Recommendations for the adjuvant use of the poly-antibiotic–resistant probiotic Bacillus clausii (O/C, SIN, N/R, T) in acute, chronic, and antibiotic-associated diarrhea in children: consensus from Asian experts

This paper proposes recommendations for probiotics in pediatric gastrointestinal diseases in the Asia-Pacific region. Evidence-based recommendations and randomized controlled trials in the region are included. Cultural aspects, health management issues and economic factors were also considered. Final recommendations were approved by utilizing a modified Delphi process and applying the Likert scale in an electronic voting process. Bacillus clausii was recommended as an adjunct treatment with oral rehydration solution for acute viral diarrhea. B. clausii may also be considered for prevention of antibiotic-associated diarrhea, Clostridium difficile-induced diarrhea, and as adjunct treatment of Helicobacter pylori. There is insufficient evidence for recommendations in other conditions. Despite a diversity of epidemiological, socioeconomical and health system conditions, similar recommendations currently apply to most Asia-Pacific countries. Ideally, these need to be validated with local randomized-controlled trials.


Introduction
Diarrhea, although a preventable disease, remains a major cause of morbidity and mortality in children worldwide, resulting in 525,000 deaths per year among those younger than 5 years [1]. Globally, the most important enteric pathogen is rotavirus [2]. The World Health Organization (WHO) recommends treatment of acute childhood diarrhea with oral rehydration salts (ORS) and continued feeding for the prevention and treatment of dehydration, as well as zinc supplementation to shorten the duration and severity of the diarrheal episode. Prospective clinical trials conducted found Bacillus clausii (O/C, SIN, N/R, T) to be effective and safe in the treatment and pre-and colonize the intestine even in the presence of antibiotics. The designations of these bacterial strains are derived from the spores' resistance to diverse antibiotics: O/C, resistant to chloramphenicol; N/R, resistant to novobiocin and rifampin; SIN, resistant to neomycin and streptomycin; T, resistant to tetracycline [1]. B. clausii with four strains, O/C, SIN, N/R and T, is marketed as suspension of spores in vials, capsule and powder sachet for oral usage, and is indicated for the treatment and prevention of intestinal dysmicrobism and subsequent endogenous avitaminosis, and acute and chronic gastrointestinal disorders in infants [3]. Poly-antibiotic resistance is attributed to the bacteria's multiple strains, with each strain having its own set of resistance to a wide range of antibiotics and this allows it to be used as adjunct with other antibiotics [1]. Moreover, B. clausii (O/C, SIN, N/R, T) demonstrates a low level of intraspecific genome activity and exhibits a high degree of genomic conservation for the last 25 years [4].

Need for probiotic recommendations in the Asian region
The interaction between diet and gut microbiota, and ultimately their effect on human health, has been the subject of huge interest and research. However, this relationship still needs to be fully characterized, particularly in case of the Asian population. While much of the function of the gut microbiome remains to be fully elucidated, it is established that the microbiota plays an important role in maintaining health [5]. The composition of microbiota is altered in certain disease states, including enteric infections, Helicobacter pylori and Clostridium difficile infection, and antibiotic-associated diarrhea (AAD), resulting in a state of dysbiosis. Dysbiosis is related to various important pathologies and many therapeutic strategies aimed at restoring the balance of the intestinal ecosystem have been implemented. These strategies include the administration of probiotics and prebiotics.
Mortality and morbidity rates remain high despite global efforts to treat diarrhea. This necessitates continued efforts on improving diarrhea management and diarrhea prevention.
This consensus paper captures an up-to-date overview, from a community of invited key opinion leaders across Asia, based on pure evidence from published literature around the scope of recommendation.

Target audience and contents
The intended target audience of this document includes pediatricians, primary care physicians and all healthcare professionals involved in the management of pediatric diarrhea. The document includes 11

Objectives
The primary objective is to develop a consensus document that would serve as a reference for the management of pediatric diarrhea in the Asian region, focusing on the use of the poly-antibiotic-resistant Bacillus clausii (O/C, SIN, N/R, T) in light of new evidence of its efficacy and safety as an adjuvant in the treatment of acute diarrhea, chronic diarrhea, and AAD.

Materials and methods
A modified Delphi process [6], a very common process that involves the combined insights of an expert panel, was utilized in developing the consensus recommendations. This was done by conducting two expert All members of the expert panel contributed to the discussions and were actively involved in every phase of the consensus recommendation process. No representative from pharmaceutical companies was involved in any part of the recommendation development process and all the experts were independent in making their choice. The first meeting was convened to discuss contemporary approaches to, and review the latest evidence in, the management of pediatric diarrhea, and present real-world experiences and consolidate best practices on the use of B. clausii in the management of pediatric diarrhea. The second meeting was convened to present and discuss the evidence that supports the consensus statements on the use of B. clausii in the management of acute diarrhea, chronic diarrhea, and AAD; to discuss, agree and finalize the consensus recommendations on the use of B. clausii in the management of acute diarrhea, chronic diarrhea, and AAD; and to finalize the next steps in the development of the consensus paper.

Scope of recommendations
The members of the expert panel developed recommendations pertaining to the use of probiotics as adjunct treatment in diarrhea, and the use of B. clausii in acute diarrhea, chronic diarrhea, and AAD.

Search strategy
The expert panel was divided into four groups based on the following topics: 1) Probiotics as adjunct treatment in diarrhea, 2) Bacillus clausii (O/C, SIN, N/R, T) in acute diarrhea, 3) Bacillus clausii (O/C, SIN, N/R, T) in chronic diarrhea, and 4) Bacillus clausii (O/C, SIN, N/R, T) in AAD. Each group was asked to search and review relevant literature based on the initial consensus statements developed, and to augment and consolidate the evidence. The approach was to review MEDLINE, Embase and Google Scholar, and to review the initially drafted consensus statements which contain some suggested references.

Search criteria
The scope of the literature search of the Probiotics group was limited to literature published within a 10year time frame (2009 to 2019), while the other groups were asked to include literature published within a wider time frame (from the 1980s to present) to gather more information given that B. clausii has been available in the market for quite a long time.

Evidence synthesis
Documents were prepared based on the initial consensus statements drafted from the first expert panel meeting. This was followed by a comprehensive literature search and review and collation of supporting evidence. The members of the expert panel did not grade the evidence; the grade and strength of evidence presented were based on the references cited.

Development of consensus recommendations
Members of the first expert panel meeting summarized the evidence and consensus statements. These were presented at the second expert panel meeting. After each discussion, each member of the expert panel voted on the proposed consensus statements. A 5-point Likert scale [7] (strongly agree, agree, neither agree or disagree, disagree, or strongly disagree) was utilized via electronic voting. All members were involved in scrutinizing the content and form of each statement, as well as how the statement was worded. Disagreements were resolved through discussion of suggested modifications, rewording and rephrasing of consensus statements, and another round of voting. The members agreed that a consensus is achieved when, combining the votes for strongly agree and agree, a vote of at least 80% is reached. The results of the consensus voting are summarized in Appendix, Table 8. The accepted statements were finalized as the expert panel's consensus recommendations.

Results
Each recommendation is presented together with relevant evidence and accompanied by supporting text, which is structured as follows.
Summary of evidence linked to recommendation statement Summary of the evidence presented    Table 2). The 2014 Use of probiotics for management of acute gastroenteritis: A position paper by the ESPGHAN Working Group for Probiotics and Prebiotics [9] likewise recommended that LGG, S. boulardii and Lactobacillus reuteri may be considered as an adjunct in the management of children with AGE.
The Asia-Pacific regional guidelines [2] likewise proposed that LGG, L. reuteri and S. boulardii should be strongly recommended for acute gastroenteritis (Table 3).
Based on the large number of high-quality randomized, controlled trials (RCTs), LGG and S. boulardii were strongly recommended as an adjunct to oral rehydration therapy in children of the Asia-Pacific region [2], based on all the summarized recommendations of professional societies (ESPG HAN/ESPID in Europe, American Academy of Pediatrics in the United States, Latin American group and the World Gastroenterology Organisation [WGO]) ( Table 4).
With probiotics being strain-specific, it should be emphasized that conclusions regarding a particular strain cannot be extrapolated to another strain. The quality of evidence is taken into account only by the number of RCTs.
Recommendation 2. Evidence has accumulated on the efficacy of probiotics in reducing the duration and severity of acute diarrhea in children Summary of evidence linked to recommendation statement The ESPGHAN/ESPID guideline [8] states that administration of effective probiotic strains reduces the duration of hospital stay and may be considered in children admitted for AGE (II, B) (strong recommendation, low-quality evidence). Administration of probiotics in hospitalized children reduced the mean length of hospitalization by 1.12 days (95% confidence interval [CI], − 1.16 to 0.38). Compelling evidence in support of effective strains is available for LGG and S. boulardii. In this ESPGHAN/ESPID paper, B. clausii (O/C, SIN, N/R, T) was included as "low quality of evidence" due to the lack of RCTs.
The duration, frequency and consistency are the three components measured in diarrhea. There were some studies that showed probiotics reduced the duration of diarrhea.  Table 9).  2. Evidence has accumulated on the efficacy of probiotics in reducing the duration and severity of acute diarrhea in children.
3. Probiotics administration may be considered as an adjunct therapy for the prevention of antibiotic-associated diarrhea.
4. Probiotics significantly reduce the risk of Clostridium difficile-associated diarrhea in adults and children. 2. Bacillus clausii has been found to be safe in clinical trials conducted in Asian children with acute diarrhea.
3. Strain-specific poly-antibiotic-resistant Bacillus clausii is efficacious in reducing the duration and frequency of diarrhea, hospital stay, and financial burden. 2. Physicians should evaluate the risk factors for the occurrence of AAD or Clostridium difficile-associated diarrhea, such as the class of antibiotics, duration of antibiotic treatment, need for hospitalization, age, comorbidities, and previous episodes of AAD or C. difficile-associated diarrhea when considering probiotics for prevention of AAD in children.
Recommendation 3. Probiotics administration may be considered as an adjunct therapy for the prevention of antibiotic-associated diarrhea Summary of evidence linked to recommendation statement The prevalence of AAD varies depending on the criteria used to diagnose it; in children, however, it ranges from approximately 5 to 40%. Evidence from several meta-analyses has consistently shown that most of the tested probiotics significantly reduce the risk of AAD in the general (mainly adult) population. A 2012 meta-analysis [10] of pooled data from 63 RCTs involving almost 12,000 participants indicated a statistically significant reduction in the risk of AAD in the probiotic groups compared with the control groups (relative risk [RR], 0.58; 95% CI, 0.50 to 0.68; p < 0.001).
Pooled evidence [10] suggests that probiotics are associated with a reduction in AAD. However, more research is needed to determine which probiotics are associated with the greatest efficacy in AAD.
In the 2018 Consensus and contentious statements on the use of probiotics in clinical practice: A South East Asian Gastro-neuro Motility Association (SEAGMA) working team report [11], the expert panel agreed that probiotics decrease the incidence of AAD in children. The evidence comprises a meta-analysis of 22 studies that showed probiotics decreased the incidence of AAD in children versus placebo (8% vs 19%).
The 2004 Bacillus clausii therapy to reduce sideeffects of anti-Helicobacter pylori treatment: Randomized, double-blind, placebo-controlled trial [12] involving 120 H. pylori-positive patients who received standard 7 days triple therapy (rabeprazole 20 mg twice a day [BID], clarithromycin 500 mg BID, amoxicillin 1 g BID) and B. clausii (2 × 10 9 spores three times a day [TID]) for 14 days (group A), or standard triple therapy and placebo for 14 days (group B) showed that the incidence of diarrhea related to anti-H. pylori antibiotic therapy was significantly lower in group A compared with group B (per protocol [PP], p < 0.05; intention-to-treat [ITT], p < 0.01) ( Table 5).

Recommendation 4. Probiotics significantly reduce the risk of Clostridium difficile-associated diarrhea in adults and children
Summary of evidence linked to recommendation statement The group generally agreed that probiotics significantly reduce the risk of Clostridium difficile-associated diarrhea (CDAD) in adults and children. The 2017 Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children [13] systematic review and meta-analysis of 31 RCTs involving 8672 patients suggests that probiotics are effective for preventing CDAD (number needed to treat for an additional beneficial outcome = 42 patients; 95% CI, 32 to 58). The ESPGHAN working group [8] proposed that probiotics (LGG and S. boulardii) may be considered for the prevention of CDAD based on the evaluation of individual cases (see Table 2).
The 2017 Timely use of probiotics in hospitalized adults prevents C. difficile infection (CDI): A systematic review and meta-regression analysis [17] of 19 studies involving 6261 subjects showed that probiotics were significantly more effective if given closer to the first antibiotic dose, with a decrement in efficacy for every day of delay in starting probiotics (p = 0.04). Probiotics given within 2 days of antibiotic initiation produced a greater risk reduction for CDI (RR, 0.32; 95% CI, 0.22 to 0.48; I 2 = 0%) compared with later administration (RR, 0.70; 95% CI, 0.40 to 1.23; I 2 = 0%) (p = 0.02). There was no increased risk for adverse events among patients given probiotics.
Moreover, the B. clausii strain O/C produces an antimicrobial substance, called clausin, that is active against the gram-positive bacteria C. difficile [15]. days. Concomitant treatment, such as ORS, zinc supplements and antibiotics prescribed for other conditions, was permitted and recorded; other probiotics and antidiarrheal drugs were prohibited. The study showed that, with B. clausii treatment, the mean duration of diarrhea was 3 days in 52.7% of patients. In the AAD subgroup, the mean duration of diarrhea was shorter in children treated with zinc compared with children without zinc supplementation (3.2 ± 1.4 d vs 3.3 ± 1.3 d). In contrast, in the viral diarrhea subgroup, the mean duration of diarrhea was longer in zinc-treated children compared with children without zinc supplementation (3.6 ± 1.4 d vs 3.3 ± 1.3 d). Moreover, the mean diarrheal episodes significantly decreased from a median of 5 episodes/day at baseline to 1 episode/day starting from the fifth day of treatment (p < 0.001). B. clausii (O/C, SIN, N/R, T) also significantly reduced the mean number of stools per day from 5.2 ± 2.0 stools at baseline to 1.3 ± 0.6 stools after 7 days of treatment (p < 0.001).
The 2017 Role of Saccharomyces boulardii and Bacillus clausii in children with acute diarrhea: A randomized controlled trial [19] involving hospitalized infants and children (6 months to 3 years of age) grouped patients to receive either ORS and zinc per WHO standard protocol for acute diarrhea (group A); ORS, zinc and S. boulardii (250 mg BID × 5 days) (group B); or ORS, zinc and B. clausii (2 × 10 9 CFU/mL BID × 5 days) (group B) and compared the reduction in the In the meta-analysis by Ianiro, et al. [1], the studies did not report any serious adverse effects related to B. clausiii (O/C, SIN, N/R, T).

Recommendation 7. Strain-specific poly-antibiotic-resistant
Bacillus clausii is efficacious in reducing the duration and frequency of diarrhea, hospital stay, and financial burden Summary of evidence linked to recommendation statement Revisiting studies [1] on probiotics showed the safety and efficacy of probiotics as adjunct to ORS and zinc ( Table 6).
The WHO recommends treatment of acute childhood diarrhea with ORS and continued feeding for the prevention and treatment of dehydration, as well as zinc supplementation to shorten the duration and severity of diarrhea. It has been suggested that probiotics modulate the immune response and are used as an adjunctive treatment. In terms of efficacy, the response to the dose of 2 billion or 4 billion spores is similar. B. clausii contributes to the restoration of intestinal microbial flora, aids in correcting avitaminosis due to antibiotics, and produces antigenic and antitoxic effects which is closely connected with its metabolic action [3]. Moreover, B. clausii (O/C, SIN, N/R, T) was found alive in the feces for up to 12 days following a single dose administration of three vials containing 2 × 10 9 CFU of B. clausii spores [20].
To date, literature surveys have yielded positive results of B. clausii in reducing the duration and frequency of diarrhea, stool consistency, hospital stay and cost. Well-designed studies have shown reduction in the duration and frequency of diarrhea, and improved consistency of stool. B. clausii as adjunct treatment reduced hospital stay and downscaled economic burden. According to the WHO, 65 to 85% of patients with gastroenteritis improves in 4 weeks. Beyond 4 weeks, the diarrhea is considered chronic. Acute diarrhea is diarrhea lasting for < 5 days, persistent diarrhea is diarrhea lasting for 5 to 14 days, and chronic diarrhea is diarrhea lasting for > 14 days.
Because probiotics are live microorganisms, they are susceptible to reduction in their cell count during product shelf storage. Responsible manufacturers build in overages so that at the end of the product's shelf-life, it does not fall below the potency declared on the label. Spore-forming probiotic strains, although not as well studied as others, do have the advantage of superior resistance to environmental stress during shelf-life. Probiotic products on the market have been shown in some cases to fail to meet label claims regarding the numbers and types of variable microbes present on the product [21].  B. subtilis (now B. clausii) (4 vials/day per orem containing 1 billion spores) to antibiotic treatment (group A) versus antibiotic alone (group B) on the incidence of gastrointestinal (GI) problems in children treated with antibiotics for middle ear or throat infection, and nasal and paranasal infections. The study showed that patients in group A had lesser GI problems (11.0% vs 37.5%) ( Table 7). The 2004 Bacillus clausii therapy to reduce sideeffects of anti-Helicobacter pylori treatment: Randomized, double-blind, placebo-controlled trial [12] involving 120 H. pylori-positive patients who received standard 7 days triple therapy (rabeprazole 20 mg twice a day [BID], clarithromycin 500 mg BID, amoxicillin 1 g BID) and B. clausii (2 × 10 9 spores three times a day [TID]) for 14 days (group A), or standard triple therapy and placebo for 14 days (group B) showed that the incidence of diarrhea related to anti-H. pylori antibiotic therapy was significantly lower in group A compared with group B (per protocol [PP], p < 0.05; intention-to-treat [ITT], p < 0.01) (see Table 5).
Thirty-three (33) studies involving 6352 participants were included in the Cochrane Database of Systematic Reviews of 2019 [23] regarding probiotics for the prevention of pediatric AAD. The probiotics assessed include Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., or Streptococcus spp. either used alone or in combination. The overall evidence suggests a moderate protective effect of probiotics in preventing AAD (NNT = 9; 95% CI, 7 to 13). Evidence suggests that probiotics may moderately reduce the duration of diarrhea by almost 1 day.
Recommendation 10. Physicians should evaluate the risk factors for the occurrence of AAD or Clostridium difficileassociated diarrhea, such as the class of antibiotics, duration of antibiotic treatment, need for hospitalization, age, comorbidities, and previous episodes of AAD or C. difficile-associated diarrhea when considering probiotics for prevention of AAD in children Conditions as infection risks and whether probiotics is effective [24] study involving 43 children (mean age, 6.7 years) who showed either positive C. difficile culture or C. difficile toxin test results showed that approximately 40% (n = 17) had pre-existing GI disorders (eg, Crohn's disease, allergic and/or eosinophilic colitis), and 60% (n = 26) had no history of GI diseases but with other medical conditions that were risk factors for CDI (eg, extra-intestinal infections like otitis media, tonsillitis); 65% (n = 28) had a history of antibiotic treatment for > 3 days. The most frequently prescribed antibiotic was amoxicillin-clavulanate (35.7%, n = 10/28 who were previously treated with antibiotics), and the most common symptom at the time of CDI diagnosis was diarrhea (72.1%). Probiotics were prescribed in 28 patients with a history of antibiotic treatment for the prophylaxis of CDI. The most common probiotics used were L. acidophilus (53.6%, n = 15), B. subtilis (now B. clausii; 46.4%, n = 13) and Streptococcus faecium (46.4%, n = 13).
Some members of the expert panel would usually recommend giving B. clausii in patients prescribed with amoxicillin-clavulanate, especially if the patient has a history of previous AAD with the same antibiotic.
Recommendation 11. Bacillus clausii can be used as coadjuvant therapy for Helicobacter pylori eradication Summary of evidence linked to recommendation statement In the 2004 Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori treatment: Randomized, double-blind, placebo-controlled trial [12], 120 adult patients, free of GI symptoms in the previous 3 months and affected by gastric H. pylori infection as confirmed by a 13 C-urea breath test were randomly assigned to receive either a triple therapy of clarithromycin 500 mg BID, amoxicillin 1 g BID and rabeprazole 20 mg BID for 7 days plus B. clausii (O/C, SIN, N/R, T) one vial TID (containing 2 × 10 9 spores) for 14 days, during eradication therapy and 1 week thereafter (group A), or triple therapy plus a placebo during eradication therapy and 1 week thereafter (group B). The results showed that H. pylori eradication was comparable between groups: ITT analysis (B. clausii group, 72.2% vs placebo group, 71.15%); PP population (B. clausii group, 78% vs placebo group, 74%). There was a significant difference between both groups in both ITT and PP populations in terms of the incidence of nausea, diarrhea and epigastric pain. In the ITT analysis, the relative risk of occurrence of nausea was reduced to half in patients treated with B. clausii compared with placebo after 1 week (RR, 0.5; 95% CI, 0.31 to 0.88) and 2 weeks (RR, 0.45; 95% CI, 0.21 to 0.96) of bacteriotherapy. A greater reduction in the risk of diarrhea was observed in the B. clausii group compared with the placebo group after 1 week (RR, 0.30; 95% CI, 0.12 to 0.76) and 2 weeks (RR, 0.38; 95% CI, 0.08 to 1.9). The relative risk of occurrence of epigastric pain after 1 week was 0.68 (95% CI, 0.48 to 0.97); the incidence of vomiting, constipation and skin rash were also lower in the B. clausii group compared with the placebo group, although the differences were not statistically significant. The individual patients' overall assessment of tolerability in the ITT population was better in the B. clausii group compared with the placebo group. The difference was statistically significant after 2 weeks of treatment (p < 0.05).
The 2017 Probiotics in 14-day triple therapy for Asian pediatric patients with Helicobacter pylori infection: A network meta-analysis [25] of 17 RCTs compared the efficacy and safety of probiotics supplemented in 14-day triple therapy in Asian pediatric patients. It was observed that the probiotic-supplemented 14-day triple therapy significantly increased H. pylori eradication rates (RR, 1.16; 95% CI, 1.07 to 1.26) and reduced the incidence of total side effects (RR, 0.40; 95% CI, 0.34 to 0.48) compared with placebo. However, further direct evidence is needed to warrant it.
The 2007 Meta-analysis: The effect of supplementation with probiotics on eradication rates and adverse events during Helicobacter pylori eradication therapy [26] review suggests that supplementation with probiotics could be effective in increasing eradication rates of anti-H. pylori antibiotic regimens and could be considered helpful for patients with eradication failure.
The mechanism by which B. clausii is used as coadjuvant therapy for H. pylori eradication is not very well understood in the pediatric population. The expert panel agreed that there should be more studies related to H. pylori.

Discussion
Based on the initial consensus statements and evidence presented, 11 recommendations on the use of probiotics and Bacillus clausii (O/C, SIN, N/R, T) have been made. The expert panel utilized a modified Delphi process which involved two face-to-face meetings. Through the modified Delphi process, the expert panel was able to discuss the latest evidence on the use of probiotics in the management of pediatric diarrhea and develop consensus recommendations that would serve as a reference for the management of pediatric diarrhea in the Asian region. The Delphi process is a well validated and widely adopted method for systematically assessing and organizing expert opinion. Developed by the RAND corporation® in the 1950s, it is based on the principle that forecasts or decisions from a structured group are more accurate. The method entails a group of experts who anonymously reply to questionnaires and subsequently receive feedback in the form of a statistical representation of the "group response", after which the process repeats itself. The goal is to reduce the range of responses and arrive at something closer to an expert consensus.

Expert guidance on issues for which evidence is lacking
The initial consensus statement on the use of probiotics for the management of chronic/persistent diarrhea in children was not directly addressed because of the limited evidence. Rather than forego stating a recommendation, the expert panel recognized the need to include a recommendation based on clinical experience that results have been largely positive, with reductions in the duration and frequency of diarrhea. Areas where current evidence is lacking may be addressed in future updates as new information and new clinical studies become available.

Cost and treatment-access considerations
New evidence has demonstrated the favorable efficacy and safety profile of B. clausii. However, the cost implications especially for developing Asian countries make it relatively inaccessible to many patients in the region.
Recommendations 5 (Bacillus clausii may be considered as adjunct to standard therapy in acute childhood diarrhea) and 9 (Probiotics administration may be considered for the prevention of AAD) help support treatment-access considerations in many resource-poor settings across the region.

Conclusion
The Asian expert panel of pediatricians, pediatric gastroenterologists and a pediatric infectious disease specialist has developed a set of general recommendations on the use of probiotics as adjunct treatment in diarrhea, and the use of Bacillus clausii (O/C, SIN, N/R, T) in acute diarrhea, chronic diarrhea, and AAD to be used as reference in the management of pediatric diarrhea to improve patient outcomes. These recommendations consolidate the current evidence on the efficacy of probiotics in reducing the duration and severity of acute diarrhea in children, and the efficacy and safety of B. clausii (O/C, SIN, N/R, T) in reducing the duration and frequency of acute diarrhea. 3. Probiotics administration should be considered as an adjunct therapy for the prevention of antibiotic-associated diarrhea.
Rejected: The original statement was revised to "Probiotics administration may be considered as an adjunct therapy for the prevention of antibiotic-associated diarrhea." and another round of voting was done.