Diarrhea is a common adverse effect of systemic antibiotic treatment. Antibiotic-associated diarrhea (AAD) occurs in 5% to 39% of patients, from the beginning and up to two months after the end of treatment [1
]. Any type of antibiotics can cause AAD. In particular, aminopenicillins, cephalosporins, and clindamycin that act on anaerobes are associated with a high risk of AAD [2
]. The symptoms range from mild and self-limiting diarrhea to severe diarrhea, the latter particularly in Clostridium difficile
The primary care sector is responsible for the bulk of antibiotic consumption in humans [3
]. Reports suggest that a major part of this antibiotic use may, in fact, be inappropriate, and efforts to reduce and target antibiotics are rightly promoted. However, when antibiotic therapy is deemed necessary, it is useful to have an easily available, cost effective, and safe method to prevent side effects associated with the issued antibiotic.
Probiotics are defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [4
]. The rationale behind the administration of probiotics in gastrointestinal disorders is based on the hypothesis that they may assist a normalization of an unbalanced gastrointestinal flora. There are many proposed mechanisms by which probiotics enhance intestinal health, including the stimulation of immunity, competition for nutrients, the inhibition of the epithelial and mucosal adherence of pathogens, the inhibition of epithelial invasion, and the production of antimicrobial substances [5
Numerous probiotic species have been tested, most commonly the Lactobacillus
genus, and Saccharomyces
genus. Previous reviews suggest that probiotics are useful in the prevention of AAD, especially in a pediatric population (RR 0.46; 95% CI 0.35 to 0.61) with a NNT of 10 [6
]. However, these reviews have mainly focused on the prevention of AAD in inpatients from secondary care settings, which was likely influenced by the intensity of antibiotic treatment (intravenous vs. oral), the type of infection, and the microbial pathogens, in turn making the translation of the results into the primary care sector less straightforward.
The objective of this systematic review and meta-analysis was thus to assess the benefits and harms of probiotics used for the prevention of antibiotic-associated diarrhea in outpatients of all ages.
The results of this review point towards a protective effect of the use of probiotics as adjunct therapy to prevent antibiotic-associated diarrhea in outpatients of all ages. Data from 17 studies with a total of 3631 patients found that the use of a probiotic may reduce the risk of AAD by 51% (RR 0.49; 95% CI 0.36 to 0.66; I2 = 58%), with no apparent increase in the risk of side effects (RD 0.00, 95% CI −0.02 to 0.02, 2.363 participants). The number needed to treat (NNT) to prevent one case of diarrhea was 11 (95% CI 6 to 13). The quality of evidence for the main outcome was categorized as moderate due to a moderate degree of heterogeneity and a high risk of bias in some trials.
A strain-specific subgroup analysis combining data from eight of the included trials showed a similar protective effect of probiotics in the prevention of AAD when compared to the overall pooled analysis. The most effective probiotic strain was L. rhamnosus GG (RR 0.29; 95% CI 0.15 to 0.57; 307 participants), followed by S. boulardii (RR 0.41; 95% CI 0.30 to 0.57; 1.139 participants). Furthermore, with this subgroup analysis, the heterogeneity from the pooled analysis (I2 = 58%) disappeared in each of the three subgroups (I2 = 0%).
Data from the seven studies applying the definition of diarrhea defined by WHO showed a similar protective effect of probiotic use to prevent AAD (RR 0.54; 95% CI 0.36 to 0.82) but with no statistically significant heterogeneity (I2 = 27%; p = 0.22). This explains some of the statistical heterogeneity, and it also demonstrates the importance of having clear and consistent definitions of outcomes in clinical trials. The quality of evidence for this outcome was categorized as high.
We also provide preliminary evidence of a possible dose-response relationship, as results indicate that higher doses were associated with fewer ADD events (higher than 5 × 109
CFU 3.6% vs. less than 5 × 109
CFU 8.9%; p
< 0.002). However, this result should be interpreted with caution as the analysis was on any probiotic species and not on specific strains. A review investigating different treatment regimens of probiotics in human studies concluded that a dose-response relationship exists within the commonly studied range of 108
CFU, meaning that, within this range, a higher dose will lead to a better response [25
]. However, the previously-mentioned Cochrane review on the prevention of pediatric AAD did not find any statistically significant difference in the use of high versus low dose probiotics (over or under 5 × 109
We did not find evidence to suggest an increase in effect when more than one probiotic strain was used to prevent AAD.
Our result was fairly consistent across a number of subgroup analyses in which RRs ranged from 0.36 to 0.58. All but two subgroup analyses yielded a statistically significant result. Of note, the analysis of studies with a low risk of bias did not produce a statistically significant result. This is concerning, and although in part may be ascribed to a low number of trials (three), this finding calls for caution in its interpretation. Nevertheless, our results are in line with a previous Cochrane review [6
] on the prevention of pediatric AAD (RR 0.46, 95% CI 0.35 to 0.61, I2
= 55%, 3898 participants), as well as a review, including hospitalized patients [26
], on the prevention and treatment of AAD regardless of age (RR 0.58, 95% CI 0.50 to 0.68, I2
= 54%, 11,811 participants).
Subgroup analyses did not further explain the substantial amount of heterogeneity across studies as heterogeneity remained evident throughout all these analyses. Combining data into a meta-analysis by probiotic species and strain level from all included studies would have been preferred, but this was not possible due to varying species, strains, and combinations of strains used in the included studies.
In most of the included studies, the types of infections/diagnoses of the subjects in the included studies were not specified. This was due to inadequate reporting of the trials. Likewise, the antibiotics used were rarely specified, but, by excluding inpatients from the analysis, some similarity regarding the diagnoses of subjects can be expected. The five most important causes of antibacterial prescribing in primary care are upper respiratory tract infection, lower respiratory tract infection, sore throat, urinary tract infection, and otitis media [27
]. Outpatients being prescribed antibiotics are likely to experience less severe and relatively common types of infections than inpatients because the latter requires hospitalization. Also, outpatients were not exposed to intravenous antibiotics. The decision to include only outpatients was made in order to lower the degree of heterogeneity and to have a patient group that more closely represents primary care patients.
Probiotics can be found in the form of yoghurt, tablets, and capsules, e.g., in dietary supplements and as non-prescription drugs from pharmacies. This makes the use of probiotics an easily available and relatively simple method of AAD prophylaxis. Furthermore, the ingestion of probiotics seems safe, and our meta-analysis found no increased risk of adverse events, including serious adverse events. This result is in line with a previous review on the safety of probiotics [28
]. The majority of adverse events that occurred such as abdominal pain, loss of appetite, nausea, headache and flu-like symptoms were most likely due to antibiotic side effects or were symptoms from the underlying infection.
Using probiotics for the prevention of antibiotic-associated diarrhea reduces the risk of AAD by 51% (RR 0.49; 95% CI 0.36 to 0.67) with a moderate quality of evidence according to GRADE. This result was confirmed in analyses of specific strains, namely Lactobacillus rhamnosus GG and Saccharomyces boulardii. Furthermore, we found preliminary evidence to suggest a dose-response relationship.
The use of probiotics appears safe. However, our study still suggests that caution be applied prior to widespread introduction of probiotic treatment for AAD as only 18% of the included studies had a low risk of bias, and these studies did not find a statistical significant reduction in the prevention of AAD.
Limitations to the findings include the paucity of data on probiotic strain level, and future studies on probiotics to prevent AAD should focus on identifying the most effective agent(s) preferable in head-to-head comparisons and follow a stringent approach to definitions of outcomes, as well as clinical scenarios, prior to the widespread recommendation of probiotics as adjunct therapy to antibiotics. Also, more data are needed to determine the safety of probiotics, and trials should define potential adverse events in advance.