Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial

Clinical Infectious Diseases, Jan 2017

Background. Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI.

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Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial

Fecal Transplant vs Vancomycin Taper • CID Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial Susy S. Hota () 0 4 5 10 Valerie Sales 0 3 4 10 George Tomlinson 0 9 10 Mary Jane Salpeter 0 5 8 Allison McGeer 0 4 7 12 Bryan Coburn 0 4 10 11 David S. Guttman 0 2 6 Donald E. Low 0 1 4 7 12 Susan M. Poutanen 0 4 7 12 0 Received 18 May 2016; editorial decision 8 September 2016; accepted 31 October 2016; published online November 9, 2016 1 D. E. L. passed away and is posthumously included as an author in recognition of his signif- icant contribution to this study. 103, Toronto General Hospital , 200 Elizabeth St, Toronto, ON M5G 2C4 , Canada 2 Centre for the Analysis of Genome Evolution and Function, University of Toronto , Toronto , Canada 3 Department of Medicine, Markham-Stouffville Hospital , Markham 4 Department of Medicine, University of Toronto 5 Department of Infection Prevention and Control, University Health Network , Toronto 6 Department of Cell and Systems Biology, University of Toronto 7 Department of Microbiology, University Health Network/Sinai Health System 8 Department of Anaesthesia, University Health Network 9 Institute of Health Policy, Management and Evaluation and Dalla Lana School of Public Health, University of Toronto 10 Department of Medicine, University Health Network 11 Toronto General Research Institute, University Health Network 12 Department of Laboratory Medicine and Pathobiology, University of Toronto (See the Editorial Commentary by Johnson and Gerding on pages 272-4.) Background. Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI. Methods. In a phase 2/3, single-center, open-label trial, participants from Ontario, Canada, experiencing recurrence of CDI were randomly assigned in a 1:1 ratio to 14 days of oral vancomycin treatment followed by a single 500-mL FT by enema, or a 6-week taper of oral vancomycin. Patients with significant immunocompromise, history of fulminant CDI, or irreversible bleeding disorders were excluded. The primary endpoint was CDI recurrence within 120 days. Microbiota analysis was performed on fecal filtrate from donors and stool samples from FT recipients, as available. Results. The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon. Conclusions. In patients experiencing an acute episode of recurrent CDI, a single FT by enema was not significantly different from oral vancomycin taper in reducing recurrent CDI. Further research is needed to explore optimal donor selection, FT preparation, route, timing, and number of administrations. Clinical Trials Registration. NCT01226992. - regimen of oral vancomycin over 6–8 weeks [3, 4]. However, as an antibiotic, vancomycin may perpetuate the problem by further interfering with the intestinal microbiota. Moreover, the effectiveness of tapering vancomycin is poorly understood. Fecal transplantation (FT), the introduction of feces from a healthy donor into the intestinal tract of someone with disrupted microbiota, is a promising salvage therapy for RCDI. Multiple systematic reviews of largely uncontrolled, heterogeneous studies, have reported success rates of 80%–93% for RCDI [5–9]. Five randomized trials have shown symptom resolution in 70%–94%; however, none of these studies compared FT to standard of care treatment and not all evaluated FT for treatment of active episodes of RCDI [10–14]. Therefore, the true effectiveness of FT, as compared to current standard of care, for treatment of an acute episode of RCDI remains uncertain. Furthermore, FTs are being manufactured and performed with considerable variability and some of these factors may affect outcome [15]. Consequently, best practice guidelines, specialist groups, and regulatory bodies have both endorsed and cautioned clinicians about FT [3, 4, 16–20]. With the hypothesis that FT was superior to oral vancomycin taper, we conducted a randomized controlled trial (RCT) comparing the effectiveness of 14 days of oral vancomycin followed by a single FT by enema with standard of care treatment, a 6-week taper of oral vancomycin, in patients experiencing an acute episode of RCDI. Design and Participants We conducted a phase 2/3, single-site, open-label RCT comparing 14 days of oral vancomycin followed by a single fecal transplant (FT) by enema with 6 weeks of oral vancomycin taper in adult patients experiencing an acute episode of RCDI. FT was performed using fresh donations from screened, healthy donors identified by the recipients. Research ethics board and Health Canada approvals were obtained. A data and safety monitoring committee monitored the trial. Participants were recruited in Ontario, Canada. Consenting adult (≥18 years of age) patients were included if they had a history of at least 2 episodes of laboratory or pathology-confirmed CDI, and had received at least one course of oral vancomycin (minimum 10  days of 500  mg total daily dose). Symptoms of CDI were self-reported and confirmed by study physicians to meet standard epidemiologic definitions of diarrhea [21]. Enzymatic immunoassay (EIA) for C. difficile toxin or polymerase chain reaction (PCR) for C. difficile toxin gene was accepted for laboratory confirmation. Exclusions included neutropenia, graft-vs-host disease, or other severe immunocompromised states; CDI requiring intensive care unit admission; evidence of active, severe colitis unresponsive to oral vancomycin; hypersensitivity or intolerance to oral vancomycin; chronic gastrointestinal diseases that may cause diarrhea; planned therapy in the next 120 days that may cause diarrhea (eg, chemotherapy); planned surgery requiring perioperative antibiotics within 120  days; pregnancy; significant bleeding disorder; or inability to tolerate FT procedure. Consenting adult (≥18  years age) potential donors were screened using a self-screening questionnaire of behaviors associated with risk for blood-borne pathogens, study physician assessment, and blood and stool testing for potentially transmissible infections. Donor screening occurred after randomization of a participant to FT and within 2 weeks of FT. Donor exclusion criteria (see Supplementary Methods 1) and screening were developed in consultation with Health Canada. Procedures Upon recurrence of CDI, participants were randomized at a 1:1 ratio to either intervention. Investigators and participants were not blinded to interventions as it would be impractical due to FT odor, and sham enemas were not endorsed by the research ethics board due to unnecessary potential risk. For vancomycin taper, participants received 14 days of vancomycin 125 mg orally every 6 hours followed by a taper over 4 weeks: vancomycin 125 mg orally every 12 hours for 1 week; then, vancomycin 125  mg orally every 24 hours for 1 week; then, vancomycin 125 mg orally every second day for 1 week; then, vancomycin 125 mg orally every third day for 1 week. Patients randomized to FT received 14 days of oral vancomycin 125 mg every 6 hours followed by one FT by enema, 48 hours after stopping vancomycin. Donors provided stool from their most recent bowel movement, no more than 48 hours before FT. Fifty grams of donated feces was homogenized with 500  mL of normal saline in a Stomacher Lab Blender using a sterile 330-µm microfilter-separated double compartment polyethylene bag. Five hundred milliliters of fecal filtrate was transferred to an enema bag and delivered immediately to the patient over 10–30 minutes. These proportions were selected based on published methodologies for FT at the time of study design [22–24]. The manufacturing of FT was validated for viability of aerobes and anaerobes using semiquantitative culture [25]. Participants were followed for 120  days. For vancomycin taper, day 0 was the first day of the 4-week taper whereas for FT, day 0 was the day of FT. Participants reported by telephone and submitted stools for testing if diarrhea occurred between days 0 and 120. Stools were also requested for microbiota analysis at baseline, day 7, and day 120. Two study visits (at days 7 and 120) and 4 telephone visits (at days 4, 21, 42, and 84)  evaluated possible CDI recurrence and adverse events. Participants who experienced RCDI were offered crossover to the alternative study treatment and followed for an additional 120 days. Outcomes The primary outcome was recurrence of symptomatic, laboratory-confirmed CDI within 120  days of the intervention, using criteria outlined in the inclusion criteria. Safety outcomes included solicited adverse events at days 4 and 7; unsolicited adverse events within 14  days of interventions; serious adverse events throughout follow-up; mortality attributable to CDI during follow-up; and all-cause mortality throughout follow-up. Other secondary outcomes included recurrence of CDI symptoms within 14 and 120 days (not laboratory-confirmed); recurrence of CDI within 120  days of crossover; days of diarrhea in the 120 days of follow-up; and CDI requiring hospital admission. Standardized questionnaires were used to assess for symptoms of RCDI and adverse events. Fecal Microbiota Analysis Fecal microbiota analysis was performed retrospectively on frozen fecal filtrate from 19 donors and stool from 3 recipients with successful outcomes (baseline; 7  days post-FT; 16 weeks post-FT, as available). DNA was extracted using PowerSoil DNA Isolation Kit (Mo Bio Laboratories, Carlsbad, California). The V4 hypervariable region of the 16S rRNA locus was interrogated using the V4-515F and V4-806R primers [26] and analyzed with QIIME [27]. Diversity indices were compared using Student t test (Supplementary Methods 2). Statistical Analyses Using a 2-sided test for comparison of 2 independent proportions, and assuming 8% recurrence in the FT group [22], 30% recurrence in the vancomycin arm [28], 80% power, and α of .05, we required 57 participants per intervention (114 participants total). Assuming 20% attrition over follow-up, 138 participants were required for randomization. We planned an interim analysis for safety and feasibility after the completion of the first 30 participants. The trial was stopped at the interim analysis and a futility analysis based on the primary outcome was added using a Bayesian approach [29]. The primary analysis was per protocol and secondary analysis was intention to treat. For the primary outcome, we calculated the posterior distribution of the risk difference and the probability that the absolute risk reduction exceeded several clinically important thresholds (any reduction, >10%, and >20%). All Bayesian analyses used uniform priors on proportions. Analyses of safety and secondary outcomes were descriptive. All analyses were done using R 3.2.1 [30]. Between January 2011 and July 2014, 140 patients were assessed for eligibility (Figure 1). Forty were ineligible on prescreening and 19 declined participation, primarily due to unwillingness to be randomized. Of the 81 consented patients, 3 met exclusion criteria and 48 (59.2%) did not experience recurrence of symptomatic, laboratory-confirmed CDI over the study period, which was required for randomization. Of these 48 patients, 2 experienced diarrhea not meeting case definition and 6 experienced self-limited diarrhea meeting case definition but with negative C.  difficile laboratory tests. Thirty patients were randomized: 14 to vancomycin taper and 16 to FT. Two patients in the vancomycin taper group withdrew—one to seek FT elsewhere and another due to repeated protocol noncompliance. Thus, 12 patients in the vancomycin taper arm and 16 in the FT arm were included in the interim analysis. Baseline characteristics were similar in both randomization groups (Table 1). Most randomized patients were women and had a history of 4–5 episodes (range, 2–9) of CDI prior to entering the trial. Thirteen (13/16) of the FT and 10 of 12 of the vancomycin taper patients had failed at least one vancomycin taper prior to enrollment. In comparison to those randomized, patients who were not randomized because they did not have an episode of RCDI were younger, had fewer recurrences, and had lower mean Charlson comorbidity scores. In the FT group, 10 of 16 participants retained at least 80% (400 cc) of the enema. Of 18 donors screened, 2 were excluded on the basis of stool and blood testing. Most donors were male (12/16) with a mean age of 50 years. Eleven (11/16) were blood relatives of the recipient and 4 (4/16) lived within the same household as the recipient at the time of donation. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence, corresponding with resolution of symptoms in 43.8% and 58.3%, respectively (Figure  2). Recurrence occurred a median of 9 days after FT treatment and 35 days after initiating vancomycin tapering (7 days after completing the vancomycin taper). There was no association between donor relatedness or shared household and FT recipient recurrence. Four of the 5 patients who failed vancomycin taper crossed over to FT. All 4 experienced recurrence of symptoms after FT. All patients who failed FT subsequently withdrew. Figure 3 shows the per-protocol absolute risk reduction estimates for CDI recurrence with FT. Although the initial plan was for intention-to-treat analysis, given the small number of participants, the 2 patients in the vancomycin group who did not complete the trial were excluded. The Bayesian 95% interval for the change in risk of CDI recurrence with FT ranged from a 2.8% reduction to a 47.3% increase. There was a posterior probability of 22.2% that the FT reduced recurrences at all and only a 2.8% probability that risk was reduced by 20% or more. The futility analysis found that if the planned total of 57 patients were randomized to each treatment group, given the current data, there was only a 3.4% probability of finding a significant benefit for FT, defined as the upper end of the onesided Bayesian 95% interval for the risk reduction lying below 0. Results of the futility analysis did not change using intention to treat. In the early period (days 0–7), abdominal pain, tenderness, and bloating were equally prevalent in the FT and vancomycin groups (Table 2). In the later period (after 7 days), abdominal pain, tenderness, bloating, mucoid stools, and smelly stools were reported more frequently in the vancomycin group. Four serious adverse events were reported in 3 patients. None was deemed related to the study interventions. One patient in the vancomycin taper group was hospitalized with fever and a urinary tract infection. One FT patient was hospitalized with anasarca and was diagnosed with end-stage liver disease. Another FT patient experienced a perforated bowel secondary to diverticulitis 35 days after FT. This patient had a longstanding history of diverticulitis; upon review with the most responsible physicians, it was decided that the FT was unlikely to be related to the perforation. No study participant experienced recurrence of CDI symptoms without laboratory confirmation within 14  days or 120 days of treatment. Patients who underwent FT experienced Nonrandomizedb (n = 48) Characteristic Any previous vancomycin taper No. of previous vancomycin tapers No. of previous hospital admissions for CDI Charlson comorbidity index score Immunosuppressiond Other antibiotic use within 3 mo of enrollment Proton pump inhibitor usee Figure  2. Cumulative incidence of Clostridium difficile infection recurrence by treatment group over 120  days. Day 0 indicates day of fecal transplant for fecal transplant group and first day of tapering protocol for vancomycin taper group. Although follow-up continued for 120  days, the y-axis ends at 60  days as there were no recurrences beyond this timepoint. a mean of 0.8 (SD, 0.8) days of diarrhea in follow-up, compared with 1.7 (SD, .4) days in the vancomycin taper group. No patients developed CDI requiring hospital admission or died. Fecal microbiota composition and diversity of 19 FT donors were consistently high, with no significant difference between Figure 3. Per-protocol analysis of absolute risk reduction of Clostridium difficile infection recurrence with fecal transplantation. Abbreviation: P (ARR), probability of absolute risk reduction. Table 2. Early and Late Adverse Events in Patients Randomized to Fecal Transplantation and Vancomycin Tapera Abdominal Early Events FT (n = 16) 1 (6.2) 4 (25.0) Late Eventsb Abbreviations: FT, fecal transplantation; VT, vancomycin taper. a Expressed as No. of reported events with percentage in brackets; early events were from days 0–7 and late events were days 7–14. b Five of the 16 patients originally randomized to FT recurred within 7 days of intervention and therefore are not included in the measurement of late adverse events. those associated with FT success and FT failure (Supplementary Figure). In 3 successful FT recipients, we demonstrated increased fecal microbiota diversity post-FT. In this trial evaluating treatment of an acute episode of RCDI, a single FT using fresh donor stools administered by enema after 14 days oral vancomycin therapy had comparable effectiveness to 6 weeks of tapered oral vancomycin, with resolution of CDI in 43.8% and 58.3% in each group, respectively. Our trial was stopped after randomization of 30 patients, on the basis of futility. FT has been widely reported as 80%–93% effective at curing RCDI [5–14]. These high success rates are derived from studies with various limitations. Most FT studies reporting effectiveness >90% are observational and methodologically heterogeneous. One RCT was stopped early, reporting 81% resolution after a single FT by nasojejunal administration, compared with 31% after 2 weeks of oral vancomycin [10]. Two weeks of oral vancomycin is associated with a higher failure rate than vancomycin taper [28], possibly contributing to the trial’s early termination. A second RCT of FT by colonoscopy stopped early for effectiveness, but it too used a comparator that was not standard of care [11]. A small randomized trial of FT by nasogastric route vs colonoscopy using a frozen inoculum reported overall CDI resolution in 90% of 20 treated patients [12]. In another randomized trial, clinical resolution occurred in 70.3% and 75% of patients randomized to fresh and frozen FT by enema, respectively (n = 219) [13]. These latter 2 studies included RCDI patients on suppressive antibiotic therapy rather than those experiencing acute recurrence. Without a control arm in either trial, it is not known what proportion of patients would have been symptom-free had their antibiotics been simply discontinued. A multicenter, double-blind randomized trial found 90.9% clinical cure in acute and chronic RCDI patients receiving donor FT compared with 62.5% in those receiving autologous FT by colonoscopy [14]. However, at one site, 90% of patients receiving autologous FT reported clinical cure, highlighting the high proportion of patients labeled as RCDI who may become symptom-free upon discontinuation of vancomycin suppressive therapy. In the aforementioned studies, multiple administrations of FT were often required to achieve resolution of CDI symptoms [5, 6, 10, 13]. Single administration of FT resulted in lower resolution of CDI: 62%, 65%, and 70% in 3 randomized trials [11– 13]. The 43.8% resolution of RCDI from a single FT observed in our study is therefore in line with previous reports. The timing of FT, patient pretreatment, patient and donor selection, FT manufacturing, route of administration, and duration of follow-up also likely have an impact on outcomes of FT [15]. We randomized patients once they experienced an acute recurrence of CDI and not during symptom-free intervals, thereby ensuring we compared patients at the same point in their disease course. Our patients were typical for those in whom FT would be considered in most jurisdictions. We based our protocols for donor feces collection, delivery, and manufacturing on published literature and an internal laboratory validation study. We demonstrated increased microbiota diversity post-FT in 3 recipients. Enema route was chosen for delivery as it was supported by data, practical, inexpensive, and well-accepted by patients [22]. Although FT may also be administered by colonoscopy or nasojejunal tube, to date, there are no definitive data demonstrating superiority of one route of administration over another [5–9, 12]. Finally, we included a long follow-up of 120 days to capture treatment failures. We pretreated FT patients with 14 days of oral vancomycin, which may have negatively impacted the intestinal microbiota such that a single FT was not sufficient for flora reconstitution. Vancomycin was discontinued 48 hours prior to FT. Subsequent data demonstrate that vancomycin remains detectable in feces for 4–5  days after discontinuation of therapy, potentially impacting the microbiota of the FT [31]. The ideal approach to donor selection has yet to be defined. We did not attempt to match our donors to recipients in any way. We demonstrated high microbiota diversity in our donor pool, regardless of recipient relatedness, shared household, or recipient outcome. We present valuable data on the effectiveness of a 6-week oral vancomycin taper, the current standard of care treatment for multiple recurrences of CDI. Vancomycin taper resulted in recurrence in 41.7% of our patients. This proportion is higher than the 0–30% recurrence rate reported in 2 older observational studies upon which current treatment recommendations are based [28, 32]. We noted that 59% of enrolled patients never experienced recurrence of disease and were therefore not randomized, despite prior histories of several CDI recurrences. Seventeen percent (8/48) of these patients experienced symptoms suggestive of postinfectious irritable bowel disease such as self-limited loose stools. As clinical features of RCDI in FT studies are often self-reported and may not be corroborated by medical assessment or laboratory confirmation, it is possible that postinfectious irritable bowel syndrome is confounding the true estimates of recurrence in some studies. Indeed, others have reported similar observations [14, 33]. A limitation of our study is the small number of randomized patients. Furthermore, our patients received FT as outpatients, so these results cannot be extrapolated to the more acutely ill. Finally, we were unable to perform a blinded study. We show a similar recurrence rate in RCDI patients treated with 14  days of oral vancomycin followed by single FT by enema compared with oral vancomycin taper. These data should be taken into consideration in CDI treatment guidelines and in the design of FT programs. More research is needed to optimize FT methodologies—specifically, donor selection, FT manufacturing, timing, route, and number of administrations. Notes Acknowledgments. We thank Michael Gardam, MD, MSc, for his support. Author contributions. S. S. H was the principal investigator for the trial. She designed the RCT, carried out the research as primary clinical study physician, oversaw conduct of the research, wrote the manuscript, and submitted it for publication. V. S., A. M., D. E. L., and S. M. P. contributed to the study design and interpretation of results. V. S. and S. M. P. assisted with patient recruitment and evaluations. S. M. P. also oversaw the laboratory aspects of FT manufacturing. G. T. performed the statistical analysis and assisted with interpretation of results. M J. S. assisted with patient assessments, collected study data, and coordinated the study. B.  C.  and D.  G.  performed intestinal microbiota sequencing and analysis and participated in interpretation of results in the context of clinical findings. All authors (excepting D. E. L.) contributed to manuscript preparation and approved the final draft. D.  E. L. is recognized posthumously for his contribution to this research. Financial support. This work was supported by the Physicians Services Incorporated Foundation (grant number PSI 10-2021); Public Health Ontario; University of Toronto Department of Medicine Integrating Challenge Grant; University Health Network; and Sinai Health System (in kind). Potential conflicts of interest. S.  S. H.  has received a grant and honoraria from serving as a consultant and on the advisory board of Cubist (Merck) Pharmaceuticals. A. M. has received honoraria for advisory board participation for Cubist (Merck), and has received research funding from GlaxoSmithKline and Merck. S.  M. 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Susy S. Hota, Valerie Sales, George Tomlinson, Mary Jane Salpeter, Allison McGeer, Bryan Coburn, David S. Guttman, Donald E. Low, Susan M. Poutanen. Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial, Clinical Infectious Diseases, 2017, 265-271, DOI: 10.1093/cid/ciw731