Introduction
Inflammatory conditions of the pouch cause a significant burden after proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). In particular, pouchitis is the most common complication after IPAA for UC.1 Although first-line antibiotic therapies for acute pouchitis are relatively well defined, the ideal regimen or sequence of antibiotics for chronic antibiotic-dependent pouchitis (CADP) and other chronic inflammatory conditions of the pouch is not known.
Traditional estimates have stated that approximately 50% of patients undergoing a proctocolectomy with IPAA for UC will develop pouchitis, although more recent evaluations have indicated that pouchitis symptoms may occur in up to 80% of patients at some point after IPAA.1 First-line treatment of acute pouchitis typically consists of a 2-week course of ciprofloxacin or metronidazole.2 Although the majority of patients will respond to first-line antibiotic treatment, up to 19% go on to develop chronic pouchitis.2 Chronic pouchitis is often further characterized by response to antibiotics: CADP is defined by greater than 4 episodes of pouchitis per year or the need for continuous antibiotics, whereas patients with chronic antibiotic refractory pouchitis (CARP) commonly require escalation to immunosuppressive therapies due to lack of response to antibiotics.
With negative impacts on quality of life, chronic pouchitis is also one of the most common causes for pouch failure or permanent diversion to a loop ileostomy. Although both metronidazole and ciprofloxacin have shown efficacy in the treatment of pouchitis in controlled trials,3,4 there is a paucity of robust evidence to support definitive algorithms for the treatment of chronic pouchitis. Often alternating courses of antibiotics at a minimally effective dose are utilized. Oral vancomycin is an antibiotic with poor systemic absorption and has been shown to be effective as monotherapy not only in patients with pouchitis but also in subgroups of patients with UC and primary sclerosing cholangitis (PSC).5–7 We aimed to evaluate the effectiveness of vancomycin in the treatment of chronic pouch-related disorders in a tertiary care referral pouch clinic.
Methods
Patient Population
We performed a retrospective cohort study examining data from patients who were treated in the University of North Carolina (UNC) Multidisciplinary Inflammatory Bowel Diseases Center. Patients were identified for potential inclusion in this study using International Classification of Diseases 9th and 10th Clinical Modification (ICD-9-CM and ICD-10-CM) coding (569.71 and K91.850). The Informatics for Integrating Biology and the Bedside (i2b2) platform through the Carolina Data Warehouse for Health was used to identify patients with pouchitis who had received vancomycin therapy. As previously described,8 i2b2 is the flagship tool developed by the i2b2 Center, a National Institutes of Health (NIH)-funded National Center for Biomedical Computing based at Partners HealthCare System.
Eligible patients for this study were required to meet the following criteria: (1) 18 years of age or older, (2) history of proctocolectomy with IPAA as a treatment for UC, and (3) treated with vancomycin for chronic pouchitis or Crohn’s-like disease of the pouch between January 1, 2010, and May 5, 2020. All patients in this study were using vancomycin for a chronic inflammatory condition of the pouch and pouch-related symptoms. Patients using vancomycin for the treatment of acute pouchitis or a Clostridioides difficile infection were excluded. Vancomycin was given in a dose of 125 mg orally twice daily. Patients were identified with ICD-9-CM and ICD-10-CM using the i2b2 platform, requiring confirmation of typical pouchitis symptoms including frequency, urgency, incontinence, or abdominal pain/discomfort.
Outcome Assessment
Clinical response to vancomycin was defined based on provider judgement at 4 weeks after initiation of therapy. The durability of therapy was assessed by measuring the proportion of patients remaining on vancomycin at 3 and 6 months after therapy initiation. Among patients undergoing pouchoscopy during the study period, the endoscopic subscore of the pouchitis disease activity index (PDAI)9 was evaluated.
Covariates
We analyzed both demographic and clinical factors that could be related to the development of pouchitis and response to therapy, including a concomitant diagnosis PSC.
Statistical Analysis
Continuous variables are summarized using median and interquartile range (IQR) and were compared using Wilcoxon-rank-sum testing. Proportions are used to express categorical variables, which were analyzed using Fisher exact and χ2 testing as appropriate. All analyses were performed using SAS (version 9.4) statistical software (SAS Institute, Cary, NC, USA). The study protocol was approved by the Institutional Review Board at UNC-Chapel Hill.
Results
Forty-one patients were treated with vancomycin for a chronic inflammatory condition of the pouch during the study period. Among these individuals, 54% were women and 85% were white (Table 1). Only 3 (7%) patients had a diagnosis of PSC. When examining inflammatory conditions of the pouch, 41% had CADP, 37% had CARP, and 22% had Crohn’s-like disease of the pouch. There was no difference in clinical response to vancomycin when analyzed by inflammatory condition of the pouch. The mean number of antibiotics utilized prior to vancomycin was 3.98 (standard deviation 1.47), with a variety of classes of antibiotics represented (Table 2).
Table 1.
Demographic and clinical characteristics of patients treated with vancomycin for inflammatory conditions of the pouch.
| No Improvement on Vancomycin at 4 weeks | Improvement on Vancomycin at 4 weeks | P | |||
|---|---|---|---|---|---|
| n = 20 | n = 21 | ||||
| n | % | n | % | ||
| Age at initiation of vancomycin (Median, IQR) | 49 | 35–59 | 44.5 | 30–53.5 | 0.456 |
| Female Sex | 8 | 40 | 14 | 67 | 0.087 |
| Race | 0.152 | ||||
| White | 19 | 95 | 16 | 76 | |
| Non-White | 1 | 5 | 5 | 24 | |
| Smoking status | 0.764 | ||||
| Never | 16 | 80 | 17 | 81 | |
| Current | 1 | 5 | 2 | 10 | |
| Former | 3 | 15 | 2 | 10 | |
| Family history of IBD | 1 | 5 | 3 | 14 | 0.317 |
| Indication for surgery | 0.614 | ||||
| Medically-refractory colitis | 17 | 85 | 17 | 81 | |
| Dysplasia or cancer | 0 | 0 | 1 | 5 | |
| Other indication | 3 | 5 | 3 | 10 | |
| Disease extent prior to surgerya | 0.982 | ||||
| Proctitis | 1 | 6 | 1 | 6 | |
| Left-sided colitis | 3 | 19 | 3 | 17 | |
| Extensive colitis | 12 | 75 | 14 | 78 | |
| Stage of IPAA Surgerya | 0.706 | ||||
| I | 3 | 18 | 4 | 24 | |
| II | 9 | 53 | 10 | 59 | |
| III | 5 | 29 | 3 | 18 | |
| Inflammatory Condition of the Pouch | 0.143 | ||||
| Chronic Antibiotic Dependent Pouchitis | 7 | 35 | 20 | 48 | |
| Chronic Antibiotic Refractory Pouchitis | 6 | 30 | 9 | 43 | |
| Crohn’s-like Disease of the Pouch | 7 | 35 | 2 | 10 | |
| Primary Sclerosing Cholangitis | 2 | 10 | 1 | 5 | 0.548 |
| No. antibiotics prior to vancomycin | 0.351 | ||||
| 1 or 2 | 2 | 10 | 3 | 14 | |
| 3 | 3 | 15 | 5 | 24 | |
| 4 | 8 | 40 | 4 | 19 | |
| 5 or more | 7 | 35 | 9 | 43 | |
| Biologic use after IPAA | 12 | 60 | 13 | 62 | 0.901 |
| Clostridioides difficile infection after IPAA | 4 | 20 | 4 | 19 | 1.000 |
Disease extent and number of stages in IPAA surgery were unknown for 7 patients.
Table 2.
Comparison of antibiotic treatment after ileal pouch-anal anastomosis among responders and non-responders to vancomycin therapy.
| No Improvement on Vancomycin at 4 Weeks | Improvement on Vancomycin at 4 Weeks | P | |||
|---|---|---|---|---|---|
| n = 20 | n = 21 | ||||
| n | % | n | % | ||
| Ciprofloxacin | 18 | 90 | 20 | 95 | 0.520 |
| Metronidazole | 19 | 95 | 18 | 86 | 0.317 |
| Levofloxacin | 7 | 35 | 8 | 38 | 0.837 |
| Rifaximin | 11 | 55 | 11 | 52 | 0.867 |
| Sulfamethoxazole-trimethoprim | 9 | 45 | 7 | 33 | 0.444 |
| Amoxicillin | 8 | 40 | 6 | 29 | 0.441 |
| Amoxicillin-clavulanic acid | 14 | 70 | 15 | 71 | 0.920 |
At 4 weeks after initiation of vancomycin, 21 patients (51%) demonstrated a clinical response. In our evaluation of durability at 3 and 6 months, 16 of the 21 responders (76%) demonstrated continued response and remained on chronic vancomycin therapy at both time points. An additional 6 patients demonstrated later response and remained on chronic vancomycin at 3 and 6 months (total clinical responders at 3 and 6 months: 22 [54%]). Among the 20 patients who did not demonstrate initial response at 4 weeks, 1 (5%) had an escalation in vancomycin dose to 125 mg orally 4 times daily and subsequently achieved clinical response at 3 and 6 months. Dose escalation was not attempted in any patients who lost response after 4 weeks.
In an analysis of the potential association of clinical factors and durability of response, no new clinical factors were identified. There was no significant difference in our comparison of change in endoscopic PDAI subscores between those patients who demonstrated clinical response at 4 weeks and those who did not (median change 1.0 vs 1.5 point decrease, P = .763).
Discussion
In this study of a refractory population with pouch-related disorders, over 50% of patients treated with vancomycin demonstrated initial and durable clinical response to therapy. Chronic inflammatory conditions of the pouch remain a debilitating condition, worsening an individual patient’s quality of life after IPAA. Objective assessment of existing therapies that offer significant benefits in symptom control is critical, as this may enhance future efforts to allow more targeted use of therapies in individual patients.
Vancomycin has previously been recommended as a first-line therapy in patients with severe pouchitis due to Clostridioides difficile infections.1 Additionally in a case report, vancomycin was effective in the treatment of PSC-associated pouchitis, with dramatic improvement in symptoms and PDAI subscore after the patient failed metronidazole, ciprofloxacin, oral and topical mesalamine, steroid enemas, and oral steroids.5 It was postulated that the effectiveness of vancomycin in PSC-associated pouchitis might be due to emerging resistance to commonly used antibiotics or delayed identification of immune-mediated pouchitis.5 In our evaluation, there was no difference in outcomes at 4 weeks specifically among patients with PSC. However, this evaluation was limited by the small number of patients with PSC in our population.
Although the pathophysiology or underlying etiology of pouchitis is not definitive, most believe that an abnormal immune response to changes in the pouch microbiota or dysbiosis are responsible. Additionally, recent evaluations among patients with pouchitis have demonstrated that even patients with pouchitis that respond to antibiotics may demonstrate significant changes in their microbiota profiles, including genetic mutations indicating resistance to commonly used therapies for pouchitis.10 Over time, these resistance patterns could theoretically lead to antibiotic-dependent disease and the use of alternative antibiotics such as vancomycin. In conjunction with other observations of patients with PSC-IBD,6,7 the potential importance of vancomycin as a therapeutic option in patients with both UC and inflammatory conditions of the pouch likely warrants further examination.
Our study is among the largest reports of the effectiveness of vancomycin as a treatment for chronic pouch-related disorders; however, there are limitations. Our retrospective evaluation relied on subjective measures of clinical response instead of prospectively collected assessments of remission. The small sample size limited our ability to selectively analyze and/or identify specific predictors of response to vancomycin, including a more detailed analysis of response among patients with PSC as noted above. We found no difference when comparing the change in endoscopic subscore of the PDAI among responders and nonresponders; however, recent reviews have questioned the relative value of the endoscopic scoring of the PDAI,11 and others have noted a lack of correlation between clinical and endoscopic evaluations of patients with an IPAA.12
In conclusion, among a refractory group of patients with chronic inflammatory conditions of the pouch, a majority demonstrated durable clinical response to therapy with vancomycin. Given a limited therapeutic armamentarium for patients with chronic pouchitis, these results should prompt further investigation into both the positioning of vancomycin as a therapy for pouchitis and the underlying microbiota profiles among clinical responders to this therapy.
Acknowledgments
The i2b2 software was used in conducting this study; i2b2 is the flagship tool developed by the i2b2 (Informatics for Integrating Biology and the Bedside) Center, an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System. The i2b2 instance at the University of North Carolina is supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002489. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Contributor Information
Gabriel Lupu, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Kimberly N Weaver, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Multidisciplinary Center for Inflammatory Bowel Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Hans H Herfarth, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Multidisciplinary Center for Inflammatory Bowel Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Edward L Barnes, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Multidisciplinary Center for Inflammatory Bowel Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Funding
This research was supported by grants from the Crohn’s & Colitis Foundation (567497) and the National Institutes of Health (K23DK127157-01).
Conflicts of Interest
G.L. has no relevant disclosures or conflicts of interest. K.W. has served as a consultant for Abbvie. H.H. has served as a consultant for Alivio, AMAG, Finch, Gilead, Lycera, Merck, Otsuka, Pfizer, PureTech, and Seres and received research support from Pfizer and Artizan Biosciences. E.B. has served as a consultant for AbbVie, Gilead, Pfizer, and Target RWE.
References
- 1. Quinn KP, Lightner AL, Faubion WA, et al. A comprehensive approach to pouch disorders. Inflamm Bowel Dis. 2019;25(3):460–471. [DOI] [PubMed] [Google Scholar]
- 2. Barnes EL, Lightner AL, Regueiro M.. Peri-operative and post-operative management of patients with Crohn’s disease and ulcerative colitis. Clin Gastroenterol Hepatol. 2020;18(6):1356–1366. [DOI] [PubMed] [Google Scholar]
- 3. Shen B, Achkar JP, Lashner BA, et al. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis. 2001;7(4):301–305. [DOI] [PubMed] [Google Scholar]
- 4. Madden MV, McIntyre AS, Nicholls RJ.. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci. 1994;39(6):1193–1196. [DOI] [PubMed] [Google Scholar]
- 5. Shen B. Oral vancomycin in the treatment of primary sclerosing cholangitis-associated pouchitis. Gastroenterol Rep. 2021;9(3):274–275. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Vaughn BP, Kaiser T, Staley C, et al. A pilot study of fecal bile acid and microbiota profiles in inflammatory bowel disease and primary sclerosing cholangitis. Clin Exp Gastroenterol. 2019;12:9–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Dao A, Abidian M, Lestrange A, et al. Oral vancomycin induces and maintains remission of ulcerative colitis in the subset of patients with associated primary sclerosing cholangitis. Inflamm Bowel Dis. 2019;25(7):e90–e91. [DOI] [PubMed] [Google Scholar]
- 8. Murphy SN, Weber G, Mendis M, et al. Serving the enterprise and beyond with informatics for integrating biology and the bedside (i2b2). J Am Med Inform Assoc. 2010;17(2):124–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis Colon Rectum. 2003;46(6):748–753. [DOI] [PubMed] [Google Scholar]
- 10. Dubinsky V, Reshef L, Bar N, et al. Predominantly antibiotic-resistant intestinal microbiome persists in patients with pouchitis who respond to antibiotic therapy. Gastroenterology. 2020;158(3):610–624.e13. [DOI] [PubMed] [Google Scholar]
- 11. Sedano R, Nguyen TM, Almradi A, et al. Disease activity indices for pouchitis: a systematic review. Inflamm Bowel Dis. 2022;28:1012–1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Ben-Bassat O, Tyler AD, Xu W, et al. Ileal pouch symptoms do not correlate with inflammation of the pouch. Clin Gastroenterol Hepatol. 2014;12(5):831–837.e2. [DOI] [PubMed] [Google Scholar]