients having recurrence were offered repeated FMT; these patients were categorized as having unsuccessful FMT because they met the recurrence outcome. Data Synthesis and Analysis Most findings are summarized narratively. Because the included studies report outcomes on small numbers of patients derived largely from case-series studies, any pooled estimate of the effect size and a surrounding CI was considered to be of questionable validity. Therefore, we report descriptive summaries of each included study and an overall percentage of patients remaining free of recurrent CDI. Role of the Funding Source This review was funded by the U.S. Department of Veterans Affairs. The funding source had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Members of a technical expert panel and peer reviewers of the evidence report provided advice and feedback. Technical expert panel members and peer reviewers were not compensated for their contributions. Results Our literature search yielded 190 abstracts or titles. We excluded 129 articles after abstract review and performed full-text reviews of 61 articles; of those, we excluded 51, leaving 10 articles. From hand-searching reference lists of systematic reviews and included studies and suggestions from technical expert panel members, we identified another 25 articles for a total of 35 included studies: 2 RCTs, 28 case-series studies, and 5 case reports (Figure). Figure. Summary of evidence search and selection. CDI = Clostridium difficile infection; FMT = fecal microbiota transplantation; RCT = randomized, controlled trial. * Included 1 RCT. FMT for Recurrent CDI Data From RCTs Two small RCTs with moderate risk of bias (11, 18) reported use of FMT for patients with recurrent CDI. The first compared FMT using a nasoduodenal tube with 2 control groups (43 patients; 1 withdrew after random assignment); 81% of FMT patients achieved resolution of symptoms within 3 months compared with 31% and 23% for the vancomycin and vancomycin-plus-bowel lavage control groups, respectively (P < 0.001 for FMT vs. both control groups) (11). The study, which we rated as moderate quality, was unblinded and done in the Netherlands. It was terminated after the investigators saw extremely low response rates in the control groups, which differed substantially from the 60% rate used for calculations of sample sizes. Patients had a mean age of 70 years, and 58% were men. Previous CDI episodes were numbered from 1 to 9. Administration of FMT was done after 4 to 5 days of oral vancomycin (500 mg 4 times daily), whereas the control groups received the same dose of vancomycin for 14 days. The second RCT compared 2 FMT treatment approaches, nasogastric tube and colonoscopy, in 20 patients. Overall, 70% of patients had resolution of symptoms; the difference between treatment approaches was not significant (60% in the nasogastric tube group and 80% in the colonoscopy group; P= 0.63) (18). This moderate-quality study was unblinded, did not include a non-FMT control group, and was done in the United States. The patients in this trial were

Review: Serenoa repens does not improve symptom scale scores in benign prostatic hyperplasia

Source Citation Tacklind J, MacDonald R, Rutks I, Stanke JU, Wilt TJ. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2012;(12):CD001423. 23235581