Pediatrics – PICO #3

Brief description of patient problem/setting (summarize the case very briefly)

In the pediatrics ER, you notice a symptomatic child with a bulging tympanic membrane and prescribe amoxicillin. The father of the child you are treating mentions that the last time his son had an ear infection and was treated with amoxicillin, he had diarrhea for days. The boy’s father read online that probiotics might shorten the duration of the diarrhea or can possibly eliminate it.

Search Question: Clearly state the question (including outcomes or criteria to be tracked)

In pediatric patients, do probiotics, given with antibiotics, shorten the course and incidence of antibiotic associated diarrhea?

Question Type: What kind of question is this? (boxes now checkable in Word)

☐Prevalence                             ☐Screening                  ☐Diagnosis

☐Prognosis                              ☒Treatment                 ☒Harms

Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? Please explain your choices.

– If meta-analysis or systematic review are not available, randomized controlled clinical trials will also offer great supporting evidence as they are carefully planned experiments, reduce the potential for bias, and allow for comparison between intervention and control groups.

– Cohort studies could also be used since they allow to follow the patients who have already received a particular treatment forward over time. This is not as reliable as randomized controlled clinical trials since patients might differ in ways other than in the variable that is being observed.

PICO search terms:

ChildrenProbioticsNo treatmentReduced duration of diarrhea
Pediatric patients PlaceboLess diarrhea
Antibiotic associated diarrhea  Reduced incidence of diarrhea
Antibiotic therapy associated diarrhea   

Search tools and strategy used:

Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.
Explain how you narrow your choices to the few selected articles.

Results found:

TRIP Database

  • Pediatric antibiotics AND Probiotics AND Placebo AND Less diarrhea – 237
  • Pediatrics antibiotic associated diarrhea AND Probiotics AND Placebo – 22


  • Children AND Antibiotic associated diarrhea AND Probiotics (in the last 10 years) – 133
  • Pediatrics AND Antibiotic associated diarrhea AND Probiotics (in the last 10 years) – 113
  • Pediatrics AND Antibiotic associated diarrhea AND Probiotics AND Placebo (in the last 10 years) – 18

One of the articles that I use below has been updated multiple times over the past 20 years with the same topic, but with more participants and trials (which I appreciated greatly). Many of the articles that I found were from abroad, so it was not the easiest to sift through. Additionally, I found many articles that had participants that were inpatient or critically ill in the hospital (that I did not use). Many articles had specific strains of probiotics that were used to look for reduced incidences of AAD, but I was looking at more generalized usage of probiotics that reduced AAD.

Identify at least 3 articles (or other appropriate reputable sources) that answer your specific question with the highest available level of evidence (you will probably need to look at more than 3 articles to get the 3 most focused and highest-level articles to address your question). Please make sure that they are Medline indexed.

Please post the citation and abstract for each article (to include the journal and authors’ names and date) and say why you chose it.
Please also note what kind of article it is (e.g. meta-analysis, cohort study, or independent blind comparison with gold standard of diagnosis, etc.).

At the bottom of each abstract, please comment on what your key points are from this article (including any points or concepts included in the article, but not present in the abstract – i.e. make the concepts understandable to the reader)

Please note that if the evidence is not in the abstract, you must clearly summarize the evidence in your posting.

Citation: Lukasik, J., Dierikx, T., Besseling-van der Vaart, I., de Meij, T., & Szajewska, H. (2022). Multispecies Probiotic for the Prevention of Antibiotic-Associated Diarrhea in Children: A Randomized Clinical Trial. JAMA Pediatrics, 176(9), 860–866.
Type of article: Randomized Clinical Trial
Abstract   OBJECTIVE To assess the effect of a multispecies probiotic on the risk of AAD in children.   DESIGN, SETTING, AND PARTICIPANTS This randomized, quadruple-blind, placebo-controlled trial was conducted from February 2018 to May 2021 in a multicenter, mixed setting (inpatients and outpatients). Patients were followed up throughout the intervention period. Eligibility criteria included age 3 months to 18 years, recruitment within 24 hours following initiation of broad-spectrum systemic antibiotics, and signed informed consent. In total, 646 eligible patients were approached and 350 patients took part in the trial.   INTERVENTIONS A multispecies probiotic consisting of Bifidobacterium bifidum W23, Bifidobacterium lactis W51, Lactobacillus acidophilus W37, L acidophilus W55, Lacticaseibacillus paracasei W20, Lactiplantibacillus plantarum W62, Lacticaseibacillus rhamnosus W71, and Ligilactobacillus salivarius W24, for a total dose of 10 billion colony-forming units daily, for the duration of antibiotic treatment and for 7 days after. MAIN OUTCOMES AND MEASURES The primary outcome was AAD, defined as 3 or more loose or watery stools per day in a 24-hour period, caused either by Clostridioides difficile or of otherwise unexplained etiology, after testing for common diarrheal pathogens. The secondary outcomes included diarrhea regardless of the etiology, diarrhea duration, and predefined diarrhea complications.   RESULTS A total of 350 children (192 boys and 158 girls; mean [range] age, 50 [3-212] months) were randomized and 313 were included in the intention-to-treat analysis. Compared with placebo (n = 155), the probiotic (n = 158) had no effect on risk of AAD (relative risk [RR], 0.81; 95% CI, 0.49-1.33). However, children in the probiotic group had a lower risk of diarrhea regardless of the etiology (RR, 0.65; 95% CI, 0.44-0.94). No differences were observed between the groups for most of the secondary outcomes, including adverse events.   CONCLUSIONS AND RELEVANCE A multispecies probiotic did not reduce the risk of AAD in children when analyzed according to the most stringent definition. However, it reduced the overall risk of diarrhea during and for 7 days after antibiotic treatment. Our study also shows that the AAD definition has a significant effect on clinical trial results and their interpretation.
Key Points: The research is comprised from a randomized clinical trial with 313 childrenThe groups were separated by a placebo group (155 children) and a probiotic group (158 children)The probiotics were multispecies that contained 8 different bacterial strainsThis study looked at whether the probiotics reduced the overall risk of diarrhea when the probiotics were given with the antibiotics and 7 days afterwardsThe study found that probiotics reduced the overall risk of diarrhea, regardless of the etiology, from 32% to 20%
Why I chose it: I chose this article because it was one of the largest clinical trials that investigated probiotics and its effect on antibiotic associated diarrhea. It was also a quadruple blind study, where the participants, care providers, investigators, and outcomes assessors where all blinded to the study, which is something I have never come across.  
Citation: Guo, Q., Goldenberg, J. Z., Humphrey, C., El Dib, R., Johnston, B. C., & Johnston, B. C. (2019). Probiotics for the prevention of pediatric antibiotic‐associated diarrhea. Cochrane Database of Systematic Reviews, 2019(5), CD004827-.
Type of article: Meta-analysis
Abstract:   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 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., or Streptococcus 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.
Key Points: This article included 6,352 participants across thirty-three studiesThe groups were separated between the probiotic group (3,232 participants) and the placebo group (3,120 participants)The incidence of antibiotic associated diarrhea after 5 days in the probiotic group was 8% (259/3232) and 19% (598/3120) in the placebo group.In another subset of groupings that had participants use higher dosed probiotics, the results were even greater. The incidence of diarrhea was 8% in the probiotic group versus 23% in the placebo groupThe incidence of adverse events (including rash, nausea, gas, flatulence, abdominal bloating, and constipation) was also reduced in the probiotics group at 4% versus the placebo group at 6%
Why I chose it: I chose this article because it was the largest study that took place that looked at how probiotics affected antibiotic associated diarrhea (AAD). This particular study was updated a multitude of times over the span of twenty years with reports on increased trials and participants. The multiple subsets of groupings (low dose, standard dose, and high dose probiotics) were also a refreshing look at how dosing affected the incidence of AAD (which I appreciated as well).
Citation: McFarland LV, Goh S. Preventing pediatric antibiotic-associated diarrhea and Clostridium difficile infections with probiotics: A meta-analysis. World J Meta-Anal 2013; 1(3): 102-120 [DOI: 10.13105/wjma.v1.i3.102]
Type of article: Meta-analysis
Abstract AIM: To assess the efficacy and safety of probiotics for preventing pediatric: (1) antibiotic associated diarrhea and (2) Clostridium difficile (C. difficile) infections. METHODS: On June 3, 2013, we searched PubMed (1960-2013), EMBASE (1974-2013), Cochrane Database of Systematic Reviews (1990-2013), CINAHL (1981-2013), AMED (1985-2013), and ISI Web of Science (2000-2013). Additionally, we conducted an extensive grey literature search including contact with National Institutes of Health Clinical Trials Registry, abstracts from annual infectious disease and gastroenterology meetings, experts in the field and correspondence with authors. The primary outcomes were the incidence of antibiotic-associated diarrhea (AAD) and C. difficile infections (CDI). Dichotomous outcomes (e.g., incidence of AAD or CDI) were pooled using a random-effects model to calculate the relative risk and corresponding 95% confidence interval (95%CI) and weighted on study quality. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic strain type, daily dose, quality of study and safety of probiotics. The overall quality of the evidence supporting each outcome was assessed using the grading of recommendations, assessment, development and evaluation criteria. RESULTS: A total of 1329 studies were identified with 22 trials (23 treatment arms and 4155 participants) meeting eligibility requirements for our review of prevention of AAD and 5 trials (1211 participants) for the prevention of CDI. Trials in adult populations, trials of uncertain antibiotic exposure or studies which did not provide incidence of AAD were excluded. We found 12 trials testing a single strain of probiotic and 10 trials testing a mixture of probiotic strains. Probiotics (all strains combined) significantly reduced the incidence of pediatric AAD (pooled RR = 0.42, 95%CI: 0.33-0.53) and significantly reduced pediatric CDI (pooled RR = 0.35, 95%CI: 0.13-0.92). Of the two strains with multiple trials, both significantly reduced pediatric AAD: Saccharomyces boulardii lyo (pooled RR = 0.43, 95%CI: 0.32-0.60) and Lactobacillus rhamnosus GG (pooled RR = 0.36, 95%CI: 0.19-0.69). There was no significant effect by type of antibiotic, or by duration or dose of probiotic. No adverse events associated were found in the 22 controlled trials relating to the use of probiotics. CONCLUSION: This meta-analysis found that probiotics significantly prevented pediatric antibiotic associated diarrhea and pediatric CDI, but the efficacy varies significantly by the strain of the probiotic.
Key Points: This study looked at 22 randomized control trials with a total of 4,155 participantsThe authors looked through many different search engines including PubMed, Cochrane Library, EMBASE, CINAHL, AMED, and ISI Web of ScienceMany different countries were represented in the 22 trials including the United States, France, Turkey, Poland, China, and many othersThe authors compared high doses of probiotics that were given versus lower doses of probioticsThe authors found that the incidence of antibiotic associated diarrhea with participants that were given the high dose of probiotics was 8.3% versus the placebo group at 20.6%The participants that were given lower doses of probiotics had incidences of AAD at 7.3% versus 15.9% with the placebo groupIn regards to adverse events, overall there were more abdominal complaints in the placebo group (57%) versus the probiotic group (27%).
Why I chose it: I chose this article because it included a vast group of participants across almost two dozen randomized control trials. This study also spanned the globe hitting on many countries and how they dealt with antibiotic associated diarrhea. I also appreciated that they looked at the dosages of probiotics and how they affected whether the participants had an increased or decreased incidence of AAD. I also noticed the same pattern of adverse events were in line with the other studies that I’ve mentioned above.

What is the clinical “bottom line” derived from these articles in answer to your question?

Diarrhea is defined by 3 or more loose stools per day. Antibiotic associated diarrhea (AAD) is a common side effect of antibiotic usage, which affects up to a quarter of patients taking different types of antibiotics. Through dozens of randomized control studies and meta-analysis, it has been shown that the usage of probiotics reduced the diarrhea that was associated with antibiotic use. It has also been shown that probiotic usage did not have adverse events associated with its usage alongside antibiotics for AAD.



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