Antibiotics for the management of constipation predominant irritable bowel syndrome and chronic constipation

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy and safety of antibiotic use for treatment of IBS‐C and chronic constipation.

Background

Constipation is a prevalent and sometimes debilitating disorder that negatively affects patients lives and is associated with high healthcare costs. In North America constipation is self reported by 55 million persons with an estimated prevalence ranging between 2% and 28% (Higgins 2004; Brandt 2005). Although constipation affects all age groups it is more common in the elderly (Talley 1996) and women (Everhart 1989). In the United States constipation leads to approximately 2.5 million physician visits per year (Sonnennerg 1989). Constipation causes a significant loss of work productivity with serious economic consequences (Dennison 2005). Constipation can significantly affect health‐related quality of life (Chang 2004) and is correlated with psychological and psychiatric symptoms (Donald 1985).

Physician and patient perceptions of chronic constipation differ greatly. Physicians often concentrate on frequency of bowel movements as a marker of severity (Herz 1996), whilst patients cite hard stool and straining as the most bothersome symptoms (Sandler 1987). A definitive diagnosis of constipation is difficult as patients normally complain of a variety of symptoms such as excessive straining, hard stool, feeling of incomplete evacuation, abdominal pain and discomfort. However the Rome criteria, and the more recent Rome III criteria, form a framework for establishing a diagnosis of constipation which is now becomming more widely accepted and clinically useful (Longstreth 2006).

The Rome III criteria for functional constipation includes the presence of 2 or more of the following symptoms for at least 3 months:

• Straining in at least 25% defaecations;

• Lumpy or hard stool in at least 25% defaecations;

• Sensation of incomplete evacuation in at least 25% defaecations;

• Sensation of anorectal obstruction / blockade in at least 25% defaecations;

• Manual manoeuvres to facilitate at least 25% defaecations (e.g. digital evacuation, pelvic floor support); and

• Fewer than 3 defaecations per week.

The American College of Gastroenterology (ACG) Chronic Constipation Taskforce have developed a simpler set of criteria and define chronic constipation as 'unsatisfactory defaecation characterised by infrequent stools, difficult stool passage or both' present for at least three months. Difficult stool passage includes straining, hard lumpy stool, difficulty passing stool, incomplete evacuation, prolonged time to stool and need for manual manoeuvres to pass stool.

The aetiology of chronic constipation still remains largely unknown. High levels of high‐amplitude propagating contractions (HAPCs) have been reported in patients with diarrhoea predominant irritable bowel syndrome (IBS‐D) (Chey 2001; Cann 1983). It has been postulated that patients with constipation predominant irritable bowel syndrome (IBS‐C) and chronic constipation may have reduced numbers of HAPCs (Cann 1983; Bazzocchi 1990; Bassotti 2003).

Primary idiopathic chronic constipation can be classified into 3 main pathophysiological groups: normal transit constipation (NTC), slow transit constipation (STC) and dyssynergic or pelvic floor dysfunction. Patients with NTC have difficulty evacuating or pass hard stools in the presence of normal transit studies. NTC is the most prevalent subtype. The pathophysiology of STC may stem from absent or a decreased number of pacemaker cells (interstitial cells of Cajal) and defects in enteric nerves (He 2000). Other factors associated with STC may include decreased colonic activity (Bassotti 1992; Rao 2004) with decreased colonic response to laxatives and meals (Bassotti 1993). Dyssynergic defaecation is the inability to co‐ordinate abdominal, recto‐anal and pelvic floor muscles. Dyssynergic or pelvic floor dysfunction may be the sole cause of constipation in some individuals or may co‐exist in patients with slow‐transit constipation or irritable bowel syndrome. Chronic constipation can be differentiated from irritable bowel syndrome by the presence of clinically important abdominal pain and discomfort associated with constipation symptoms. However considerable overlap remains between the two conditions.

Treatment goals in chronic constipation are to improve symptoms and restore bowel function, accelerate colonic transit, stimulate gut motility ultimately to facilitate defaecation (Bleser 2005). A wide range of pharmacological agents have been used in attempts to treat this difficult disorder. Poor understanding of the pathophysiological mechanisms coupled by the complexicity of central and enteric interactions may explain the lack of sustained success of any single drug agent.

Antibiotics are an emerging therapeutic option, potentially negating for the need for chronic daily pharmacotherapy (Frissora 2007). Antibiotics offer an exciting alternative, targeting specific pathogenic mechanisms compared to traditional symptom‐directed pharmacotherapies. The potential utility of antibiotics has been supported by a growing body of evidence demonstrating the important role of bacteria in the pathogenesis of IBS. Various mechanisms have been targeted, but the hypothesis that small bacterial intestinal overgrowth (SBIO) is central to the pathogenesis of IBS has recently gained attention (Lin 2004), and may work by altering intraluminal flora (Celik 1995). Rifaximin, a non‐absorbed oral antibiotic has a broad spectrum bactericidal activity in vitro and has been extensively investigated for the treatment of irritable bowel syndrome (Pimentel 2006) and has shown an improvement in patients' self‐reported global symptoms. Bloating and gas, potentially from bacterial fermentation of dietary starch, are among the main symptoms of IBS, regardless of subtype, and antibiotics could be particularly efficacous in IBS‐C.

The macrolide erythromycin is a prokinetic agent that acts via motilin receptors on cholinergic neurons and on smooth muscle cells present in the human gastrointestinal system (Coulie 1998). Prokinetic effects in patients with upper gastrointestinal dysmotility are well documented and studies have demonstrated an acceleration of intestinal and colonic transit time in healthy individuals (Landry 1995). Further work identified motilin receptors in the human colon (Feighner 1999) and has stimulated in vitro studies and clinical trials (Sharma 1995).

Objectives

To assess the efficacy and safety of antibiotic use for treatment of IBS‐C and chronic constipation.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials comparing antibiotic agents to placebo or active comparators for treatment of IBS‐C and chronic constipation will be considered for inclusion. Quasi‐randomised studies will also be considered for inclusion.

Types of participants

Participants will be patients with IBS‐C or chronic constipation. Patients with constipation due to secondary causes (e.g mechanical obstruction, endocrine/ metabolic disorders, neurological conditions, psychological conditions, pregnancy, pharmacological agents) will be excluded.

Types of interventions

Patients receiving a single antibiotic drug (e.g. erthyromycin) will be compared to others receiving a placebo, diet modification (fibre), psychosocial intervention or untreated control groups.

Types of outcome measures

The primary outcome will be global improvement of symptoms. Secondary outcomes will include improvement in abdominal pain, distension, stool frequency, bowel transit time, adverse events, and withdrawals due to adverse events.

Search methods for identification of studies

1. Electronic searches The following electronic databases will be searched: Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE (1966‐ present), EMBASE (1980 ‐ present), and the IBD/FBD Group Specialised Register.

The following search strategy will be used to identify relevant randomised trials: #1 constipation OR chronic constipation OR idiopathic chronic constipation OR colonic inertia OR gastrointestinal motility OR colonic motility OR intestinal dysmotility OR irritable bowel‐ constipation predominant syndrome OR functional colonic diseases #2 antibiotics OR erythromycin OR vancomycin OR rifaximin OR neomycin #3 #1 AND #2

2. Referencing searching The references of all identified studies will be inspected for more trials.

3. Personal contact The first author of each included study will be contacted for information regarding unpublished trials.

4. Drug company The manufacturers of antibiotics will be contacted for additional data and information.

Data collection and analysis

Study selection Two authors (US and RLN) will independently assess relevant abstracts and titles identified by literature search against the predefined inclusion criteria. Any disagreement among the authors will be resolved by consensus.

Assessment of methodological quality Three authors (US, RLN and OMA) will assess the risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Factors to be assessed will include: 1) sequence generation (i.e. was the allocation sequence adequately generated?); 2) allocation sequence concealment (i.e. was allocation adequately concealed?); 3) blinding (i.e. was knowledge of the allocated intervention adequately prevented during the study?); 4) incomplete outcome data (i.e. were incomplete outcome data adequately addressed?); 5) selective outcome reporting (i.e. are reports of the study free of suggestion of selective outcome reporting?); and 6) other potential sources of bias (i.e. was the study apparently free of other problems that could put it at a high risk of bias?).

A judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias.

Data Extraction Two authors (US and OMA) will independently extract data from the included studies. Any disagreement will be resolved by consensus or by consultation with a third party. If needed the authors of the primary studies will be contacted for clarification of data and additional information.

Statistical analysis Review Manager (RevMan 5.0.15) will be used to analyse data. Analyses will be performed using the intention to treat principle. Data from individual trials will be combined for meta‐analysis when the interventions and controls are similar. Dichotomous data will be calculated as relative risk (RR) with 95% confidence intervals (95% CI). The weighed mean difference (WMD) with 95% CI will be calculated for continuous outcomes. A fixed effects model will be used unless statistically significant heterogeneity exists between the studies. A random effects model will be employed if heterogeneity exists. A chi‐square test will be used to assess heterogeneity (a P value of 0.10 will be regarded as statistically significant). If statistically significant heterogeneity is identified, the included studies will be examined for sources of both clinical and methodological heterogeneity.

Subgroup analyses We intend to explore the following potential sources of heterogeneity using aub‐group analyses or meta‐regression: 1. intervention ‐ different types/ class of antibiotic agent and different control; 2. different dosages of antibiotic agent; 3. different duration of treatment; and 4. different length of follow‐up period.

Sensitivity analyses Sensitivity analyses will be conducted based on the following: a. only including patients whose outcome is known (i.e. number of patients who completed the study used as denominator); b. random effects versus fixed effects models; and c. study quality.

Publication Bias The possibility of a publication bias will be investigated through the construction of funnel plots (trial effects versus trial size).

What's new

Date	Event	Description
24 October 2018	Amended	Protocol withdrawn

Declarations of interest

None Known.

Notes

This protocol is being withdrawn as it is out of date.

Withdrawn from publication for reasons stated in the review