1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References


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.


  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

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.[1] 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’.[2] Probiotic administration has been linked to modulation of gut mucosal immunity, barrier function, metabolism and direct interaction with pathogenic bacteria.[3] 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.[4]

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.[7]

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.


  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

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.


  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

This meta-analysis was conducted and is presented in adherence with the PRISMA statement recommendations.[8]

Search strategy

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.

Table 1. Inclusion criteria and variables assessed and recorded for each probiotic study
Study featuresProbiotic(s) used
Randomised, double-blinded, placebo-controlled study
Study duration
Raw data available from manuscript on the total number of subjects and responders in
-Placebo arm
-Probiotic arm
Antibiotic(s) administered and their indication
Study populationMean age
Gender distribution
DiarrhoeaIncidence (study definition)
Recorded incidence of Clostridium difficile, pseudomembranous colitis (NOT an inclusion criteria)
Risk of BiasAssessed 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)

Data extraction

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.[9]

Table 2. Characteristics of studies included in the meta-analysis
Author, year publishedNIncidence of AAD n (N)Population, SettingMean age (years)Antibiotic/IndicationProbioticsTiming of diarrhoea reporting (days from initiation of antibiotics unless specified)Treatment duration (mean days unless specified)Risk of bias
  1. COPD, chronic obstructive pulmonary disease; H. pylori, Helicobacter pylori; L. GG, Lactobacillus GG.

Armuzzi [16]601 (30)8 (30)Adults, Asymptomatic40H. pylori eradicationL. GG7714Low
Arvola [33]1193 (61)9 (58)Infants and Children, In-patient, out-patient4.5VariousL. GG148.5Duration of therapyHigh
Beausoleil [34]897 (44)16 (45)Adults, In-patient70.9VariousL. acidophilus and L. casei21 days following completion of antibiotic and probiotic9.4Duration of therapyUnclear
Can [35]1511 (73)7 (78)Adults, In-patient23.9VariousS.boulardii28 days from completion of antibioticsVariable, mean not reportedNot reportedUnclear
Cimperman [36]231 (13)5 (10)Adults, In-patient51VariousL. reuteri14 days from completion of probiotic/placebo14.828High
Cindoruk [37]1249 (62)19 (62)Adults, Out-patient48H. pylori eradicationS.boulardii281414Low
Correa [38]15713 (80)24 (77)Infants, In-patient1.8VariousB. lactis, S. termophilus30 (only two cases occurred after treatment, mean incubation 4 days)Mean not reported15Unclear
Cremonini [5]833 (63)6 (20)Adults, Asymptomatic39.5H. pylori eradication3 probiotic groups: a) L. GG, b) S. boulardii, c) Bifidobacteria, Lactobacilli28714Low
Gao [40]25537 (171)37 (84)Adults, In-patient60VariousL. acidophilus, L casei21 days following completion of probiotic/placebo8.3Duration + 5 daysHigh
Gotz [41]793 (36)9 (43)Adult, In-patient64.5AmpicillinL. acidophilus and L. bulgaricusDuration of antibiotics (median incubation period: 3 days)Median doses = 205Unclear
Hickson [42]1137 (57)19 (56)Adults, In-patient73.8VariousL. bulgaricus, L. casei, S. termophilus28 days from completion of probiotic/placeboVariableDuration + 7 daysUnclear
Jirapinyo [43]183 (8)8 (10)Infants, In-patient0.6VariousL. acidophilus, B. infantisNot specified but latest case was 7 days from initiation of antibioticsVariable7High
Koning [44]389 (19)15 (19)Adults, Healthy volunteers26.9AmoxicillinEcological (B. bifidum, B. lactis, B. longum, E. faecium, L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus, L. salivarius)13714Unclear
Koning [45]3013 (17)9 (13)Adults with COPD, In-patient pulmonary rehab61.4Various (COPD exacerbation)B. bifidum, B. lactis, E. faecium, L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus, L. salivarius14714High
Kotowska [46]2469 (119)29 (127)Children, In-patient, out-patient4.8VariousS. boulardii14 days from completion of antibiotic8.1Duration of therapyLow
LaRosa [47]9814 (48)31 (50)Children, In-patient, out-patient6.6VariousL. sporogenes, fructo-oligosaccharideNot specified1010Low
Lewis [48]697 (33)5 (36)Adults, In-patient76VariousS. boulardiiDuration of study (no follow-up out of hospital)7Duration of therapyUnclear
Lonnermark [49]1636 (80)5 (83)Adults, In-patient, out-patient45VariousL. plantarum7 days from completion of probiotic/placebo11Duration + 7 daysLow
McFarland [50]1937 (97)14 (96)Adults, In-patient41.5Beta-lactamsS. boulardii7 weeks following completion of probiotic/placebo (median incubation 18 days, range 3–56)7.2 (reported for cephalosporins only)Duration + 3 daysLow
Myllyluoma [51]474 (23)2 (24)Adults, Healthy volunteers55.6H. pylori eradicationL. GG, L. rhamnosus, P. freudenreichii ssp. shermanii, B. breve7 (follow-up was for 36 days but results reported are for 7)728Low
Nista [52]1005 (50)15(50)Adults, Asymptomatic44.5H. pylori eradicationB. Clausii7714Unclear
Orrhage [53]306 (20)7 (10)Adults, healthy37ClindamycinB. longum28721Unclear
Psaradellis [54]43747 (216)65 (221)Adults, In-patient/out-patient58.8VariousL. acidophilus, L. casei21 days following completion of probiotic9.7Duration + 5 daysHigh
0zynski [55]2409 (120)20 (120)Children, Out-patient4.6VariousL. rhamnosus14 days following completion of antibiotics (mean incubation 6 days)8.1Duration of therapyLow
Safdar [56]394 (23)6 (16)Adults, In-patient69.1VariousFlorajen (L. acidophillus)14 days from completion of antibiotics9.5 (based on reported mean probiotic/placebo duration)Duration + 14Low
Song [57]2144 (103)8 (111)Adults, In-patient60.5VariousL. rhamnosus, L. acidophilus141214High
Surawicz [58]18011 (116)14 (64)Adults, In-patient47.5VariousS. boulardiiDuration of probiotics (not defined as AAD if occurrence is within 8 days)Mean not reported (>3 days)Duration + 14 daysHigh
Szajewska [59]642 (34)6 (30)Children, In-patient12.1H. pylori eradicationL. GG2177Low
Szymanski [58]781 (40)2 (38)Children, In-patient, out-patient7.5VariousB. longum, L. rhamnosus, L. plantarum14 days from completion of antibiotics8.5Duration of therapyLow
Tankanow [61]3810 (15)16 (23)Children, Out-patient2.4AmoxicillinL. acidophilus and L. bulgaricus121010High
Thomas [62]26739 (133)40 (134)Adults, In-patient55.8VariousL. GG211214Low
Vanderhoof [63]1887 (93)25 (95)Children, Out-patient4VariousL. GG1010Duration of therapyLow
Wenus [64]632 (34)8 (29)Adults, In-patient57.5VariousL. GG, L.Acidophilus, Bifidobacterium Bb-1214≥ 714Unclear
Wunderlich [65]452 (23)6 (22)Adults, In-patient, out-patient33VariousE. faecium777High

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.[10] 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.[10] 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[11] 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.[12] A P value <0.10 indicated a significant statistical heterogeneity across studies, thus a random effects model was used.[13] 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.

Assessment of publication bias

Publication bias was determined by the funnel plot of Beggs & Mazumbar's rank correlation test[14] and by Egger's intercept test using a random effects models.[15]


  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Eligible studies

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.


Figure 1. Meta-analysis flow.

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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.

Table 3. Description of studies categorised as high or unclear risk of bias
High Risk
Arvola [33]28.7% attrition rate.
Cimperman [36]The majority of subjects that withdrew did so for GI side effects, and most withdrew from the placebo group.
Psaradellis [54]This study was conducted by paid employees of JSS medical research Inc which was paid by the manufacturer to conduct the study.
Gao [40]‘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 [43]The methods were not adequately described, and the attrition rate was not described. Unblinding may have occurred.
Koning [45]38% attrition rate.
Song [57]Possible bias in allocation as envelopes sealed by investigators.
Surawicz [58]High attrition rate and patients developing diarrhoea within 72 h were excluded.
Tankanow [61]Possible unblinding as there were unequal drop-outs and one of the reasons was for ‘taste’, as well as 37% attrition.
Wunderlich [65]Study objective was to assess AAD in patients with diarrhoea and AAD which introduces possible selection bias.
Unclear risk
Beausoleil [34]The methods were not adequately described.
Can [35]The methods were not adequately described. It was not mentioned whether all participants completed study.
Correa [38]The methods were not adequately described.
Gotz [41]The methods were not adequately described.
Hickson [42]Randomisation method was not clearly described.
Koning [44]Randomisation method was not clearly described.
Lewis [48]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 [52]The methods were not adequately described.
Orrhage [53]The methods were not adequately described.
Wenus [64]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).


Figure 2. Forest plot showing random effects (RE) relative risk (RR) estimates with the corresponding 95% CI for the development of AAD (probiotic vs. placebo arms) in all studies.

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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).


Figure 3. Forest plots showing random effects (RE) relative risk (RR) estimates with the corresponding 95% CI for the development of AAD (probiotic vs. placebo arms) in adult (Figure 3a) and paediatric studies (Figure 3b).

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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).

Subgroup analyses

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.

Table 4. Subgroup analyses of pooled relative risks
 N studiesTotal NEffect Estimate95% CIHeterogeneity (I2, P)
  1. H. pylori, Helicobacter pylori.

All3441380.530.44–0.6344%, 0.004
By probiotic
 Lactobacillus GG88470.400.20–0.8167%, 0.003
 Saccaromyces boulardii710040.460.30–0.7027%, 0.23
 Any lactobacilli2428170.560.45–0.6950%, 0.003
 Bifidobacteria106020.550.37–0.8248%, 0.04
H. pylori eradication64780.370.20–0.6936%, 0.16
Exluding H. pylori eradication2836550.560.46–0.6743%, 0.009
By population, setting
 All Adult2429210.530.43–0.6644%, 0.01
 Adult, in-patient1316930.520.38–0.7254%, 0.01
 Adult, out-patient and combined in/out47690.680.49–0.959%, 0.35
 Adult, asymptomatic63580.420.24–0.7547%, 0.09
 All paediatric1012460.480.35–0.6536%, 0.12
 Paediatric, in-patient32390.480.30–0.770%, 0.79
 Paediatric, out-patient and combined in/out710050.460.30–0.7157%, 0.03
By risk of bias
 Low Risk1418880.480.35–0.6851%, 0.01
 Unclear Risk108890.480.37–0.633%, 0.41
 Low/Unclear risk2427770.480.39–0.6037%, 0.04
 High risk1013560.620.46–0.8452%, 0.03
By comparative duration
 Equal Duration1615230.490.38–0.6326%, 0.17
 Probiotics longer by at least 7 days1212980.530.38–0.7555%, 0.01

Publication bias

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.


Figure 4. Begg's funnel plot SE (effect estimate) versus the effect estimate for each study. Each study is represented by a single dot. Log relative risk (RR) from the random-effect model was used as the effect estimate. The overall effect estimate is indicated by the vertical line. The two diagonal lines represent 95% CI.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

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.[1] 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.[1]

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.[68] 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.[69]

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).[6] 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[37] 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.[6]

Probiotic administration is usually purported as devoid of side effects.[4] 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.[75]

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.


  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Declaration of personal and funding interests: None.


  1. Top of page
  2. Summary
  3. Introduction
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References
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