Method:
The purpose of this systemic review of literature was to determine if prophylactic use of probiotics, in patients (over 18 years), who are on long term antibiotic treatment, reduce the incidences of AAD and CDAD. It also aims to ascertain what probiotic dosing is effective in this process and what would be the effective duration of treatment?
The study included all the available randomized controlled trials that were done in order to assess the effectiveness of probiotics for prevention of AAD and CDAD. As a part of the analysis only those studies that were published between 2007 and 2017 were included as a part of the study. Additionally, the analysis was limited to the studies that were published in English language and were available as free full-text. Studies comprising of adult patients above 18 years, both males and females, who were on antibiotics treatments for at least a week or more were included in this review. While all previously published systemic review and meta-analysis were excluded in order to avoid the introduction of bias through the previous reviews. Also, studies including patients with pre-existing GI disease such as inflammatory bowel disease and irritable bowel syndrome as well as patients with compromised immune status were not participants in any of the studies included in the analysis because these patients are at an increased risk for developing CDAD (Centers for Disease Control and Prevention [CDC], 2008). Finally all studies conducted on or included children or subjects younger than 18 years of age were removed from the pool.
A comprehensive search was conducted to identify all relevant studies on probiotic efficacy for AAD and CDAD. The search was conducted in three separate steps. First, PUBMED, MEDLINE and CINAHL databases were searched for articles published from 2007-2017, using keywords such as Probiotics, Antibiotic Associated Diarrhea, C. diff. and the combination of the three. followed by an analysis of the text words contained in the title and abstract and of the index terms used to describe the article in an effort to identify key words. Secondly the studies were filtered for the all duplicate records and those were removed from the pool. Finally, all abstracts were evaluated first to determine if studies met the study inclusion criteria of adults 18–80 years of age, use of antibiotics, and studies evaluating efficacy of prophylactic or concurrent use of probiotics compared with antibiotics alone. Free full- text versions of chosen studies were then obtained for a thorough review. All articles not meeting the inclusion criteria were finally excluded. These articles were evaluated using an excel sheet which is attached to the appendix of the study.
All studies are subject to bias, however in order to have accurate results, bias needs to be avoided or reduced at the least. To assess the bias all the studies included in the analysis were evaluated based on questions from QUADS2 questionnaire. The studies were assessed for selection bias. To reduce the risk of bias most studies included in the pool were only randomized control trials while previously published meta-analysis and systemic review of literature were removed. To assess for performance bias only studies that included some kind of probiotic for treatment of AAD and CDAD and were on antibiotics were kept as a part of the pool while studies in which patients were at high risk of developing the disease even without use of antibiotic were eliminated. Additionally the studies were also assessed for reporting bias by evaluating that pool included studies that had not only positive but also those that had a negative outcome.
Results :
A review of literature was conducted to determine whether the administration of probiotics along with antibiotic therapy would decrease the incidences of ADD and CDAD in the adult population based on studies conducted in the last 10 years. Based on the keywords and the inclusion exclusion criteria mentioned in the method’s section 74 articles were identified out of which 59 were reviewed after removing duplicate articles. Of the 59 articles, 38 were removed since they did not meet inclusion criteria. Of these 38, 15 studies not related to AAD or CDAD. 4 studies conducted on pediatric population. 10 were meta-analysis or systemic reviews. 9 were abstracts only. Remaining 21 articles were screened for full text and eligibility and of these 8 were removed since they were either observational studies or included subjects less than 18 years of age finally leaving 13 studies in the pool. The entire process of selection has been reprented in a flow diagram which is a part of Appendix 2.
The studies evaluated had some similarities and some differences all included patients over 18 years of age who were hospitalized and were on antibiotics for over 48 hours. All studies included were randomized control trials. The sample size and the type of probiotic strain administered to these patients were different in each study. Additionally, these studies were conducted in different parts of the world. Even after these discrepancies one common thread making them a part of the study was their aim to determine the efficacy of probiotics in treatment of ADD and CDAD.
A systemic review of literature conducted shows that the probiotics did not have concrete evidence to show that they prevent ADD and CDAD among patients on antibiotic treatment. The summary of the studies has been included in the table attached in Appendix 3. The studies included although have a low risk since they are randomized trials still a low risk of selection bias is possible since most subjects that were studies were hospitalized and the nosocomial infections can be common. So it might be difficult to distinguish between the ones caused by antibiotic or due to other reasons.
Appendix 1:
Key words
Yield from PubMed
2007-2017
Yield from CINAHL
2007-2017
Yield from MEDLINE
2007-2017
Probiotics
13496
5172
9311
Antibiotic Associated Diarrhea
17412
183
334
Clostridium difficile
13435
3260
5725
c. diff
11660
124
71
Probiotics AND Antibiotic Associated Diarrhea
2902
117
105
Probiotics AND Clostridium difficile
2206
252
Probiotics AND C. diff.
100
4
1
Appendix2:
Source
Number of Subjects
Age range of Subjects
Primary Inclusion Criterion
Important result/conclusion
Bias Rating
1.Allen S. et. al., NHS jounal Library 2013
2981
65 years
Subjects exposed to one or more oral or parenteral antibiotics and were without pre-existing diarrheal disorders
The study showed no evidence that administration of probiotic reduced occurrence of ADD in elderly population
Low
2. Klarin et. al.,
Journal of Anesthesiology Scandanavia 2008
22
Patients > 18 years of age
Patients in ICU for longer than 3 days and were on antibiotics
Enteral administration of the probiotic bac- terium Lp299v to critically ill patients treated with anti- biotics reduced colonization with C. difficile.
Low
3. Hickson et.al., British Medical Journal 2007
Patients > 50 years of age
Patients who were hospitalized and placed on antibiotics
Consumption of a probiotic drink containing L casei, L bulgaricus, and S thermophilus can reduce the incidence of antibiotic associated diarrhea and C difficile associated diarrhea. This has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50.
Low
5. Helps et. al., International Journal of Probiotics and Prebiotics (2015)
85
Patients > 18 years of age
Patients hospitalized in renal wards and were on antibiotics for over 48 hours
This double-blind randomized placebo-controlled study was not able to demonstrate any reduction in AAD or CDAD in patients with kidney disease who have commenced antibiotics within the past 2 days.
Low
6. Safdar et.al., Journal Of Clinical Pharmacy & Therapeutics (2008)
40
Patients > 18 years of age
Military veterans who were hospitalized and were on antibiotics for over 48 hours
The study was not able to demonstrate positive effects of probiotics in preventing AAD and CDAD
High
7. Wright et. al., Australasian Journal On Ageing (2015)
87
Patients 65+ years old
Patients hospitalized for treatment and were administered antibiotics for more than 48 hours
No significant difference was seen between the control and experimental group
High
8. Wang et.al., American Journal Of Gastroenterology (2010)
255
Patients 50-77 years of age
Patients hospitalized for more than 5 days and were administered antibiotics for more than 48 hours
Probiotic blend of Lactobacillus acidophilus CL1285® + Lactobacillus casei LBC80R® (Bio-K + CL1285) studied in this clinical trial was effective in reducing risk of AAD and, in particular, CDAD and was well tolerated in hospitalized adult patients on antibiotic therapy.
Low
9. Selinger et.al.,
Journal of Hospital Infection (2013)
229
Patients > 18 years of age
Hospitalized patients who were treated for antibiotics for more than 48 hours.
SL#3 is associated with a significant reduction in the incidence of AAD in average-risk hospital inpatients exposed to systemic antibiotics.
Low
10. Song et.al., Journal of Korean Medical Science (2010)
214
Patients > 18 years of age
Hospitalized patients who were treated for antibiotics for more than 48 hours.
Lacidofil helps to maintain normal bowel pattern in patients on antibiotics.
Low
11. Ouwehand et. al., Vaccine (2014)
503
Patients 30-70 years of age
Hospitalized patients who were treated for antibiotics for more than 48 hours.
Probiotic strains reduce risk of ADD and CDAD
Low
12. Pozzoni et.al., The American Journal Of Gastroenterology ( 2012)
562
Patients over 50 years of age
Hospitalized patients who were treated for antibiotics for more than 48 hours.
S. boulardii was shown to be unable to prevent the development of AAD
Low
13. Gao et. al. American Journal Of Gastroenterology (2010)
255
Patients 50-70 years of age
Hospitalized patients who were treated for antibiotics for more than 48 hours.
e proprietary probiotic blend of Lactobacillus acidophilus CL1285 Lactobacillus casei LBC80R® (Bio-K + CL1285) studied in this clinical trial was e ective in reducing risk of AAD and, in particular, CDAD and was well tolerated in hospitalized adult patients on antibiotic therapy.
Appendix 3: PRISMA 2009 Flow Diagram
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097
For more information, visit www.prisma-statement.org.
References:
Allen, S., Wareham, K., Wang, D., Bradley, C., Sewell, B., Hutchings, H., & … Phillips, C. (2013). A high-dose preparation of lactobacilli and bifidobacteria in the prevention of antibiotic-associated and
Clostridium difficile diarrhoea in older people admitted to hospital: a multicentre, randomised, double-blind, placebo-controlled, parallel arm trial (PLACIDE). Health Technology Assessment, 17(32), 1-140. doi:10.3310/hta17570
Klarin, B., Wullt, M., Palmquist, I., Molin, G., Larsson, A., & Jeppsson, B. (2008). Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics. Acta Anaesthesiologica Scandinavica, 52(8), 1096-1102. DOI: 10.1111/j.1399-6576.2008.01748.x
Hickson, M., Dsouza, A. L., Muthu, N., Rogers, T. R., Want, S., Rajkumar, C., & Bulpitt, C. J. (2007). Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: Randomised double blind placebo controlled trial. British Medical Journal, 335(7610), 80-80. doi:10.1136/bmj.39231.599815.55
Helps, A., Bell, E., & Mactier, R. (2015). Prospective randomized double-blind study of efficacy of probiotic milk drink in reducing the incidence of the Antibiotic-Associated Diarrohea and Clostridium difficile diarrhea. International Journal of Probiotics & Prebiotics, 10(4), 145-151.
Safdar, N., Barigala, R., Said, A., & McKinley, L. (2008). Feasibility and tolerability of probiotics for prevention of antibiotic-associated diarrhoea in hospitalized US military veterans. Journal Of Clinical Pharmacy & Therapeutics, 33(6), 663-668. doi:10.1111/j.1365-2710.2008.00980.
Wright, K., Wright, H., & Murray, M. (2015). Probiotic treatment for the prevention of antibiotic-associated diarrhoea in geriatric patients: A multicentre randomised controlled pilot study. Australasian Journal On Ageing, 34(1), 38-42. doi:10.1111/ajag.12116
Xing Wang, G., Mubasher, M., Chong Yu, F., Reifer, C., & Miller, L. E. (2010). Dose–Response Efficacy of a Proprietary Probiotic Formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for Antibiotic-Associated Diarrhea and Clostridium difficile-Associated Diarrhea Prophylaxis in Adult Patients. American Journal Of Gastroenterology, 105(7), 1636-1641. doi:10.1038/ajg.2010.11
Selinger, C., Bell, A., Cairns, A., Lockett, M., Sebastian, S., & Haslam, N. (2013). Probiotic VSL#3 prevents antibiotic-associated diarrhoea in a double-blind, randomized, placebo-controlled clinical trial. Journal of Hospital Infection, 84(2), 159-165. doi:10.1016/J.JHIN.2013.02.019
Song, H., Kim, J., Jung, S., Kim, S., Park, H., & Jeong, Y. et al. (2010). Effect of ProbioticLactobacillus(Lacidofil® Cap) for the Prevention of Antibiotic-associated Diarrhea: A Prospective, Randomized, Double-blind, Multicenter Study. Journal Of Korean Medical Science, 25(12) 1784-1791. http://dx.doi.org/10.3346/jkms.2010.25.12.1784
Ouwehand, A., DongLian, C., Weijian, X., Stewart, M., Ni, J., Stewart, T., & Miller, L. (2014). Probiotics reduce symptoms of antibiotic use in a hospital setting: A randomized dose response study. Vaccine, 32(4), 458-463. http://dx.doi.org/10.1016/j.vaccine.2013.11.053
Pozzoni, P., Riva, A., Bellatorre, A. G., Amigoni, M., Redaelli, E., Ronchetti, A., & … Colli, A. (2012). Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial. The American Journal Of Gastroenterology, 107(6), 922-931. doi:10.1038/ajg.2012.56\
Gao, X. W., Mubasher, M., Fang, C. Y., Reifer, C., & Miller, L. E. (2010). Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients. The American Journal Of Gastroenterology, 105(7), 1636-1641. doi:10.1038/ajg.2010.11