Intervention Review

Probiotics for the prevention of pediatric antibiotic-associated diarrhea

  1. Bradley C Johnston1,*,
  2. Joshua Z Goldenberg2,
  3. Per O Vandvik3,
  4. Xin Sun1,
  5. Gordon H Guyatt1

Editorial Group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group

Published Online: 9 NOV 2011

Assessed as up-to-date: 24 MAY 2010

DOI: 10.1002/14651858.CD004827.pub3

Database Title

Additional Information

How to Cite

Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD004827. DOI: 10.1002/14651858.CD004827.pub3.

Author Information

  1. 1

    McMaster University, Department of Clinical Epidemiology and Biostatistics, Hamilton, Ontario, Canada

  2. 2

    Bastyr University, Seattle, WA, USA

  3. 3

    Norwegian Knowledge Centre for the Health Services, Oslo, Norway

*Bradley C Johnston, Department of Clinical Epidemiology and Biostatistics, McMaster University, 1200 Main Street West, 2C12, Hamilton, Ontario, L8N 3Z5, Canada. bradley.johnston@sickkids.ca. bjohnst@mcmaster.ca.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 9 NOV 2011

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Abstract

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Background

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.

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, 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trials, nutra/pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials.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.

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 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.

Main results

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; I2 = 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; I2 = 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; I2 = 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).

Authors' conclusions

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.

 

Plain language summary

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Probiotics for the prevention of pediatric antibiotic-associated diarrhea (AAD)

Antibiotic-associated diarrhea (AAD) occurs when antibiotics disturb the natural balance of "good" and "bad" bacteria in the intestinal tract causing harmful bacteria to multiply beyond their normal numbers. The symptoms of AAD include frequent watery bowel movements and crampy abdominal pain. Probiotics are found in dietary supplements or yogurts and contain potentially beneficial bacteria or yeast. Probiotics may restore the natural balance of bacteria in the intestinal tract. Sixteen studies were reviewed and provide the best available evidence. The studies tested 3432 children (2 weeks to 17 years of age) who were receiving probiotics co-administered with antibiotics to prevent AAD. The participants received probiotics (Lactobacilli spp., Bifidobacterium spp., Streptococcus spp., or Saccharomyces boulardii alone or in combination), placebo (pills not including probiotics), other treatments thought to prevent AAD (i.e. diosmectite or infant formula) or no treatment. The studies were short-term, ranging in length from 10 days to 3 months. Analyses showed that probiotics may be effective for preventing AAD. Probiotics were generally well tolerated, and minor side effects occurred infrequently, with no significant difference between probiotic and control groups. Side effects reported in the studies include rash, nausea, gas, flatulence, vomiting, increased phlegm, chest pain, constipation, taste disturbance, and low appetite. The current data suggest that Lactobacillus rhamnosus and Saccharomyces boulardii at a high dosage of 5 to 40 billion CFU/day may prevent the onset of ADD, with no serious side effects documented in otherwise healthy children. This benefit for high dose probiotics needs to be confirmed by a large well designed randomized study. No conclusions about the effectiveness and safety of other probiotic agents for pediatric AAD can be drawn. More refined studies are also needed that evaluate strain specific probiotics and report both the effectiveness (e.g. incidence and duration of diarrhea) and safety of probiotics.

 

摘要

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

背景

益生菌對於小兒抗生素相關性腹瀉的預防效果

抗生素改變胃腸道內微生物的平衡。益生菌可藉由恢復胃腸道內微生物以預防抗生素相關性腹瀉(AAD)。抗生素經常被使用在孩童，而且抗生素相關性的腹瀉常見在這族群中。

目標

評估益生菌對於預防孩子抗生素相關性腹瀉的效力和副作用(任何特定的菌株或者劑量)。 評估當孩子使用抗生素時，同時給予益生菌時相關的副作用。

搜尋策略

作者搜尋從開始到2006年8月MEDLINE，EMBASE，CENTRAL，CINAHL，AMED，the Web of Science的資料庫，同時也涵括從開始到2005年專科的註冊包括Cochrane IBD/FBD Review Group，CISCOM，Chalmers PedCAM Research Register和臨床試驗的註冊資料。我們寫信給試驗的作者，藥廠公司，以及請求該領域的專家提供進行中或者未發表試驗的額外訊息。我們手工搜尋會議記錄，論文摘要，以及涵括和相關文章的參考文獻。

選擇標準

隨機，平行，對照(安慰劑，試驗的治療，或者沒有治療)的試驗比較共同給予益生菌和抗生素時對於0到18歲的孩童因抗生素使用引起的腹瀉之預防效果。 。

資料收集與分析

由二名作者(BCJ，AS) 獨立進行方法學的品質評估和資料的萃取。二分類的數據(腹瀉的發生率，副作用)的結合使用集合起來的相關危險(pooled relative risks)，而連續性的數據(腹瀉的平均時間，平均每日的腹瀉頻率)使用加權平均差別(weighted mean differences)以及他們對應的95%信賴區間(confidence intervals)。不利的事件以危險性差別(risk difference)來總結。 對於腹瀉發生率全部結合的結果來說，邏輯推理的敏感性分析(priori sensitivity analyses)包括完成計劃書療程(per protocol)與治療意向(intention to treat)，隨機與固定效應和方法學上的品質標準。益生菌的菌種，劑量，抗生素相關性腹瀉的定義，以及抗生素的品項進行子群的分析。

主要結論

有10個研究符合收案標準。 試驗包括使用單一益生菌，如Lactobacilli spp., Bifidobacterium spp., Streptococcus spp., 或Saccharomyces boulardii，或者是合併以上菌種的治療。6個研究使用單一益生菌，4個研究合併2益生菌菌種。針對9個試驗利用完成計劃書療程分析發現腹瀉發生率益生菌使用優於對照組(RR 0.49; 95% CI 0.32 to 0.74)。不過，治療意向分析顯示整體而言結果並沒有顯著的差異(RR 0.90; 95% CI 0.50 to 1.63)。 10個研究有5個研究監視不良事件(n = 647)，結果並沒有任一個嚴重的事件發生。

作者結論

益生菌預防兒童的抗生素相關性腹瀉是很有希望的。雖然以完成計劃書療程分析法和高品質研究分析的結果顯示治療成效有統計學和臨床上地意義性，而以治療意向分析法估計並不具統計學上地顯著。 未來研究應該包含益生菌的菌種和最有希望證據(例如, Lactobacillus GG，Lactobacillus sporogenes，Saccharomyces boulardii每天5到400的colony forming units。到目前為止的研究並沒有證實治療有效的年齡(例如,嬰兒或更大的孩子)或者使用的時間(例如,5天或10天)。未來的研究以抗生素相關性腹瀉易於改變的指標和可反應臨床醫師，父母和孩子認為重要的事情設定為研究的主要評估結果將會有助益。現有的數據顯示益生菌是有希望的，但是常規地建議益生菌預防兒童的抗生素相關性腹瀉還言之過早。

翻譯人

本摘要由臺中榮民總醫院王建得翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

常規地建議益生菌預防兒童的抗生素相關性腹瀉還言之過早。 益生菌預防兒童的抗生素相關性腹瀉的研究。我們回顧10個研究並提出最佳證據。整體而言，這些研究的品質大致不錯。有1986為小孩子(0 到18歲)使用抗生素的同時並用益生菌以預防兒童的抗生素相關性腹瀉。這些孩子接受單一益生菌 Lactobacilli spp., Bifidobacterium spp., Streptococcus spp.或Saccharomyces或者是合併以上多種菌種的治療，安慰劑，其他被認為可預防兒童抗生素相關性腹瀉的治療(例如diosmectite，一種止瀉藥或嬰兒配方奶)，或是沒有治療。研究的時間很短暫從15天到3個月。 什麼是抗生素相關性腹瀉以及益生菌能夠預防它的發生嗎? 當抗生素干擾腸道好菌和害菌的正常平衡時會導致有害的細菌偶而地複製時而超過他們在腸道應有的正常數量，這種現象導致訴抗生素相關性腹瀉的發生。抗生素相關性腹瀉的症狀包括頻繁的水瀉以及痙攣性的腹痛。益生菌是食物的添加物含有有益處的細菌或酵母菌。益生菌被認為可以恢復腸道細菌的自然平衡。 這些研究的結果顯示什麼？ 這些研究分析只有顯示完成研究的病人，益生菌可以有效地預防抗生素相關性腹瀉。然而，較嚴謹地分析，將中途退出研究的病人計算為治療失敗時，結果並沒有顯示益生菌和比較組有任何差異。. 益生菌的安全性如何? 益生菌大致市可被病人接受而且很少發生副作用。 底線是什麼? 雖然從現有的數據顯示益生菌是有希望的，但是仍沒有足夠的證據建議常規地使用益生菌預防兒童抗生素相關性腹瀉。

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