Original Title: Avis sur l'usage des probiotiques en prévention des diarrhées associées à Clostridium difficile chez les patients hospitalisés et sous antibiothérapie, au Québec

Authors' objectives: Clostridium difficile-associated diarrhea (CDAD) is a major health problem with serious consequences that can occur in patients on antibiotics and especially in the elderly and persons weakened by specific clinical conditions. Several infection control and antibiotic surveillance measures have been put in place in the past 10 years to limit the number of CDAD cases in health-care facilities, and to improve their CDAD rates, some of them have added the use of probiotics. To ensure appropriate probiotic use in the prevention of CDAD, the Ministère de la Santé et des Services sociaux (MSSS) asked INESSS to evaluate the evidence and to produce a clinical relevance assessment report. The primary objective of the report was to determine the efficacy, in terms of their benefits for preventing CDAD, of different preparations of probiotic agents commercially available in Canada and, if applicable, to determine the role of these products among preventive measures.

Authors' results and conclusions: RESULTS: The development of CDAD is a multifactorial phenomenon that raises a great deal of uncertainty. The impact on the health and quality of life of those affected makes this infection very debilitating. According to estimates, after a first episode, 20% to 30% of patients will experience a recurrence during their lifetime, and 40% to 60% of them will experience multiple recurrences. In Québec, the baseline risk of CDAD in health-care facilities appears to be approximately 0.45%. The presence of one or more risk factors increases a patient’s individual risk. These factors include antibiotic use, where the baseline risk of CDAD increases from 1.6- to 10.6-fold, depending on the class or generation and on whether the patient is in hospital or in the community. In studies carried out in Canada from 2003 to 2014, the rates observed ranged from 0.9% to 5.8%. Prevention modalities other than infection control and antibiotic use surveillance measures have been recommended to limit cases of CDAD in health-care facilities and the community, including the use of probiotics. Recognizing the health benefits of certain microorganisms referred to as “probiotic” is nothing new, but their use has not been universally adopted by the medical community, especially in the context of CDAD prevention. Despite the plausibility of their microbiological, metabogenic and immunological efficacy, there is still some uncertainty regarding the impact of probiotics on alleviating the symptoms associated with C. difficile infection or on protection against this type of infection. According to a number of experts on probiotics [McFarland, 2016; Hill et al., 2014; Maidens et al., 2013; Ritchie and Romanuk, 2012; Lomax and Calder, 2009], their efficacy differs from strain to strain, and it would be a mistake, when examining a specific health benefit, not to make a distinction between the different taxonomic groups and microbial species, strains and genera by assuming that all probiotic agents interact with the host in the same way. This is why INESSS conducted a systematic review and performed analyses stratified according to the nature and composition of the probiotic preparations. The evaluation reveals that, with the exception of two preparations with, at best, a low level of scientific evidence for well-defined populations and epidemiological contexts, for most of the probiotic preparations used in the identified studies, the scientific evidence of CDAD prevention benefits, both in adults and children, is insufficient. In children on antibiotics, the agent Saccharomyces boulardii, at a dose of 500 mg per day, showed a certain benefit in preventing CDAD in two studies where the baseline CDAD rate in the control group was greater than 5 %. This probiotic agent, which is recognized by Health Canada for reducing the risk of developing AAD, but not CDAD, is produced by different manufacturers. The other preparation with a low level of scientific evidence of efficacy is that consisting of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80Rand Lactobacillus rhamnosus CLR2. It was patented by Bio-K Plus International Inc., and the health claim in the prevention of CDAD is approved by Health Canada. The observed benefits were obtained with a daily dose of 50 or 100 × 109 CFU in hospitalized adults on antibiotics, and the baseline CDAD rate in the control group was, in two of the three studies, greater than 5%. Currently, the mean CDAD rate in Québec is less than 5%. The analysis of the safety literature shows that the serious adverse effects associated with probiotics are rare but that, in exceptional cases, their administration can lead to bacteremia or fungemia in more vulnerable individuals. Although most of the authors of the published systematic reviews conclude that probiotics seem to be effective in preventing CDAD (low level of evidence), the published clinical practice guidelines (CPGs) generally do not advocate the use of probiotics for this indication. Furthermore, most Québec health-care facilities do not use probiotics in CDAD prevention, although most of them have instituted infection prevention and control and microbial management measures in conjunction with an antibiotic governance program (coordination of efforts to improve antibiotic use) in order to obtain Accreditation Canada accreditation. A comparative analysis of CDAD risk reductions according to the type of preventive measure, including the use of probiotics, found a low level of efficacy evidence for all the measures, this because of the studies’ methodological limitations. In theory, each measure targets relatively different stages of the life cycle of the C. difficile bacterium and that of the infection. They are therefore not in competition. Rather, they are complementary, if we recognize their respectively attributed operating mechanisms. However, infection prevention and control, disinfection and antibiotic governance measures are broader in scope than probiotic use. Consultations with the stakeholders provided an opportunity to raise a number of social, societal, professional and organizational concerns regarding the use of probiotics in CDAD prevention. The evaluation of all the evidence does not show any sufficient benefits, compared to the problems raised, to make a recommendation in favour of the systematic or ad hoc use of probiotics, for which the level of scientific evidence of CDAD prevention benefits is low. CONCLUSION: In Québec, given the current state of knowledge, it would be premature to offer probiotics to all hospitalized patients on antibiotics, given the low level of scientific evidence regarding their efficacy, and considering the benefits of the other infection prevention and control measures and of the antibiotic governance programs, all of which are broader in scope. Until new data are available from studies of good methodological quality of the efficacy of probiotics, for which the level of scientific evidence is currently low or insufficient, and given the confounding factors that have not yet been considered in published studies carried out in a context where infection prevention and antibiotic surveillance measures are standardized, the use, based on a population-based approach, of probiotics in health-care facilities is not recommended, except in a research context.

Authors' recommendations: (Saccharomyces boulardi)i: Given the current state of knowledge, offering or administering on a systematic or ad hoc basis a probiotic preparation consisting of Saccharomyces boulardii is not recommended, apart from a research context. (Lactobacillus casei Shirota): Not recommended, apart from a research context. (Lactobacillus plantarum 299v): Not recommended, apart from a research context. (Lactobacillus rhamnosus GG): Not recommended, apart from a research context. (Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R and Lactobacillus rhamnosus CLR2): Not recommended, apart from a research context. (Lactobacillus acidophilus CUL60, Lactobacillus acidophilus CUL21, Bifidobacterium bifidum CUL20 and Bifidobacterium lactis CUL34): Not recommended, apart from a research context.

Authors' methods: A knowledge mobilization approach including a global analysis of the pathophysiological, epidemiological, technological and clinical aspects, and of the issues relating to the applicability, acceptability and implementation of such a practice was used to evaluate all the evidence and develop recommendations. The latter are based on the level of scientific evidence and were adapted to the Québec context after triangulating experiential, contextual and scientific data. The scientific data were collected upon conducting a systematic review of clinical practice guidelines (CPGs), a systematic review of primary studies of the efficacy and safety of probiotics together with meta-analyses according to the nature and composition of the preparations, and narrative reviews concerning the pathophysiology, epidemiology and technological aspects specific to probiotics. Consultations with different stakeholders enabled us to gather other types of data, which were enriched by means of grey literature searches.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/avis-sur-lusage-des-probiotiques-en-prevention-des-diarrhees-associees-a-clostridium-difficile-chez-les-patients-hospitalises-et-sous-antibiotherapie-au-quebec.html

Year Published: 2017

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/avis-sur-lusage-des-probiotiques-en-prevention-des-diarrhees-associees-a-clostridium-difficile-chez-les-patients-hospitalises-et-sous-antibiotherapie-au-quebec.html

Requestor: Minister of Health

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec