Background:

Antibiotic-associated diarrhoea (AAD) occurs most commonly in older people admitted to hospital and within 12 weeks of exposure to broad-spectrum antibiotics. Although usually a mild and self-limiting illness, the 15–39% of cases caused by Clostridium difficile infection [C. difficile diarrhoea (CDD)] may result in severe diarrhoea and death. Previous research has shown that probiotics, live microbial organisms that, when administered in adequate numbers, are beneficial to health, may be effective in preventing AAD and CDD.

Objectives:

To determine the clinical effectiveness and cost-effectiveness of a high-dose, multistrain probiotic in the prevention of AAD and CDD in older people admitted to hospital.

Design:

A multicentre, randomised, double-blind, placebo-controlled, parallel-arm trial.

Setting:

Medical, surgical and elderly care inpatient wards in five NHS hospitals in the UK.

Participants:

Eligible patients were aged ≥ 65 years, were exposed to one or more oral or parenteral antibiotics and were without pre-existing diarrhoeal disorders, recent CDD or at risk of probiotic adverse effects. Out of 17,420 patients screened, 2981 (17.1%) were recruited. Participants were allocated sequentially according to a computer-generated random allocation sequence; 1493 (50.1%) were allocated to the probiotic and 1488 (49.9%) to the placebo arm.

Interventions:

Vegetarian capsules containing two strains of lactobacilli and two strains of bifidobacteria (a total of 6 × 10¹⁰ organisms per day) were taken daily for 21 days. The placebo was inert maltodextrin powder in identical capsules.

Main outcome measures:

The occurrence of AAD within 8 weeks and CDD within 12 weeks of recruitment was determined by participant follow-up and checking hospital laboratory records by research nurses who were blind to arm allocation.

Results:

Analysis based on the treatment allocated included 2941 (98.7%) participants. Potential risk factors for AAD at baseline were similar in the two study arms. Frequency of AAD (including CDD) was similar in the probiotic (159/1470, 10.8%) and placebo arms [153/1471, 10.4%; relative risk (RR) 1.04; 95% confidence interval (CI) 0.84 to 1.28; p = 0.71]. CDD was an uncommon cause of AAD and occurred in 12/1470 (0.8%) participants in the probiotic and 17/1471 (1.2%) in the placebo arm (RR 0.71; 95% CI 0.34 to 1.47; p = 0.35). Duration and severity of diarrhoea, common gastrointestinal symptoms, serious adverse events and quality of life measures were also similar in the two arms. Total health-care costs per patient did not differ significantly between the probiotic (£8020; 95% CI £7620 to £8420) and placebo (£8010; 95% CI £7600 to £8420) arms.

Conclusion:

We found no evidence that probiotic administration was effective in preventing AAD. Although there was a trend towards reduced CDD in the probiotic arm, on balance, the administration of this probiotic seems unlikely to benefit older patients exposed to antibiotics. A better understanding of the pathogenesis of AAD and CDD and the strain-specific effects of probiotics is needed before further clinical trials of specific microbial preparations are undertaken. Evaluation of the effectiveness of other probiotics will be difficult where other measures, such as antibiotic stewardship, have reduced CDD rates.

Trial registration:

This trial is registered as ISRCTN70017204.

Funding:

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 57. See the NIHR Journals Library website for further project information.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 06/39/02. The contractual start date was in May 2008. The draft report began editorial review in January 2013 and was accepted for publication in April 2013. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Stephen Allen has undertaken research in probiotics supported by Cultech Ltd, Baglan, Port Talbot, UK; the Children and Young People’s Research Network, Cardiff University, Wales; the Knowledge Exploitation Fund, Welsh Development Agency and the National Ankylosing Spondylitis Society, UK. He has also been an invited guest at the Yakult Probiotic Symposium in 2011 and received research funding from Yakult, UK, in 2010.