Probiotics for the prevention of antibiotic-associated diarrhea

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada.
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 11/2011; 11(11):CD004827. DOI: 10.1002/14651858.CD004827.pub3
Source: PubMed


Antibiotics alter the microbial balance within the gastrointestinal tract. Probiotics may prevent antibiotic-associated diarrhea (AAD) via restoration of the gut microflora. Antibiotics are prescribed frequently in children and AAD is common in this population.
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.
MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and the Web of Science (inception to May 2010) 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trials, nutra/pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials.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.
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.
Study selection, data extraction as well as methodological quality assessment using the risk of bias instrument was conducted independently and in duplicate by two authors. Dichotomous data (incidence of diarrhea, adverse events) were combined using a pooled relative risk and risk difference (adverse events), and continuous data (mean duration of diarrhea, mean daily stool frequency) as weighted mean differences, along with their corresponding 95% confidence intervals. 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 were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, antibiotic agent as well as risk of bias.
Sixteen studies (3432 participants) met the inclusion criteria. Trials included treatment with either Bacillus spp., Bifidobacterium spp., Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., or Streptococcus spp., alone or in combination. Nine studies used a single strain probiotic agent, four combined two probiotic strains, one combined three probiotic strains, one product included ten probiotic agents, and one study included two probiotic arms that used three and two strains respectively. The risk of bias was determined to be high in 8 studies and low in 8 studies. Available case (patients who did not complete the studies were not included in the analysis) results from 15/16 trials reporting on the incidence of diarrhea show a large, precise benefit from probiotics compared to active, placebo or no treatment control. The incidence of AAD in the probiotic group was 9% compared to 18% in the control group (2874 participants; RR 0.52; 95% CI 0.38 to 0.72; I(2) = 56%). This benefit was not statistically significant in an extreme plausible (60% of children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea) intention to treat (ITT) sensitivity analysis. The incidence of AAD in the probiotic group was 16% compared to 18% in the control group (3392 participants; RR 0.81; 95% CI 0.63 to 1.04; I(2) = 59%). An a priori available case subgroup analysis exploring heterogeneity indicated that high dose (≥5 billion CFUs/day) is more effective than low probiotic dose (< 5 billion CFUs/day), interaction P value = 0.010. For the high dose studies the incidence of AAD in the probiotic group was 8% compared to 22% in the control group (1474 participants; RR 0.40; 95% CI 0.29 to 0.55). For the low dose studies the incidence of AAD in the probiotic group was 8% compared to 11% in the control group (1382 participants; RR 0.80; 95% CI 0.53 to 1.21). An extreme plausible ITT subgroup analysis was marginally significant for high dose probiotics. For the high dose studies the incidence of AAD in the probiotic group was 17% compared to 22% in the control group (1776 participants; RR 0.72; 95% CI 0.53 to 0.99; I(2) = 58%). None of the 11 trials (n = 1583) that reported on adverse events documented any serious adverse events. 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 0.02).
Despite heterogeneity in probiotic strain, dose, and duration, as well as in study quality, the overall evidence suggests a protective effect of probiotics in preventing AAD. Using 11 criteria to evaluate the credibility of the subgroup analysis on probiotic dose, the results indicate that the subgroup effect based on dose (≥5 billion CFU/day) was credible. Based on high-dose probiotics, the number needed to treat (NNT) to prevent one case of diarrhea is seven (NNT 7; 95% CI 6 to 10). However, a GRADE analysis indicated that the overall quality of the evidence for the primary endpoint (incidence of diarrhea) was low due to issues with risk of bias (due to high loss to follow-up) and imprecision (sparse data, 225 events). The benefit for high dose probiotics (Lactobacillus rhamnosus or Saccharomyces boulardii) needs to be confirmed by a large well-designed randomized trial. More refined trials are also needed that test strain specific probiotics and evaluate the efficacy (e.g. incidence and duration of diarrhea) and safety of probiotics with limited losses to follow-up. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Future trials would benefit from a standard and valid outcomes to measure AAD.

Download full-text


Available from: Bradley C Johnston
  • Source
    • "Probiotics are preparations of bacteria and yeasts that are considered to confer a beneficial health effect when taken in an adequate amount [6]. Probiotics have been studied extensively for their effects in preventing and treating a multitude of conditions, including the treatment of lactose intolerance, traveller’s diarrhoea and the prevention and treatment of nosocomial diarrhoea [7-10]. In acute diarrhoea, a reduction in the frequency of diarrhoeal symptoms has been reported in adults and children treated with probiotics. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Diarrhoeal disease is a major global health problem, particularly affecting children under the age of 5 years. Besides oral rehydration solution, probiotics are also commonly prescribed to children with acute watery diarrhoea in some settings. Results from randomised clinical trials (RCTs) in which investigators studied the effect of probiotics on diarrhoeal symptoms have largely shown a positive effect; yet, the overall quality of the data is limited. In Vietnam, probiotics are the most frequently prescribed treatment for children hospitalised with acute watery diarrhoea, but there is little justification for this treatment in this location. We have designed a RCT to test the hypothesis that an oral preparation of Lactobacillus acidophilus is superior to placebo in the treatment of acute watery diarrhoea in Vietnamese children. Methods This RCT was designed to study the effect of treatment with L. acidophilus (4 × 109 colony-forming units/day) for 5 days for acute watery diarrhoea against a placebo in 300 children ages 9 to 60 months admitted to hospitals in Vietnam. Clinical and laboratory data plus samples will be collected on admission, daily during hospitalisation, at discharge, and at follow-up visits for a subset of participants. The primary end point will be defined as the time from the first dose of study medication to the start of the first 24-hour period without diarrhoea as assessed by the on-duty nurse. Secondary endpoints include the time to cessation of diarrhoea as recorded by parents or guardians in an hourly checklist, stool frequency over the first 3 days, treatment failure, rotavirus and norovirus viral loads, and adverse events. Discussion The existing evidence for the use of probiotics in treating acute watery diarrhoea seems to favour their use. However, the size of the effect varies across publications. An array of different probiotic organisms, doses, treatment durations, study populations, designs, settings, and aetiologies have been described. In this trial, we will investigate whether probiotics are beneficial as an adjuvant treatment for children with acute watery diarrhoea in Vietnam, with the aim of guiding clinical practice through improved regional evidence. Trial registration Current Controlled Trials ISRCTN88101063
    Full-text · Article · Jan 2013 · Trials
  • Source
    • "[104]. In a more recent study, including 3432 children and adolescents between 0–18 years of age, positive results were observed to probiotics, but in a subgroup analysis was indicated that higher doses (≥5 billion CFU/day) are more effective than lower probiotic doses (<5 billion CFU/day) (P = 0.010) [105]. According to Johnston et al. [105], the incidence of antibiotic-associated diarrhea for high-dose studies in the probiotic and placebo groups was, respectively, 8% and 22% (1474 participants; RR 0.40; 95% CI 0.29–0.55). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The bacterial colonization is defined immediately after birth, through direct contact with maternal microbiota and may be influenced during lactation. There is emerging evidence indicating that quantitative and qualitative changes on gut microbiota contribute to alterations in the mucosal activation of immune system leading to intra- or extra-intestinal diseases. A balance between pathogenic and beneficial microbiota throughout childhood and adolescence is important to gastrointestinal health, including protection against pathogens, inhibition of pathogens, nutrient processing (synthesis of vitamin K), stimulation of angiogenesis, and regulation of host fat storage. Probiotics can promote an intentional modulation of intestinal microbiota favoring the health of the host. This paper is a review about modulation of intestinal microbiota on prevention and adjuvant treatment of pediatric gastrointestinal diseases.
    Full-text · Article · Oct 2012 · Gastroenterology Research and Practice
  • Source
    • "If prebiotic supplementation reduces the risk of Necrotizing Enterocolitis (NEC) or improves feed tolerance in very low birth weight infants is yet to be established [8,9]. Recent systematic reviews (published from 2005 to 2009) on the use of probiotics or prebiotics in preterm infants have focused on prevention of NEC and / or sepsis, impact on diarrhea [31-34]. These reviews focused on studies that used breast milk and mixed feeds (formula combined with breast milk). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Previous reviews (2005 to 2009) on preterm infants given probiotics or prebiotics with breast milk or mixed feeds focused on prevention of Necrotizing Enterocolitis, sepsis and diarrhea. This review assessed if probiotics, prebiotics led to improved growth and clinical outcomes in formula fed preterm infants. Methods Cochrane methodology was followed using randomized controlled trials (RCTs) which compared preterm formula containing probiotic(s) or prebiotic(s) to conventional preterm formula in preterm infants. The mean difference (MD) and corresponding 95% confidence intervals (CI) were reported for continuous outcomes, risk ratio (RR) and corresponding 95% CI for dichotomous outcomes. Heterogeneity was assessed by visual inspection of forest plots and a chi2 test. An I2 test assessed inconsistencies across studies. I2> 50% represented substantial heterogeneity. Results Four probiotics studies (N=212), 4 prebiotics studies (N=126) were included. Probiotics: There were no significant differences in weight gain (MD 1.96, 95% CI: -2.64 to 6.56, 2 studies, n=34) or in maximal enteral feed (MD 35.20, 95% CI: -7.61 to 78.02, 2 studies, n=34), number of stools per day increased significantly in probiotic group (MD 1.60, 95% CI: 1.20 to 2.00, 1 study, n=20). Prebiotics: Galacto-oligosaccharide / Fructo-oligosaccharide (GOS/FOS) yielded no significant difference in weight gain (MD 0.04, 95% CI: -2.65 to 2.73, 2 studies, n=50), GOS/FOS yielded no significant differences in length gain (MD 0.01, 95% CI: -0.03 to 0.04, 2 studies, n=50). There were no significant differences in head growth (MD −0.01, 95% CI: -0.02 to 0.00, 2 studies, n=76) or age at full enteral feed (MD −0.79, 95% CI: -2.20 to 0.61, 2 studies, n=86). Stool frequency increased significantly in prebiotic group (MD 0.80, 95% CI: 0.48 to 1.1, 2 studies, n=86). GOS/FOS and FOS yielded higher bifidobacteria counts in prebiotics group (MD 2.10, 95% CI: 0.96 to 3.24, n=27) and (MD 0.48, 95% CI: 0.28 to 0.68, n=56). Conclusions There is not enough evidence to state that supplementation with probiotics or prebiotics results in improved growth and clinical outcomes in exclusively formula fed preterm infants.
    Full-text · Article · Aug 2012 · Nutrition Journal
Show more