As part of AP&T's peer-review process, a technical check of this meta-analysis was performed by Dr Y. Yuan.
Meta-analysis: probiotics in antibiotic-associated diarrhoea
Article first published online: 24 APR 2012
© 2012 Blackwell Publishing Ltd
Alimentary Pharmacology & Therapeutics
Volume 35, Issue 12, pages 1355–1369, June 2012
How to Cite
Videlock, E. J. and Cremonini, F. (2012), Meta-analysis: probiotics in antibiotic-associated diarrhoea. Alimentary Pharmacology & Therapeutics, 35: 1355–1369. doi: 10.1111/j.1365-2036.2012.05104.x
- Issue published online: 14 MAY 2012
- Article first published online: 24 APR 2012
- Manuscript Accepted: 2 APR 2012
- Manuscript Revised: 1 APR 2012
- Manuscript Revised: 6 MAR 2012
- Manuscript Received: 21 FEB 2012
Diarrhoea is a common occurrence in association with antibiotic administration. Earlier studies and meta-analyses have suggested that probiotic administration reduces the incidence of antibiotic-associated diarrhoea (AAD).
To estimate the reduction in risk of AAD with administration of probiotics in randomised placebo-controlled trials and to identify factors associated with such reduction.
Meta-analysis of randomised, double-blinded, placebo-controlled trials including patients treated with antibiotics and administered a probiotic for at least the duration of the antibiotic treatment. The outcome was incidence of diarrhoea irrespective of the presence of Clostridium difficile or the development of pseudomembranous colitis. Meta-analysis and meta-regression methods were used to synthesise data and to assess influence of: mean age, duration of antibiotics, risk of bias and incidence of diarrhoea in the placebo group on outcomes. Subgroup analyses explored effects of different probiotic species, patient populations and treatment indications.
A total of 34 studies were included with 4138 patients. The pooled relative risk (RR) for AAD in the probiotic group vs. placebo was 0.53 (95% CI 0.44–0.63), corresponding to a number needed to treat (NNT) of 8 (95% CI 7–11). The preventive effect of probiotics remained significant when grouped by probiotic species, population age group, relative duration of antibiotics and probiotics, study risk of bias and probiotic administered. The pooled RR for AAD during treatment for Helicobacter pylori (H. pylori) was 0.37 (95% CI 0.20–0.69), corresponding to a NNT of 5 (95% CI 4–10).
This updated meta-analysis confirms earlier results supporting the preventive effects of probiotics in AAD.
Antibiotic-associated diarrhoea (AAD) remains a prevalent condition in both in-patient and out-patient settings. The prevalence of AAD is estimated at 5–39% and is associated with increased costs and hospital length of stay. AAD is a separate clinical entity from Clostridium difficile (C. difficile)-induced diarrhoea and from C. difficile-associated pseudomembranous colitis. The occurrence of AAD can be a limiting factor to adherence to antibiotic regimens and to successful completion of treatment.
Probiotics are ‘live microorganisms, which, when consumed in adequate amounts, confer a health benefit on the host’. Probiotic administration has been linked to modulation of gut mucosal immunity, barrier function, metabolism and direct interaction with pathogenic bacteria. These effects have been the rationale for the use of probiotics in a variety of conditions affecting the gastrointestinal tract, including travellers' diarrhoea, inflammatory bowel disease, irritable bowel syndrome, bacterial overgrowth and C. difficile infection.
Probiotics have been used empirically for the treatment and prevention of AAD. Previous meta-analyses of adult and paediatric randomised trials of various probiotics in AAD have estimated an average relative risk (RR) of development of AAD while on probiotics of approximately 0.4.[5, 6] Furthermore, probiotic supplementation during multiple antibiotic regimens for Helicobacter pylori (H. pylori) eradication regimens has been proposed as a potential option in guidelines based on results for clinical trials.
The research of probiotics continues to expand and clinical trials continue to proliferate, and a number of high-quality, randomised, placebo-controlled trials have been published since the previous systematic reviews and meta-analyses on this topic.
The aim of the present study was to provide an updated meta-analysis of randomised, controlled trials of probiotics in the prevention of AAD. The research questions were (i) Do probiotics reduce the incidence of AAD? (ii) Do probiotics reduce the incidence of AAD during treatment for H. pylori? (iii) Do the effects of probiotics in AAD vary between children and adults? and (iv) What probiotic species are more efficacious in preventing AAD? For the purpose of this meta-analysis, studies of the effect of probiotic in preventing occurrence and treating C. difficile-associated diarrhoea and colitis were not included.
This meta-analysis was conducted and is presented in adherence with the PRISMA statement recommendations.
We conducted a comprehensive literature search of MEDLINE, Cochrane Controlled Trial Register and EMBASE databases (1966–2011). The search terms included combinations of the following keywords: probiotic, diarrhoea, antibiotic therapy and randomised controlled trials (RCTs) as well as common probiotic species as Lactobacillus, S. boulardii, Saccaromyces, LGG, Bifidobacterium. For example, the PubMed search text was: [(probiotics OR bifidobacterium OR saccharomyces boulardii OR lactobacillus) AND (antibiotics AND diarrhoea)] AND (Clinical Trial[ptyp] AND English[lang]). A manual search of the references listed by studies retrieved from the online databases and from previously published systematic reviews was also performed to identify additional studies of interest. The search was limited a priori to studies that were double-blinded, placebo-controlled, parallel group RCTs published as a full text papers in English.
Selection of studies
Details of inclusion criteria and definition of outcome variables assessed and extracted are outlined in Table 1. We included studies with concurrent administration of probiotics and antibiotics where the primary or secondary aim was to study the incidence of diarrhoea during or after antibiotic administration in a probiotic and placebo group. Specific inclusion criteria were the following: (i) description of diarrhoea as a definite outcome, (ii) report of the number of subjects experiencing diarrhoea in the therapeutic or placebo group at the end or during the antibiotic treatment, and (iii) no use of other antidiarrhoeal medications as part of the therapeutic regimen during antibiotic administration (Table 1). The definition for diarrhoea was left to the individual studies.
|Study features||Probiotic(s) used|
|Randomised, double-blinded, placebo-controlled study|
|Raw data available from manuscript on the total number of subjects and responders in|
|Antibiotic(s) administered and their indication|
|Study population||Mean age|
|Diarrhoea||Incidence (study definition)|
|Recorded incidence of Clostridium difficile, pseudomembranous colitis (NOT an inclusion criteria)|
|Risk of Bias||Assessed in each of the following categories and summarised according to Cochrane Handbook:|
|Random sequence generation (selection bias)|
|Allocation and concealment (selection bias)|
|Blinding of participants and personnel (performance bias)|
|Incomplete outcome data (attrition bias)|
|Selective reporting (reporting bias)|
|Other bias (e.g. conflict of interest)|
Two investigators (FC, EV) extracted data. Any discrepancies regarding individual study inclusion, data extraction and interpretation were resolved by consensus prior to the final analysis. Details of the extracted data are presented in Table 2. Study variables were grouped in the following categories: study design, demographics, antibiotic(s) used, treatment duration, diarrhoea incidence, probiotic(s) used and risk of bias. Risk of bias was assessed according to the recommendations of the Cochrane Group.
|Author, year published||N||Incidence of AAD n (N)||Population, Setting||Mean age (years)||Antibiotic/Indication||Probiotics||Timing of diarrhoea reporting (days from initiation of antibiotics unless specified)||Treatment duration (mean days unless specified)||Risk of bias|
|Armuzzi ||60||1 (30)||8 (30)||Adults, Asymptomatic||40||H. pylori eradication||L. GG||7||7||14||Low|
|Arvola ||119||3 (61)||9 (58)||Infants and Children, In-patient, out-patient||4.5||Various||L. GG||14||8.5||Duration of therapy||High|
|Beausoleil ||89||7 (44)||16 (45)||Adults, In-patient||70.9||Various||L. acidophilus and L. casei||21 days following completion of antibiotic and probiotic||9.4||Duration of therapy||Unclear|
|Can ||151||1 (73)||7 (78)||Adults, In-patient||23.9||Various||S.boulardii||28 days from completion of antibiotics||Variable, mean not reported||Not reported||Unclear|
|Cimperman ||23||1 (13)||5 (10)||Adults, In-patient||51||Various||L. reuteri||14 days from completion of probiotic/placebo||14.8||28||High|
|Cindoruk ||124||9 (62)||19 (62)||Adults, Out-patient||48||H. pylori eradication||S.boulardii||28||14||14||Low|
|Correa ||157||13 (80)||24 (77)||Infants, In-patient||1.8||Various||B. lactis, S. termophilus||30 (only two cases occurred after treatment, mean incubation 4 days)||Mean not reported||15||Unclear|
|Cremonini ||83||3 (63)||6 (20)||Adults, Asymptomatic||39.5||H. pylori eradication||3 probiotic groups: a) L. GG, b) S. boulardii, c) Bifidobacteria, Lactobacilli||28||7||14||Low|
|Gao ||255||37 (171)||37 (84)||Adults, In-patient||60||Various||L. acidophilus, L casei||21 days following completion of probiotic/placebo||8.3||Duration + 5 days||High|
|Gotz ||79||3 (36)||9 (43)||Adult, In-patient||64.5||Ampicillin||L. acidophilus and L. bulgaricus||Duration of antibiotics (median incubation period: 3 days)||Median doses = 20||5||Unclear|
|Hickson ||113||7 (57)||19 (56)||Adults, In-patient||73.8||Various||L. bulgaricus, L. casei, S. termophilus||28 days from completion of probiotic/placebo||Variable||Duration + 7 days||Unclear|
|Jirapinyo ||18||3 (8)||8 (10)||Infants, In-patient||0.6||Various||L. acidophilus, B. infantis||Not specified but latest case was 7 days from initiation of antibiotics||Variable||7||High|
|Koning ||38||9 (19)||15 (19)||Adults, Healthy volunteers||26.9||Amoxicillin||Ecological (B. bifidum, B. lactis, B. longum, E. faecium, L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus, L. salivarius)||13||7||14||Unclear|
|Koning ||30||13 (17)||9 (13)||Adults with COPD, In-patient pulmonary rehab||61.4||Various (COPD exacerbation)||B. bifidum, B. lactis, E. faecium, L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus, L. salivarius||14||7||14||High|
|Kotowska ||246||9 (119)||29 (127)||Children, In-patient, out-patient||4.8||Various||S. boulardii||14 days from completion of antibiotic||8.1||Duration of therapy||Low|
|LaRosa ||98||14 (48)||31 (50)||Children, In-patient, out-patient||6.6||Various||L. sporogenes, fructo-oligosaccharide||Not specified||10||10||Low|
|Lewis ||69||7 (33)||5 (36)||Adults, In-patient||76||Various||S. boulardii||Duration of study (no follow-up out of hospital)||7||Duration of therapy||Unclear|
|Lonnermark ||163||6 (80)||5 (83)||Adults, In-patient, out-patient||45||Various||L. plantarum||7 days from completion of probiotic/placebo||11||Duration + 7 days||Low|
|McFarland ||193||7 (97)||14 (96)||Adults, In-patient||41.5||Beta-lactams||S. boulardii||7 weeks following completion of probiotic/placebo (median incubation 18 days, range 3–56)||7.2 (reported for cephalosporins only)||Duration + 3 days||Low|
|Myllyluoma ||47||4 (23)||2 (24)||Adults, Healthy volunteers||55.6||H. pylori eradication||L. GG, L. rhamnosus, P. freudenreichii ssp. shermanii, B. breve||7 (follow-up was for 36 days but results reported are for 7)||7||28||Low|
|Nista ||100||5 (50)||15(50)||Adults, Asymptomatic||44.5||H. pylori eradication||B. Clausii||7||7||14||Unclear|
|Orrhage ||30||6 (20)||7 (10)||Adults, healthy||37||Clindamycin||B. longum||28||7||21||Unclear|
|Psaradellis ||437||47 (216)||65 (221)||Adults, In-patient/out-patient||58.8||Various||L. acidophilus, L. casei||21 days following completion of probiotic||9.7||Duration + 5 days||High|
|0zynski ||240||9 (120)||20 (120)||Children, Out-patient||4.6||Various||L. rhamnosus||14 days following completion of antibiotics (mean incubation 6 days)||8.1||Duration of therapy||Low|
|Safdar ||39||4 (23)||6 (16)||Adults, In-patient||69.1||Various||Florajen (L. acidophillus)||14 days from completion of antibiotics||9.5 (based on reported mean probiotic/placebo duration)||Duration + 14||Low|
|Song ||214||4 (103)||8 (111)||Adults, In-patient||60.5||Various||L. rhamnosus, L. acidophilus||14||12||14||High|
|Surawicz ||180||11 (116)||14 (64)||Adults, In-patient||47.5||Various||S. boulardii||Duration of probiotics (not defined as AAD if occurrence is within 8 days)||Mean not reported (>3 days)||Duration + 14 days||High|
|Szajewska ||64||2 (34)||6 (30)||Children, In-patient||12.1||H. pylori eradication||L. GG||21||7||7||Low|
|Szymanski ||78||1 (40)||2 (38)||Children, In-patient, out-patient||7.5||Various||B. longum, L. rhamnosus, L. plantarum||14 days from completion of antibiotics||8.5||Duration of therapy||Low|
|Tankanow ||38||10 (15)||16 (23)||Children, Out-patient||2.4||Amoxicillin||L. acidophilus and L. bulgaricus||12||10||10||High|
|Thomas ||267||39 (133)||40 (134)||Adults, In-patient||55.8||Various||L. GG||21||12||14||Low|
|Vanderhoof ||188||7 (93)||25 (95)||Children, Out-patient||4||Various||L. GG||10||10||Duration of therapy||Low|
|Wenus ||63||2 (34)||8 (29)||Adults, In-patient||57.5||Various||L. GG, L.Acidophilus, Bifidobacterium Bb-12||14||≥ 7||14||Unclear|
|Wunderlich ||45||2 (23)||6 (22)||Adults, In-patient, out-patient||33||Various||E. faecium||7||7||7||High|
To avoid the inclusion of duplicated data that may lead to an overestimation of placebo effects in final analysis, retrieved studies were carefully appraised and examined by comparison of geographical locations, author names and period of study, as discussed in the Cochrane Handbook for Systematic Reviews of Interventions. The six domains assessed for bias are listed in Table 1 and the criteria used to judge a study as ‘high’ or ‘low’ risk were those outlined in Chapter 8 of the Cochrane Handbook. A study was given an overall rating of ‘high risk’ if one or more of the six domains was assessed to be high risk, a rating of ‘low risk’ if all domains were assessed to be ‘low risk’ and ‘unclear risk’, if all domains were either ‘low risk’ and ‘unclear risk’.
Meta-analysis and subgroup analyses
All statistical analyses were performed using JMP v.7, RevMan v. 5.1 and Comprehensive Meta-Analysis 2.2. First, the RR and 95% CI of diarrhoea on probiotic treatment vs. placebo treatment was calculated for each study based on the per protocol (PP) sample size, and we performed a sensitivity analysis based on primary authors' defined ITT sample. Statistical heterogeneity across the various studies was then tested with the use of Q-statistic. A P value <0.10 indicated a significant statistical heterogeneity across studies, thus a random effects model was used. In addition to the main (overall) analysis, multiple subgroup analyses were performed, yielding a pooled RR including and excluding studies of H. pylori treatment, paediatric populations and grouping studies by risk of bias, relative duration of antibiotics and probiotics and by probiotic species used. The overall number needed to treat (NNT) and its 95% CI were also computed using pooled raw events for the overall analysis and for the H. pylori subgroup analysis.
Potential association between the response to probiotic administration and study-related variables was studied by meta-regression using unrestricted maximum likelihood models. The log odds ratio of diarrhoea during antibiotic therapy was the dependent variable in the meta-regression model. Independent study-level variables were: (i) the risk of bias (using a scale of low, uncertain and high risk of bias), (ii) individual study mean patient age (iii) probiotic type and (iv) incidence of diarrhoea in the placebo group.
The literature search identified 203 articles that met the search criteria. Figure 1 shows the flow of this meta-analysis. Sixteen studies were excluded after full text review.[16-31] After the screening process, 34 parallel-design, double-blinded, placebo-controlled, randomised trials published in English were included.[32-65] The studies were published between 1979 and 2011.
Patients' characteristics, study design and interventions of the trials included are summarised in Table 2. Ten trials were conducted in paediatric populations, the remainder in adult patients. Mean age in the paediatric and adult trials was 5 and 52 years respectively. The probiotics used included lactobacilli, bifidobacteria, enterococci, streptococci, the yeast S. boulardii and combinations of these species. The duration of antibiotic and probiotic supplementation was variable but ranged from a minimum of 3 days to several weeks.
Fourteen studies were assessed to have a low risk of bias. In 10 studies, the risk was unclear and 10 studies were assessed as high risk. The justification for these classifications is outlined in Table 3.
|Arvola ||28.7% attrition rate.|
|Cimperman ||The majority of subjects that withdrew did so for GI side effects, and most withdrew from the placebo group.|
|Psaradellis ||This study was conducted by paid employees of JSS medical research Inc which was paid by the manufacturer to conduct the study.|
|Gao ||‘Bio-K + International (Laval, Quebec, Canada) provided financial support for this clinical trial. Sprim Advanced Life Sciences helped with study planning, conduct and analysis and with paper development’.|
|Jirapinyo ||The methods were not adequately described, and the attrition rate was not described. Unblinding may have occurred.|
|Koning ||38% attrition rate.|
|Song ||Possible bias in allocation as envelopes sealed by investigators.|
|Surawicz ||High attrition rate and patients developing diarrhoea within 72 h were excluded.|
|Tankanow ||Possible unblinding as there were unequal drop-outs and one of the reasons was for ‘taste’, as well as 37% attrition.|
|Wunderlich ||Study objective was to assess AAD in patients with diarrhoea and AAD which introduces possible selection bias.|
|Beausoleil ||The methods were not adequately described.|
|Can ||The methods were not adequately described. It was not mentioned whether all participants completed study.|
|Correa ||The methods were not adequately described.|
|Gotz ||The methods were not adequately described.|
|Hickson ||Randomisation method was not clearly described.|
|Koning ||Randomisation method was not clearly described.|
|Lewis ||The methods were not adequately described and did not exclude subjects taking laxatives. The incidence of diarrhoea identical to number taking laxatives but it was not stated if these were the same patients.|
|Nista ||The methods were not adequately described.|
|Orrhage ||The methods were not adequately described.|
|Wenus ||The methods were not adequately described.|
The definition of the event of diarrhoea varied across trials, with most studies considering as diarrhoea a daily bowel frequency of at least 3 bowel movements daily, while some also used stool consistency. When combined, the studies included enrolled 4138 patients, of which 2154 received probiotic supplementation.
There was significant heterogeneity across studies (P = 0.0005), thus a random effects model was thus chosen to calculate pooled estimates of treatment effects.
Effect of probiotics on antibiotic-associated diarrhoea
When including all studies of adult and paediatric populations, probiotics resulted in a pooled RR of AAD of 0.53 (95% CI 0.44–0.63) compared to placebo (Figure 2). This risk reduction corresponded to an average NNT of 8 (95% CI 7–11).
The pooled RR among the 10 paediatric studies was 0.48 (95% CI 0.35–0.65) similar to the pooled RR of 0.53 (95% CI 0.43–0.66) from the 24 adult studies (Figures 3a and b).
The pooled RR from 6 studies during H. pylori treatment was 0.37 (95% CI 0.20–0.69) corresponding to a NNT of 5 (95% CI 4–10), while the pooled RR excluding studies during H. pylori treatment was 0.56 (95% CI 0.46–0.67), corresponding to a NNT of 9 (95% CI 7–12).
An analyses based on the ITT sample size, where provided by authors, yielded similar RRs to the analysis based on the PP sample size (data available upon request).
No effect on the outcome was detected by risk of bias (intercept −0.75, slope 0.10, P = 0.12) mean patient age (intercept −0.71, slope 0.0046, P = 0.06), duration of antibiotics (intercept −0.84, slope 0.040, P = 0.26), or incidence of diarrhoea in the placebo group (intercept −0.67, slope 0.003, P = 0.25).
Table 4 summarises the pooled RRs from subgroup analyses of trials according to probiotic used, indication, population, setting, relative treatment duration of antibiotics and probiotics and risk of bias. Lactobacilli were the most used probiotic species, with 24 studies, including 8 studies testing the effect of Lactobacillus GG. Saccharomyces boulardii was tested in 7 studies and 10 studies used bifidobacteria (including, as part of a combination). The pooled estimates of the preventative effects on AAD appeared consistent across the probiotic species administered. The pooled RR for studies with low risk of bias was obtained, combining 14 studies assessed as low risk yielding a RR of 0.50 (95% CI 0.37–0.67), which was similar to the RR of 0.45 (95% CI 0.33–0.61) for the 10 studies with unclear risk of bias.
|N studies||Total N||Effect Estimate||95% CI||Heterogeneity (I2, P)|
|Lactobacillus GG||8||847||0.40||0.20–0.81||67%, 0.003|
|Saccaromyces boulardii||7||1004||0.46||0.30–0.70||27%, 0.23|
|Any lactobacilli||24||2817||0.56||0.45–0.69||50%, 0.003|
|H. pylori eradication||6||478||0.37||0.20–0.69||36%, 0.16|
|Exluding H. pylori eradication||28||3655||0.56||0.46–0.67||43%, 0.009|
|By population, setting|
|All Adult||24||2921||0.53||0.43–0.66||44%, 0.01|
|Adult, in-patient||13||1693||0.52||0.38–0.72||54%, 0.01|
|Adult, out-patient and combined in/out||4||769||0.68||0.49–0.95||9%, 0.35|
|Adult, asymptomatic||6||358||0.42||0.24–0.75||47%, 0.09|
|All paediatric||10||1246||0.48||0.35–0.65||36%, 0.12|
|Paediatric, in-patient||3||239||0.48||0.30–0.77||0%, 0.79|
|Paediatric, out-patient and combined in/out||7||1005||0.46||0.30–0.71||57%, 0.03|
|By risk of bias|
|Low Risk||14||1888||0.48||0.35–0.68||51%, 0.01|
|Unclear Risk||10||889||0.48||0.37–0.63||3%, 0.41|
|Low/Unclear risk||24||2777||0.48||0.39–0.60||37%, 0.04|
|High risk||10||1356||0.62||0.46–0.84||52%, 0.03|
|By comparative duration|
|Equal Duration||16||1523||0.49||0.38–0.63||26%, 0.17|
|Probiotics longer by at least 7 days||12||1298||0.53||0.38–0.75||55%, 0.01|
The funnel plot using random effects (Figure 4), and Egger's intercept test (intercept −1.41, P = 0.001) suggested a lack of publications reporting negative results, thus supporting the presence of a negative publication bias.
This meta-analysis of 34 clinical trials supports the efficacy of probiotics in the prevention of AAD, expanding information from earlier meta-analyses. Our analysis shows that the preventive effect of probiotic administration is present across different probiotic species, is observed equally in children and adults, and appears to be independent of the concomitant antibiotics used and of the indication for the antibiotic treatment. The overall effect remains statistically significant even when restricting the analysis to studies with low risk of bias.
This meta-analysis tackles a clinically relevant issue. The incidence of AAD is variable yet remarkable, estimated between 5% and 39% of subjects undergoing any antibiotic treatment. Antibiotic-associated diarrhoea results in patient discomfort, potential loss of adherence to treatment, increased costs and can lengthen hospital stays in the in-patient setting.
The pathophysiological determinants of AAD are probably multiple. For instance, certain antibiotics, such as erythromycin and other macrolides, possess gastroduodenal prokinetic effects through agonistic activity on the motilin receptor. Most antibiotics may also significantly affect the composition and balance of the normal gut flora, in turn altering the bacterial breakdown of carbohydrates and the concentration of conjugated and unconjugated bile acids in the gut, which may result in alteration in the bowel habits from osmotic and motor mechanisms. Alteration of the gut microecology may favour excess proliferation of organisms that possess the potential for inducing greater water and electrolyte secretion, or that may act as true pathogens even in individuals with preserved mucosal immunity, such as C. difficile, Klebsiella ocitoca, staphylococci and candida spp.[66, 67] In these settings, supplementation with probiotics during antibiotic treatment has been proposed to enhance the gut mucosal barrier function of the host, to favour competitive exclusion of potentially proliferating pathogen species among commensal bacteria, and to positively affect the host's immune response. In addition, certain probiotics may have direct anti-microbial effects against specific pathogens. For example, a bacteriocin produced by L. Salivarius was shown to be protective against Listeria monocytogenes, and S. Boulardii can directly bind to C. difficile-produced toxin A.
The supplementation of probiotics during antibiotic treatment to treat or prevent AAD is currently not a standard of care. Prior meta-analyses of probiotics for the prevention of AAD have shown similar risk reductions. Two meta-analyses, including 9 and 22 studies reported RRs (95% CI) of 0.37 (0.26, 0.53) and 0.40 (0.27, 0.57), respectively.[5, 70] A more recent meta-analysis, which included 25 studies, reported a risk reduction of 0.43 (95% CI: 0.31–0.58). The present meta-analysis includes 20 of the 25 studies analysed previously, excluding the remaining studies for various inadequate design and reporting issues,[19, 25, 31, 71, 72] and includes 14 new studies published since the previous meta-analysis. Our estimates suggest a similar reduction in the risk of developing AAD while on a probiotic, compared to placebo.
A greater risk reduction was seen in the pooled analysis of studies of H. pylori eradication regimens. Possible explanations for this difference are both biological and methodological. The beneficial effect of probiotics on gastrointestinal (GI) symptoms, such as diarrhoea, may be enhanced when the concomitant antibiotic treatment is used to treat a GI condition. In addition, the antibiotic regimens for H. pylori often include multiple agents and commonly are associated with diarrhoea. It is also possible that H. pylori infection results in a more prominent bacterial flora imbalance, which may be the basis for a greater perceived effect of probiotic administration. Clinical studies of H. pylori eradication also used defined antibiotic regimens, and all but one study were conducted in asymptomatic volunteers, resulting in more homogeneity in study protocol and patient population within and between studies.
Strengths of the present meta-analysis in addition to the larger number of studies included are the adherence to updated consensus guidelines (PRISMA) including an assessment of risk of bias rather than quality or adequate reporting of methods, and the numerous sensitivity analyses performed.
Our results should also be interpreted in the context of several limitations. Our inclusion criteria and search strategy may have missed clinical trials with non-diarrhoea primary outcomes but in which the incidence of diarrhoea was explicitly measured. For example, all studies on H. pylori with the primary outcome of H. pylori eradication may not have been retrieved; however, this strategy also limits the search to studies published by investigators with a specific interest in the outcome of diarrhoea and potentially non-retrieved studies could conceivably had less rigorous collection of data on the outcome of diarrhoea (for example, patient self-report). The pooled estimate of probiotic efficacy resulted from studies that varied in the populations studied (adult vs. paediatric, in-patient vs. out-patient), in nature and modalities of intervention (probiotic strains and their doses, antibiotics used, duration of treatment) and in the outcomes considered (definitions of diarrhoea and its incidence, duration of follow-up). We attempted to ascertain the impact of these factors on our estimates by means of meta-regression using the log odds ratio of diarrhoea during antibiotic therapy in the placebo group as the dependent variable, and by subgroup analyses. While the presence of risk factors for AAD has not been studied and therefore cannot be accounted for, the patient populations in the included studies may have differed in their underlying risk for AAD.
Subgroup analyses by type of probiotic showed similar effects for the most commonly studied probiotic strains. These sensitivity analyses suggest an efficacy shared by most probiotics in the prevention of AAD.
With the exception of studies in H. pylori eradication, there was considerable between-study and within-study variability of the antibiotics regimens administered, thereby preventing a reliable subgroup analysis of effect by antibiotic administered. Notably, there was also substantial variability in the underlying overall health conditions of the study participants. Such variability, however, could also suggest that the effects of probiotics are generalisable to wider patient populations. An additional limitation is that the review was limited to studies published in English and to full text articles. A high-quality meta-analysis including non-English language papers published until 2006, however, points to effect sizes similar to those observed in the present analysis.
Probiotic administration is usually purported as devoid of side effects. In patients who are in critical conditions and in those with severe immune compromise, potential harmful effects of probiotics have been reported.[73, 74] We did not systematically extract data related to adverse events and thus number needed to harm was not calculated; however, there were no serious adverse effects related to probiotics reported in any of the studies. Finally, while we report a NNT to aid in the interpretation of the findings, we recognise the limitations of this summary statistic when applied to pooled results especially when there is significant heterogeneity across studies.
In conclusion, this meta-analysis shows the preventive effect of probiotic supplementation on the incidence of AAD to be relatively consistent across different probiotic species used, various antibiotic regimens and indications, including H. pylori eradication, and in adult and paediatric populations.
Declaration of personal and funding interests: None.
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