EBM Final Project

Clinical Question: Do probiotics decrease the likelihood of antibiotic associated diarrhea in pediatric patients? 

PICO Question

Population: Pediatric patients taking antibiotics

Intervention: Probiotics

Comparison: No probiotics 

Outcome: Lower incidence of antibiotic associated diarrhea

 

Search Strategy:

Database: Pubmed, Google Scholar, Cochrane

Search terms: probiotics for prevention of antibiotic-associated diarrhea

Articles returned: 223 (Pubmed), 19,300 (Google Scholar), 3 (Cochrane)

 

Articles Chosen

Article 1: Probiotics for the prevention of pediatric antibiotic associated diarrhea: A systematic review

Qin Guo, Joshua Z Goldenberg, Claire Humphrey, Regina El Dib, Bradley C Johnston

 

ABSTRACT: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490796/

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.

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Qin Guo, Joshua Z Goldenberg, Claire Humphrey, Regina El Dib, Bradley C Johnston	Systematic Review – Level 1	33 studies (6352 participants) – randomized, parallel, controlled trials in children 0-18 years receiving abx compared to probiotics to placebo Studies obtained from MEDLINE, Embase, CENTRAL, CINAHL, and the Web of Science	Incidence of AAD – defined as the disturbance of bacteria in the intestinal tract which can cause natural bacteria to multiply beyond normal numbers – causing frequent water bowel movements and crampy abdominal pain –  in probiotic group versus control group  Secondary outcome:  Did probiotics cause any harms (side effects)	Analyses showed that probiotics are effective for preventing AAD – 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)– demonstrating moderate reduction (11% fewer will suffer diarrhea)  Furthermore – evidence suggests that higher dose probiotics (>5 billion CFUs per day) reduce the incidence of AAD– 8% (162/2029) of the high dose probiotics group had AAD compared to the 23% of the control group (462/2009) – 15% fewer suffer diarrhea	Did not search conference proceedings or dissertation abstracts in updated search. Only one study assessed changes in microbiome characteristics before and after abx and probiotic administration demonstrating no important differences. Aggregate data meta-analysis does not allow the SR to fully explore participants (e.g. sex) and intervention level variables (# of abx prescribed) that may be associated with AAD – 19 studies had loss to follow up ranging from 1% to 46%

 Article 2: 

Can probiotic yogurt prevent diarrhea in children on antibiotics? A double-blind, randomized, placebo-controlled study

Michael J Fox, Kiran D K Ahuja, Iain K Robertson, Madeleine J Ball, Rajaraman D Eri 

https://pubmed.ncbi.nlm.nih.gov/25588782/

ABSTRACT 

Objective: To estimate the efficacy of a probiotic yogurt compared to a pasteurized yogurt for the prevention of antibiotic-associated diarrhea in children. 

Design and setting: This was a multisite, randomized, double-blind, placebo-controlled clinical trial conducted between September 2009 and 2012. The study was conducted through general practices and pharmacies in Launceston, Tasmania, Australia. 

Participants and interventions: Children (aged 1–12 years) prescribed antibiotics, were diarrhea to receive 200 g/day of either yogurt ( probiotic) containing Lactobacillus rhamnosus GG (LGG), Bifidobacterium lactis (Bb-12) and Lactobacillus acidophilus (La-5) or a pasteurized yogurt ( placebo) for the same duration as their antibiotic treatment.

Outcomes: Stool frequency and consistency were recorded for the duration of treatment plus 1 week. Primary outcome was stool frequency and consistency, classified at different levels of diarrhea severity. Due to the small number of cases of diarrhea, comparisons between groups were made using Fisher’s exact analysis. 

Results: 72 children commenced and 70 children (36 placebo and 34 probiotic) completed the trial. There were no incidents of severe diarrhea (stool consistency ≥6, ≥3 stools/day for ≥2 consecutive days) in the probiotic group and six in the placebo group (Fisher’s exact p=0.025). There was also only one episode of minor diarrhea (stool consistency ≥5, ≥2 stools/day for ≥2 days in the probiotic group compared to 21 in the placebo group (Fisher’s exact p<0.001). The probiotic group reported fewer adverse events (1 had abdominal pain, 1 vomited and 1 had headache) than the placebo group (6 had abdominal pain, 4 had loss of appetite and 1 had nausea). 

Conclusions: A yogurt combination of LGG, La-5 and Bb-12 is an effective method for reducing the incidence of antibiotic-associated diarrhea in children.

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Michael J Fox, Kiran D K Ahuja, Iain K Robertson, Madeleine J Ball, Rajaraman D Eri August 27, 2014	1- RCT	There was a total of 70 children that completed the trial, 36 being on the placebo and 34 on the probiotic. The children were between ages of 1-12.  This was a double-blind, randomized, placebo-controlled study.	Primary outcome: efficacy of probiotic yogurt in prevention of diarrhea, classified at different levels of severity (less severe: stool frequency >2/day for 2 or more days with stool consistency >5 on the BSS), (more severe >3 days with stool consistency >6 on the BSS).	– A probiotic yogurt is an effective method for reducing the incidence of antibiotic-associated diarrhea in children. Additionally, the probiotic group demonstrated fewer adverse events such as abdominal pain, vomiting, headache compared to the placebo group.	– The effects on stool were only recorded for the duration of the antibiotic treatment plus 1 week – so there may have been other incidences that were not recorded. This time frame was chosen because AAD usually begins in the first 2 weeks of beginning antibiotic treatment. Additionally, the study relied on self reported data by the parents or children – so children at school may have had less complete recording. Lastly, it took a long time to recruit the patients (almost 3 years) which introduces selection bias.

Article 3:

Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Outpatients—A Systematic Review and Meta-Analysis

Authors: Sara Blaabjerg, Daniel Maribo Artzi, and Rune Aabenhus

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745464/#:~:text=A%20common%20adverse%20effect%20of,of%20an%20unbalanced%20gastrointestinal%20flora. 

Abstract:

The objective of this systematic review was to assess the benefits and harms of probiotics used for the prevention of AAD in an outpatient setting. A search of the PubMed database was conducted and yielded a total of 17 RCTs with 3631 participants to be included in the review. A meta-analysis was conducted for the primary outcome: the incidence of AAD. The pooled results found that AAD was present in 8.0% of the probiotic group compared to 17.7% in the control group (RR 0.49, 95% CI 0.36 to 0.66; I2 = 58%), and the species-specific results were similar regarding the probiotic strains L. rhamnosus GG and S. boulardii. However, the overall quality of the included studies was moderate. A meta-analysis of the ten trials reporting adverse events demonstrated no statistically significant differences in the incidence of adverse events between the intervention and control group (RD 0.00, 95% CI −0.02 to 0.02, 2.363 participants). The results suggest that probiotic use may be beneficial in the prevention of AAD among outpatients. Furthermore, the use of probiotics appears safe.

Types of studies include: 

All included studies were prospective, randomized, controlled trials with placebo, active, or no treatment control arms.

Patient population: The 17 studies included a total of 3631 patients. The patient population was restricted to outpatients taking oral antibiotics, as trials randomizing hospitalized patients were excluded. The recruitment and evaluation of patients took place in private practices, pharmacies, or hospitals (ambulatory settings, outpatient clinics, etc.).

All studies included both males and females.

Main outcome: 

Incidence of Antibiotic-Associated Diarrhea All of the 17 included studies reported the incidence of diarrhea and the number of patients randomized to each group. The incidence of AAD in the probiotic group was 8.0%, compared to 17.7% in the control group. The overall pooled results showed that the use of probiotics produced a statistically significant reduction in the incidence of AAD: RR 0.49; 95% CI 0.36 to 0.66.

Conclusions:

Using probiotics for the prevention of antibiotic-associated diarrhea reduces the risk of AAD by 51% (RR 0.49; 95% CI 0.36 to 0.67) with a moderate quality of evidence according to GRADE. This result was confirmed in analyses of specific strains, namely Lactobacillus rhamnosus GG and Saccharomyces boulardii. Furthermore, we found preliminary evidence to suggest a dose-response relationship.

The use of probiotics appears safe. However, our study still suggests that caution be applied prior to widespread introduction of probiotic treatment for AAD as only 18% of the included studies had a low risk of bias, and these studies did not find a statistical significant reduction in the prevention of AAD.

Limitations to the findings include the paucity of data on probiotic strain level, and future studies on probiotics to prevent AAD should focus on identifying the most effective agent(s) preferable in head-to-head comparisons and follow a stringent approach to definitions of outcomes, as well as clinical scenarios, prior to the widespread recommendation of probiotics as adjunct therapy to antibiotics. Also, more data are needed to determine the safety of probiotics, and trials should define potential adverse events in advance.

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Blaabjerg, Sara Artzi, Maribo Artzi Aabenhus, Rune	Systemic review and meta analysis	17 studies through MEDLINE/ PUBMED. Total 3631 patients in 17 studies.  All randomized controlled trials in which probiotics were given to prevent antibiotic-associated diarrhea and in which the use of probiotics was compared to either a placebo or an active alternative prophylaxis or in which no treatment were considered for inclusion. All ages were included, but some trails included only children under 15 and some included children and adults	Primary outcome: Incidence of antibiotic-associated diarrhea (AAD) Secondary outcomes: Incidence of AAD using the criteria defined by WHO: This analysis used the definition of diarrhea authored by WHO. Diarrhea is defined as “the passage of three or more loose or liquid stools per day (or more frequent passage than is normal for the individual)”. Antibiotic-associated diarrhea was considered in cases of a subject having diarrhea in relation to their treatment with antibiotics.	All of the 17 included studies reported the incidence of diarrhea and the number of patients randomized to each group. The incidence of AAD in the probiotic group was 8.0%, compared to 17.7% in the control group. The overall pooled results showed that the use of probiotics produced a statistically significant reduction in the incidence of AAD: RR 0.49; 95% CI 0.36 to 0.66 Using probiotics for the prevention of antibiotic-associated diarrhea reduces the risk of AAD by 51% (RR 0.49; 95% CI 0.36 to 0.67) with a moderate quality of evidence according to GRADE.	Risk was biased into 3 categories: high disk, low and unclear. The quality of reporting was low, 11 trails lacked adequate information to assess one or more of the parameters, making the bias unclear.  For the blinding of participants, nearly half of the studies were evaluated as having a “high risk of bias” because the participants in the control group did not receive any kind of placebo matching the probiotic(s) given to the intervention group. Loss of follow up was substantial in 3 trails.  Definition of diarrhea was different throughout all the studies included.  The overall quality of the included studies was moderate, due to high risk of bias.  A meta-analysis of the ten trials reporting adverse events demonstrated no statistically significant differences in the incidence of adverse events between the intervention and control group.

Article 4: Probiotics for the Prevention and Treatment of Antibiotic-Associated Diarrhea

A Systematic Review and Meta-analysis

• Authors: Susanne Hempel, Sydne J Newberry, Alicia R Maher, Zhen Wang, Jeremy N V Miles, Roberta Shanman, Breanne Johnsen, Paul G Shekelle

Link: https://jamanetwork.com/journals/jama/fullarticle/1151505

Abstract

Context: Probiotics are live microorganisms intended to confer a health benefit when consumed. One condition for which probiotics have been advocated is the diarrhea that is a common adverse effect of antibiotic use.

Objective: To evaluate the evidence for probiotic use in the prevention and treatment of antibiotic-associated diarrhea (AAD).

Data sources: Twelve electronic databases were searched (DARE, Cochrane Library of Systematic Reviews, CENTRAL, PubMed, EMBASE, CINAHL, AMED, MANTIS, TOXLINE, ToxFILE, NTIS, and AGRICOLA) and references of included studies and reviews were screened from database inception to February 2012, without language restriction.

Study selection: Two independent reviewers identified parallel randomized controlled trials (RCTs) of probiotics (Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus) for the prevention or treatment of AAD.

Data extraction: Two independent reviewers extracted the data and assessed trial quality.

Results: A total of 82 RCTs met inclusion criteria. The majority used Lactobacillus-based interventions alone or in combination with other genera; strains were poorly documented. The pooled relative risk in a DerSimonian-Laird random-effects meta-analysis of 63 RCTs, which included 11 811 participants, indicated a statistically significant association of probiotic administration with reduction in AAD (relative risk, 0.58; 95% CI, 0.50 to 0.68; P < .001; I(2), 54%; [risk difference, -0.07; 95% CI, -0.10 to -0.05], [number needed to treat, 13; 95% CI, 10.3 to 19.1]) in trials reporting on the number of patients with AAD. This result was relatively insensitive to numerous subgroup analyses. However, there exists significant heterogeneity in pooled results and the evidence is insufficient to determine whether this association varies systematically by population, antibiotic characteristic, or probiotic preparation.

Conclusions: The pooled evidence suggests that probiotics are associated with a reduction in AAD. More research is needed to determine which probiotics are associated with the greatest efficacy and for which patients receiving which specific antibiotics.

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Susanne Hempel, Sydne J Newberry, Alicia R Maher, Zhen Wang, Jeremy N V Miles, Roberta Shanman, Breanne Johnsen, Paul G Shekelle	Systematic review and meta- analysis	Twelve electronic databases were searched (DARE, Cochrane Library of Systematic Reviews, CENTRAL, PubMed, EMBASE, CINAHL, AMED, MANTIS, TOXLINE, ToxFILE, NTIS, and AGRICOLA). 63 RCTs, which included 11,811 participants. Participants of all ages treated with antibiotics, regardless of the indication and the patients’ underlying symptomatology, were included.	The primary outcome was the number of participants with diarrhea in each treatment group. We also extracted other relevant outcomes such as the severity of diarrhea or measures of stool consistency. We extracted probiotics-related adverse effects such as infections because of the administered organism. All reports of diarrhea were considered (as main treatment effects, reasons for dropouts, or adverse effects). This analysis used the original study’s definition of diarrhea, which ranged from uncomplicated diarrhea to severe diarrhea with complications such as electrolyte imbalance, and included outcomes such as watery stool, stool consistency, self-reported diarrhea, and physician-defined diarrhea.	The principal finding of this review is that using probiotics as adjunct therapy reduces the risk of AAD, with an RR of 0.58. The result was consistent across a number of subgroup and sensitivity analyses. In 20 RCTs, adjunct probiotics treatment was associated with a statistically significant benefit on the number of participants with AAD (RR, 0.55; 96% CI, 0.42 to 0.72; P < .001; I2, 47%; NNT, 10). Trials that reported AAD incidence after cessation of antibiotic therapy (7 RCTs) indicated that the number of participants experiencing AAD was lower in the probiotics groups than in control groups (RR, 0.44; 95% CI, 0.20 to 0.99; P = .047; I2, 0%; NNT, 75).	The main limitations to this result are residual unexplained heterogeneity (evidence is insufficient to determine whether this association varies systematically by population, antibiotic characteristic, or probiotic preparation), poor documentation of the probiotic strains, and lack of assessment of probiotic-specific adverse events. Most trials either did not specify the follow-up period, or the assessment was explicitly limited to the time of antibiotics treatment.

 Conclusion(s): Using probiotics as adjunct therapy reduces the risk of antibiotic associated diarrhea.

 Clinical Bottom Line:

• After appraising each of the articles we found that: 
  • Probiotics are generally effective at decreasing the incidence of antibiotic associated diarrhea 
  • Probiotics were generally not associated with any major adverse effects and demonstrated protective effects over other antibiotic associated side effects (abdominal pain, vomiting, headache). 
• LGG, La-5 and Bb-12 are 3 strains of probiotics that are effective in reducing the incidence of antibiotic-associated diarrhea in children

Further studies should: 

• Further research needs to document which specific strains of probiotics help prevent antibiotic associated diarrhea 
• Establish one definition of diarrhea among all studies 
• Provide placebo to the control group 
• Establish a post-antibiotic treatment time frame to study the incidence of diarrhea