Vancomycin Taper and Risk of Failure of Fecal Microbiota Transplantation in Patients With Recurrent Clostridium difficile Infection

Abstract

We retrospectively analyzed a cohort of 109 subjects treated for recurrent Clostridium difficile infection with fecal microbiota transplantation (FMT) at a tertiary referral center between 2011 and 2014 to determine risk factors for FMT failure. In a multivariate analysis, failure to use an oral vancomycin taper preceding FMT was associated with a significant risk of FMT failure (odds ratio, 0.15; 95% confidence interval, .007–.40).

Recurrent Clostridium difficile infection (rCDI) occurs in 15%–45% of patients and contributes to the reservoir for new infections [1, 2]. The optimal strategy to manage these recurrences remains unknown. Recent studies suggest that fecal microbiota transplantation (FMT) may be the most effective therapy for rCDI, with effectiveness approaching 90% [1, 3–5]. However, in some cases, FMT is ineffective and the reason for this is poorly understood. To better define the risk factors for FMT failure, we conducted a retrospective cohort study, comparing FMT successes with FMT failures.

MATERIALS AND METHODS

The FMT program for patients with refractory CDI or rCDI started January 2011. Data have been collected prospectively on all FMT recipients. To determine the risk factors for rCDI following FMT, we conducted a retrospective study of patients who underwent FMT from 28 January 2011 through 9 December 2014, comparing those who were successful vs those whose infection recurred following FMT. The study was approved by the Mayo Clinic Institutional Review Board. The eligibility criteria for FMT were as follows:

• 1. Refractory disease: unresponsive to standard therapy.

  • a. Failure defined as persistent diarrhea, abdominal pain, leukocytosis >15000 cells/μL, or leukopenia <2000 cells/μL or colitis after 5 days of appropriate therapy such as high-dose vancomycin (2 g/day) or vancomycin followed by rifaximin or fidaxomicin followed by any other regimen.

  • b. Determine suitability for colonoscopy vs alternative delivery of fecal transplant via upper endoscopy, nasogastric tube, nasojejunal tube, pouchoscopy, or enema, etc.

OR

• 2. Recurrent disease: 2 failed treatments and on the third round of medication and 2 positive C. difficile tests within 6 months, and

• 3. Positive C. difficile toxin assays (minimum of 2 in recent history), and

• 4. Presence of diarrhea (≥4–10 watery stools per day).

The donor screening protocol and FMT technique have been described previously [3, 6]. All FMT candidates were screened by one of the authors (R. O., R. L. P.) for eligibility.

FMT failure was defined as return of >3 liquid stools per day for 2 consecutive days during the first 12 weeks after the procedure, with a confirmatory C. difficile toxin B polymerase chain reaction or enzyme immunoassay on stool. FMT successes were patients who received FMT and had no evidence of C. difficile recurrence within 12 weeks following FMT.

The electronic health records of the patients were reviewed to confirm identification as successes or failures. Characteristics of FMT patients who were abstracted are presented in Table 1, and FMT technical characteristics that were abstracted in Table 2.

FMT was administered nasoenteroscopically with delivery into the jejunum in 6 patients, and, colonoscopy into the terminal ileum and cecum in 103 patients.

Statistical Analysis

Continuous variables were compared by analysis of variance F test and categorical outcome variables with the Fisher exact test. Variables with P < .10 on univariate analysis were considered for inclusion in a multivariate logistic regression model to identify factors associated with recurrence following FMT. Vancomycin taper, number of prior relapses, and presence of gastrointestinal disease (Crohn’s disease, ulcerative colitis) and diarrhea were included in the model. Statistical software (SAS version 9.4, SAS Institute) was used for analysis. P < .05 was considered statistically significant.

RESULTS

During the study period, 109 patients underwent an FMT procedure. Demographics are displayed in Table 1. Ten patients (9.2%) had a confirmed recurrence, and 99 (90.8%) were treatment successes. Ten patients were hospitalized at the time of FMT; however, none of the 10 patients who had FMT failure were hospitalized at the time of FMT. Mean time to recurrence from FMT was 35.7 (range, 2–76) days. All patients with recurrence were offered treatment with oral vancomycin followed by repeat FMT, and the second FMT results were not included in this analysis. Two patients, 1 in each group, had received a previous FMT done elsewhere, and were included in the analysis. Technical variables of the FMT procedure are presented in Table 2.

The univariate analysis identified the following variables for inclusion in the multivariate analysis: number of relapses before FMT (P = .09), treatment with oral vancomycin for standard duration of 10–14 days (P = .09), treatment with prolonged vancomycin taper for ≥6 weeks (P = .08), presence of underlying inflammatory bowel disease (P = .09), computed tomography with colitis in any previous episode (P = .04), and number of liquid stools per day (P = .07) (Table 1). No FMT technical variable achieved a P value <.10 in univariate analysis. In the multivariate analysis, 2 variables that remained significant were receipt of a vancomycin taper (odds ratio [OR], 0.11; 95% confidence interval, .02–.64; P = .01) and >6 episodes of diarrhea per day (OR, 0.13; 95% CI, .02–.79; P = .03) (Supplementary Table). In the failure group, 60% of patients received vancomycin taper, in contrast with 83.8% in the FMT successes (Table 2). Controlling for number of relapses and presence of underlying inflammatory bowel disease, the number needed to treat with a vancomycin taper to prevent FMT failure was 5.8 (95% CI, 5.1–16.1).

DISCUSSION

The findings of our study suggest that failure to receive a tapered course of oral vancomycin before FMT is a modifiable risk factor for subsequent FMT failure. Patients who did not receive this taper preceding FMT were 89% more likely to fail. Previous studies of FMT reported success and failure rates but did not address the reasons for failure. Two recently published reports did not look specifically at vancomycin taper as a variable for FMT failure [7–9].

The exact mechanism by which FMT successfully treats recurrent and refractory cases of CDI is currently unknown. Use of a prolonged tapered course of oral vancomycin preceding FMT may allow partial microbiota replenishment while reducing the fecal concentration of vegetative C. difficile. In contrast, standard therapeutic courses of vancomycin may reduce C. difficile stool concentrations while allowing a disrupted microbiota to persist [9].

A recent randomized control trial comparing 14 days of vancomycin therapy followed by FMT via enema vs a 6-week taper of oral vancomycin was terminated early after the interim analysis showed a similar failure rate with both approaches (56.2% vs 41.7%) [10]. The authors postulated that presence of vancomycin in stools for 4 or 5 days after the last dose was a reason for the poor results in the arm that received vancomycin followed by FMT.

Our results suggest that patients who taper vancomycin over a prolonged period before FMT may have greater likelihood of a successful FMT than those who receive FMT shortly after completion of standard-of-care dosing. The presence of vancomycin in stools at the time of FMT may hinder FMT success [10]. Perhaps tapered regimens offer an advantage by having less vancomycin in stools at the time of FMT.

Other studies have assessed potential reasons for FMT failure, but used different designs and definitions [7]. On univariate analysis they found the use of non-CDI antibiotics within 8 weeks of FMT, history of CDI-related hospitalization, presence of pseudomembranous colitis at FMT, inpatient status at FMT, serum albumin concentration <3 g/dL, and presence of severe or severe-complicated CDI at FMT [7] as risk factors. In their multivariate analysis, only 3 variables were predictors of early FMT failure: severe or severe-complicated CDI, inpatient status at FMT, and number of prior CDI hospitalizations.

In a retrospective review of 201 patients who received FMT for recurrent or refractory CDI, or both [8], a multivariate analysis found that female sex, previous hospitalization, and previous surgical operation within 90 days of CDI were associated with FMT failure, suggesting hospital-acquired CDI as a potential predictor of FMT failure. These two studies differed in several ways from ours: including the definition of recurrence, multiple prior FMTs and route of administration. In both of the studies [8, 9], risk of FMT failure was associated with severe CDI and prior hospitalizations for CDI. Our patient population differed from these studies because the primary indication for FMT of our patients was multiple rCDIs, and only 10 patients were hospitalized at the time of FMT and had severe-complicated CDI. This difference is likely to be responsible, at least in part, for the different findings in our study.

We recognize that our study has several limitations. Our study was retrospective, from a single referral center with smaller numbers of patients and different FMT failure rates than the other studies [7, 8]. Because patients were referred to our center, we did not control the specific details of their preceding antibiotic regimens or the exact format of the oral vancomycin taper. As most patients were treated by other providers before referral, the vancomycin taper regimens were not standardized. Specific data for the reason for failure were not collected prospectively; hence, some variables may have not been collected or are not available for analysis, such as severity of prior CDI episodes, hospitalizations outside our facility, and compliance with previous treatments. We did not perform microbiota analysis on fecal specimens before or after FMT to assess the impact of this factor. Nevertheless, our data suggest that no relationship exists between FMT failure and specific donor, as reported by other investigators [11].

Last, we cannot discount the possibility that some of the patients may have had postinfectious irritable bowel syndrome with a positive C. difficile result with polymerase chain reaction due to colonization [12]. We attempted to correct for this by excluding patients who did not meet our program’s eligibility criteria.

In conclusion, our findings suggest that failure to receive a prolonged, tapered course of oral vancomycin before FMT is a modifiable risk factor for FMT failure for patients with multiple recurrent CDIs. This study adds to the knowledge of potential risk factors for FMT failure and suggests an opportunity to further improve the outcome of patients referred for FMT. Future studies of FMT outcomes should include assessment of the pre-FMT antimicrobial regimens and their effect on the pre-FMT microbiota.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Note

Potential conflicts of interest. R. O. has received reported compensation to his institution for board membership in Rebiotix (microbiota company), compensation to his institution for studies with Rebiotix, Crestovo, and Merck, and reimbursement for meeting expenses. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

Author notes