Mini-CAT

Group Members: Akram Ishmael, Robert Levine, Siddharth Shah, Tamanna Yeasmin

Case: Moshe, a 4 year old patient with strep throat will need to be treated with antibiotics. Last time he was on antibiotics he developed diarrhea. His mother wonders whether taking probiotics will lessen the chance of diarrhea developing. What can you tell her?

 

Clinical Question: Please state this as briefly as possible based on the scenario provided

In pediatric patients who need antibiotics for strep throat, does the addition of probiotics vs. antibiotics alone lower the probability of developing diarrhea?

 

PICO Question:

Identify the PICO elements (Recalling that some questions do not have all the elements)

• P → Pediatric patients taking antibiotics
• I → Adding on probiotics
• C → Antibiotics alone
• O → Lower incidence of diarrhea

 

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on

 

Terms Used:

• P: Pediatrics patients on antibiotics, Antibiotic Associated Diarrhea, Children on antibiotics
• I: Probiotics, Yogurt probiotics
• C: Antibiotics with no diarrhea prophylaxis, Antibiotics with non-probiotic diarrhea prophylaxis
• O: Diarrhea prevalence, duration, severity, incidence

 

Databases Used: PubMed, Trip Medical Database

• PubMed: “Probiotics preventing diarrhea” → 64 results using filters: Meta-analysis, Systematic Review, within 10 years
• PubMed: “Probiotics in children for diarrhea ” → 40 results using filters: Meta – Analysis, within 10 years
• Trip: “Probiotics for antibiotic associated diarrhea in children” → 32 results using filters: Systematic Review

 

How the final articles were chosen:

• The articles were chosen based on relevance to clinical practice (making sure the studies were done in the pediatric population), high level of evidence (systematic review or meta-analysis), and date of publication (within the last 10 years)

Articles Chosen for Inclusion (please copy and paste the abstract with link):

1. Probiotics for the Prevention of Pediatric Antibiotic-Associated Diarrhea, 2019
2. Probiotics for Antibiotic-Associated Diarrhea in Pediatrics: A Review of Clinical Effectiveness and Guidelines, 2019
3. Which Probiotic Is the Most Effective for Treating Acute Diarrhea in Children? A Bayesian Network Meta-Analysis of Randomized Controlled Trials, 2021
4. Saccharomyces boulardii in the Prevention of Antibiotic-Associated Diarrhoea, 2015

 

Article 1: Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

https://pubmed.ncbi.nlm.nih.gov/31039287/ 

Background: Antibiotics alter the microbial balance commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via providing gut barrier, restoration of the gut microflora, and other potential mechanisms of action.

 

Objectives: The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children.

 

Search methods: MEDLINE, Embase, CENTRAL, CINAHL, and the Web of Science (inception to 28 May 2018) were searched along with registers including the ISRCTN and Clinicaltrials.gov. We also searched the NICE Evidence Services database as well as reference lists from relevant articles.

 

Selection criteria: Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion.

 

Data collection and analysis: Study selection, data extraction, and risk of bias assessment were conducted independently by two authors. Dichotomous data (incidence of AAD, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea) as mean difference (MD), along with corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For studies reporting on microbiome characteristics using heterogeneous outcomes, we describe the results narratively. The certainty of the evidence was evaluated using GRADE.

 

Main results: Thirty-three studies (6352 participants) were included. Probiotics assessed included Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. The risk of bias was determined to be high in 20 studies and low in 13 studies. Complete case (patients who did not complete the studies were not included in the analysis) results from 33 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control.After 5 days to 12 weeks of follow-up, the incidence of AAD in the probiotic group was 8% (259/3232) compared to 19% (598/3120) in the control group (RR 0.45, 95% CI 0.36 to 0.56; I² = 57%, 6352 participants; NNTB 9, 95% CI 7 to 13; moderate certainty evidence). Nineteen studies had loss to follow-up ranging from 1% to 46%. After making assumptions for those lost, the observed benefit was still statistically significant using an extreme plausible intention-to-treat (ITT) analysis, wherein the incidence of AAD in the probiotic group was 12% (436/3551) compared to 19% (664/3468) in the control group (7019 participants; RR 0.61; 95% CI 0.49 to 0.77; P <0.00001; I² = 70%). An a priori available case subgroup analysis exploring heterogeneity indicated that high dose (≥ 5 billion CFUs per day) is more effective than low probiotic dose (< 5 billion CFUs per day), interaction P value = 0.01. For the high dose studies the incidence of AAD in the probiotic group was 8% (162/2029) compared to 23% (462/2009) in the control group (4038 participants; RR 0.37; 95% CI 0.30 to 0.46; P = 0.06; moderate certainty evidence). For the low dose studies the incidence of AAD in the probiotic group was 8% (97/1155) compared to 13% (133/1059) in the control group (2214 participants; RR 0.68; 95% CI 0.46 to 1.01; P = 0.02). Again, assumptions for loss to follow-up using an extreme plausible ITT analysis was statistically significant. For high dose studies the incidence of AAD in the probiotic group was 13% (278/2218) compared to 23% (503/2207) in control group (4425 participants; RR 0.54; 95% CI 0.42 to 0.70; P <0.00001; I² = 68%; moderate certainty evidence).None of the 24 trials (4415 participants) that reported on adverse events reported any serious adverse events attributable to probiotics. Adverse event rates were low. After 5 days to 4 weeks follow-up, 4% (86/2229) of probiotics participants had an adverse event compared to 6% (121/2186) of control participants (RD 0.00; 95% CI -0.01 to 0.01; P < 0.00001; I² = 75%; low certainty evidence). Common adverse events included rash, nausea, gas, flatulence, abdominal bloating, and constipation.After 10 days to 12 weeks of follow-up, eight studies recorded data on our secondary outcome, the mean duration of diarrhea; with probiotics reducing diarrhea duration by almost one day (MD -0.91; 95% CI -1.38 to -0.44; P <0.00001; low certainty evidence). One study reported on microbiome characteristics, reporting no difference in changes with concurrent antibiotic and probiotic use.

 

Authors’ conclusions: The overall evidence suggests a moderate protective effect of probiotics for preventing AAD (NNTB 9, 95% CI 7 to 13). Using five criteria to evaluate the credibility of the subgroup analysis on probiotic dose, the results indicate the subgroup effect based on high dose probiotics (≥ 5 billion CFUs per day) was credible. Based on high-dose probiotics, the NNTB to prevent one case of diarrhea is 6 (95% CI 5 to 9). The overall certainty of the evidence for the primary endpoint, incidence of AAD based on high dose probiotics was moderate due to the minor issues with risk of bias and inconsistency related to a diversity of probiotic agents used. Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction by almost one day. The benefit of high dose probiotics (e.g. Lactobacillus rhamnosus orSaccharomyces boulardii) needs to be confirmed by a large well-designed multi-centered randomized trial. It is premature to draw firm conclusions about the efficacy and safety of ‘other’ probiotic agents as an adjunct to antibiotics in children. Adverse event rates were low and no serious adverse events were attributable to probiotics. Although no serious adverse events were observed among inpatient and outpatient children, including small studies conducted in the intensive care unit and in the neonatal unit, observational studies not included in this review have reported serious adverse events in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation.

 

Article 2: Probiotics for Antibiotic-Associated Diarrhea in Pediatrics: A Review of Clinical Effectiveness and Guidelines

https://www.ncbi.nlm.nih.gov/books/NBK544613/ 

Research Questions

1. What is the clinical effectiveness of probiotics (with or without concurrent antibiotics) for preventing and treating antibiotic-associated diarrhea in the pediatric population?
2. What are the evidence-based guidelines regarding the use of probiotics (with or without  concurrent antibiotics) for the prevention and treatment of antibiotic-associated diarrhea  in the pediatric population?

 

Key Findings:

Evidence of limited quality from nine systematic reviews suggested favourable effects of probiotics on antibiotic-associated diarrhea (AAD) relative to placebo, no additional treatment, or other non-probiotic treatment comparators. However, clinical evidence regarding the conditions under which probiotics were effective (e.g., specific dosing regimens, other outcomes, and indications) was sparse.

 

Two evidence-based guidelines recommended the use of probiotics for the treatment of AAD and one guideline recommended probiotics for the treatment of Clostridium difficile-associated diarrhea

 

Article 3: Which Probiotic Is the Most Effective for Treating Acute Diarrhea in children? A Bayesian Network Meta-Analysis of Randomized Controlled Trials

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8706888/

Acute diarrhea is a major cause of morbidity and mortality in children under five. Probiotics are beneficial for treating acute diarrhea in children, but unclear which specific probiotic is the most effective. We performed a Bayesian network meta-analysis to examine the comparative effectiveness of probiotics. By searching EMBASE, PubMed, and the Cochrane Library up to 31 March 2021, randomized clinical trials (RCTs) on probiotics for treating acute diarrhea in children were included. Primary outcomes included the duration of diarrhea and diarrhea lasting ≥2 days, and secondary outcomes included the mean stool frequency on day 2 and duration of hospitalization, fever, and vomiting. We assessed the certainty of the evidence of outcomes according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline. Eighty-four studies with twenty-one different interventions in 13,443 children were included. For the primary outcomes, moderate evidence indicated that, Lactobacillus reuteri [mean difference (MD) = −0.84 day; 95% confidence interval (CI), −1.39, −0.29], Bifidobacterium lactis (MD = −0.98 day; 95%CI, −1.82, −0.14), Saccharomyces boulardii (MD = −1.25 day; 95%CI, −1.59, −0.91), Lactobacillus species (spp.) plus Bifidobacterium spp. plus Saccharomyces spp. (MD = −1.19 day; 95%CI, −1.81, −0.58), and Bacillus spp. plus Enterococcus spp. plus Clostridium spp. (MD = −1.1 day; 95%CI, −1.84, −0.35) significantly reduced the duration of diarrhea when compared with placebo. Saccharomyces boulardii [Odds ratio (OR) = 0.22; 95%CI, 0.11, 0.41] and Lactobacillus reuteri (OR = 0.23; 95%CI, 0.090, 0.60) significantly reduced the risk of diarrhea lasting ≥2 days when compared with placebo or no treatment, with moderate evidence. Among all probiotics, Saccharomyces boulardii may be the most effective in reducing both duration of diarrhea (compared with placebo) and risk of diarrhea lasting ≥2 days (compared with placebo or no treatment), with moderate evidence. To be conclusive, Saccharomyces boulardii may be the most effective probiotic for treating acute diarrhea in children, followed by several other single-strain and multi-strain probiotics.

 

 

Article 4: Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea

https://onlinelibrary.wiley.com/doi/10.1111/apt.13344 

Background: Antibiotic-associated diarrhoea is a common complication of antibiotic use, but it can be prevented with administration of probiotics.

 

Aim: To update our 2005 meta-analysis on the effectiveness of Saccharomyces boulardii in preventing antibiotic-associated diarrhoea in children and adults.

 

Methods: The Cochrane Library, MEDLINE, and EMBASE databases were searched up until May 2015, with no language restrictions, for randomised controlled trials; additional references were obtained from reviewed articles. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines.

 

Results: Twenty-one randomised controlled trials (4780 participants), among which 16 were new trials, met the inclusion criteria for this updated systematic review. Administration of S. boulardii compared with placebo or no treatment reduced the risk of antibiotic-associated diarrhoea (as defined by the study investigators) in patients treated with antibiotics from 18.7% to 8.5% (risk ratio, RR: 0.47; 95% CI: 0.38–0.57, number needed to treat, NNT: 10; 95% CI: 9–13). In children, S. boulardii reduced the risk from 20.9% to 8.8% (6 randomised controlled trials, n=1653, RR: 0.43, 95% CI: 0.3–0.6); in adults, from 17.4% to 8.2% (15 randomised controlled trials, n=3114, RR: 0.49, 95% CI: 0.38–0.63). Moreover, S. boulardii reduced the risk of Clostridium difficile-associated diarrhoea; however, this reduction was significant only in children (2 randomised controlled trials, n = 579, RR: 0.25; 95% CI: 0.08–0.73) and not in adults (9 randomised controlled trials, n = 1441, RR: 0.8, 95% CI: 0.47–1.34).

Conclusions: This meta-analysis confirms that S. boulardii is effective in reducing the risk of antibiotic-associated diarrhoea in children and adults.

 

Summary of the Evidence

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Zengbin, Li Guixan, Zhu Chao, Li Hao, Lai Xin, Liu Leih Zhang 11/29/2021	Systematic Review / Meta-analyses	●       Two large RCT involving almost 1000 children ●       Meta-analysis of 84 studies involving 13,443 children	What probiotic is the most effective in treating acute diarrhea?	●       A multi-strain probiotics effectively treated acute diarrhea in children. ●       Saccharomyces boulardii was found to be the most effective probiotic for treating children with acute diarrhea	Does not state dosage of probiotic used, and only follows acute diarrhea. Does it work for long-term diarrhea, and if patient is on antibiotics.
Guo Q, Goldenberg JZ, Humphrey C, El Dib R, Johnston BC. (2019)	Systematic Review / Meta-analyses	●       33 RCT totaling 6,352 subjects (3232 treatment, 3120 controls) population included children aged 3 days to 17 years who were receiving antibiotics ●       Studies analyzed were conducted between 1999 and 2017 ●       Intervention consisted of patients receiving probiotics ●       Control was alternative diarrhea prophylaxis or no prophylaxis	If probiotics were associated with decreased prevalence of diarrhea   If probiotics decreased the duration of antibiotic induced diarrhea   Study also compared the prophylactic benefit of high vs low dose probiotics	●       Antibiotic associated diarrhea in the probiotic group = 8% (259/323) ●       Higher dose probiotics reduced the incidence of AAD greater than low dose probiotics ●       AAD in the control group was 19% (598/3120) ●       For every 9 children treated, probiotics will prevent one case of diarrhea. (RR 0.45, 95% CI 0.36 to 0.56; I² = 57%, 6352 participants; NNTB 9, 95% CI 7 to 13; moderate certainty evidence) ●       Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day were most effective	Loss to follow-up was substantial in 20% of the trials; only 21 (out of 33) studies used a double blind procedure   In total, 20 trials were categorized at a potential high risk for bias due to lack of blinding or loss to follow up, and 13 trials categorized as a low risk   Only 24 of 33 studies included adverse events suggesting a reporting basis so they increased the bias rating for these studies
Casey Gray, Camille Dulong, Charlene Argáez (March 25, 2019)	Systematic Review	Studies comprised 9 systematic reviews, 3 RCTs, 2 evidence-based guidelines, and no observational studies ●       Articles published between 2014 and 2019 ●       Systematic reviews presented data on a total of 21,649 children up to 18 years of age	Clinical effectiveness: e.g., Clostridium difficile infection prevention, preventing AAD, shortening length of stay   Safety: e.g., side effects, adverse reactions	●       Evidence from 9 systematic reviews suggested favorable effects of probiotics on AAD relative to placebo, no additional treatment, or other non-probiotic treatment comparators ●       No evidence of an increased risk of AAD or CDAD with probiotics was identified ●       S. boulardii was shown to be better at preventing AAD relative to comparators groups in three reviews.	Clinical evidence regarding conditions under which probiotics were effective (e.g., specific dosing regimens, other outcomes, and indications) was sparse   Evidence from neonates or severely immunocompromised children regarding the safety of probiotics is divided
Szajewska H. (July 27, 2015)	Systematic Review / Meta-analysis	21 RCTs with 4780 participants	Incidence of AAD when probiotics were used vs. no probiotics	S. boulardii is effective in reducing the risk of AAD in children and adults,	Potential sources of bias in the majority of studies.

 

Conclusion(s):

• Probiotics decreased the prevalence and duration of AAD
  • More specifically, saccharomyces boulardii was found to be the most effective probiotic in two out of the four studies analyzed.
• Probiotics were more effective than alternative forms of AAD Prophylaxis
• High dose probiotics were more effective than low dose

 

Clinical Bottom Line:

Please include an assessment of the worth to practice

Children with antibiotic associated diarrhea may experience less diarrhea or shorter durations of diarrhea when taking probiotics compared to those that do not. In many studies, the effectiveness of treatment with S. boulardii was shown to have favorable results relative to comparator groups. This is helpful in practice for children and parents who are reluctant to take antibiotics due to adverse effects they may have experienced previously.