Preventing acute diverticulitis. any roles for non-absorbable antibiotics? in search of evidence: a systematic review, meta-analysis, and trial sequential analysis
Background: Hospital admissions for diverticulitis, a complication of diverticular disease, are very much on the increase. Prevention of diverticulitis could cut costs and save lives.
Aims: To identify whether the risk of the first episode of diverticulitis (primary prevention) or recurrence of diverticulitis (secondary prevention) can be reduced in patients with diverticular disease using non-absorbable antibiotics (mainly rifaximin).
Methods: The studies were identified by searching PubMed and CENTRAL from 1990 to May 2022. The methodological quality of each study was also evaluated. The outcome of the meta-analysis was the occurrence of a first or subsequent episode of diverticulitis. In addition, a trial sequential analysis was performed to evaluate whether the results would be subject to type I or type II errors.
Results: Primary prevention: the risk difference was statistically significant in favor of rifaximin (-0,019, or -1.9%, CI -0,6 to -3,3%). There was no evidence of heterogeneity (I2 0%). At one year, two years, and eight years of age, the NNT was 62, 52, and 42, respectively. The level of evidence had a moderate degree of certainty. Secondary prevention: the risk difference was statistically significant in favor of rifaximin (- 0,24, or -24%, CI -47 to -2%). There was evidence of heterogeneity (I2 92%); NNT resulted in 5. The grade level was low.
Conclusions: Rifaximin can lower the risk of a first episode of diverticulitis. However, the cost-benefit ratio currently appears too high. Rifaximin could also reduce the risk of a second episode, but the quality of the evidence is low.
Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022379258.
Doctors and patients face several decisions in appropriate management after the first episode of left colon diverticulitis. Episodes of acute diverticulitis are generally uncomplicated (causing only localized inflammation), but complicated diverticulitis, defined as inflammation associated with an abscess, fistula, hemorrhage, or perforation (1–3), occurs in about 12% of cases (4). Relapses occur in about 8% to 36% of patients between 1 and 10 years (2, 3), and prevention is of great importance. Evidence for the use of various pharmacological and surgical interventions to prevent diverticulitis recurrence has evolved over time (5–11).
The purpose of this meta-analysis is to identify whether the risk of the first episode of diverticulitis or of recurrence of diverticulitis in symptomatic uncomplicated diverticular disease (SUDD) can be reduced using non-absorbable antibiotics (mainly rifaximin), through the identification of published randomized and observational studies.
We followed GRADE guidance 24 and used a framework that considers the certainty of evidence from randomized and non-randomized studies then in an integrative fashion (12).
A first analysis of the evidence gathered for the role of non-absorbable antibiotics based only on symptoms in SUDD appeared in 2011 (13). One of the authors is in the editorial team of this paper.
According to the 2022 latest American guidelines for internists, evidence is very uncertain (insufficient) for treatments to prevent recurrence (like probiotics, combinations of mesalamine and rifaximin, combinations of mesalamine and probiotics, and burdock tea) (14).
The most studied drug for preventing diverticulitis is mesalamine. However, the latest American guidelines definitively exclude a role for this agent in preventing relapses (strong recommendation; high-certainty evidence) (14), following the results of the last meta-analysis (15).
This meta-analysis could help figure out if nonabsorbable antibiotics might play a role in lowering the risk of diverticulitis and, if so, what studies should be done.
Details of our systematic review are registered in the PROSPERO database under the number .
Materials and methods
The studies were identified by searching PubMed, and the Cochrane Central Register of Controlled Trials from 1990 to May 2022.
The search strategy for both databases used the following string
((((((diverticulitis OR diverticular)))) AND (((recurrence OR relapse OR rehospitalization))))) NOT ((((((diverticulitis OR diverticular)))) AND (((recurrence OR relapse OR rehospitalization)))) AND ((((clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials as topic[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading])))).
The search strategy was completed on May 30, 2022
The identified records were screened by titles, abstracts, and keywords. Papers with potential eligibility were then obtained for full-text review. No language limits were imposed. We supplemented the electronic search by scanning the reference lists of relevant publications, including review articles and guidelines. When published data were insufficient for our analyses, additional details were sought from the investigators of the corresponding clinical trials.
The flow chart of the items identified and those then eliminated was developed with the help of Prisma 20202 software (https://doi.org/10.1002/cl2.1230).
The PICO question format (18) was used to figure out who was eligible first.
● Patients: patients with symptomatic, uncomplicated diverticular disease (SUDD) who have never had diverticulitis or have only had it.
● Intervention: long term administration of rifaximin. The allowable dose was 800 mg per day in cycles of 7–10 consecutive days per month.
● Comparators/controls: standard of care, placebo, or mesalamine.
● Outcome: the occurrence of a diverticulitis episode, whether first-time or recurring.
● Study design: randomized, non-randomized, and observational studies if peer-reviewed and published in full.
All patients suffered from SUDD, defined as a syndrome characterized by recurrent abdominal symptoms attributed to diverticula in the absence of other macroscopically evident alterations other than the presence of diverticula.
Diverticulitis was predefined as abdominal pain attributed to diverticular disease and one of the following findings: (1) requiring hospitalization or surgery; or (2) described as acute and presenting with fever, and/or being evaluated with computed tomography. Prevention of the first episode of diverticulitis was considered “primary prevention” (PP) when the complication had never appeared previously or “secondary prevention” (SP) when it appeared after the first episode. All articles passed through a systematic review by a team of 3 physicians (MK, SC, and AEM), and methodological criteria and the results were recorded. Studies that fulfilled the inclusion criteria were evaluated by a blinded review done independently by the same 3 authors to tabulate subject demographics, study design, definition of outcomes, and frequencies of diverticulitis using a standardized data form. Disagreement was resolved by consensus.