NIHR Signal Probiotics can prevent bacterial diarrhoea in hospital patients receiving antibiotics

Published on 1 May 2018

Giving probiotics to people taking antibiotics reduces the chance of them developing diarrhoea caused by Clostridium difficile (C. difficile) bacteria by 60%. One case of Clostridium-associated diarrhoea was prevented for every 42 people receiving probiotics. They appear to work best for patients at more than 5% risk of Clostridium infection.

When antibiotics disturb healthy gut bacteria, Clostridium bacteria may multiply to toxic levels, causing diarrhoea and serious intestinal complications. Probiotics can be found in dietary supplements or yoghurts but are increasingly sold as capsules and contain live bacteria or yeast that may counteract these effects.

This updated Cochrane review pooled 39 trials comparing patients who did and did not receive probiotics. Results were consistent when taking account of the type of probiotic, inpatient or outpatient setting, or whether for adults or children.

Probiotics may be suitable for use in high-risk patients needing antibiotics, for example, older adults with underlying illness. Probiotics aren’t regulated as medicines, and national guidance here and overseas does not recommend them for standard use.

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Why was this study needed?

Use of broad-spectrum antibiotics, those that cover a wide range of bacteria, is associated with overgrowth of C. difficile bacteria in the bowel. Older hospitalised patients with multiple illnesses are at highest risk. The bacteria can spread in hospitals between vulnerable patients in close contact with each other and staff in the hospital. Infection is associated with longer hospital stays and increased mortality risk.

Since 2007, NHS trusts have been required to report all cases of C. difficile infection. Better prevention, recognition and management, along with the restricted use of broad-spectrum antibiotics, has led to a rapid decline in infections over the past decade. In 2016-17, nearly 13,000 cases were reported compared with 55,500 in 2007-08. However, the extent of the decline has recently levelled off. So there is still a need for better prevention.

This Cochrane update adds eight trials since the last 2013 review assessing the effectiveness and safety of probiotics in adults and children receiving antibiotics.

What did this study do?

The review identified 39 randomised controlled trials including 9,955 people receiving antibiotics. Most trials compared probiotics with placebo, some compared with no treatment and a few compared different doses of probiotic.

Trial settings and populations varied but the majority comprised adult hospital inpatients. Six trials included children; six took place in the UK. Trials used different formulations, strains and doses of probiotics, sometimes given alongside antibiotics, sometimes after. Only studies assessing probiotics for the prevention of C. difficile rather than treatment were included.

Around two-thirds of trials had high or unclear risk of bias, including the possibility that researchers were aware which group patients were being assigned to. However, the effect on C. difficile-associated diarrhoea was similar across studies. The authors assigned a moderate level of certainty for this outcome.

What did it find?

  • Patients receiving probiotics were 60% less likely to have diarrhoea associated with C. difficile bacteria (risk ratio [RR] 0.40, 95% confidence interval [CI] 0.30 to 0.52; 31 trials, 8,672 participants). Diarrhoea developed in 1.5% of patients receiving probiotics compared with 4% of the control group. Forty-two people would need to receive probiotics to prevent one case of diarrhoea.
  • There was no clear difference in results for adults or children, inpatients or outpatients, when considering probiotic dose, trial quality or when different assumptions were made for missing data.
  • Probiotics had the greatest effect in trials of patients at highest baseline risk of C. difficile-associated diarrhoea (above 5% risk), which developed in 3.5% receiving probiotics vs 11.6% without (RR 0.30, 95% CI 0.21 to 0.42; 13 trials, 2,454 participants). Only 12 higher risk patients would need treatment to prevent one case of the diarrhoea. Probiotics did not have statistically significant effect in sub-analysis of studies recruiting lower risk patients.
  • The most common adverse effects across both probiotic and control groups were gastrointestinal symptoms and fever. There was a suggestion that incidence of adverse effects may be slightly lower in people receiving probiotics, but the quality of evidence was very low. No serious effects were attributed to probiotics.

What does current guidance say on this issue?

Guidance from Public Health England (2013) on the management and treatment of C. difficile infections does not recommend the use of probiotics for the prevention of antibiotic-associated diarrhoea or C. difficile infections. This was based on insufficient evidence of effectiveness in trials/reviews published up to 2012. Public Health England advised that the area had been underexplored and that further research was needed.

What are the implications?

This updated Cochrane review provides new evidence suggesting that probiotics may be beneficial for hospitalised patients at risk of C. difficile infection.

Cost effectiveness was not assessed. Probiotics may be seen as a relatively low-cost intervention. However, probiotics are classed as food supplements and as such are not subject to mandatory testing or quality control. They are contraindicated in severely unwell or immuno-compromised patients, which may limit their use in some settings.

Guidance could useful consider this latest evidence and offer recommendations around which strains, formulations and dosages are safe and effective for different, particularly high-risk, patient groups.

Citation and Funding

Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;12:CD006095. 

The Cochrane Inflammatory Bowel Disease Group has received funding from Crohn’s and Colitis Canada between 2016 and 2018.

Bibliography

Department of Health and Social Care and Public Health England. Clostridium difficile: how to deal with the problem. London: Department of Health and Social Care and Public Health England; 2008.

NHS Choices. Clostridium difficile. London: Department of Health; updated 2016.

NHS Choices. Probiotics. London: Department of Health; updated 2016.

NHS Improvement. Clostridium difficile infection objectives for NHS organisations in 2018/19, guidance on sanction implementation and notification of changes to case attribution definitions from 2019. London: NHS Improvement; 2018.

NICE. Clostridium difficile infection: risk with broad-spectrum antibiotics: Evidence Summary. ESMPB1. London: National Institute for Health and Care Excellence; 2015.

PHE. Updated guidance on the management and treatment of Clostridium difficile infection. London: Public Health England; 2013.

Why was this study needed?

Use of broad-spectrum antibiotics, those that cover a wide range of bacteria, is associated with overgrowth of C. difficile bacteria in the bowel. Older hospitalised patients with multiple illnesses are at highest risk. The bacteria can spread in hospitals between vulnerable patients in close contact with each other and staff in the hospital. Infection is associated with longer hospital stays and increased mortality risk.

Since 2007, NHS trusts have been required to report all cases of C. difficile infection. Better prevention, recognition and management, along with the restricted use of broad-spectrum antibiotics, has led to a rapid decline in infections over the past decade. In 2016-17, nearly 13,000 cases were reported compared with 55,500 in 2007-08. However, the extent of the decline has recently levelled off. So there is still a need for better prevention.

This Cochrane update adds eight trials since the last 2013 review assessing the effectiveness and safety of probiotics in adults and children receiving antibiotics.

What did this study do?

The review identified 39 randomised controlled trials including 9,955 people receiving antibiotics. Most trials compared probiotics with placebo, some compared with no treatment and a few compared different doses of probiotic.

Trial settings and populations varied but the majority comprised adult hospital inpatients. Six trials included children; six took place in the UK. Trials used different formulations, strains and doses of probiotics, sometimes given alongside antibiotics, sometimes after. Only studies assessing probiotics for the prevention of C. difficile rather than treatment were included.

Around two-thirds of trials had high or unclear risk of bias, including the possibility that researchers were aware which group patients were being assigned to. However, the effect on C. difficile-associated diarrhoea was similar across studies. The authors assigned a moderate level of certainty for this outcome.

What did it find?

  • Patients receiving probiotics were 60% less likely to have diarrhoea associated with C. difficile bacteria (risk ratio [RR] 0.40, 95% confidence interval [CI] 0.30 to 0.52; 31 trials, 8,672 participants). Diarrhoea developed in 1.5% of patients receiving probiotics compared with 4% of the control group. Forty-two people would need to receive probiotics to prevent one case of diarrhoea.
  • There was no clear difference in results for adults or children, inpatients or outpatients, when considering probiotic dose, trial quality or when different assumptions were made for missing data.
  • Probiotics had the greatest effect in trials of patients at highest baseline risk of C. difficile-associated diarrhoea (above 5% risk), which developed in 3.5% receiving probiotics vs 11.6% without (RR 0.30, 95% CI 0.21 to 0.42; 13 trials, 2,454 participants). Only 12 higher risk patients would need treatment to prevent one case of the diarrhoea. Probiotics did not have statistically significant effect in sub-analysis of studies recruiting lower risk patients.
  • The most common adverse effects across both probiotic and control groups were gastrointestinal symptoms and fever. There was a suggestion that incidence of adverse effects may be slightly lower in people receiving probiotics, but the quality of evidence was very low. No serious effects were attributed to probiotics.

What does current guidance say on this issue?

Guidance from Public Health England (2013) on the management and treatment of C. difficile infections does not recommend the use of probiotics for the prevention of antibiotic-associated diarrhoea or C. difficile infections. This was based on insufficient evidence of effectiveness in trials/reviews published up to 2012. Public Health England advised that the area had been underexplored and that further research was needed.

What are the implications?

This updated Cochrane review provides new evidence suggesting that probiotics may be beneficial for hospitalised patients at risk of C. difficile infection.

Cost effectiveness was not assessed. Probiotics may be seen as a relatively low-cost intervention. However, probiotics are classed as food supplements and as such are not subject to mandatory testing or quality control. They are contraindicated in severely unwell or immuno-compromised patients, which may limit their use in some settings.

Guidance could useful consider this latest evidence and offer recommendations around which strains, formulations and dosages are safe and effective for different, particularly high-risk, patient groups.

Citation and Funding

Goldenberg JZ, Yap C, Lytvyn L, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2017;12:CD006095. 

The Cochrane Inflammatory Bowel Disease Group has received funding from Crohn’s and Colitis Canada between 2016 and 2018.

Bibliography

Department of Health and Social Care and Public Health England. Clostridium difficile: how to deal with the problem. London: Department of Health and Social Care and Public Health England; 2008.

NHS Choices. Clostridium difficile. London: Department of Health; updated 2016.

NHS Choices. Probiotics. London: Department of Health; updated 2016.

NHS Improvement. Clostridium difficile infection objectives for NHS organisations in 2018/19, guidance on sanction implementation and notification of changes to case attribution definitions from 2019. London: NHS Improvement; 2018.

NICE. Clostridium difficile infection: risk with broad-spectrum antibiotics: Evidence Summary. ESMPB1. London: National Institute for Health and Care Excellence; 2015.

PHE. Updated guidance on the management and treatment of Clostridium difficile infection. London: Public Health England; 2013.

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

Published on 20 December 2017

Goldenberg, J. Z.,Yap, C.,Lytvyn, L.,Lo, C. K.,Beardsley, J.,Mertz, D.,Johnston, B. C.

Cochrane Database Syst Rev Volume 12 , 2017

BACKGROUND: Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though probiotics have the highest quality evidence among cited prophylactic therapies. OBJECTIVES: To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children. SEARCH METHODS: We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search. 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. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, 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 risk ratio (RR) and corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. Continuous outcomes (e.g. length of hospital stay) 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 analyses were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias as well as a post hoc subgroup analysis on baseline risk of CDAD (low 0% to 2%; moderate 3% to 5%; high > 5%). The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria. MAIN RESULTS: Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. AUTHORS' CONCLUSIONS: Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk </=5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.

Expert commentary

C. difficile associated diarrhoea caused by antibiotics is still the most frequent cause of diarrhoea in hospitals, with a mortality of up to 20%: its prevention is of enormous importance.

It may be tempting now to revise current practice guidelines so that they include a recommendation that clinicians prescribe probiotics routinely to patients given antibiotics, especially in those with a high risk of C. difficile associated diarrhoea.

However, three questions need answering first. Which is the best probiotic? How do we prospectively identify patients at high risk of acquiring C. difficile associated diarrhoea? And what would be the cost-effectiveness of this approach? 

David Rampton, Professor of Clinical Gastroenterology, Barts & The London School of Medicine & Dentistry