Clinical Question:
A 4YOM diagnosed with otitis media is prescribed amoxicillin. His mother is concerned because she says the last time he took amoxicillin for an ear infection, he developed diarrhea for multiple days. She said she researched the subject and read that supplementary probiotics could be helpful in preventing this adverse effect, and she asked if I recommend she gives them to him.
PICO Question:
In children prescribed antibiotics, does probiotic supplementation reduce the incidence of antibiotic-associated diarrhea?
P: children taking antibiotics, Pediatric patients taking antibiotics
I: Probiotic supplementation, Probiotic use
C: No probiotics, Placebo
O: Incidence of antibiotic-associated diarrhea (AAD), Prevention of antibiotic-associated diarrhea (AAD)
Search Strategy:
In searching for my articles, my strategy had a few different components. First, I limited my search results to be for articles from the past 10 years. Furthermore, given the number of high level articles I was seeing, I wanted to ensure that my chosen articles were highest level, so I began my searches by adding “systematic review” as either a keyword or a search filter – Not only because they provide the highest level of evidence, but also because I know that my search question is fairly broad and rigorously researched, so I expected reviews to be plentiful. From there, I browsed abstracts and chose articles most specific to my PICO question, sometimes going back to remove the “systematic review” keyword in order to broaden my results.
1. CUNY York OneSearch
probiotic antibiotic diarrhea children systematic review → 2014-2024 → 68 results
I scrolled through the first 10 results. I prioritized peer-reviewed level 1 evidence studies with open access. I looked for articles from American journals. I looked for titles that best matched my PICO keywords.
The Fadin et al. article was the 1st result.
The Guo et al. article was the 5th result.
2. NIH PMC
probiotic antibiotic diarrhea children systematic review → 2014 – 2024 → 33 results
I scrolled through the first 10 results. I looked for articles from American journals. I looked for titles that best matched my PICO keyword.
The Szajewska et al. review was the 1st result
The Yang et al. review was the 8th result
3. Google Scholar
Being familiar with it, I know the Google Scholar algorithm tends to generate many more results than other search engines do. I opted to include more keywords in my search than I did on the other search engines, in hopes of making my results more selective and applicable to my PICO.
probiotic antibiotic diarrhea children pediatrics systematic review → 2014-2024 → 16,200 results
I opened and appraised an article, but I realized it was a narrative review that was not very applicable.
The Hayes et al. review was the 5th result.
I scrolled through the first page of results but was only seeing the articles I had already selected, as well as earlier versions of the same studies – I decided to return to PubMed for my 6th article.
4. NIH PMC
pediatric antibiotic induced diarrhea probiotics → newest first
Given that I was seeing so many of the same studies repeatedly, I wanted to look with the filter of “newest first” to mix up the first generated page of results. This also ensures I include the most recent data. I removed “review” or “systematic review” to broaden my results.
The Lukasik et al. study was the 6th result.
Articles Chosen for Inclusion:
Article 1: Probiotics in the Management of Antibiotic-Associated Diarrhea in Children
Citation
Fadin L, Vieira K, Toledo A, da Silva A, Pereira V, Winkelstroter L. Probiotics in the Management of Antibiotic-Associated Diarrhea in Children. Topics in Clinical Nutrition. 2023; 38 (3): 211-223. doi: 10.1097/TIN.0000000000000332.
Abstract
This review aimed to evaluate probiotic use to prevent antibiotic-associated diarrhea in children. A total of 1564 studies of randomized clinical trials published in English were found using PubMed, Cochrane, and Virtual Health Library (MEDLINE/LILACS). A meta-analysis included 4 trials in subgroup Lactobacillus rhamnosus (95% confidence interval [CI]: 0.17-0.49; P < .00001), 2 trials in subgroup L reuteri (95% CI: 0.51-1.77; P = .87), and 5 groups in subgroup association of species of probiotics (95% CI: 0.21-1.71; P = .33). The findings suggest that L rhamnosus alone may be useful in preventing antibiotic-associated diarrhea in children.
Article 2: Probiotics for the prevention of pediatric antibiotic‐associated diarrhea
Citation
Guo Q, Goldenberg JZ, Humphrey C, El Dib R, Johnston BC. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev. 2019;4(4):CD004827. Published 2019 Apr 30. doi:10.1002/14651858.CD004827.pub5
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 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.
Citation
Yang Q, Hu Z, Lei Y, et al. Overview of systematic reviews of probiotics in the prevention and treatment of antibiotic-associated diarrhea in children. Front Pharmacol. 2023;14:1153070. Published 2023 Jul 24. doi:10.3389/fphar.2023.1153070
Abstract
Background: Antibiotics alter the microbial balance commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent and treat AAD by providing the gut barrier and restoring the gut microflora. This study will overview the Systematic Reviews (SRs) of probiotics in preventing and treating AAD in children. It will also assess the reporting, methodological, and evidence quality of the included SRs to provide evidence for their clinical practice. Methods: After searching PubMed, Embase, Cochrane Library, CNKI, CBM, VIP, and WanFang Data databases, and finally included SRs of probiotics in the prevention and treatment of AAD in children, which were published before 1 October 2022. The reporting, methodological, and evidence quality of the included SRs were assessed by PRISMA 2020 statement, AMSTAR 2 tool, and GRADE system. Results: A total of 20 SRs were included, and the results of PRISMA 2020 showed that 4 out of 20 SRs with relatively complete reporting, and the others within some reporting deficiencies, with scores ranging from 17 points to 26.5 points; the results of AMSTAR 2 showed that 3 SRs belonged to moderate quality level, 10 SRs belonged to low-quality level and 7 SRs being extremely low-quality level; the results of the GRADE system showed that a total of 47 outcomes were reported for the included SRs, three were high-level evidence quality, 16 were medium-level evidence quality, 24 were low-level evidence quality, and four were extremely low-level evidence quality; the results of the Meta-analysis showed that high doses (5-40 billion CFUs per day) of probiotics had a significant effect in the prevention of AAD, but it is too early to conclude the effectiveness and safety of other probiotic drugs for AAD in children, except for Lacticaseibacillus rhamnosus and Saccharomyces boulardii. Conclusion: Current evidence shows that probiotics effectively prevent and treat AAD in children, and the effect of probiotics on pediatric AAD may be a potential dose-response effect. However, the conclusion should be treated with caution due to deficiencies in the methodological, reporting, and evidence quality of the included SRs. Therefore, the methodological, reporting, and evidence quality of relevant SRs still need further improvement.
Article 4: Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Children
Citation
Szajewska H, Canani RB, Guarino A, et al. Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Children. J Pediatr Gastroenterol Nutr. 2016;62(3):495-506. doi:10.1097/MPG.0000000000001081
Abstract
This article provides recommendations, developed by the Working Group (WG) on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, for the use of probiotics for the prevention of antibiotic-associated diarrhea (AAD) in children based on a systematic review of previously completed systematic reviews and of randomized controlled trials published subsequently to these reviews. The use of probiotics for the treatment of AAD is not covered. The recommendations were formulated only if at least 2 randomized controlled trials that used a given probiotic (with strain specification) were available. The quality of evidence (QoE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation guidelines. If the use of probiotics for preventing AAD is considered because of the existence of risk factors such as class of antibiotic(s), duration of antibiotic treatment, age, need for hospitalization, comorbidities, or previous episodes of AAD diarrhea, the WG recommends using Lactobacillus rhamnosus GG (moderate QoE, strong recommendation) or Saccharomyces boulardii (moderate QoE, strong recommendation). If the use of probiotics for preventing Clostridium difficile-associated diarrhea is considered, the WG suggests using S boulardii (low QoE, conditional recommendation). Other strains or combinations of strains have been tested, but sufficient evidence is still lacking.
Article 5: Probiotics for the Prevention of Pediatric Antibiotic-Associated Diarrhea
Citation
Hayes SR, Vargas AJ. Probiotics for the Prevention of Pediatric Antibiotic-Associated Diarrhea. Explore (NY). 2016;12(6):463-466. doi:10.1016/j.explore.2016.08.015
Abstract
Background: Antibiotics are frequently prescribed in children. They alter the microbial balance within the gastrointestinal tract, commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via restoration of the gut microflora.
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, AMED, and the Web of Science (inception to November 2014) were searched along with specialized registers including the Cochrane IBD/FBD review group, CISCOM (Centralized Information Service for Complementary Medicine), NHS Evidence, the International Bibliographic Information on Dietary Supplements, as well as trial registries. Letters were sent to authors of included trials, nutraceutical and pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were also searched.
Selection criteria: Randomized, parallel, controlled trials in children (0-18 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 methodological quality assessment using the risk of bias instrument were conducted independently and in duplicate by two authors. Dichotomous data (incidence of diarrhea and adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea and mean daily stool frequency) as mean difference (MD), along with their corresponding 95% confidence interval (95% CI). For overall pooled results on the incidence of diarrhea, sensitivity analyses included available case versus extreme-plausible analyses and random- versus fixed-effect models. To explore possible explanations for heterogeneity, a priori subgroup analysis was conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, and risk of bias. We also conducted post hoc subgroup analyses by patient diagnosis, single versus multi-strain, industry sponsorship, and inpatient status. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.
Main results: Overall, 23 studies (3938 participants) met the inclusion criteria. Trials included treatment with either Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., or Streptococcus spp., alone or in combination. Eleven studies used a single-strain probiotic, four combined two probiotic strains, three combined three probiotic strains, one combined four probiotic strains, two combined seven probiotic strains, one included ten probiotic strains, and one study included two probiotic arms that used three and two strains, respectively. The risk of bias was determined to be high or unclear in 13 studies and low in 10 studies. Available case (patients who did not complete the studies were not included in the analysis) results from 22/23 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo, or no treatment control. The incidence of AAD in the probiotic group was 8% (163/1992) compared to 19% (364/1906) in the control group (RR = 0.46; 95% CI: 0.35-0.61; I2 = 55%, 3898 participants). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate. This benefit remained statistically significant in an extreme-plausible (60% of children lost to follow-up in probiotic group and 20% lost to follow-up in the control group had diarrhea) sensitivity analysis, where the incidence of AAD in the probiotic group was 14% (330/2294) compared to 19% (426/2235) in the control group (RR = 0.69; 95% CI: 0.54-0.89; I2 = 63%, 4529 participants). None of the 16 trials (n = 2455) that reported on adverse events documented any serious adverse events attributable to probiotics. Meta-analysis excluded all but an extremely small non-significant difference in adverse events between treatment and control (RD = 0.00, 95% CI: -0.01 to 0.01). The majority of adverse events were in placebo, standard care, or no treatment group. Adverse events reported in the studies include rash, nausea, gas, flatulence, abdominal bloating, abdominal pain, vomiting, increased phlegm, chest pain, constipation, taste disturbance, and low appetite. AUTHORS׳ CONCLUSIONS: Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. Our pooled estimate suggests a precise (RR 0.46; 95% CI: 0.35-0.61) probiotic effect with an NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5-40 billion colony-forming units/day may be appropriate given the modest NNT and the likelihood that adverse events are very rare. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Although no serious adverse events were observed among otherwise healthy children, serious adverse events have been observed in severely debilitated or immunocompromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation. Until further research has been conducted, probiotic use should be avoided in pediatric populations at risk for adverse events. Future trials would benefit from a standard and valid outcomes to measure AAD.
Citation
Łukasik J, Guo Q, Boulos L, Szajewska H, Johnston BC. Probiotics for the prevention of antibiotic-associated adverse events in children-A scoping review to inform development of a core outcome set. PLoS One. 2020;15(5):e0228824. Published 2020 May 29. doi:10.1371/journal.pone.0228824
Abstract
Introduction: Routine use of probiotics during antibiotic therapy in children remains a subject of discussion. To facilitate synthesis of individual study results and guideline formulation, it is important to assess predefined, similar, and clinically important outcomes. Core outcome sets are a proposed solution for this issue. The aim of this review was to document choice, design, and heterogeneity of outcomes in studies that assessed the effects of probiotics used for the prevention of antibiotic-associated adverse events in children.
Methods: A scoping literature search covering three major databases was performed. Studies that evaluated oral probiotics’ use concomitant with antibiotic therapy in children were included. Data on outcome definitions, measurement instruments, and follow-up were extracted. The outcomes were assigned to predefined core areas and domains. Data were analyzed descriptively.
Results: Thirty-seven studies were included in this review. Diarrhea, the most commonly reported outcome, had diagnostic criteria clearly defined only in 21 studies. In total, 16 different definitions of diarrhea were identified. Diarrhea duration, severity, and etiology were reported in 9, 4, and 7 studies, respectively. Twenty studies assessed gastrointestinal symptoms other than diarrhea. Seven studies reported outcomes related to resource use or the economic impact of the intervention. Only 2 studies assessed outcomes related to life impact. None of the studies predefined adverse events of probiotic use.
Conclusions: Identified outcomes were characterized by substantial heterogeneity. The majority of outcomes were not designed to evaluate endpoints of real-life relevance. Results from this review suggest the need for a new core outcome set consisting of outcomes important for decision-making.
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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 |
| Fadin et al. (2023) | Level I | Articles had to meet the following criteria: (i) studies evaluating the effectiveness of probiotic use in AAD; (ii) studies in children from 0 to 17 years of age; and (iii) studies using a randomized, placebo-controlled study design. A total of 1564 records were identified. Of these, 40 records were selected by title and abstract and 12 full-text articles were included in the analysis. All included similar data including probiotic regimen (single or multistrain), daily dose administered, and the duration of probiotic treatment, in addition to the diagnosis that motivated the use of antibiotic treatment | 1. incidence of AAD by the percentage extracted to demonstrate the effectiveness of using probiotics 2. duration of follow-up3. duration of days of diarrhea. | Majority of studies demonstrated that the probiotic group had a lower incidence of AAD in children, with the exception of 2. Both tested the organism L reuteri. Suggesting its low efficacy in reducing incidence of pediatric AAD. The most significant result was the reduction of the risk of AAD by approximately 95%, using the highest probiotic dose (2 × 10 10 CFU/2× daily) of L rhamnosus | Variations in methodological quality among the selected studies. Different definitions of AAD or diarrhea, as well as the different units of measurement used to refer to the amount of probiotic applied and the time of administration. |
| Guo et al. (2019) | Level I | Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment Thirty‐three studies (6352 participants) were included. | Incidence of diarrhea secondary to antibiotic use Secondary: Mean duration of diarrheaAdverse event rates | Overall evidence suggests a moderate protective effect of probiotics for preventing AAD (NNTB 9, 95% CI 7 to 13). The subgroup effect based on high dose probiotics (≥ 5 billion CFUs per day) was most credible (NNTB 6 (95% CI 5 to 9). Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction by almost one day. | Data from studies testing different probiotic species were pooled. The overall certainty of the evidence for the primary endpoint, incidence of AAD, based on high dose probiotics was moderate due to the issues with risk of bias and inconsistency related to a diversity of probiotic agents used. |
| Szajewska et al. (2016) | Level I | previously completed systematic reviews and of randomized controlled trials (RCTs) published through November 2015 21 RCTs involving 3255 children were included | Incidence of diarrhea/AAD and C difficile-associated diarrhea (all as defined by the investigators) | 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) If the use of probiotics for preventing AAD is considered, they recommend using L rhamnosus GG or S boulardii (moderate quality of evidence; strong recommendation). | The quality of each SR included, and then also of each RCT included in each SR, varied widely. Many trials included unclear random sequence generation, unclear or no allocation concealment, and unclear or no blinding of participants and personnel. Methods and analyses performed also varied between included SRs. |
| Yang et al. (2022) | Level I | SRs of probiotics in the prevention and treatment of AAD in children, which were published before 1 October 2022 A total of 20 SRs were included | incidence of AAD; adverse effects; duration of diarrhea; total effective rate; mean hospital stay; incidence of CDAD; mean stool frequency; cure rate; antidiarrheal time. | High doses (5–40 billion CFUs per day) of the probiotic organisms L. rhamnosus and S. boulardii had a significant effect in the prevention of AAD They also improve the overall efficiency and clinical cure rate, shorten the duration of diarrhea, mean frequency of diarrhea, the average hospitalization time and antidiarrheal time, and the incidence of adverse effects was low, the safety of probiotics was good. | The results of existing evidence show that the methodological, reporting and evidence quality of SRs of probiotics for AAD in children are generally low. There is still a need to improve the quality of evidence-based evidence to better explain the clinical application value of probiotics for AAD in children in the future. The results of this study need to be applied with reasonable interpretation. |
| Hayes and Vargas, (2016) | Level I | Randomized, parallel, controlled trials in children (0–18 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. Overall, 23 studies (3938 participants) met the inclusion criteria. | incidence of AAD Adverse events attributable to probiotics | Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. Pooled estimate suggests a probiotic effect with an NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5–40 billion colony-forming units/day may be appropriate given the modest NNT and the likelihood that adverse events are very rare. | Heterogeneity and high risk of bias in some studies Variable definitions of diarrhea with respect to the frequency, duration, and consistency of bowel movements significantly modified the reported benefit of probiotic treatment on the risk of AAD. |
| Lukasik et al., 2020 | Level I | Studies that evaluated oral probiotics’ use concomitant with antibiotic therapy in children were included. Eligible studies could be RCTs, non-randomized trials (NRTs), or observational studies (e.g., cohort studies, case-control studies) and had to be conducted in a population of children up to 18 years of age. Thirty-seven studies were included in this review. 32 were RCTs. | Incidence of diarrhea was the most commonly reported outcome Diarrhea duration, severity, and etiology were reported in 9, 4, and 7 studies, respectively. | Outcomes reported in studies on probiotic use in children receiving antibiotic therapy are characterized by substantial heterogeneity. In the majority of trials, the outcomes and outcome measures are not designed to evaluate outcomes of real-life relevance such as patient and parent reported quality of life. Results from this review suggest the need for a new core outcome set with endpoints that cover the span of domains and outcomes important to patients, families and clinicians for decision-making. | Essentially, this large SR concluded that the studies they analyzed were far too heterogenous to even find helpful to be analyzed together. The discussion moreso lists out how every variable considered is limited by severe heterogeneity having to do with differences in definition of variables, clinical setting, adverse effects evaluated, and more. I thought this study was important to include because it has many of the same articles as the other studies, but was deemed invaluable. |
Conclusion(s):
| Fadin et al. (2023) | Studies testing the organism L reuteri did not find it to have a significant effect on reducing pediatric AAD, implying its low efficacy. All studies testing other organisms demonstrated that the probiotic group had a lower incidence of AAD. The most significant result was the reduction of the risk of AAD by approximately 95%, using the highest probiotic dose (2 × 10^10 CFU/2× daily) of L rhamnosus. |
| Guo et al. (2019) | Overall evidence suggests a moderate protective effect of probiotics for preventing AAD. The most significant effect was seen using high dose probiotics (≥ 5 billion CFUs per day). Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction by almost one day. |
| Szajewska et al. (2016) | 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%. The microorganisms L rhamnosus GG or S boulardii demonstrated the most significant effect. |
| Yang et al. (2022) | High doses (5–40 billion CFUs per day) of the probiotic organisms L. rhamnosus and S. boulardii had a significant effect in the prevention of AAD. They also improve the overall efficiency and clinical cure rate, as well as shorten the duration of diarrhea, mean frequency of diarrhea, average hospitalization time and antidiarrheal time. |
| Hayes and Vargas (2016) | Moderate quality evidence suggests a protective effect of probiotics in preventing AAD, with an NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5–40 billion colony-forming units/day seems most appropriate. |
| Lukasik et al. (2020) | This review is unable to come to clinically applicable conclusions, because outcomes reported in studies are characterized by substantial heterogeneity. In the majority of trials, the outcomes and outcome measures are not designed to evaluate outcomes of real-life relevance such as patient and parent reported quality of life. Results from this review suggest the need for a standardized outcome set with endpoints that cover topics that are important to patients, families and clinicians for decision-making. |
Five of six appraised systematic reviews found an overall significant protective benefit of probiotic supplementation against antibiotic-associated diarrhea in children. Each of these five reviews concluded that this effect is dose-dependent, recommending high doses of 5 to 40 billion colony-forming units/day. These reviews also all concluded that the microorganism Lactobacillus rhamnosus had the most significant protective effect, with most also finding Saccharomyces boulardii to be of greater efficacy than other organisms. Dissimilarly, the final review that I appraised was unable to come to any conclusions regarding the efficacy of probiotics in preventing antibiotic-associated diarrhea in children. This is because the authors believe that the studies they analyzed, some of which have overlapping inclusion criteria with the other reviews that I appraised, were of low level evidence and have too much heterogeneity when it comes to the operationalization of variables and outcomes. Therefore, the authors state that their pooled analysis could not be used to confidently make clinical recommendations.
Clinical Bottom Line:
Weight of the Evidence
1. Guo et al. (2019)
This is a Cochrane Review with a large sample and rigorous selection process, updating and building on a Cochrane published a few years early, thus I weigh it highest.
2. Lukasik et al. (2020)
This study came out one year after the Guo et al. article and has similar aims, methods, and articles analyzed, making it an important comparator. However, keeping that in mind, this study concluded that too much heterogeneity existed between the articles to draw conclusions, which to me indicates that the researchers were extremely rigorous and responsible about their research. Thus, I weigh it second.
3. Fadin et al. (2023)
This is the newest study I found, but is relatively smaller compared to other articles I chose. I still weigh it highly given its recency, but find the methods and magnitude to be inferior to Guo et al.
4. Yang et al. (2022)
This is the second most recent study analyzed, and it’s a systematic review of systematic reviews. Although this makes it a more robust study, it also increases the likelihood of homogeneity between the SRs and the RCTs they individually contain, which is something I am wary of given the conclusions of Lukasik et al.
5. Hayes and Vargas (2016)
This is an older study, so I weigh it less heavily. Compared to the Szajewska study from 2016, this study only analyzes randomized, parallel, controlled trials, which likely will have less heterogeneity compared to the other study. Given the conclusions of Lukasik et al., I believe that means stronger evidence.
6. Szajewska et al. (2016)
As mentioned above, this is an older study that analyzes SRs, making it possibly outdated and also increasing the likelihood of heterogeneity amongst the studies analyzed. Thus, I weigh it the least.
Magnitude of any effects
Of the five reviews that reported effects, each reported moderate evidence of the protective effects of probiotics in general against pediatric antibiotic-associated diarrhea. The specific microorganisms L. rhamnosus or S.boulardii at 5–40 billion colony-forming units/day were consistently shown to have a strong level of evidence demonstrating its protective effect. Unfortunately, the range of doses, frequency, and duration were too heterogeneous between each article and their analyzed studies to draw conclusions on such parameters.
Clinical significance
To answer my patient’s mother’s question, I would tell her it seems worthwhile to pursue probiotic supplementation over the course of her child’s amoxicillin course, and that I specifically recommend daily probiotic supplementation of greater than 5 billion CFU of L. rhamnosus. This specific microorganism and dose consistently shows a strong protective benefit against antibiotic-associated diarrhea, without significant additional adverse effects. Specifically, high-dose L. rhamnosus seems to prevent antibiotic-associated diarrhea from occurring at all in some patients. In others, it seems to decrease the duration of diarrheal symptoms when they do occur. It seems to completely prevent diarrheal symptoms in anywhere between 1-in-6 to 1-in-10 patients, depending on the study. It seems to decrease symptom duration by at least 1 day according to multiple studies.
I would caution this mother that this practice requires further research to be more precise, but generally, the benefits demonstrated are significant and far outweigh any risks. Given heterogeneity between studies, more research is required to establish which treatment schedule is most ideal, but many studies researched coadministration on the same days that antibiotics are given, so I would be comfortable advising that.
Other considerations
It’s important to keep in mind what Lukasik et al. concluded in 2020, which is that the existing body of research was too heterogenous for a pooled analysis. It’s evident that more research is required to formally guide clinical practice. All of the appraised reviews, including the ones who made recommendations for high-dose L. rhamnosus supplementation, acknowledged issues with heterogeneity and low-level evidence in their included studies. They still felt data was adequate to draw conclusions, and while I agree that the data supports high-dose L. rhamnosus supplementation despite these study limitations, it’s clear that higher level research needs to be completed in order to better validate these findings. Specifically, standardizing a definition of diarrhea seems most important. At this point, I think pursuing research only on L. rhamnosus and S. boulardii would be most worthwhile, as these two organisms seem to be the most promising and this would eliminate heterogeneity between microorganisms tested.
References/PDFs
CAT_Probiotics.pdf
Guo_et_al-2019-Cochrane_Database_of_Systematic_Reviews.pdf
J pediatr gastroenterol nutr – 2016 – Szajewska – Probiotics for the Prevention of Antibiotic‐Associated Diarrhea in.pdf
Probiotics in the Management of Antibiotic-Associated Diarrhea in Children_A Systematic Review and Meta-analysis of Randomized and Controlled Trials.pdf
Hayes and Vargas.pdf
Lukasik et al.pdf
Yang et al..pdf
