Antibiotic-associated diarrhea (AAD) is a common and challenging complication observed in the ambulatory and hospital settings alike that occurs in up to a third of all patients treated with antibiotics (1). It is defined as diarrhea that occurs in relation to antibiotic treatment with the exclusion of other etiologies. This relation does not necessarily translate into an immediate adverse reaction to antibiotics, because AAD may occur after a few weeks and even up to a few months after the administration of the antibiotics (2). Thus, in the latter situation, caution is needed to differentiate AAD from an episode of infectious gastroenteritis. The risk of AAD is higher when there is a use of aminopenicillins without/with clavulanate, cephalosporins, clindamycin, and, in general, any antibiotic that is active against anaerobes (3). Almost any oral and intravenous antibiotic treatment can, however, cause AAD (3). Clinically, AAD may present as mild diarrhea, but it can present as well as fulminant pseudomembranous colitis. Usually, no pathogen is identified. In the most severe forms and in an increasing number of patients with chronic conditions such as those with inflammatory bowel diseases, cystic fibrosis, and cancer, however, the causative agent is often identified as Clostridium difficile(4).
The use of probiotics, defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host,” (5) and/or fermented products such as yogurt has been reported as a measure to prevent the occurrence of AAD. The rationale for the use of these products relies on the hypothesis that AAD is caused by dysbiosis that is triggered by antibiotic use and that the probiotic intervention favorably modulates the intestinal microbiota (1).
The aim of this position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Working Group (WG) on Probiotics and Prebiotics is to provide recommendations for the use of probiotics for preventing AAD in children.
The same methodology that had been used previously by the WG for developing guidelines on the use of probiotics for the management of acute gastroenteritis (6) was applied for developing the present position paper. In brief, the document provides a review of previously completed systematic reviews and of randomized controlled trials (RCTs) published subsequently to these reviews. For systematic reviews/meta-analyses, the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects (DARE) were searched. For subsequently published trials (starting from the date of the most recent search in the included reviews), CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, and EMBASE were searched up to July 2015 and again in November 2015.
The focus was on 6 taxonomic groups (Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus). The list of individual probiotics to be considered was established based on the results of the Cochrane review evaluating probiotics for preventing AAD in children (7) and the list of commonly used probiotics developed by the World Gastroenterology Organization (8).
The WG is aware that taxonomically equivalent probiotic microorganisms may be supplied by different manufacturers. At least 1 study indicated that the manufacturing process may influence properties of probiotic bacteria (9). At present, whether or not these manufacturing differences translate into differences in vivo, as well as clinical outcomes, however, remains unclear. Consequently, the taxonomically equivalent probiotics are presented jointly, regardless of the manufacturer. The WG also realizes that the same brand may have a different composition in different locations; nevertheless, this position paper deals with strain(s) rather than brands or commercial names. Finally, depending on the country, the same probiotic microorganism(s) may be available as food supplements, available as registered pharmaceutical products, and/or incorporated into foods (10). In this document, the effectiveness of probiotics was analyzed regardless of the registration status. Health care professionals and consumers should, however, be aware of possible variations in the manufacturing and safety profiles of the products, which may be different when the strain is registered as a drug and also with regard to the claims allowed.
The primary outcome measures were diarrhea/AAD and C difficile-associated diarrhea (all as defined by the investigators).
To assess the methodological quality of the included RCTs (included in the previously published meta-analyses and subsequently published RCTs not included in the systematic reviews), the Cochrane Collaboration's tool for assessing risk of bias was used. This tool includes the following criteria: adequacy of sequence generation, allocation concealment, and blinding of participants, personnel and outcome assessors; incomplete outcome data; and selective reporting (11).
For reporting the effect, the results for individual studies and pooled statistics are reported as the risk ratio (RR) between the experimental and control groups with 95% confidence intervals (95% CIs). In other circumstances, we report the findings as reported by the authors of the included studies.
When synthesizing the evidence, each section presents a summary of the evidence followed by the key recommendations. The GRADE system, developed by the Grading of Recommendations Assessment, Development and Evaluations Working Group (12), was used to grade the strength of evidence and grades of recommendations used in these guidelines. In brief, the GRADE system offers 4 categories of the quality of the evidence (ie, high, moderate, low, and very low) and 2 categories of the strength of recommendation (ie, strong or conditional [weak]) (Table 1). The GRADE system suggests presenting recommendations in the active voice (13). Thus, we used the wording “the WG recommends” for strong recommendations, and “the WG suggests” for conditional [weak] recommendations.
As in our previous document (6), the WG adopted the position of the US Food and Drug Administration Guidance for Industry (14) that at least 2 adequate and well-controlled studies, each convincing on its own, are needed to establish the effectiveness of an intervention. Consequently, the recommendations were formulated only if at least 2 RCTs that used a given probiotic were available. If there was only 1 RCT, regardless of whether or not it showed a benefit, no recommendation was formulated. Moreover, if the strain specification was not given and/or the probiotic product was not otherwise identifiable, no recommendation was made.
For the sake of completeness, we report the pooled data (meta-analysis) of all probiotic trials. No recommendation on the use of probiotics in general was, however, made, because pooling data on different probiotics has been repeatedly questioned (15). Instead, because various probiotic strains differ in their effects, preference was given to reporting evidence and recommendations related to a specific probiotic strain or their combinations separately.
A draft of the position paper was sent to the WG members for review and further comments. All of the critical feedback was discussed through e-mail or during personal contacts, and changes were incorporated as necessary. Recommendations were formulated and graded. The WG members voted anonymously on each recommendation using an online electronic survey tool (SurveyMonkey Inc, Palo Alto, CA, www.surveymonkey.com). Any disagreement following voting was resolved by discussion, and for all recommendations, a full consensus was reached. A finalized document was submitted to the ESPGHAN Council for final acceptance before publication.
The WG recommendations may need to be modified by different countries considering differences in health care systems, local values and preferences, including availability, quality, and costs of probiotics, and should help local policy makers to decide whether to use routinely probiotics with documented efficacy for preventing AAD in children receiving antibiotics based on local cost-effectiveness analysis. This is particularly important in low- and middle-income countries.
Clearly, an individual patient's risk of developing AAD or C difficile-associated diarrhea depends on a number of factors such as class of antibiotic(s), duration of antibiotic treatment, age, need for hospitalization, comorbidities, and previous episodes of AAD or C difficile-associated diarrhea (1–3). These risk factors should be considered when making decisions on the use of probiotics in children for preventing AAD or C difficile-associated diarrhea. The WG acknowledges that the judicious use of antibiotics remains the best method of preventing AAD.
The conclusions of this document may require revision in the future as new information becomes available. It is the intention of the WG to revise the recommendations not later than 5 years from now and produce an updated document.
A number of systematic reviews and meta-analyses have shown that probiotics as a group are effective in preventing AAD (7,16,17).
A 2012 meta-analysis by Hempel et al (16) collected data from 82 RCTs that evaluated the efficacy of probiotics for preventing AAD in subjects of all ages. Probiotics, as a group, reduced the risk of AAD (63 RCTs, n = 11,811 participants, RR 0.58, 95% CI 0.50–0.68). Sixteen RCTs were carried out in infants and young children and reported a reduced risk of AAD with probiotic administration (RR 0.55, 95% CI 0.38–0.80). In the majority of trials, Lactobacillus-based interventions, alone or in combination with other genera, were used. Strains were poorly documented. The quality of evidence was low. Of 63 included trials, 59 lacked adequate information to assess the overall risk of bias. There was no placebo group in some trials. Included trials used different definitions of diarrhea/AAD, and in some, no definition of these outcomes was provided. Moreover, significant heterogeneity between trials for both primary and secondary outcomes was detected. The authors concluded that the evidence is insufficient to determine whether this association varies systematically by population, antibiotic characteristic, or probiotic preparation.
A 2013 systematic review with a meta-analysis assessed the efficacy and safety of probiotics for preventing C difficile-associated diarrhea or C difficile infection in adults and children (17). A complete case analysis (ie, participants who completed the study) showed that compared with placebo or no treatment, administration of probiotics reduced the risk of C difficile-associated diarrhea by 64% (23 RCTs, n = 4213, RR 0.36, 95% CI 0.26–0.51) in adults and children. In children, probiotic administration reduced the risk of C difficile-associated diarrhea from 5.9% to 2.3% (3 RCTs, n = 605, RR 0.40, 95% CI 0.17–0.96) (17).
For this report, 21 RCTs involving 3255 children were included (18–38). Among them, 11 RCTs were included in 2 strain-specific systematic reviews initiated as part of the development of these guidelines (39,40). One unpublished study (29) was identified in the systematic review by Johnston et al (7). For characteristics of the included RCTs, see Table 2, and for a methodological quality summary, see Figure 1. The pooled results of 21 RCTs showed that compared with placebo or no intervention, probiotics as a class reduced the risk of AAD by 52% (21.2% vs 9.1%, respectively; RR 0.48, 95% CI 0.37–0.61) (Fig. 2). Only 2 probiotics were evaluated in >1 RCT. These were Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii. Compared with placebo, the administration of probiotics also reduced the risk of C difficile-associated diarrhea (4 RCTs, n = 938, RR 0.34, 95% CI 0.15–0.76) (Fig. 3).
PROBIOTICS WITH RECOMMENDATIONS
L rhamnosus GG (LGG)
RECOMMENDATION. If the use of probiotics for preventing AAD in children is considered, the WG recommends using L rhamnosus GG.
QUALITY OF EVIDENCE: Moderate.
STRENGTH OF RECOMMENDATION: Strong
A 2015 systematic review with a meta-analysis (40) identified 5 relevant RCTs (445 participants) (18–22). The methodological quality of the trials varied (Fig. 1). Only 1 trial was at a low risk of bias. In the remaining trials, the limitations included unclear random sequence generation, unclear or no allocation concealment, and unclear or no blinding of participants and personnel. Intention-to-treat analysis was performed in only 1 trial. Using the GRADE, the overall quality of evidence was rated as moderate (Table S1, http://links.lww.com/MPG/A587).
Compared with placebo or no treatment, LGG administration in children reduced the risk of AAD, regardless of the reason for which probiotics were used (ie, as part of Helicobacter pylori eradication or for other reasons), from 23% to 9.6% (5 RCTs, n = 445, RR 0.48, 95% CI 0.26–0.89; number needed to treat, NNT, 8, 95% CI 6–40) (Fig. 2). No significant heterogeneity was found (χ2 = 6.61, P = 0.16, I2 = 40%). Only 1 trial (19) evaluated the effect of LGG on the risk of C difficile-associated diarrhea in children and found no effect (RR 0.95, 95% CI 0.06–14.85) (Fig. 3).
The optimal daily dose of LGG for preventing AAD remains unclear (40). In children, the best effect (reduction in the risk of AAD by 71%) was achieved with the highest dose (1–2 × 1010 CFU) (18). A similar effect size was, however, not achieved in another trial using the same dose (19), perhaps because of a lower baseline risk of AAD. In adults, there was no clear link between the effect size and the LGG dose.
RECOMMENDATION. If the use of probiotics for preventing AAD in children is considered, the WG recommends using S boulardii for preventing AAD in children.
QUALITY OF EVIDENCE: Moderate.
STRENGTH OF RECOMMENDATION: Strong.
RECOMMENDATION. If the use of probiotics for preventing C difficile-associated diarrhea in children is considered, the WG suggests using S boulardii.
QUALITY OF EVIDENCE: Low.
STRENGTH OF RECOMMENDATION: Conditional.
A 2015 systematic review with a meta-analysis (39) identified 6 relevant RCTs (1653 participants) (23–28). The methodological quality of the trials varied. Only 1 trial was at a low risk of bias. In the remaining trials, the limitations included unclear random sequence generation, unclear or no allocation concealment, and unclear or no blinding of participants and personnel. Intention-to-treat analysis was performed in only 2 trials. Using the GRADE, the overall quality of evidence for AAD and C difficile-associated diarrhea was rated as moderate and low, respectively (Tables S2 and S3, http://links.lww.com/MPG/A587).
Compared with placebo or no treatment, S boulardii administration in children reduced the risk of diarrhea, regardless of the reason for which probiotics were used (ie, as part of H pylori eradication or for other reasons), from 20.9% to 8.8% (6 RCTs, n = 1653, RR 0.43, 95% CI 0.30–0.60, NNT 9, 95% CI 7–12). No significant heterogeneity was found (χ2 = 8.26, P = 0.14, I2 = 39%) (Fig. 2).
The administration of S boulardii also reduced the risk of C difficile-associated diarrhea in children (2 RCTs, n = 579, RR 0.25, 95% CI 0.08–0.73) (Fig. 3).
The optimal dose of S boulardii has not been established. A 2015 meta-analysis showed that various doses of S boulardii were used with no clear dose-dependent effect (39). Until more data on the optimal dose of S boulardii become available, a daily dose of not <250 mg but not >500 mg in children and not >1000 mg in adults could be used to match the doses used in RCTs.
PROBIOTICS WITH INSUFFICIENT EVIDENCE TO MAKE A RECOMMENDATION
A 2011 Cochrane review (7) identified 1 unpublished RCT (29). Compared with no intervention, administration of Bacillus clausii (strain specification not given) had no effect on the risk of AAD (n = 323, RR 0.43, 95% CI 0.11–1.62).
Mixtures of Probiotics
Bacillus lactis/Streptococcus thermophilus
One RCT (n = 157) conducted in inpatients who were children (aged 6–36 months) showed that compared with the control formula, the administration of infant formula supplemented with B lactis Bb-12 and Streptococcus thermophilus significantly reduced the risk of AAD (31.2% vs 16.3%, respectively; RR 0.52, 95% CI 0.29–0.95, NNT 7, 95% CI 4–62) (30).
L acidophilus/L bulgaricus
One small RCT (n = 38) showed that compared with placebo (lactose), administration of L acidophilus/L bulgaricus (strain specification not given) had no effect on the risk of AAD (RR 0.96, 95% CI 0.61–1.5) (31).
L acidophilus/Bifidobacterium infantis
One small RCT (n = 18) showed that compared with placebo (sugar), administration of L acidophilus/B infantis (strain specification not given) had no effect on the risk of AAD (8/10 vs 3/8, respectively; RR 0.47, 95% 0.18–1.21) (32).
L acidophilus/Bifidobacterium breve
One small RCT (n = 40) showed no cases of AAD in either the L acidophilus/B infantis (strain specification not given) group or the placebo (sugar) group (0/20 vs 0/20, respectively). Thus, the efficacy of this probiotic combination could not be evaluated (37).
L rhamnosus GG/Bb-12/L acidophilus La-5
In a multisite, double-blind, placebo-controlled RCT, children (n = 70), age 1 to 12 years, who were prescribed antibiotics were randomized to receive 200 g/day of either a yogurt containing L rhamnosus GG, Bb-12 and L acidophilus La-5 or a pasteurized placebo yogurt (containing Streptococcus thermophilus plus L bulgaricus) for the same duration as their antibiotic treatment. Compared with the placebo group, children in the probiotic group experienced a significant reduction in the risk of diarrhea (RR 0.05, 95% CI 0.01–0.35) (33).
B longum PL03/L rhamnosus KL53A/L plantarum PL02
One RCT (n = 78) showed that compared with placebo, the administration of B longum, L rhamnosus, and L plantarum had no effect on the risk of AAD (RR 0.47, 95% CI 0.04–5.03) (34).
L rhamnosus E/N, Oxy, Pen
One RCT involving 240 children showed that compared with placebo, the administration of L rhamnosus (strains E/N, Oxy and Pen) reduced the risk of any diarrhea (RR 0.45, 95% CI 0.21–0.95), but it did not have an effect on the risk of C difficile-associated diarrhea (RR 0.43, 95% CI 0.11–1.62) (35).
L acidophilus/L rhamnosus/L bulgaricus/L casei/Str thermophilus/B infantis/B breve
One RCT involving 66 children showed that compared with placebo, the administration of L acidophilus/L rhamnosus/L bulgaricus/L casei/Str thermophilus/B infantis/B breve (strain specification not given) reduced the risk of diarrhea (RR 0.25, 95% CI 0.06–1.09) (38).
One RCT evaluated the effect of kefir (ie, a fermented milk containing Lactococcus lactis, Lactococcus plantarum, Lactococcus rhamnosus, Lactococcus casei, Lactococcus lactis subspecies diacetylactis, Leuconostoc cremoris, B longum, B breve, Lactobacillus acidophilus, and 1 yeast, Saccharomyces florentinus) on the risk of AAD. There was no significant difference between the kefir group and the group receiving heat-treated kefir (RR 0.83, 95% CI 0.41–1.67) (36).
Yogurt is a form of fermented milk that contains symbiotic cultures of Streptococcus thermophilus and L delbrueckii subsp. bulgaricus. A 2015 systematic review with a meta-analysis identified 2 relevant RCTs, both low in methodological quality. Compared with no intervention, yogurt consumption had no effect on the risk of AAD (2 RCTs, n = 314, RR 0.45; 95% CI 0.11–1.75) (41).
The WG abstained from evaluating the safety of probiotics, as this was thoroughly reviewed in 2011 by the US Agency for Healthcare Research and Quality (for review, (42)). Although probiotics are safe for use in otherwise healthy populations, caution should be taken in specific patient groups. Risk factors for adverse events include immunosuppression, prematurity, critical illness, presence of structural heart disease, presence of a central venous catheter, and the potential for translocation of probiotics across the bowel wall. There is a lack of data that specifically address the safety of probiotics for preventing AAD in these vulnerable populations. The risk of side effects is, however, greater in people who have severe underlying health conditions.
- The WG questions pooling different probiotic strains together in a meta-analysis. Probiotic effects against AAD are strain specific; thus, the efficacy and safety of each should be established and recommendations for using these strains should be made accordingly.
- The safety and clinical effects of 1 probiotic microorganism should not be extrapolated to other probiotic microorganisms.
- A lack of evidence regarding the efficacy of a certain probiotic(s) does not mean that future studies will not establish efficacy in preventing AAD.
- There is a lack of data that specifically address the safety of probiotics for preventing AAD in children who have severe underlying health conditions.
- The WG recommends choosing a probiotic, the efficacy of which has been confirmed in well-conducted RCTs, from a manufacturer who has a regulated quality control of factors including the composition and content of the probiotic agent.
- Risk factors for the occurrence of AAD or C difficile-associated diarrhea such as class of antibiotic(s), duration of antibiotic treatment, age, need for hospitalization, comorbidities, and previous episodes of AAD or C difficile-associated diarrhea should be considered when making decisions on the use of probiotics in children for preventing AAD.
- If the use of probiotics for preventing AAD is considered, the WG recommends using L rhamnosus GG or S boulardii (moderate quality of evidence; strong recommendation).
- If the use of probiotics for preventing C difficile-associated diarrhea is considered, the WG suggests using S boulardii (low quality of evidence; conditional recommendation).
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