Background
Antibiotics are widely prescribed; however they can cause disturbances in gastrointestinal flora which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live organisms thought to balance the gastrointestinal flora.

Objectives
The primary objectives were to assess the efficacy and safety of probiotics for preventing Clostridium difficile-associated diarrhea (CDAD) or C. difficile infection in adults and children.

Search methods
On February 21, 2013 we searched PubMed (1966-2013), EMBASE (1966-2013), Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1), CINAHL (1982-2013), AMED (1985-2013), and ISI Web of Science. Additionally, we conducted an extensive grey literature search including contact with industry representatives.

Selection criteria
Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion.

Data collection and analysis
Two authors independently and in duplicate extracted data and assessed risk of bias using pre-constructed, and piloted, data extraction forms. Any disagreements were resolved by a third adjudicator. For articles published in abstract form only, further information was sought by contacting principal authors. The primary outcome was the incidence of CDAD. Secondary outcomes included the incidence of C. difficile infection, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the relative risk and corresponding 95% confidence interval (95% CI). Continuous outcomes (e.g. length of hospital) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias.The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria.

Main results
A total of 1871 studies were identified with 31 (4492 participants) meeting eligibility requirements for our review. Overall 11 studies were rated as a high risk of bias due mostly to missing outcome data. A complete case analysis (i.e. participants who completed the study) of those trials investigating CDAD (23 trials, 4213 participants) suggests that probiotics significantly reduce this risk by 64%. The incidence of CDAD was 2.0% in the probiotic group compared to 5.5% in the placebo or no treatment control group (RR 0.36; 95% CI 0.26 to 0.51). Sixteen of 23 trials had missing CDAD data ranging from 5% to 45%. These results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and were similar whether considering trials in adults versus children, lower versus higher doses, different probiotic species, or higher versus lower risk of bias. Our judgment is that the overall evidence warrants moderate confidence in this large relative risk reduction. We downgraded the overall quality of evidence for CDAD to ‘moderate’ due to imprecision. There were few events (154) and the calculated optimal information size (n = 8218) was more than the total sample size. With respect to the incidence of C. difficile infection, a secondary outcome, pooled complete case results from 13 trials (961 participants) did not show a statistically significant reduction. The incidence of C. difficile infection was 12.6% in the probiotics group compared to 12.7% in the placebo or no treatment control group (RR 0.89; 95% CI 0.64 to 1.24). Adverse events were assessed in 26 studies (3964 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 20% (RR 0.80; 95% CI 0.68 to 0.95). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. For the short-term use of probiotics in patients that are not immunocompromised or severely debilitated, we consider the strength of this evidence to be moderate.

Authors' conclusions
Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile-associated diarrhea.

Probiotics for the prevention of Clostridium difficile‐associated diarrhea in adults and children

Background
Probiotics may be effective in reducing the duration of acute infectious diarrhoea.

Objectives
To assess the effects of probiotics in proven or presumed acute infectious diarrhoea.

Search methods
We searched the trials register of the Cochrane Infectious Diseases Group, MEDLINE, and Embase from inception to 17 December 2019, as well as the Cochrane Controlled Trials Register (Issue 12, 2019), in the Cochrane Library, and reference lists from studies and reviews. We included additional studies identified during external review.

Selection criteria
Randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent.

Data collection and analysis
Two review authors independently applied inclusion criteria, assessed risk of bias, and extracted data. Primary outcomes were measures of diarrhoea duration (diarrhoea lasting ≥ 48 hours; duration of diarrhoea). Secondary outcomes were number of people hospitalized in community studies, duration of hospitalization in inpatient studies, diarrhoea lasting ≥ 14 days, and adverse events.

Main results
We included 82 studies with a total of 12,127 participants. These studies included 11,526 children (age < 18 years) and 412 adults (three studies recruited 189 adults and children but did not specify numbers in each age group). No cluster‐randomized trials were included. Studies varied in the definitions used for "acute diarrhoea" and "end of the diarrhoeal illness" and in the probiotic(s) tested. A total of 53 trials were undertaken in countries where both child and adult mortality was low or very low, and 26 where either child or adult mortality was high.

Risk of bias was high or unclear in many studies, and there was marked statistical heterogeneity when findings for the primary outcomes were pooled in meta‐analysis. Effect size was similar in the sensitivity analysis and marked heterogeneity persisted. Publication bias was demonstrated from funnel plots for the main outcomes.

In our main analysis of the primary outcomes in studies at low risk for all indices of risk of bias, no difference was detected between probiotic and control groups for the risk of diarrhoea lasting ≥ 48 hours (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 2 trials, 1770 participants; moderate‐certainty evidence); or for duration of diarrhoea (mean difference (MD) 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer; 6 trials, 3058 participants; very low‐certainty evidence).

Effect size was similar and marked heterogeneity persisted in pre‐specified subgroup analyses of the primary outcomes that included all studies. These included analyses limited to the probiotics Lactobacillus rhamnosus GG and Saccharomyces boulardii. In six trials (433 participants) of Lactobacillus reuteri, there was consistency amongst findings (I² = 0%), but risk of bias was present in all included studies. Heterogeneity also was not explained by types of participants (age, nutritional/socioeconomic status captured by mortality stratum, region of the world where studies were undertaken), diarrhoea in children caused by rotavirus, exposure to antibiotics, and the few studies of children who were also treated with zinc. In addition, there were no clear differences in effect size for the primary outcomes in post hoc analyses according to decade of publication of studies and whether or not trials had been registered.

For other outcomes, the duration of hospitalization in inpatient studies on average was shorter in probiotic groups than in control groups but there was marked heterogeneity between studies (I² = 96%; MD ‐18.03 hours, 95% CI ‐27.28 to ‐8.78, random‐effects model: 24 trials, 4056 participants). No differences were detected between probiotic and control groups in the number of people with diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53; 9 studies, 2928 participants) or in risk of hospitalization in community studies (RR 1.26, 95% CI 0.84 to 1.89; 6 studies, 2283 participants).

No serious adverse events were attributed to probiotics.

Authors' conclusions
Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer, and we are uncertain whether probiotics reduce the duration of diarrhoea. This analysis is based on large trials with low risk of bias.

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Probiotics for treating acute infectious diarrhoea

Probiotics and prebiotics play an important role in human nutrition. In recent years there has been a significant increase in research on the characterization and verification potential health benefits associated with the use of probiotic and prebiotic. The main effects attributed to selected probiotics/prebiotic products have been proved by clinical trials, while others have been acquired on the basis of in vitro tests which require in vivo transposition in order to be validated. The main clinical reports in the literature for the application of probiotic have been done for the treatment of infectious diseases including viral, bacterial or antibiotic associated diarrhoea, relief of chronic bowel inflammatory diseases, immuno-modulation, lowering of serum cholesterol, decreased risk of colon cancer, improve lactose digestion, reduce allergies, and effect on intestinal microbiota. Although the large investigation for the health benefits, information on probiotic species, a specific strain-therapeutic application, and sufficient dosages, is not sufficiently studied to allow practical and rational consumption. Moreover, prebiotic oligosaccharides although provided curative and nutritional values, they are poorly understood in regard to their origin, the processes employed to generate them, their fermentation profiles, and dosages required for health effects. The present review summarizes guidelines reported on the literature in regard to clinician or therapeutic trials of probiotic and prebiotic.

An overview of the last advances in probiotic and prebiotic field

Probiotics have preventive as well as curative effects on several types of diarrhea of different etiologies. Prevention and therapy(oralleviation)ofdiarrheahavebeensuccessfullyinvestigatedfornumerousdietaryprobioticstoestablishprobiotic propertiesand to justify health claims (the medicinal use of probiotic food and the therapy of gastrointestinal diseasesitself may not be advertised under current food laws). Other probiotic microorganisms (e.g., Lactobacillus rhamnosus GG, L. reuteri, certain strains of L. casei, L. acidophilus, Escherichia coli strain Nissle 1917, and certain bifidobacteria and enterococci (Enterococcus faecium SF68) as well as the probiotic yeast Saccharomyces boulardii have been investigated with regard to their medicinal use, either as single strains or in mixed-culture probiotics. However, the effects on humans have been assessed mainly in smaller (n , 100) randomized, controlled clinical studies or in open label trials, but large intervention studies and epidemiological investigations of long-term probiotic effects are largely missing. Perhaps with the exception of nosocomial diarrhea or antibiotic-associated diarrhea, the results of these studies are not yet sufficient to give specific recommendations for the clinical use of probiotics in the treatment of diarrhea. J. Nutr. 137: 803S‐811S, 2007.

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Probiotics and Prebiotics: Effects on Diarrhea

A vast and diverse array of microbial species displaying great phylogenic, genomic, and metabolic diversity have colonized the gastrointestinal tract. Resident microbes play a beneficial role by regulating the intestinal immune system, stimulating the maturation of host tissues, and playing a variety of roles in nutrition and in host resistance to gastric and enteric bacterial pathogens. The mechanisms by which the resident microbial species combat gastrointestinal pathogens are complex and include competitive metabolic interactions and the production of antimicrobial molecules. The human intestinal microbiota is a source from which Lactobacillus probiotic strains have often been isolated. Only six probiotic Lactobacillus strains isolated from human intestinal microbiota, i.e., L. rhamnosus GG, L. casei Shirota YIT9029, L. casei DN-114 001, L. johnsonii NCC 533, L. acidophilus LB, and L. reuteri DSM 17938, have been well characterized with regard to their potential antimicrobial effects against the major gastric and enteric bacterial pathogens and rotavirus. In this review, we describe the current knowledge concerning the experimental antibacterial activities, including antibiotic-like and cell-regulating activities, and therapeutic effects demonstrated in well-conducted, placebo-controlled, randomized clinical trials of these probiotic Lactobacillus strains. What is known about the antimicrobial activities supported by the molecules secreted by such probiotic Lactobacillus strains suggests that they constitute a promising new source for the development of innovative anti-infectious agents that act luminally and intracellularly in the gastrointestinal tract.

Anti-Infective Activities of Lactobacillus Strains in the Human Intestinal Microbiota: from Probiotics to Gastrointestinal Anti-Infectious Biotherapeutic Agents

AimTo evaluate the effective dose of Lactobacillus rhamnosus GG (LGG) as probiotic in acute watery diarrhea (AWD) in Indian children.SettingHospital-based study.DesignRandomized, controlled, blinded trial.MethodsAll patients of AWD admitted over 1 year were included in the study. They were randomize

Efficacy of high-dose Lactobacillus rhamnosus GG in controlling acute watery diarrhea in Indian children: a randomized controlled trial.

Aim: To evaluate the role of Lactobacillus rhamnosus GG (LGG) as probiotic in acute watery diarrhoea (AWD).



Setting:  Hospital-based study.



Design:  Randomised, controlled, blinded trial.



Patients and Method:  All patients of AWD (n = 684) admitted over 1-year period were invited to participate in the study as per predefined inclusion and exclusion criteria and were randomised to intervention and control groups. After adequate rehydration the intervention group (n = 330) received ORS with probiotic powder containing 60 million cells of LGG, while the control group (n = 332) received ORS alone twice daily for a minimum period of 7 days or till diarrhoea ceased. During the study period all patients received ORS and/or IV fluids for ongoing losses, and nutritional supplementation. None of them received any antibiotic or antidiarrhoeal medication. After exclusion of 16 patients, 646 (323 in each arm) patients completed the study. The daily frequency and total duration of diarrhoea and vomiting and the length of hospital stay were studied. Data were analysed by SPSS-10 software. Statistical significance was calculated by Student's t-test and χ2-test.



Results: Rotavirus was isolated in 75.85%. There was no significant difference between treatment groups in the daily frequency or duration of diarrhoea or vomiting or in the length of hospital stay. No complication was observed from the use of LGG.



Conclusion: LGG supplementation does not decrease the frequency and duration of diarrhoea and vomiting in children with AWD, and does not reduce hospital stay in these patients.

Efficacy of Lactobacillus rhamnosus GG in acute watery diarrhoea of Indian children: A randomised controlled trial

AimTo evaluate the role of Lactobacillus rhamnosus GG (LGG) as probiotic in persistent diarrhea (PD) in children of North Bengal, India.SettingHospital-based study.DesignRandomized, double-blind controlled trial.Patients and MethodsAll patients of PD admitted over a period of 2 years were included i

Effect of Lactobacillus rhamnosus GG in persistent diarrhea in Indian children: a randomized controlled trial.

Background: Neonatal tetanus (NNT), a preventable disease, remains an important cause of infant mortality in developing countries such as India. Objectives: To evaluate the demographic and clinical data of NNT in North Bengal, India and determine the risk factors for mortality. Methods: Hospital records of all cases of NNT admitted over a 7-year period (1997–2003) were analysed. Demographic data, clinical presentation, progression and outcome were evaluated and comparisons made between the group who survived and those who died. Results: The overall mortality was 66.3%. The group who survived had a significantly greater mean bodyweight on admission, later onset of the disease and were hospitalised early. Risus sardonicus, generalised rigidity, fever, intercurrent infections and respiratory arrest were significantly more common in the fatal group. Conclusion: Although over the 7 years improvement was observed in admissions for NNT, maternal literacy and the economic status of families, there is a p...

Risk factors for mortality from neonatal tetanus: 7 years experience in North Bengal, India

We report an unusual cause of profuse rectal bleeding in a child from an Indian rural community.

Pranab Kumar Chandra

Papers

Efficacy of high-dose Lactobacillus rhamnosus GG in controlling acute watery diarrhea in Indian children: a randomized controlled trial.

Efficacy of Lactobacillus rhamnosus GG in acute watery diarrhoea of Indian children: A randomised controlled trial

Effect of Lactobacillus rhamnosus GG in persistent diarrhea in Indian children: a randomized controlled trial.

Risk factors for mortality from neonatal tetanus: 7 years experience in North Bengal, India

A leech in the large bowel.