(# of subjects/ studies, cohort definition etc. )

participants) met the inclusion criteria

treatment, placebo, or no treatment in the pediatric population

review’s findings suggest that efficacy may be more closely tied to

probiotic dosage, as opposed to the

specific probiotic species and number of strains.

However, more safety data are needed to determine both safe dosing and safe types of microbes for probiotics

because there was substantial unexplained

variability between individual

studies in the analysis (authors list this as an improvement compared to previous study

2. high risk of bias in some studies — risk of bias determined to be high or unclear in 13 studies and low in 10 studies

3.  Variable definitions of diarrhea with respect to the frequency,

duration, and consistency of bowel

movements

4. sparse studies on side effects to treatment with probiotics

need for definitions of diarrhea, related

symptoms, and negative outcomes to be standardized

# of subjects = 3255 children

# of References and Total # of Subjects for Recommendation on:

–       Lactobacillus rhamnosus GG: 5 References; N = 445 subjects

–       Saccharomyces boulardii: 6 References; N = 1,653 subjects

Note: All remaining Probiotics (and combinations) studied had one reference, thus recommendations were not made for them

Probiotics reduced risk of AAD by 52% versus placebo or no intervention (9.1% versus 21.2%; RR 0.48, 95% CI 0.37-0.61). For this measure, 21 RCTs, N = 3255 were evaluated.

Probiotics reduced risk of C difficile-associated diarrhea versus placebo (RR 0.34, 95% CI 0.15-0.76). For this measure, 4 RCTs, N = 938 were evaluated.

Lactobacillus rhamnosus GG (LGG):

LGG reduced the risk of AAD from 23% to 9.6% (RR 0.48, 95% CI 0.26-0.89, NNT 8, 95% CI 6-40). For this measure, 5 RCTs, N = 445 were evaluated. Future studies should assess for optimal dose as this is unknown.

Recommendation: The WG (Working Group on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) recommends using LGG for prophylactically for the prevention of AAD in children (Quality of Evidence: Moderate, Strength of Recommendation: Strong)

Saccharomyces boulardii:

S. boulardii reduced the risk of diarrhea from 20.9% to 8.8% (RR 0.43, 95% CI 0.30-0.60, NNT 9, 95% CI 7-12). For this measure, 6 RCTs, N = 1653 were evaluated. Future studies should assess for optimal dose as this is unknown.

S. boulardii reduced the risk of C difficile– associated diarrhea (RR 0.25, 95% CI 0.08-0.73).  For this measure, 2 RCTs, N = 579 were evaluated.

Recommendation: WG recommends using S. boulardii prophylactically for the prevention of AAD in children.

WG recommends using S. boulardii prophylactically for the prevention of C difficile-associated diarrhea in children.

Remaining Probiotics:

Insufficient evidence to make recommendations (see Abstract – at least 2 RCTs to make a recommendation)

WG Acknowledgements:

–       Using antibiotics selectively (judiciously) is the best way to prevent AAD

–       Though safety was not evaluated here, WG advises that caution should be considered regarding the use of Probiotics in certain patients (e.g. immunosuppression, prematurity, critical illness, presence of structural heart disease, presence of a central venous catheter, and the potential for translocation of probiotics across the bowel wall)

–       Received research support (in the form of study products only i.e. Probiotics) from Biogaia and Dicofarm

–       Has participated as a speaker on probiotics/microbiota-related subjects for many companies including the two from which she obtained the “research support” described above

Guarino, A:

–       Received support from Biocodex, Dicofarm, and Mead Johnson Nutrition

Other Authors:

–       Though disclosures are clearly made, many authors have been associated (i.e. clinical investigator, speaker, advisory board member, consultant, etc.) with companies such as Arla, Biogaia, Biocodex, etc. These companies are actively involved in microbiota-research and the creation of products like Probiotics

Pooled Results (Probiotics Overall):

–       Inclusion of one unpublished study

–       Methodological quality summary revealed variability among the 21 RCTs including risks of bias (e.g. selection, performance, detection, etc.)

LGG Studies:

–       Of the 5 RCTs evaluated, Intention-to-treat analysis was performed in only one

S. boulardii Studies:

–       Of the 6 RCTs evaluated, Intention-to-treat analysis was performed in only two

# of subjects=1438

Used the following search terms:

–       Antibiotic Associated Diarrhea (Diarrhoea)

–       Clostridium difficile

–       Psuedomembranous Colitis

–       Probiotics

The following limitations were placed on the search:

–       Age: 0-12y

–       Prevalence of AAD

–       Onset of AAD (How many days after starting antibiotic?)

–       Antibiotics associated with the development of AAD

–       Clostridium difficile associated AAD

–       Incidence of AAD with administration of probiotics

Thailand Study:

–       6.2% of 225 children developed AAD

–       Higher incidence (though STATISTICALLY INSIGNIFICANT) of AAD in children prescribed amoxicillin/clavulanate (16.7%) compared to amoxicillin (6.9%) and erythromycin (11.1%)

–       NO ASSOCIATION between younger age or high dosage of antibiotics used and development of AAD

USA Study:

–       11% (or 71 children) of 650 children on various antibiotics developed AAD

–       >⅔ of those who developed AAD saw its onset during therapy

–       15% of those who developed AAD saw its onset the week following stopping antibiotic

–       17% experienced AAD during antibiotic treatment that continued after discontinuing antibiotic therapy

–       AAD begins 5.3±3.5 days after starting antibiotic

–       Mean duration of AAD = 4±3 days

–       Highest Incidence of AAD: 2mo. to 2 years age group (18%)

–       Statistically significant difference between onset of AAD associated with amoxicillin/clavulanate compared with all other antibiotics combined (P=0.003): amoxicillin/clavulanate (23%), Pen G and V (3%), Pen A and M (11%), Cephalosporins (9%), Macrolides (8%), trimethoprim-sulphamethoxazole (6%), and Erythromycin (16%)

–       No difference between incidence of AAD between entero-hepatic administration and oral antibiotics

–       Relative Risk for onset of AAD in child receiving Amoxicillin/Clavulanate = 2.43 and 3.5 when child was <2y

Possible Causes of AAD:

–       Osmotic Diarrhea (secondary to disruption of normal enteric flora, functional disturbances of intestinal carbohydrates and bile acids metabolism)

–       Drugs may affect intestinal mucosa and motility (e.g. erythromycin – accelerates rate of gastric emptying and amoxicillin-clavunate – stimulates small bowel motility

Clostridium difficile associated AAD

–       CDI responsible for 10-20% of cases of AAD

Incidence of community acquired CDI

–       increasing in pediatric population

–       Study from Children’s Medical Center in USA (2001-2006): 513 patients with CDI. Incidence of CDI increased in outpatient setting (e.g. ED) from 1.18 cases versus 2.47 cases per 1,000 visits, P = 0.02. On the other hand, incidence of CDI decreased in inpatients (1.024 cases versus 0.680 cases per 1,000 patient-days, P = 0.004).

Treatment

–       Most AAD would respond to ONLY discontinuation/change of antibiotic

Prevention

–       A Cochrane Review suggests that Probiotics are effective in preventing AAD in children (RR 0.49; 95% CI 0.32 to 0.74)

–       Though, intention to treat analysis showed non-significant overall results (RR 0.90; 95% CI 0.50 to 1.63)

–       NNT to prevent one case of AAD = 10 (NNT 10; 95% CI 7 to 18)

–       A meta-analysis (the one listed below Szajewska H, Ruszcynski M, and Radzikowski A) showed that treatment with probiotics compared with placebo effectively reduced risk of AAD from 28.5% to 11.9% (RR, 0.44, 95% CI 0.25 to 0.77). NNT 7.

–       Another meta-analysis reported reduction of AAD in children with the use of probiotics over placebo (RR 0.43, 95% CI 0.25-0.75), though when intention-to-treat analysis was performed, the results were insignificant (RR 1.01, 95% CI 0.64-1.61)

–       Another study (a subgroup analysis specific to Lactobacillus GG, L. sporogens or Saccharomyces boulardii) reported RR 0.36, 95% CI 0.25-0.53, favoring the use of probiotics in preventing AAD.

Areas of Future Research

–       Must include  cost-effective analysis of Probiotic use

–       Must concentrate on specific probiotics (to avoid ineffective probiotics from diluting results of specific probiotics. I.e. to prevent what would be otherwise significant results from becoming insignificant.

–       Additionally, varying definitions of AAD (more stringent versus a standard definition of AAD) influence results

–       Studies evaluating Probiotics as a whole may be diluting the effects of truly effective organisms

# of Subjects=766

Clinical Setting: Both in-patient and out-patient

Secondary Measures: mean duration of diarrhea, the need for discontinuation of the antibiotic treatment, hospitalization to manage and the diarrhea (in outpatients) or intravenous rehydration in any of the study groups and adverse events.

Incidence of diarrhea/AAD and  of c. difficile associated diarrhea

Probiotics were effective in preventing  incidence AAD in children with antibiotics for any reason but especially for respiratory tract infections. In patients treated daily with antibiotics, 1 less child out of 7 would develop diarrhea  (NNT 7, 95% CI 5-10).

Risk Reduction: AAD and c. difficile

The reduction of the risk of AAD was associated with the use of Lactobacillus GG (2 RCT, 307 participants, RR 0.3, 95% CI 0.15 to 0.6, NNT 6, 95% CI: 4–13), Saccharomyces boulardii (1 RCT, 246 partic- ipants, RR 0.2, 95% CI 0.07-0.6, NNT 8, 95% CI 5-15), or B. lactis & Streptococcus thermophilus (1 RCT, 157 participants, RR 0.5, 95% CI 0.3 to 0.95, NNT 7, 95% CI 4-62). In contrast, the use of either L. acidophilus/Bifidobacterium in-fantis (1 RCT, 18 participants, RR 0.5, 95% CI 0.2 to 1.2) or L. acidophilus/L. bulgaricus (1 RCT, 38 participants, RR 0.96, 95% CI 0.6 to 1.5) was not associated with a significant reduction of the risk of AAD.

2  RCTs suggested a relationship between probiotic use and lower rick of c.difficile diarrhea in the probiotic vs control group ((RR 0.38, 95% CI 0.12 to1.18, fixed effect model).

discontinuation of the antibiotic treatment, hospitalization to manage and the diarrhea (in outpatients) or intravenous rehydration in any of the study groups and adverse events risks were not shown to be associated with probiotic use.

mean duration of diarrhea

Mean duration results were inconclusive.

Future Recommendations: 1. Which populations with high risk of AAD benefit from probiotics. 2. Determine efficacy of various probiotic strains. 3. Probiotic  strain and efficacy to best prevent AAD caused by C. difficle or antibiotics which can cause diarrhea. 4. Effective doses and schedule 5. Weigh additional risks/benefits of probiotics preventing ADD in pediatric populations

Reporting bias: only one study measured the need for discontinuation of the antibiotic treatment, hospitalization to manage and the diarrhea (in outpatients) or intravenous rehydration in any of the study groups and adverse events.

Though many RCTs were blinded, most did not state if it was the researchers, participants, or both whom were blinded.

Limited Population:

Sample sizes were limited to children and to relatively small number of participants in limited geography. Demographics of participants were not listed.

No intention-to-treat

analysis

Potentially outdated research (2006).

Validity

Parameters for diarrhea differed between RCTs, which could skew validity of data.