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Probiotics against antibiotic-associated diarrhoea in elderly patients 

Probiotics can help to prevent or alleviate antibiotics-associated diarrhoea (AAD). Nevertheless, probiotics are rarely prescribed to elderly patients receiving antibiotics. A frequently cited argument is that there is no evidence. However, the evidence for the efficacy of probiotics in AAD (both in adults and children), shown by several meta-analyses and other research, is growing. There have also been several studies of probiotics given to elderly patients undergoing antibiotics treatment. The results of these studies were inconsistent. What could be the reason for this? 

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The efficacy of probiotics in AAD has been the focus of extensive research. Because many of these studies involved small numbers of participants, a number of systematic reviews and meta-analyses were performed to be able to calculate the effect of probiotics on AAD prevention more accurately. Six recent meta-analyses (the oldest dating to 2011) conclude that probiotics have a protective effect against AAD. (1–6) There is even a Cochrane review (the highest standard in clinical research) concluding that probiotics have a protective effect in children taking antibiotics. (7) Only two meta-analyses included subanalyses focusing on the effect in elderly patients. (2,6) Neither one found a statistically significant effect, which would mean that probiotics do not protect elderly patients against AAD. However, when we look at randomized, placebo-controlled clinical studies with probiotics in elderly patients receiving antibiotics, a significant effect is shown in three out of the six RCTs published since 2006. (8–13) 

 

 

 

A Cochrane review (2015) concludes that probiotics have a protective effect in children taking antibiotics.

 

 

There are several possible causes for this difference. First of all, the efficacy of a probiotic depends on the bacterial strains it contains, because the properties of individual strains can differ, even if they share the same name. For instance, two probiotic products that both contain Lactobacillus acidophilus can affect the body in different ways if each product contains a different subspecies. When bacterial strains are selected that do not have the properties required to counteract AAD, the lack of any effect shouldn’t come as a surprise.

However, selecting the right strains is not the only factor, as efficacy also depends on the timing of the start of the probiotics treatment (concurrent with, halfway into, or following the course of antibiotics) or on dosage (low or high doses). Research has shown that the sooner probiotics treatment is started, the more effective it will be. (15) Other research has shown that a high dose (≥109 CFU) is more effective than a low dose (≤108 CFU). (16) The form of administration can also play a role in the efficacy of a probiotic. Is it a dairy-based product or a powder? Is the powder dissolved in a liquid or taken in capsule form? Are carrier substances and excipients used to help the bacteria survive the acid environment in the stomach to ensure they reach the gut alive? 

 

 

The sooner probiotics treatment is started, the more effective it will be

Capsules and dairy-based probiotics are held in the stomach longer than a powder dissolved in water taken on an empty stomach. Food and dairy create a higher stomach pH and that is beneficial for the probiotic bacteria, but the digestive enzymes and bile acid released when food enters the jejunum are not. Excipients that help them survive the stomach will ensure that more live bacteria make it to the gut to do their work there.

 

Finally, efficacy also depends on the number of different bacterial strains the probiotic product contains. Various studies have shown that a multispecies probiotic (a product containing multiple strains of different bacterial species) is more effective than a monostrain (containing a single bacterial strain) or monospecies (containing different strains of a single species) product. (17,18) 

Also, most of the studies did not take into account the type of antibiotic that was prescribed. The risk of AAD varies considerably between types of antibiotics. If a treatment group contained more people taking antibiotics with a high AAD risk than the control group, this would explain why no significant effect was found. Another consideration is that people can respond differently to antibiotics – some only get very mild or no diarrhoea, even if they are given an antibiotic with a high AAD risk. When participants’ risk of diarrhoea is low, a larger sample size will be required to be able to find an effect. In addition, the outcome measure (prevention of AAD or alleviation of AAD) may also be a deciding factor for the degree to which an effect is found. For instance, an RCT examining the effect of probiotics on the incidence of AAD in adults aged 18-70 found that the selected probiotic did not reduce the incidence of AAD but did reduce its duration. (19) 

 

 

 

 

Probiotics against AAD in elderly patients _917

 

 

All this can explain why only half of the RCTs found an effect in elderly patients. Another reason no effect was identified could be the small number of participants, resulting in an under- or overestimation of the effect. Performing a meta-analysis, in which participants of different studies are grouped together, will increase the likelihood of the real effect being identified. However, a drawback of a meta‑analysis focusing on probiotics is its considerable heterogeneity, in that it lumps together different types of participants (with and without health conditions, just turned 65 or almost 80 years old, etc.), types of probiotics, dosages and timing of the start of probiotics treatment. All of these elements influence the eventual outcome of an RCT. 

 

A biological explanation for no effect having been found in elderly AAD patients could be a change in their microbiota. The diversity and stability of the microbiota decline with age (20,21), with research showing that the microbiota in elderly people differs from that in under-65s. (22) There is a difference between the microbiota of healthy elderly people and that of vulnerable elderly people. (23,24) Polypharmacy, the concomitant use of several drugs, is another factor frequently seen in elderly patients. Some of these drugs may affect the microbiota as well, such as proton pump inhibitors omeprazole and pantoprazole that many elderly people use. (25) Also, some drugs are known to cause diarrhoea as a side effect, which probiotics will not be able to influence

 

 

There is a difference between the microbiota of healthy elderly people and that of vulnerable elderly people

In short, there are many different reasons why probiotics are found to be effective in some RCTs focusing on elderly patients with AAD and not in other RCTs. RCTs that did find an effect were those in which a multispecies product was used in high doses, which patients were started on within two days of starting antibiotics. Future studies may take more account of these elements and find a clearer effect as a result.

 

 

 

 

References

1. Avadhani, A. & Miley, H. Probiotics for prevention of antibiotic-associated diarrhea and Clostridium difficile-associated disease in hospitalized adults--a meta-analysis. J. Am. Acad. Nurse Pract. 23, 269–74 (2011).
2. Hempel, S., Newberry, S., Maher, A. & Wang, Z. Probiotics for the Prevention and Treatment of Antibiotic-Associated Diarrhea. JAMA (2012). at <http://www.kalbemed.com/Portals/6/komelibnew/2014/04/2012hempelProbioticsforthePrevention.pdf>
3. Videlock, E. J. & Cremonini, F. Meta-analysis: Probiotics in antibiotic-associated diarrhoea. Aliment. Pharmacol. Ther. 35, 1355–1369 (2012).
4. Pattani, R., Palda, V. A., Hwang, S. W. & Shah, P. S. Probiotics for the prevention of antibiotic-associated diarrhea and Clostridium difficile infection among hospitalized patients: systematic review and meta-analysis. Open Med. 7, (2013).
5. Szajewska, H. & Kołodziej, M. Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. Aliment. Pharmacol. Ther. 42, 1149–57 (2015).
6. Jafarnejad, S. et al. Probiotics Reduce the Risk of Antibiotic-Associated Diarrhea in Adults (18-64 Years) but Not the Elderly (>65 Years): A Meta-Analysis. Nutr. Clin. Pract. 0884533616639399 (2016). doi:10.1177/0884533616639399
7. Goldenberg, J. Z. et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst. Rev. Art. No.: CD004827 (2015). doi:10.1002/14651858.CD004827.pub4
8. Beausoleil, M. et al. Effect of a fermented milk combining Lactobacillus acidophilus Cl1285 and Lactobacillus casei in the prevention of antibiotic-associated diarrhea: a randomized, double-blind, placebo-controlled trial. Can. J. Gastroenterol. 21, 732–6 (2007).
9. Hickson, M. et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 335, 80 (2007).
10. Safdar, N., Barigala, R., Said, A. & McKinley, L. Feasibility and tolerability of probiotics for prevention of antibiotic-associated diarrhoea in hospitalized US military veterans. J. Clin. Pharm. Ther. 33, 663–8 (2008).
11. Allen, S. J. et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 382, 1249–1257 (2013).
12. Dietrich, C. G., Kottmann, T. & Alavi, M. Commercially available probiotic drinks containing Lactobacillus casei DN-114001 reduce antibiotic-associated diarrhea. World J. Gastroenterol. 20, 15837–44 (2014).
13. Wright, K., Wright, H. & Murray, M. Probiotic treatment for the prevention of antibiotic-associated diarrhoea in geriatric patients: A multicentre randomised controlled pilot study. Australas. J. Ageing 34, 38–42 (2015).
14. Ramos, C. L., Thorsen, L., Schwan, R. F. & Jespersen, L. Strain-specific probiotics properties of Lactobacillus fermentum, Lactobacillus plantarum and Lactobacillus brevis isolates from Brazilian food products. Food Microbiol. 36, 22–9 (2013).
15. Rehman, A. et al. Effects of probiotics and antibiotics on the intestinal homeostasis in a computer controlled model of the large intestine. BMC Microbiol. 12, 47 (2012).
16. Ouwehand, A. C. A review of dose-responses of probiotics in human studies. Benef. Microbes 1–10 (2016). doi:10.3920/BM2016.0140
17. Chapman, C. M. C., Gibson, G. R. & Rowland, I. Health benefits of probiotics: are mixtures more effective than single strains? Eur. J. Nutr. 50, 1–17 (2011).
18. Timmerman, H. M., Koning, C. J. M., Mulder, L., Rombouts, F. M. & Beynen, A. C. Monostrain, multistrain and multispecies probiotics--A comparison of functionality and efficacy. Int. J. Food Microbiol. 96, 219–33 (2004).
19. Chatterjee, S. et al. Randomised Placebo-controlled Double Blind Multicentric Trial on Efficacy and Safety of Lactobacillus acidophilus LA-5?? and Bifidobacterium BB-12 for Prevention of Antibiotic-Associated Diarrhoea. J. Assoc. Physicians India 61, 708–712 (2013).
20. Biagi, E. et al. Ageing and gut microbes: perspectives for health maintenance and longevity. Pharmacol. Res. 69, 11–20 (2013).
21. Rondanelli, M. et al. Review on microbiota and effectiveness of probiotics use in older. World J. Clin. cases 3, 156–62 (2015).
22. Claesson, M. J. et al. Composition , variability , and temporal stability of the intestinal microbiota of the elderly. 1–6 (2010). doi:10.1073/pnas.1000097107
23. van Tongeren, S. P., Slaets, J. P. J., Harmsen, H. J. M. & Welling, G. W. Fecal microbiota composition and frailty. Appl. Environ. Microbiol. 71, 6438–42 (2005).
24. Claesson, M. J. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–84 (2012).
25. Jackson, M. A. et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 65, 749–56 (2016).

 

 

 

Probiotics against AAD in elderly patients

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