Probiotics have been assessed in the prevention of antibiotic-associated diarrhoea (AAD) but studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. However, two recent meta-analyses detected large reductions in the risk of AAD and C difficile infections. In the Lancet, researchers report the findings of the PLACIDE trial, a pragmatic efficacy trial in older inpatients who would be representative of those admitted to NHS and similar secondary care institutions. This study was conducted at five centres in England and Wales and is the largest trial to be reported in this setting (n=2941).
The study involved 1493 patients randomised to a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 1010 organisms, one per day for 21 days, and 1488 assigned to matching placebo. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment.
According to the modified intention-to-treat analysis (1470 and 1471 on active and placebo, respectively, included in analyses of primary endpoints):
• AAD (including CDD) occurred in 159 (10.8%) participants in the microbial preparation group and 153 (10.4%) participants in the placebo group (relative risk 1.04; 95% CI, 0.84 to 1.28; p=0.71).
• CDD was an uncommon cause of AAD and occurred in 12 (0.8%) participants in the microbial preparation group and 17 (1.2%) participants in the placebo group (0.71; 0.34 to 1.47; p=0.35).
• 578 (19.7%) participants had ≥1 serious adverse event; the frequency of which was similar in the two study groups and none was attributed to participation in the trial.
The researchers note several weaknesses to their study such as difficulty recruiting eligible patients despite attempts to minimise the exclusion criteria, due to the unwillingness of people already receiving medicines to take an additional preparation. Ethnic diversity was also low in the study but was representative of the local older populations. In addition, many episodes of AAD were of short duration and stool samples for testing were not obtained in about 40% of participants with diarrhoea though the proportion of stools tested in the study was much the same in the two groups and, in view of the absence of efficacy of the microbial preparation against AAD, they thought it was unlikely that these missing samples biased the estimate of intervention effect against CDD. They therefore concluded that their findings do not provide statistical evidence to support recommendations for the routine use of microbial preparations for the prevention of AAD and CDD.
A comment article notes that this study is rigorous, with central randomisation, use of placebo control, careful allocation concealment, and thorough follow-up for evidence of AAD or CDD. The author discusses why the study findings differ from the large positive effects detected in previous meta-analyses, especially since the sample size in PLACIDE dwarfs that of any previous studies in the discipline. He recreates the forest plot from the previous meta-analysis of the effect of probiotic use on the outcome of C difficile infection and noted that the 95% CIs of the PLACIDE result visually overlap those of previous studies, and there is no statistical evidence of additional heterogeneity. Furthermore, addition of the PLACIDE results barely shifted the risk reduction estimate, from 0•34 (95% CI 0•24—0•49) to 0•39 (0•29—0•54).
It was also noted that although the sample size of PLACIDE was very large, the event rate was much lower than predicted (about 10% ADD vs. prediction of 20%; 1% occurrence of CDD vs. prediction of 4%). The Comment suggests that perhaps the PLACIDE trial was negative because its 95% CIs were unable to rule out a potential 16% reduction in occurrence of AAD and a potential 66% reduction in CDD. Alternatively, the results of this large trial might outweigh the results of any meta-analysis as most previous probiotic research has involved small, single centre studies of variable quality, particularly as a third of meta-analyses do not accurately predict the results of subsequent large RCTS. Thus the author of the Comment concludes that “at the very least, the low absolute risk reductions in PLACIDE question the cost-effectiveness of probiotics,” noting that a cost—consequence analysis funded by a probiotic manufacturer established that the incidence of CDD must > 1•2% for this strategy to produce cost savings. He adds however that lactobacilli and bifidobacteria are only two types of non-pathogenic bacteria, and one needs to consider whether they can really tip the balance of a diverse gut ecosystem.
The Health Protection Agency (HPA) in its updated guidance on the management and treatment of Clostridium difficile infection could not recommend the use of probiotics for the prevention of AAD or CDI at present due to insufficient definitive data and called for further research.