6/6/2016 EED INTERVENTIONS: PRE- AND PRO-BIOTIC SAFETY Produced by: Dietrich, C.; Kidane, L.; Babigumira, J. EED Interventions |
Agenda Agenda ¨ Timeline ¨ Project Background and Objectives ¨ Key Takeaways ¨ Approach & Rationale ¨ Methods ¨ Results ¨ Discussion and Next Steps EED Interventions 6/6/2016 |
Timeline Timeline Scoping = Check-In Point Confirm work plan • and scope Strategize • approach Landscape Analysis Review relevant literature & • extract data Relay initial findings & finalize results • EED Interventions 6/6/2016 |
Project Background and Objectives Work Order to the UW START Team Background The Enteric and Diarrheal Disease Team of the Bill & Melinda Gates Foundation previously engaged the START team to conduct a landscape analysis of intervention trials for Environmental Enteric Dysfunction (EED). During the course of this analysis, an additional but parallel track of work was identified to do a similar landscape analysis for pre- and pro- biotic interventions for growth faltering that may be caused by EED. Objectives To examine pre- and pro-biotic interventions Diagnosis of EED by gut biopsy is an invasive and resource-intensive process and is often not feasible in vulnerable populations. Having previously focused on EED biomarkers in Phase I, outcomes of interest for this review include safety and efficacy endpoints for pre- and pro- biotic use in infants and children. EED Interventions 6/6/2016 |
Takeaways Key Takeaways ¨ Very few studies conducted in LMICs ¨ Bifidobacteria and Lactobacillus are the most common genus of bacteria studied; GOS, most common prebiotic ¨ Majority of studies demonstrated no differences in SAEs, adverse events and tolerability between interventions and controls ¤ If there were differences, typically pre- and pro-biotics had positive effects ¨ Difficult to detect significant growth changes in healthy children EED Interventions 6/6/2016 |
Approach & Rationale Probiotic and Prebiotic Safety with Stunting Endpoints ¨ Focus on the inclusion of a stunting measures such as growth velocity or LAZ ¨ Probiotic or prebiotic as an intervention, no observational studies ¨ Expanded to populations beyond LMICs ¨ Analyze safety and efficacy of probiotics in children ¤ Adverse events ¤ Infection EED Interventions 6/6/2016 |
Methods Targeted Database and Search Phase 1 efficacy and safety ¨ Database: Embase ¨ 'phase 1 trial'/exp OR 'phase 1 trial' OR 'safety' OR 'safety'/exp OR safety OR ('safety' OR 'safety'/exp OR safety AND efficacy) AND ('probio<c'/exp OR 'probio<c' OR 'prebio<c'/exp OR 'prebio<c' OR 'lactobacillus'/exp OR 'lactobacillus' OR 'vsl3'/exp OR 'vsl3' OR 'bacillus'/exp OR 'bacillus' OR 'bifidobacterium'/exp OR 'bifidobacterium' OR 'escherichia coli nissle 1917' OR 'e. coli nissle 1917' OR 'streptococcus thermophilus'/exp OR 'streptococcus thermophilus' OR 'saccharomyces'/exp OR 'saccharomyces') AND ([newborn]/lim OR [infant]/lim OR [child]/lim OR [preschool]/lim OR [school]/lim) AND [humans]/lim AND [english]/lim ¨ 403 hits EED Interventions 6/6/2016 |
Methods Inclusion and Exclusion Criteria Inclusion Exclusion ¨ Prospective studies investigating ¨ Retrospective studies, editorials prebiotics and probiotics and reviews ¨ Human Subjects ¨ Animal models/in vitro studies ¨ Children <18 ¨ Adults, including provision to pregnant mothers ¨ Safety and efficacy trials ¨ Combination interventions ¤ Key words: tolerability, safety, adverse events ¤ E.g. Abx+probiotics ¤ Bactermia or microbiome related ¨ Oral health, potentially non- to potentially harmful bacteria ingested ¨ Prioritized: Growth ¨ No indication of safety other measurements than non-stunting endpoint EED Interventions 6/6/2016 |
Methods Literature Review Flowchart Title Review Embase Search Results: (n=403) • ~27% of titles originally qualified for full text review • Prioritized abstracts with growth Abstract Review measurements (n=214) Exclusions (n=189) Full Text Review (n=110) Exclusions Prioritized Articles (n=104) (n=25) Exclusions (n=4) EED Interventions 6/6/2016 |
Results Ages Represented Earliest age of enrollment in trials 14 12 10 8 6 4 2 0 In Utero - Birth - ≤ 4 1 - 2 months 3 - 6 months 6 - 12 months 1 - 4 years Birth weeks EED Interventions 6/6/2016 |
Results Prebiotics Covered Galacto-oligosaccharide (GOS) Combo prebiotic Fructo- LCPUFA GOS-scFOS oligosaccharides short-chain fructo-oligosaccharides Combo prebiotic (scFOS) with LCPUFA EED Interventions 6/6/2016 |
Results Probiotics Covered Bifidobacterium Lactobacillus Propionibacterium Streptococcus Bifidobacterium animalis ssp. lactis Lactobacillus fermentum Propionibacterium Bifidobacterium breve Lactobacillus paracasei freudenreichii Bifidobacterium infantis Lactobacillus reuteri Streptococcus thermophilus Bifidobacterium lactis Lactobacillus rhamnosus Bifidobacterium longum Lactobacillus rhamnosus GG Lactobacillus salivarius EED Interventions 6/6/2016 |
Results Serious Adverse Events Studies: Serious Adverse Events None related to study formula 2 No sepsis detected related to probiotic 6 organisms Mentioned SAEs but not explicit on relationship to study formulas 8 1 Not reported 4 Related to Study Formula EED Interventions 6/6/2016 |
Results Infections Intervention Resulted in Significant Intervention Resulted in Significant Negative Result for Infections or Positive Result for Infections or Infection- related Endpoints Infection-related Endpoints Antibiotics Respiratory infections B. lactis; Streptococcus thermophilus L. Salivarius B. breve + Combo prebiotic LGG + B. breve + Propionibacterium + • 7 studies reported non-significant GOS differences in a variety of infectious Drugs for functional GI disorders outcomes B. breve + Combo prebiotic • 2 NEC; 3 GI related GI infection • 4 Abx, 4 Respiratory infections L. fermentum + GOS • Otitis media, mean titres for Infection anti-bodies, hospitalization Combo prebiotic + B. breve EED Interventions 6/6/2016 |
Results Adverse Events: General • Bifidobacterium lactis Vomiting • Bifidobacterium lactis & Streptococcus thermophilus Colic & Irritability • Oligofructose, & Long-chain inulin Loose stools • GOS, Lactobacillus paracasei , Bifidobacterium animalis ssp. lactis Rash EED Interventions 6/6/2016 |
Results Adverse Events: Diarrhea • Bifidobacterium breve • chicory-derived neutral oligofructose, long-chain inulin, & pectin- Frequency derived acidic oligosaccharide (pAOS) • Bifidobacterium longum • Lactobacillus rhamnosus • Inulin & Fructo-oligosaccharide Relative Risk • LCPUFA • Lactobacillus salivarius Episodes EED Interventions 6/6/2016 |
Results Tolerability: General • Bifidobacterium lactis Mean daily volume of formula intake • Oligosaccharide, Lactobacillus rhamnosus, Bifidobacterium longum Yellow stool • Oligosaccharide, Lactobacillus rhamnosus, & Colic Bifidobacterium longum • scFOS Frequency of vomiting • Oligosaccharide, Lactobacillus rhamnosus, Bifidobacterium longum Green stool EED Interventions 6/6/2016 |
Results Tolerability: Stool Frequency • Bifidobacterium longum , Lactobacillus rhamnosus , GOS/scFOS • BMOS, Lactobacillus rhamnosus, Bifidobacterium longum • Bifidobacterium longum, GOS, Fructo-oligosaccharides • Lactobacillus paracasei, Bifidobacterium animalis, GOS • Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve, Propionibacterium freudenreichii spp shermanii JS, GOS EED Interventions 6/6/2016 |
Results Tolerability: Improved Stool Consistency • Bifidobacterium longum, Lactobacillus rhamnosussc, FOS • Oligosaccharide, Lactobacillus rhamnosus, Bifidobacterium longum • GOS • Lactobacillus paracasei, Bifidobacterium animalis, GOS • scFOS EED Interventions 6/6/2016 |
Results Length and Weight Results - LBW ¨ Hosni et al, 2012 ¤ Extremely low-birth-weight infants ¤ Enteral feeding ¤ LGG - 500 million CFU + Bifidobacterium infan:s - 500 million CFU ¤ Growth velocity: 14.9 ± 6.5 g/day vs. 12.6 ± 4.5 g/day (p=0.05) ¨ Hays et al, 2015 ¤ LBW infants (GA between 25 and 31 weeks, birthweight: 700-1600 g) ¤ Bifidobacterium lac:c; Bifidobacterium longum; or combina<on ¤ No significant differences in LAZ, WAZ, weight gain or head circumference in comparison with those in the control group EED Interventions 6/6/2016 |
Results Length and Weight Results – Healthy Infants ¨ Non-significant differences across the majority of studies, as expected ¨ Firmansyah et al, 2011 ¤ Change in WAZ – ITT (12 to 16 months) ¤ Syn: 0.11 ± 0.40 vs. Ctl: 0.02 ± 0.40 ¨ Gil-campos et al, 2011 ¤ LAZ : p=0.021; Syn higher than Ctl w/ Pre (curves shown in Fig. 3) ¤ Length gain (cm/day) : Syn higher than Ctl w/ Pre p = 0.038 EED Interventions 6/6/2016 |
Results Microbiota Composition GOS scFOS scFOS Bifidobacteria Bifidobacteria Bifidobacteria Lactobacilli Lactobacilli B. longum , L. rhamnosus , L. salivarius B. lactic and B. longum Inulin, & FOS Lactobacilli/ Bifidobacterium spp Lactobacilli Enterococci Enterobacteria Clostridia Bacteroides EED Interventions 6/6/2016 |
Results Microbiota Composition B. breve and Oligofructose BMOS prebio<c combo Bifidobacterium Bifidobacterium Bifidobacteria Enterobacteriaceae C. histolyticum Lactobacilli E. rectale /C. Clostridia coccoides EED Interventions 6/6/2016 |
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