Re: 소장세균 과증식에 리팍시민(항생제)투여로 주사(rosacea) 를 치료하는 논문

[문형철]

beyond reason

주사비 피부질환은 위산이 부족함

그리고 소장세균 과증식을 치료하는 리팍시민 10일 투여(1200mg)투여로 아래와 같은 치료효과

리팍시민에 대한 뉴스

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장내세균 조절을 통해 위장관질환(intestinal disease)을 치료하는 항생제 요법이 새로운 선택으로 주목받고 있다. 장내세균총을 구성하는 유익균은 보호하고(eubiotic effects) 유해균의 활동은 억제하는(antibiotic effects) 리팍시민 요법을 지칭하는 말이다. 리팍시민은 이 같은 기전을 통해 장내세균 생태계의 균형을 조절·유지하는 데 도움을 줌으로써 신체 항상성을 개선시키는 것으로 보고되고 있다.

장질환 병태생리 따른 치료 다변화
환자의 삶의 질에 악영향을 주거나 심각하게는 목숨까지 위협할 수도 있는 장질환은 다양한 병태생리만큼이나 다변화된 치료전략을 요하고 있다. 대표적인 사례를 과민성장증후군(Irritable Bowel Syndrome, IBS)에서 찾아볼 수 있다.

IBS는 기저질환 없이 복통 혹은 복부 불편감이 배변습관의 변화를 동반해 발생하는데, 명확한 단일원인에 의한 것이 아닌 여러 인자의 상호작용을 통해 유발되는 것으로 인식되고 있다. 원인인자로는 소화관 운동의 변화, 내장 과민성, 유전적 요인, 장내세균총의 변화, 뇌·장관 상호 연관성, 스트레스에 대한 이상반응 등 다양한 요인들이 연관성을 보이며 증상을 초래하는 것으로 이해된다.

따라서 IBS의 치료목표는 다양한 병태생리를 고려해 가장 불편한 증상을 완화시켜 삶의 질을 끌어올리는 것이라는 데 학계의 합의가 이뤄지고 있다. 가이드라인에서도 생활습관 개선과 함께 주된 증상에 따라 하제, 위장관기능개선제, 진경제, 지사제, 항생제 등 약물치료를 권고한다.

항생제 치료로 장내세균총 불균형 조절
대표적 장질환의 병태생리학적 원인으로 장내세균총의 변화가 꼽힌다는 점에 주목할 필요가 있다. 전문가의 설명에 따르면, 장내세균총은 인체에 유익한 균과 유해한 균이 균형을 이루고 있다. 이 장내세균총의 다양성과 균형이 무너지면 장질환을 비롯한 여러 질병의 발생 가능성이 높아진다. 바로 이 장내미생물군의 불균형을 조절하는 전략으로 리팍시민 항생제 요법이 임상에 적용되고 있으며, 궁극적인 타깃은 장질환 증상완화에 맞춰져 있다.

유익균 보호효과
최근 European Medical Journal Gastroenterology 2015;4:66-71에 실린 학술토론 보고서에는 리팍시민의 장내세균 조절효과와 궁극적으로 장질환 증상완화에 미치는 임상혜택이 잘 요약돼 있다. 이 보고서는 스페인 개최 ‘유럽위장관질환주간’ 학술대회에서 ‘장내세균총 균형과 장질환 항생제 치료’ 주제의 심포지엄 논의내용을 발췌한 것으로, 세계적 석학들이 한자리에 모여 리팍시민이 장내세균총 균형에 어떤 영향을 미치는지에 대한 학술적 논의를 진행했다.

이탈리아 로마가톨릭대학의 Antonio Gasbarrini 교수는 리팍시민이 장내세균 중 인체에 유익한 균에 대해 항균(antibiotic effects)이 아닌 보호효과(eubiotic effects)를 발휘한다는 점을 강조했다. “동물실험에서 리팍시민 투여 시 장내세균총의 전체조합에 혼란을 초래하지 않은 상태에서 Bifidobacterium, Faecalibacterium prausnitzii, lactobacilli 등 유익균을 증가시키며  장내세균총 균형에 긍정적인 영향을 미치는 등 잠재적 유익균 보호효과가 시사됐다”는 설명이다.

인간 대상의 관찰연구에서도 리팍시민의 장내세균 보호효과가 보고됐다. IBS, 크론병, 게실염, 간섬유화 등 다양한 소화기질환 환자들을 대상으로 1일 1200mg 리팍시민 요법의 효과를 관찰한 결과, 치료종료 시점에서 lactobacilli 균주의 유의한 증가가 확인됐고 이는 치료 후 1개월 시점까지 유지됐다(P＜0.0001). Gasbarrini 교수는 “lactobacilli 균주의 증가가 리팍시민의 항염증효과에 영향을 미칠 수도 있을 것으로 여겨진다”며 “이러한 장내세균 보호효과와 궁극적인 장내세균총 조절혜택이 소화기질환 치료에 크게 기여할 것”이라고 부연했다.

장내세균 조절
독일 오토본구에릭케대학의 Peter Malfertheiner 교수는 게실염 치료에 있어 리팍시민의 혜택에 대해 보고했다. 그는 “게실염(Symptomatic Uncomplicated Diverticular Disease, SUDD)의 치료목표는 질환의 병태생리학적 기전을 타깃으로 증상의 정도를 완화시키고 급성 게실염 재발을 예방하는 것”이라며 “일부 임상연구에서 리팍시민이 장내세균총의 균형을 조절·유지하며 게실염 환자에 임상혜택을 제공했다”고 밝혔다.

TARGET 1·2·3

 

미국 시더스-사이나이의료원의 Mark Pimental 교수는 대규모 임상연구(TARGET 1, TARGET 2, TARGET 3)를 통해 IBS 환자에서 리팍시민의 효과를 설명했다.

TARGET 1·2 연구에서 리팍시민은 치료 후 4주 시점까지 위약 대비 증상완화 효과를 입증했을 뿐 아니라, 치료 후 3개월 시점까지 효과의 지속성을 나타냈다. 치료 후 첫 4주 동안 IBS 증상의 충분한 완화를 경험한 환자의 비율은 TARGET 1 연구에서 40.8% 대 31.2%(P=0.01), TARGET 2에서 40.6% 대 32.2%(P=0.03), 두 연구를 합쳐 분석한 경우에는 40.7% 대 31.7%(P＜0.01)로 리팍시민군이 통계적으로 유의한 임상혜택을 나타냈다.

복부팽만 증상의 충분한 완화 역시 TARGET 1에서 39.5% 대 28.7%(P=0.005), TARGET 2에서 41.0% 대 31.9%(P=0.02), 두 연구 종합분석에서 40.2% 대 30.3%(P＜0.001)로 리팍시민군에서 보다 많은 환자들이 혜택을 경험했다.

장질환 환자에서 리팍시민의 유효성·안전성 및 효과의 지속성을 보기 위한 TARGET 3 연구에서는 리팍시민 그룹에서 보다 많은 환자들이 치료에 반응을 보인 것으로 나타났다. 또 리팍시민 치료 후 증상의 중증도가 기저시점 수준으로 회귀하지 않았다. 

                                                         
[expert opinion]

위장관질환 치료제로서 리팍시민의 효과

 

우리 인체에는 위에서 대장으로 갈수록 그 세균의 개수가 증가하여 장에는 총 인체세포의 10배인 1014개의 세균이 존재하고 사람의 변을 관찰하면 거의 세균 덩어리로 이루어져 있다. 다양한 장내 미생물무리는 비흡수성 탄수화물, 단백질, 탈락된 상피세포, 점액 등을 능동적으로 대사하여 장상피 장벽(barrier) 형성과 강화 등의 장상피 항상성 유지, 인체 내로 영양분 흡수와 교환, 에너지 획득, 장 면역계의 발달 및 면역반응 등에 중요한 역할을 한다.

하지만 이 항상성을 유지하기 위한 상호관계가 깨지거나 항생제 과용 등으로 장내 미생물무리의 불균형(dysbiosis)이 초래되면 인체의 건강과 질병에 영향을 미치는 것은 잘 알려진 사실이다. 즉 인체와 장내 미생물무리 간의 균형이 무너질 경우 점막 면역체계에 변화가 일어나 염증반응이 일어나거나 대장의 감각 및 운동기능에 큰 장애가 일어날 수 있다.

또한 장내 미생물무리의 변화로 인해 장내의 가스 종류와 양이 달라져 복부팽창 등의 증상이 나타나 기능성질환의 원인이 되고 있다. 이러한 미생물무리의 인체 내에서의 역할 및 기능이 알려지면서 최근 프로바이오틱스(probiotics)의 복용이 크게 늘고 있으나, 그 효과와 안전성에 대해 많은 연구와 적용 가이드라인이 필요한 상황이다.

리팍시민은 반합성 rifamycin 근간 항생제이며, 기존의 항생제와는 달리 위장관 흡수가 매우 적고 그 작용기전이 세균의 위장관 점막에의 부착(adherence)을 방해하는 항생제이다. 이러한 리팍시민 투여는 과증식 세균을 억제하고 정상 미생물무리 조성을 회복시키는 보호효과(eubiotic effects)를 발휘하는데, 특히 설사형과 변비형 과민성장증후군 환자에서의 치료효과가 이중맹검 무작위 시험으로 입증되어 최근 미국식품의약국(FDA)에서 설사형 과민성장증후군 치료제로 인정받은 바 있다.

또한 우리나라에서 최근 급격히 증가하고 있는 65세 이상 노령인구의 장에서는 젊은 연령층보다 기본적으로 장내 미생물무리의 다양성이 감소하여, 항생제 등의 외부인자에 의해 미생물무리의 불균형이 쉽게 발생하고 결과적으로 Clostridium difficile 감염에 의한 위막성 대장염이 늘고 있어 향후 큰 문제가 될 가능성을 시사하고 있다.

반갑게도 리팍시민이 Clostridium difficile 균주를 억제하고 손상된 정상 미생물무리를 회복시키는 등 위막성 대장염 치료에 매우 효과적임을 증명하고 있다. 따라서 이러한 노령층 증가 동향에 발맞추어 다양한 유산균 제제의 연구와 더불어 장내세균 조절을 통한 위장관질환(intestinal disease) 치료제로서의 리팍시민 요법에 대한 더 많은 연구를 통해 게실염, 만성염증성장질환이나 과민성장증후군의 예방과 치료에 큰 진전이 있기를 기대한다.

The 2008 study by Italian investigators found that SIBO was present in 52 of 113 (46%) consecutive rosacea patients. The FDA-approved antibiotic rifaximin (Xifaxan®) was given to 28 of these 52 patients. Of these 28 patients, 20 (71%) experienced clearing of their rosacea lesions and 6 (21%) had significant improvement in their overall rosacea symptoms.

Rosacea and small intestinal bacterial overgrowth: preval‎ence and response to rifaximin. 

Accepted for publication in the Journal American Academy of Dermatology, 2013.

The pathophysiology of rosacea involves dysregulation of innate and adaptive immunity, neurovascular changes, chronic inflammation, and, possibly, infections. A new pathogenic mechanism was recently suggested after a relationship was observed in a study where 46% of prospective rosacea patients had small intestinal bacterial overgrowth (SIB0). After therapy with rifaximin, a non-absorbed, gut-active antibiotic, complete resolution of cutaneous lesions in 78% of the SIBO patients was observed. Small intestinal bacterial overgrowth may alter immunity and trigger rosacea by increasing tumor necrosis factor- or other cytokines, suppressing interleukin-17, and stimulating the Th1-mediated immune response. Furthermore, gut bacteria have been shown to mimic immunogens associated with extraintestinal disease (ie, multiple sclerosis).

The aim of this pilot study was to determine the preval‎ence of SIBO in patients with rosacea seen in a gastroenterology clinic and determine the efficacy of rifaximin in patients with indirect evidence of SIBO (i.e., a positive lactulose breath test). The study protocol received institutional review board (Sterling IRB, Atlanta, GA) approval. Most rosacea patients were identified during physical examination before receiving a screening colonoscopy. Rosacea was diagnosed by a dermatologist in 57 cases. Four patients with medicine-refractory ocular rosacea were referred by ophthalmologists. Two cases of rosacea were diagnosed by the investigator. In addition to the ocular cases (3 had facial erythema), 9 had papulopustular and 50 had erythematotelangiectatic rosacea. All patients underwent a lactulose breath test, with a positive test result for SIBO defined as an increase in hydrogen or methane levels >20 ppm from baseline within 90 minutes. Preval‎ence of SIBO was compared to 2 control groups. Patients with SIBO received 400 mg rifaximin (Xifaxan®; Salix Pharmaceuticals, Inc, Raleigh, NC) 3 times daily for 10 days. Patients completed a self-report questionnaire using a 4-point rosacea improvement scale 10 days after ending rifaximin therapy. A repeat physical examination was performed in 70% of patients treated with rifaximin.

A total of 32 of 63 patients (51%; 6 males and 26 females) with rosacea were diagnosed with SIBO compared with 7 of 30 general population controls (23%; relative risk, 2.1; 95% confidence interval, 1.1-

4.3; P = .02) and 3 of 30 completely healthy controls (10%; relative risk, 5.0; 95% confidence interval, 1.7- 15.1; P < .001). Of the SIBO patients, 28 were treated with rifaximin: 46% reported cleared or m arkedly improved rosacea, 25% reported moderately improved rosacea, and 11% reported mildly improved rosacea. All 4 patients with ocular rosacea and SlBO reported marked improvement. Rosacea was unchanged in 18% of patients.

In this study, a subset of rosacea patients with indirect evidence of SIBO was identified and a significant majority improved after treatment with a non-absorbable antibiotic. A study screening rosacea patients in a dermatology clinic using a lactulose breath test for evidence of SIBO and a double blind clinical study to determine the efficacy of rifaximin in these patients would greatly contribute to an understanding of the potential impact of these findings.

ROSACEA AND SIBO

September 12, 2014

I am a big believer that a happy gut means better overall health, including skin health. Just like the skin, the gut has its own unique microbiome (the microorganisms in a particular environment), and if the microbiome gets disrupted, there are consequences not just for the digestive system, but for other organs as well.  Digestive Wellness, by Elizabeth Lipski, PhD, is a great book for those who want to learn about this stuff.

Rosacea is a complex skin disorder which likely has many causes, not one.  In this blog, I want to discuss data presented at the American College of Gastroenterology Annual Scientific Meeting in November, 2011, and reported in the Journal of the American Academy of Dermatology in May 2013, and I have included the short version below.

“To the Editor: The pathophysiology of rosacea involves dysregulation of innate and adaptive immunity, neurovascular changes, chronic inflammation, and, possibly, infections.1 A new pathogenic mechanism was recently suggested after a relationship was observed in a study where 46% of prospective patients with rosacea had small intestinal bacterial overgrowth (SIBO).2 After therapy with rifaximin, a nonabsorbed, gut-active antibiotic, complete resolution of cutaneous lesions in 78% of the patients with SIBO was observed. SIBO may alter immunity and trigger rosacea by increasing tumor necrosis factor-alfa or other cytokines, suppressing interleukin-17, and stimulating the T helper 1-mediated immune response.3 Furthermore, gut bacteria have been shown to mimic immunogens associated with extraintestinal disease (ie, multiple sclerosis).4

The aim of this pilot study was to determine the preval‎ence of SIBO in patients with rosacea seen in a gastroenterology clinic and determine the efficacy of rifaximin in patients with indirect evidence of SIBO (ie, a positive result on lactulose breath test). The study protocol received approval from Sterling Institutional Review Board, Atlanta, Ga. Most patients with rosacea were identified during physical examination by their gastroenterologists before receiving a screening colonoscopy. Rosacea was diagnosed by a dermatologist in 57 cases. Four patients with medicine-refractory ocular rosacea were referred by ophthalmologists. Two cases of rosacea were diagnosed by the investigator. In addition to the ocular cases (3 had facial erythema), 9 had papulopustular and 50 had erythematotelangiectatic rosacea. All patients underwent a lactulose breath test, with a positive test result for SIBO defined as an increase in hydrogen or methane levels greater than 20 ppm from baseline within 90 minutes. Preval‎ence of SIBO was compared to 2 control groups. Patients with SIBO received 400 mg of rifaximin 3 times daily for 10 days. Patients completed a self-report questionnaire using a 4-point rosacea improvement scale 10 days after ending rifaximin therapy. A repeated physical examination was performed in 70% of patients treated with rifaximin.

A total of 32 of 63 patients (51%; 6 male and 26 female) with rosacea were given the diagnosis of SIBO compared with 7 of 30 general population control subjects (23%; relative risk, 2.1; 95% confidence interval, 1.1-4.3; P = .02) and 3 of 30 completely healthy control subjects (10%; relative risk, 5.0; 95% confidence interval, 1.7-15.1; P < .001). Of the patients with SIBO, 28 were treated with rifaximin: 46% reported cleared or markedly improved rosacea, 25% reported moderately improved rosacea, and 11% reported mildly improved rosacea. All 4 patients with ocular rosacea and SIBO reported marked improvement. Rosacea was unchanged in 18% of patients. In this study, a subset of patients with rosacea and indirect evidence of SIBO was identified and a significant majority improved after treatment with a nonabsorbable antibiotic. A study screening patients with rosacea in a dermatology clinic using a lactulose breath test for evidence of SIBO and a double-blind clinical study to determine the efficacy of rifaximin in these patients would greatly contribute to an understanding of the potential impact of these findings.”

http://www.jaad.org/article/S0190-9622%2812%2902330-4/fulltext

In short, when patients who had Small Intestine Bacterial Overgrowth (SIBO) AND Rosacea, who were treated for the SIBO with an antibiotic called Rifaximin, not only did the digestive symptoms get better, but the rosacea improved as well!!!!!!!!!  What does this tell me, and how has it changed my practice? Well, although why rosacea and SIBO are connected is still not totally clear, there IS a connection in at least a subset of patients.  And now, for any patient with moderate or worse rosacea, I am suggesting a SIBO breath test, which can be performed at home, or in many gastroenterologist’s offices.  It is a non-invasive test, but does take a few hours.  For the patients that come back SIBO positive, they are getting treated with Rifaximin.  The good news?  Many of those patients are having improvements in their rosacea!  The bad news?  Not ALL patients with SIBO and rosacea get better rosacea-wise when they are treated.  Some do, some do not, and I cannot explain yet why that is.

Sooooo…. more work needs to be done, but this is a promising step in offering hope to those who suffer from rosacea. And for me, further proof that we cannot ignore the rest of the body when we think about skin disease.

Systematic review with meta‐analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth

L. Gatta 

 

C. Scarpignato

First published: 12 January 2017

 

https://doi.org/10.1111/apt.13928

 

Citations: 35

As part of AP&T's peer‐review process, a technical check of this meta‐analysis was performed by Dr Y Yuan. The Handling Editor for this article was Professor Roy Pounder, and it was accepted for publication after full peer‐review.

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Summary

Background

Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome, characterised by an increased number and/or abnormal type of bacteria in the small bowel. Over the past decades, rifaximin has gained popularity for this indication despite its use is not evidence based.

Aim

To perform a systematic review and meta‐analysis to summarise evidence about the efficacy and safety of rifaximin to eradicate SIBO in adult patients.

Methods

MEDLINE, EMBASE, CCRCT, Scopus and Web of Science were searched from inception to March 16, 2015 for RCTs and observational studies. Furthermore, abstract books of major European, American and Asian gastroenterological meetings were also examined.

Results

Thirty‐two studies involving 1331 patients were included. The overall eradication rate according to intention‐to‐treat analysis was 70.8% (95% CI: 61.4–78.2; I2 = 89.4%) and to per protocol analysis 72.9% (95% CI: 65.5–79.8; I2 = 87.5%). Meta‐regression identified three covariates (drug dose, study design and co‐therapy) independently associated with an increased eradication rate. The overall rate of adverse events was 4.6% (95% CI: 2.3–7.5; I2 = 63.6%). In the subset of studies (n= 10) allowing the analysis, improvement or resolution of symptoms in patients with eradicated SIBO was found to be 67.7% (95% CI: 44.7–86.9; I2 = 91.3%).

Conclusions

Rifaximin treatment seems to be effective and safe for the treatment of SIBO. However, the quality of the available studies is generally poor. Well‐designed RCTs are needed to substantiate these findings and to establish the optimal regimen.

Introduction

Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome characterised by an increased number and/or abnormal type of bacteria in the small bowel, and it is a well‐recognised cause of maldigestion and malabsorption.1, 2

The recent discovery of an association between SIBO and functional gut symptoms, albeit controversial, has renewed interest in this mimicry. SIBO represents indeed an umbrella term, under which some different functional (e.g. irritable bowel syndrome, chronic constipation, diarrhoea) or organic (e.g. inflammatory bowel disease, coeliac disease, diverticular disease, etc.) conditions can be included, as – in each of them – bacterial proliferation (and consequent inflammation) may, at least in part, trigger similar abdominal symptoms.1

The overall, true preval‎ence of SIBO – which is usually under‐diagnosed – is unknown.2, 3Indeed, patients may not seek healthcare and SIBO may not be properly diagnosed by medical investigations. In addition, the diagnostic yield depends on the methodology adopted, so that results from different studies are difficult to compare.4, 5

The mainstay of the SIBO treatment is based on the use of antimicrobial agents, whose aims should not be to eradicate the entire bacterial flora but rather to modify the intestinal microecology in order to get symptoms relief.1 Ideally, the choice of antimicrobials should reflect in vitro susceptibility testing, but this is usually impractical because intestinal bacterial cultures need invasive methodology to collect samples under sterile conditions.6 Therefore, hydrogen breath test (HBT) is widely used as non‐invasive means to diagnose SIBO. As consequence, in clinical practice antibiotic treatment, which should cover both aerobic and anaerobic bacteria, remains primarily empiric.4-6

Several antibiotic regimens proved to be effective over the past 50 years, with treatment success ranging from 27% to 100%.7 Till the end of 90s, only systemic antimicrobials were used, whose adverse events (AEs) and detrimental effects on gut microbiota are today well known.8 Poorly absorbed antibiotics, unlike systemic ones, allow localised targeting of enteric pathogens and are associated with minimal risk of systemic toxicity or AEs. The restricted use of drugs only for enteric‐infections should also reduce the development of widespread resistance, especially of enterobacteria, a major limitation of current antibiotics.8

Rifaximin is a product of synthesis experiments designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal absorption while retaining good antibacterial activity.9-11 Both experimental and clinical pharmacology have clearly shown that this compound is a poorly absorbed antibiotic with a broad spectrum of antibacterial activity, covering Gram‐positive and Gram‐negative microorganism, both aerobes and anaerobes.10-13

Rifaximin fulfils all the characteristics set by DuPont and Ericsson14 for the ideal antimicrobial that should be used for the treatment of gastrointestinal infections (including dysbiosis and SIBO). As a consequence, over the past decades, rifaximin has been largely used to treat SIBO1, 7 even if there is currently a lack of a critical summary of evidence. To bridge this gap, a systematic review and meta‐analysis of randomised and nonrandomised studies was performed to eval‎uate the clinical effectiveness of and safety rifaximin to eradicate SIBO in adult patients.

Methods

Search strategy and study selection

This meta‐analysis was developed according to the PRISMA15 and to the MOOSE16statement guidelines. A search of the medical literature was conducted using MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Scopus and Web of Science from inception to 16 March 2015. Detailed eligibility criteria for study inclusion are provided in Table 1. The search strategy had two sets of terms joined together with the ‘AND’ operator. The first included the condition of interest: ‘small intestine, intestinal diseases, bacteria, bacterial infections, blind loop syndrome, breath tests, glucose, lactulose, xylose, sucrose, irritable bowel syndrome’ (both as Medical Subject Heading terms and free text term), and ‘small bowel bacterial overgrowth, small intestine bacterial overgrowth, SIBO, small bowel, small intestine, malabsorption, syndromes, irritable bowel syndrome (IBS), functional diseases, HBT, glucose breath test, lactulose breath test, xylose test, sucrose breath test, jejunal aspirate’ (as free text term). The second included the treatment eval‎uated: ‘rifaximin’ (as subject heading and free text term in Embase and as free text term in the other databases). A search of the abstract books from the Digestive Disease Week (2000–2014), American College of Gastroenterology (2004–2014), United European Gastroenterology Week (2000–2014), British Society of Gastroenterology (2001–2014), and Asian Pacific Digestive Week (2003–2014), was also performed. Bibliographies of all identified relevant studies were used to perform a recursive search. There were no language restrictions. Abstracts of the papers identified by the initial search were eval‎uated independently and in a blinded manner by the two authors for appropriateness. The primary outcome was to assess the efficacy of rifaximin to eradicate SIBO, and the secondary outcome was to eval‎uate its safety.

Table 1. Inclusion criteria

Randomised controlled trials (RCTs) and observational studies using rifaximin to eradicate SIBO

Patients aged ≥18 years

Test to diagnose SIBO reported

Criteria to consider a test positive for SIBO reported

Follow‐up performed to assess eradication

Rifaximin regimens reporteda

Studies not including patients with neoplastic diseases

• a Studies using cyclic treatment of rifaximin or reporting more than one dosage of rifaximin tested but not indicating the number of patients treated with each dosage were not included.

Data extraction

The two reviewers independently extracted data concerning the efficacy and the safety of rifaximin using predesigned data extraction forms, as dichotomous data. In addition, the following clinical data were extracted for each trial: rifaximin regimen (dose and duration), type of study (randomised controlled trial (RCT), cohort studies, etc.), type of test used to diagnose and follow‐up SIBO, sample size, time between end of treatment and eradication assessment (follow‐up), country where the study was carried out, concomitantly use of fibre, mesalazine, pre‐ or probiotics, AEs, whether the study was performed in a gastrointestinal (GI) setting, and if presence of IBS was specifically assessed. Finally, the studies reporting lower GI symptom assessment before and after treatment with rifaximin were identified and eval‎uated. Any disagreement was resolved by discussion between the two Authors. Distinction between cohort and case series was made according to the definition provided by Dekkers and co‐workers'.17 Risk of bias for RCTs was assessed as described in the Cochrane handbook.18 The Newcastle–Ottawa scale (NOS, possible highest score: 9) was used to assess the quality of case–control studies if included.19 Cohort studies and case series were eval‎uated using the 20‐items quality appraisal checklist developed by the Institute of Health Economics (IHE, Canada).20

Data synthesis and statistical analysis

Data for primary and secondary outcomes were pooled from all kinds of studies using a random effects model as there is generally no reason to assume that trials included in the analysis are identical in the sense that the true effect size is exactly the same in all the studies.21, 22 In case of cross‐over studies, data from first and second period were combined, if possible. Intention‐to‐treat analysis (ITT) was adopted where possible. To obtain an estimate of the maximum potential benefits, a per protocol analysis was also performed.23 Where possible, data from RCTs were pooled using a random effects model,21 results expressed as relative risk (RR) for success of SIBO eradication, and number need to treat (NNT) calculated as described in the Cochrane handbook.24 Heterogeneity between trials was assessed by χ2 test for heterogeneity, and I2 statistic with 95% CIs was also calculated.25 Its value ranges from 0% to 100%, with 0% representing no observed heterogeneity, and larger values indicating increasing heterogeneity. A value below 25% was chosen to represent low levels of heterogeneity.25 When the degree of statistical heterogeneity was greater than this cut‐off, for both primary and secondary outcomes, possible explanations were investigated with sub‐group analysis and meta‐regression, using the residual maximum likelihood with random effects weighting and the Knapp and Hartung t‐distribution.26 Prior to analysis, adjusted proportions were calculated using a logit transformation.27 For the primary outcome, only studies where intention‐to‐treat analysis was possible were considered, and the covariates used in meta‐regression and sub‐group analysis were: (i) duration of treatment; (ii) dosage of rifaximin; (iii) type of study (dichotomised as RCT or no‐RCT); (iv) type of test used to diagnose and follow‐up SIBO; (v) sample size of the study (dichotomised as ≥50 patients vs. <50 patients); (vi) time between end of treatment and eradication assessment categorised as: within 7 days after the end of treatment; within 2–4 weeks after the end of treatment; and >4 weeks after the end of treatment; (vii) country where the study was performed (dichotomised as Italy vs. not Italy since most studies were performed in this Country); (viii) concomitantly use of fibre, mesalazine, pre‐ or probiotics (dichotomised as not concomitant use vs. concomitant use). For the secondary outcome, covariates used in meta‐regression and sub‐group analysis were: (i) duration of treatment; (ii) dosage of rifaximin; (iii) type of the study; (iv) sample size of the study; (v) country where the study was performed; (vi) concomitantly use of fibre, mesalazine, pre‐ or probiotics.

We also performed a sub‐group analysis to eval‎uate the eradication rate in patients with IBS and in patients enrolled in extra‐gastrointestinal settings (e.g. patients with diabetes, rosacea, etc).

Studies reporting lower GI symptom assessment before and after treatment with rifaximin were eval‎uated in order to identify those showing symptoms relief after therapy from those which did not.

StatsDirect v. 3.0.165 (StatsDirect, Ltd., Cheshire, UK) and stata (StataCorp, 2013, Stata Statistical Software: Release 13.1; StataCorp LP, College Station, TX, USA) were used to generate Forest plots for primary and secondary outcomes with 95% CIs, as well as Funnel plots. The latter were assessed for evidence of asymmetry and possible publication bias or other small study effects using the Egger's linear regression.28 Stata and Comprehensive Meta‐Analysis v. 3.3.070 (Biostat, Inc., Englewood, NJ, USA) were used to perform meta‐regression analyses.

Results

The search strategy employed identified 292 citations, 227 of which were excluded after examining title and abstract. There was a total of 65 studies that were retrieved and eval‎uated in more detail. Of these, 33 were excluded for various reasons, leaving 32 studies29-60 (2 of which were abstracts36, 54) that were eligible for inclusion involving 1331 patients as shown in Figure 1. 24 studies were cohort studies,29, 32, 33, 35-37, 39-43, 45, 46, 49, 50, 52-60 seven randomised controlled trials (RCTs).30, 31, 34, 44, 47, 48, 51 Finally, one study was a randomised cross‐over study38: since all patients received rifaximin (before or after placebo), they were all included in the proportion meta‐analysis for pooled eradication rates and pooled AEs rate. In two studies, rifaximin was used in patients under mesalazine therapy,30, 35 in other two studies, rifaximin was given to patients taking also fibres,38, 51and in one study, it was employed in association with probiotics.37

Figure 1

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PRISMA flow diagram of the systematic review.

The glucose hydrogen breath test (GHBT) and the lactulose hydrogen breath test (LHBT) were used to diagnose and follow‐up SIBO in 17 (53.1%),30, 31, 34, 36, 37, 40-42, and 13 studies (40.6%)29, 32, 33, 35, 38, 39, 43, 45, 46, 50, 55, 57, 58 respectively. Two studies47, 56used both breath tests to identify SIBO. However, only one56 of those assessed also eradication by combined GHBT and LHBT.

Doses of rifaximin used ranged from 600 mg/die to 1600 mg/die, and duration of treatment ranged from 5 to 28 days. Seventy‐five percentage of the studies were performed in Italy. Detailed characteristics of studies included in the meta‐analysis are provided in Table S1A. No RCT was at low risk of bias (Table S1B). Quality cohort studies ranged between 10/20 and 18/20, according to quality appraisal checklist developed by the IHE20 (Table S1C). ITT eval‎uation was possible in all but six studies.37, 38, 41, 45, 52, 55

Overall eradication rates

Intention‐to‐treat analysis

Intention‐to‐treat analysis was possible in 26 studies29-36, 39, 40, 42-44, 46-51, 53, 54, 56-60including 1141 patients. The pooled eradication rate of SIBO was 70.8% (95% CI: 61.4–78.2; Figure 2) with evidence of significant heterogeneity (Cochrane Q: P < 0.0001; I2 = 89.4%; 95% CI: 86.1–91.6), and Funnel plot asymmetry (Egger test: −4.16; 95% CI: −6.40 to −1.93; P<0.0001, Figure S1A). Being only two the studies where both breath tests were used,47, 56these were not included in the regression and sub‐group analysis.

Figure 2

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Forest plot of SIBO eradication rate according to ITT analysis.

Meta‐regression showed that eradication significantly increased for unit increase in dosage of rifaximin (Figure 3), in non‐RCTs, and in studies where fibres, mesalazine, pre‐ or probiotics were concomitantly used with rifaximin (Table S1D). A sub‐group analysis was also performed according to the same variables used for the meta‐regression analysis (Table S1E).

Figure 3

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Meta‐regression plot: logit of eradication rate vs. daily dose of rifaximin (adjusted for all the other covariates eval‎uated).

Per protocol analysis

The PP analysis included overall 1274 patients from all the 32 studies (the 26 studies where ITT analysis was possible,29-36, 39, 40, 42-44, 46-51, 53, 54, 56-60 and from additional 6 trials where only PP analysis could be accomplished37, 38, 41, 45, 52, 55). The pooled eradication rate of SIBO was 72.9% (95% CI: 65.5–79.8) with evidence of significant heterogeneity (Cochrane Q: P < 0.0001; I2 = 87.5%; 95% CI: 83.8–90.0), and Funnel plot asymmetry (Egger test: −3.47; 95% CI: −5.28 to −1.67; P = 0.0005, Figures S1B and S1C).

Eradication rates in IBS patients

Fourteen studies37, 39, 41, 42, 44, 45, 48-50, 53-55, 58, 59 were performed in patients with IBS. In 4 of them42, 44, 48, 58 it was not possible to extract data concerning the SIBO eradication rate, leaving 10 studies available for the analysis.

Intention‐to‐treat analysis was possible in six studies39, 49, 50, 53, 54, 59 involving 311 patients. The pooled eradication rate of SIBO was 71.6% (95% CI: 56.7–84.4; Figure 4) with evidence of significant heterogeneity (Cochrane Q: P < 0.0001; I2 = 86.4%; 95% CI: 70.3–92.0), but without evidence of Funnel plot asymmetry (Egger test: −4.80; 95% CI: −15.4–5.86; P = 0.279, Figure S1D).

Figure 4

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Forest plot of SIBO eradication rate in IBS patients according to ITT analysis.

The PP analysis included overall 427 patients from all the 10 studies (the eight studies where ITT analysis was possible plus additional four trials where only PP analysis could be accomplished37, 41, 45, 55). The pooled eradication rate of SIBO was 75.4% (95% CI: 65.0–84.5; Figure S1E) with evidence of significant heterogeneity (Cochrane Q: P < 0.0001; I2 = 81.7%; 95% CI: 65.2–88.5), barely without evidence of Funnel plot asymmetry (Egger test: −3.73; 95% CI: −7.69–0.23; P = 0.067, Figure S1F).

Eradication rates in non‐GI settings

Seven studies32, 40, 43, 46, 47, 56, 60 involving 182 patients were performed in non‐GI settings.

According to ITT analysis, the reported overall eradication rate was 74.0% (95% CI: 62.9–83.7; Figure S1G) with evidence of significant heterogeneity (Cochrane Q: P = 0.0149; I2 = 62%; 95% CI: 0–81.4), and without evidence of Funnel plot asymmetry (Egger test: −3.61; 95% CI: −7.94–0.71; P = 0.08; Figure S1H).

According to PP analysis, the overall eradication rate reported was 76.8% (95% CI: 69.2–83.6; Figure S1I) without evidence of significant heterogeneity (Cochrane Q: P = 0.2424; I2 = 24.5%; 95% CI: 0–67.9), but with evidence of Funnel plots asymmetry (Egger test: −2.62; 95% CI: −5.01 to −0.239; P = 0.036; Figure S1J).

Comparative studies

Rifaximin vs. placebo

Only one RCT47 compared rifaximin alone to placebo and it was performed in patients with rosacea. 87.5% (95% CI: 71.0–96.4) of the 32 patients randomised to rifaximin were eradicated, whilst all patient (n = 20) randomised to placebo remained positive. Those were successively treated with rifaximin and the eradication found was 85.0% (95% CI: 64.0–94.8), giving an overall eradication rate of 86.5% (95% CI: 74.2–94.4). No data on AEs were reported in this study.

Rifaximin vs. other antimicrobials

In two studies rifaximin (1200 mg for 7 days) was compared to chlortetracycline (333 mg t.d.s for 7 days)31 or metronidazole (750 mg/die for 7 days)48 respectively, including overall 168 patients. According to ITT analysis, the overall eradication rate was 61.6% (95% CI: 51.1–71.6) and 37.6% (95% CI: 21.1–55.6) in patients randomised to rifaximin and other antimicrobials respectively, with a difference in eradication rate of 24% (95% CI: 6.2–35.5) in favour of rifaximin. The pooled RR of eradicating SIBO was 1.50 (95% CI: 1.11–2.04; Figure S1K) without evidence of significant heterogeneity (Cochrane Q: P = 0.418; I2 = 0%). Egger's test was not performed due to the low number of the studies. NNT was 5 (95% CI: 2–43). According to PP analysis, the overall eradication rate was 64.6% (95% CI: 53.9–74.6) and 42.5% (95% CI: 27.7–58.6) in patients randomised to rifaximin and other antimicrobials respectively, with a difference that was not significant (P = 0.079). The pooled RR of eradicating SIBO was 1.53 (95% CI: 0.95–2.45; Figure S1L), without evidence of significant heterogeneity (Cochrane Q: P = 0.256; I2 = 22.4%).

In the first study, there were no AEs.31 In the second study,48 AEs were significantly more frequent in the metronidazole (22.5%; 95% CI: 14.4–33.5) than in rifaximin group (8.5%; 95% CI: 3.9–17.2; difference in AEs: 14.1%; 95% CI: 2.1–26). Furthermore, six patients (8.5%; 95% CI: 3.9–17.2) in the metronidazole group were obliged to discontinue the study due to the severity of AEs.

Combination studies

Rifaximin plus fibres

In two studies38, 51 rifaximin was given in patients taking fibres. The first one was a randomised crossover trial where patients with SIBO and symptomatic uncomplicated diverticular disease taking insoluble fibre (i.e. bran) were randomised to receive rifaximin or placebo.38 The eradication rates found according to PP analysis were 83.3% (95% CI: 55.1–95.3) for rifaximin and 10% (95% CI: 1.8–40.4) for placebo with a difference in eradication significantly in favour of rifaximin (difference in eradication: 73.3%; 95% CI: 32.8–90.9). During the second phase of the study, patients not eradicated with placebo were treated with rifaximin reporting an eradication rate of 77.7% (95% CI: 39.9–97.1). The overall eradication rate (including the first and the second period) was 80.9% (95% CI: 59.9–92.3). AEs were not reported in details. However, no patient had to discontinue the study due to AEs of rifaximin.

The second study51 was a RCT where patients with SIBO were randomised to receive either rifaximin alone or in combination with partially hydrolysed guar gum. The eradication rate found in the latter group was 85% (95% CI: 70.1–94.2) according to ITT analysis and 87.1% (95% CI: 72.5–95.7) according to PP analysis, and it was significantly higher than that obtained in patients treated with rifaximin alone (62.1%; 95% CI: 44.7–77.5 according to both ITT and PP analysis; difference for eradication rate according to ITT analysis: 22.8%; 95% CI: 3.18–41.5; difference for eradication rate according to PP analysis: 25%; 95% CI: 5.6–43.4).51AEs were not reported in details. However, no patient had to discontinue the study due to AEs of rifaximin.

Rifaximin plus mesalazine

In two studies rifaximin was given in patients taking mesalazine. The first study was a quite small RCT 30 where patients with Crohn's disease and SIBO were randomised to receive either rifaximin or placebo. After the end of treatment, SIBO was eradicated in all patients receiving rifaximin (100%; 95% CI: 59.0–100), and in only 28.5% (95% CI: 3.6–70.9) of those randomised to placebo (difference in eradication: 71.4%; 95% CI: 23.2–92.1). No data on AEs were reported.

The second study was a performed in patients with acute uncomplicated diverticular disease of the colon35 where rifaximin was able to eradicate SIBO in all patients treated (100%; 95% CI: 93.3–100).

Rifaximin plus probiotics

In one study37 SIBO positive patients were treated with rifaximin followed by a cycle of probiotics (Lactobacilli and Bifidobacteria based preparation) for twenty‐day. Follow‐up was performed 4–5 months after the end of treatment and revealed an eradication rate of 82.6% (95% CI: 61.2–95). Treatment did not cause any significant AEs.

Symptom relief

The eval‎uation of studies assessing symptoms before and after treatment with rifaximin (Table S1F) showed that different symptoms were measured in different ways. A thorough analysis of these studies pointed out that symptoms improved after therapy in a large proportion (≥75%) of trials, an effect seen more frequently in studies including IBS patients (Table S1F and Figure S1M). Furthermore, it was possible to extract and pool data concerning the improvement or resolution of symptoms (according to the definitions provided by the investigators) before and after eradication in only 10 trials.29, 30, 32, 33, 38, 41, 45, 46, 51, 57 The overall improvement or resolution of symptoms in eradicated patients was 67.7% (95% CI = 44.7–86.9; Figure S1N), with evidence of heterogeneity (Cochrane Q: P < 0.0001; I2 = 91.3%; 95% CI: 86.9–93.7), but without Funnel plot asymmetry (Egger test: 7.97959; 95% CI: −1.290–17.249, P = 0.0833; Figure S1O).

Adverse events

Adverse events were reported in 17 studies involving 815 patients where only rifaximin was used.31, 32, 34, 39-44, 46, 48, 50, 53, As shown in Figure 5, the overall rate of AEs was 4.6% (95% CI = 2.3–7.5), with evidence of heterogeneity (Cochrane Q: P = 0.0002; I2 = 63.6%; 95% CI: 31.2–77.1), but without Funnel plot asymmetry (Egger test: 0.8794; 95% CI: −0.543–2.301, P = 0.2074; Figure S1P). Meta‐regression and sub‐group analysis revealed that non‐RCTs presented a significant lower incidence of AEs, when compared to RCTs (Table S1G and Table S1H).

Figure 5

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Forest plot of adverse events in patients taking rifaximin alone.

Only in one study55 the 0.47% (95% CI = 0.01–10.6) of patients who experience AEs had to discontinue the therapy prematurely for this reason.

A case of C. difficile infection (CDI) – post treatment – was reported to occur in one patient of a study were rifaximin was used at the dosage of 1200 mg daily for 4 weeks. However, no information about either the time elapsed between the end of antibiotic therapy and the occurrence of the CDI or the presence of concurrent risk factors for the infection was provided.58 The same paper reported also a case of anaphylaxis to rifaximin, again without providing any information on the severity of this AE.

Discussion

Small intestinal bacterial overgrowth is a very heterogeneous syndrome characterised by an increased number and/or abnormal type of bacteria in the small bowel,3 and is becoming a common finding in clinical practice. The management of SIBO should be centred on identifying and correcting underlying causes, treating the overgrowth, and addressing the nutrition deficiencies, where detected.3, 61

Several broad‐spectrum systemic antibiotics such as fluoroquinolones, metronidazole, tetracycline, amoxicillin‐clavulanic acid, chloramphenicol, etc., have been used to manage SIBO.7 However, they are usually associated with several and sometimes severe AEs.61, 62

Rifaximin is a poorly absorbed antibiotic that has been largely used to treat SIBO over the past decades.10, 11 Both experimental and clinical pharmacology clearly show that this compound displays a broad spectrum of antibacterial activity, covering Gram‐positive and Gram‐negative organisms, both aerobic and anaerobic.10, 11 Being virtually non‐absorbed, its bioavailability within the gastrointestinal tract is rather higher with intraluminal and faecal drug concentrations largely exceeding the minimal inhibitory concentration values observed in vitro against a wide range of pathogenic organism. Furthermore, it has been found that rifaximin is able to preserve colonic flora and increase the relative abundance of Lactobacilli and Bifidobacteria, showing ‘eubiotic’ effects.63, 64

The results of our meta‐analysis provide evidence that rifaximin is clinically effective in eradicating SIBO. A significant heterogeneity was found and multivariate meta‐regression identified three covariates (namely the drug dose, the study design and co‐therapy) independently associated with an increased eradication rate. Two studies reported a dose‐dependent eradication rate: the higher the daily dose of rifaximin, the higher the eradication rate.34, 44 In addition, the treatment success was significantly higher in non‐randomised trials.65 Despite RCTs are usually preferred to eval‎uate the efficacy of therapeutic interventions, a large amount of evidence is often accumulated through non‐randomised studies. For this reason, we decided to include them in our analysis. It is worthwhile mentioning that RCTs and non‐randomised studies show a high correlation in their estimates of efficacy. However, it is more frequent to find larger treatment effects in non‐randomised studies compared to than the opposite.66-68 This was indeed the case in our study. Finally, concomitant administration of rifaximin with fibres (both soluble and insoluble), probiotics (Lactobacilli and Bifidobacteria), or mesalazine, three gut microbiota‐directed therapies,69-75 consistently gave higher eradication rate. The global effectiveness of rifaximin in eradicating SIBO was maintained in the sub‐group of patients with IBS, where a significant heterogeneity was still present. It is worth mentioning that the IBS studies were all non‐RCTs.

The analysis of the studies including symptom eval‎uation points to an association between symptom improvement and rifaximin treatment. It was possible to eval‎uate the effect of eradication on symptoms only in 10 studies. Symptoms improved or disappeared in more than two‐thirds of patients (67.7%). However, the sample size was relatively small (205 patients overall) and there was also an incomplete ‘outcome bias’ since, in most studies, data regarding symptoms in non‐eradicated patients were not available. Therefore, the above findings should be interpreted with caution. Nevertheless, two recent studies76, 77have shown that a positive H2BT does predict symptomatic response to antibiotic therapy in patients with IBS. A thoughtful Editorial78 actually suggested that breath testing for SIBO could represent a mean to enrich rifaximin responders amongst IBS patients. By using SIBO as a biomarker of IBS, the therapeutic gain of rifaximin over placebo, reported by the TARGET trials,79 may well be extended to reach a clinically significant figure.

All the studies included in our meta‐analysis employed to diagnose SIBO (as well as to eval‎uate eradication) GHBT or LHBT, which – although widely used – are less sensitive and specific than bacterial culture, till now considered as the gold standard.6 Each substrate has its own advantages and disadvantages, with GHBT favouring specificity over sensitivity, while the reverse is true for LHBT.80 However, whatever breath test is used, the effectiveness of rifaximin in eradicating SIBO remains the same, as evidenced by meta‐regression analysis.

Several antimicrobials have been found effective in reducing gas production, albeit with various success rates for (review see 7). However, only few head to head comparisons were performed. Conversely from our study, a recent meta‐analysis on antibiotic efficacy in treating SIBO narrowed the inclusion criteria to RCTs, showing that antibiotics were more effective than placebo (OR: 2.55; 95% CI: 1.29–5.04).81 In their subsequent analysis on efficacy of rifaximin vs. placebo, the Authors selected three RCTs, two of which were not included in our own meta‐analysis. The first trial82 was performed in children whilst our study was devoted to adults only. The second study83 had some methodological drawbacks. Since LHBT was performed after randomisation, patients did receive treatment independently from the presence of SIBO. Additionally, two criteria for establishing SIBO diagnosis were used, which produced significantly different results (55% positivity with the first criteria vs. 8% positivity with the second criterion). Finally, several different outcomes were adopted to eval‎uate rifaximin efficacy, which makes difficult to compare the results obtained with other studies.

Besides efficacy, our systematic review carefully looked at rifaximin safety and tolerability. Evidence for harms of medical interventions is important when weighting the benefits and risks of treatments in clinical decision‐making. However, such evidence is often suboptimal.84, 85 We found that 4.6% of patients treated with rifaximin reported AEs, but only the 0.47% of them had to discontinue the therapy. Meta‐regression revealed that, among the covariates analysed, only non‐RCTs were significantly associated with a lower rate of AEs when compared to RCTs. Although non‐RCTs are considered conservative in estimating risks of harms (as it happened in our study), eval‎uation of a broad range (i.e. randomised as well non‐randomised) of studies can help to build a complete picture of any potential harm and improve the generalisability of the analysis, without loss of validity.86

When considering the results of this meta‐analysis, several important limitations should be acknowledged. As with any systematic review and meta‐analysis, the results rely on the quality and reporting of the trials. There were no studies using culture to diagnose and follow‐up the eradication. We found a significant heterogeneity among trials and for this reason meta‐regression analysis was performed. However, the results of this analysis are to be interpreted with caution as meta‐regression has its own limitations. Covariates used were merely related to the study design and not to the clinical condition. Furthermore, since meta‐regression describes observational associations across trials, it can suffer from confounding. In addition, as the number of studies and sample size do influence the results of meta‐regression, the lack of an association does not necessarily mean its ‘true’ absence88The associations found in a meta‐regression should therefore be considered more hypothesis‐generating and not regarded as proof of causality.87, 88 Only 25% of studies included in the meta‐analysis were RCTs.30, 34, 38, 44, 47, 48, 51, 89 No RCT resulted to be at low risk of bias, and all had problems with concealment of allocation and blinding.90Furthermore, for the sake of homogeneity, it was possible to pool the results of only two RCTs.31, 48 Most of the studies included were therefore non‐RCTs, which are susceptible to selection bias and, as mentioned before, tend to find larger effects.68, 91-93 Moreover, data concerning the improvement or resolution of symptoms in eradicated patients were limited. Finally, funnel plots asymmetry suggested not only publication bias but the presence of other types of biases, depending on other sources (e.g. heterogeneity, poor methodological quality, etc.).94 All the above limitations clearly affect the quality and the strength of the provided evidence and, therefore, the results of this meta‐analysis should be considered with caution.95

In conclusion, rifaximin therapy is effective and safe for the treatment of SIBO. Since the quality of the available studies is generally poor, well‐designed, large RCTs (with well‐established criteria to assess SIBO and to eval‎uate symptoms before and after therapy according to the eradication status) are needed to substantiate these findings and to establish the optimal regimen (i.e. daily dose and duration) of rifaximin to treat this increasingly common condition.

Authorship

Guarantors of the article: Dr Luigi Gatta and Professor Carmelo Scarpignato.

Author contributions: Luigi Gatta and Carmelo Scarpignato designed the study, did the literature search, analysed and interpreted the data, wrote and critically reviewed the paper.

All authors approved the final version of the manuscript.

Acknowledgements

We are indebted to Jonathan Belsey, MB BS (Sudbury, UK) for the useful suggestions dealing with the statistical approach to data analysis. We are also grateful to the following investigators for providing us with additional data concerning their studies: Prof. R.W. McCallum (El Paso, USA), Dr L. Lombardo (Torino, Italy), Prof. M. Pimentel (Los Angeles, USA), Dr R. D'Incà (Padova, Italy), Prof. A. Gasbarrini (Rome, Italy), Dr A. De Stefano (Pavia, Italy), Dr E. Cerda (Mexico).

Declaration of personal interests: Dr Luigi Gatta has no conflicts of interest to disclose while Professor Carmelo Scarpignato is member of the Speakers' Bureau and of the Scientific Advisory Board of Alfa Wassermann, the manufacturer and marketer of rifaximin.

Declaration of funding interests: None.