Probiotics. Objectives: AusPharm gratefully acknowledges the financial support provided by the sponsors of our CPD program, MIMS

Transcription

1 Probiotics Probiotics or good bacteria are live micro-organisms, such as bacteria or yeast, which when taken in large enough quantities, are claimed to improve and maintain the health of the gastrointestinal tract. Probiotics are thought to improve the balance of organisms that inhabit the gut, counteract disturbances to this balance, and reduce the risk of colonisation by pathogenic bacteria. The World Health Organisation defines probiotics as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host". Objectives: After completing this activity, pharmacists should be able to: List the conditions for which good evidence of efficacy for probiotics exists Detail the strains of probiotics most efficacious for various conditions Counsel consumers on the efficacy and benefits of probiotics Construct a therapeutic trial with consumers. This activity has been accredited for 1 hour of Group One CPD (1 CPD Credit) that may be converted to 2 Group Two CPD Credits upon successful completion of the corresponding assessment for inclusion on an individual pharmacist's CPD Record. Accreditation number: A14049AP0. The competency standards addressed by this activity include (but may not be limited to) 6.2.2, 6.3.1, Author: Debbie Rigby B.Pharm, Grad Dip Clin Pharm, Adv Dip Nutr Pharm, CGP, AACPA, ASCP, FPS Debbie Rigby is a consultant clinical pharmacist from Brisbane. Since graduation with a Bachelor of Pharmacy from the University of Queensland she has since obtained a Graduate Diploma in Clinical Pharmacy, Certification in Geriatric Pharmacy, Advanced Diploma in Nutritional Pharmacy and certification as an Asthma Educator. Debbie is the Chair of the Australian Association of Consultant Pharmacy (AACP) Board and member of the National Advisory Group of AACP, as well as a Director of the National Prescribing Service (NPS) Board. Debbie is also a Fellow of PSA and the American Society of Consultant Pharmacists (ASCP). Academic appointments include Adjunct Senior Lecturer at University of Queensland and James Cook University. She is also on the Australian & New Zealand Continence Journal Editorial Committee. Debbie has a special interest in geriatric pharmacotherapy and chronic disease self-management, regularly conducts medication review services as an accredited pharmacist and provides many presentations to pharmacists, nurses, general practitioners, allied health professionals and consumers. In 2001 Debbie was awarded the PSA Australian Pharmacist of the Year, in 2002 the PSA Qld Bowl of Hygeia and in 2008 was the inaugural recipient of the AACP Consultant Pharmacist Award. AusPharm gratefully acknowledges the financial support provided by the sponsors of our CPD program, MIMS

2 Probiotics Introduction Probiotics or good bacteria are live micro-organisms, such as bacteria or yeast, which when taken in large enough quantities, are claimed to improve and maintain the health of the gastrointestinal tract. Probiotics are thought to improve the balance of organisms that inhabit the gut, counteract disturbances to this balance, and reduce the risk of colonisation by pathogenic bacteria. The World Health Organisation defines probiotics as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host". Prebiotics such as oligofructose, fructo-oligosaccharides and inulin are found in non-digestible food ingredients (e.g. onions, garlic, asparagus, leeks, artichoke, bananas, tomatoes, oats, soy beans) that may benefit the host by selectively stimulating the growth of particular intestinal flora. Probiotics and prebiotics are sometimes combined in one preparation - so-called "synbiotics". Challenges for community pharmacists in providing advice to consumers on the use of probiotics include a wide diversity of products and claims on the market, direct-to-consumer advertising, variances in quality control, stability and formulations of products, and the requirement to match the type of probiotic with the disease indication. The efficacy of probiotics has been shown to be both strain-specific and disease-specific. Therapeutic trial It is well acknowledged that many complementary medicines lack high quality evidence of efficacy and safety, and some have evidence of no efficacy. If a consumer wishes to use probiotics, pharmacists can help them construct a therapeutic trial, with specific and measurable outcomes that are time-limited. A time period, which may be supported by evidence or guided by the quantity in the product, should be discussed to help avoid unnecessary costs and continuation of therapy with no discernable benefit. It may be helpful to keep a diary to determine any benefit, and side effects. Sources Probiotics are commonly consumed as part of fermented foods with specially added active live cultures, such as in yogurt, acidophilus milk, some cheeses, buttermilk, fermented cabbage (sauerkraut, kimchi), tempeh, miso and kefir; or as dietary supplements. Probiotics are defined by its genus (e.g. lactobacillus), species (e.g. rhamnosus) and strain (e.g. GG). Strains of Bifidobacteria and Lactobacilli are found naturally in breast milk and thought to contribute to normal gut development and function. In newborns, bifidobacteria make up 95% of the gut s microbial population but this decreases to 25% in adults. Strains of Lactobacillus and Bifidobacterium bacteria are the most commonly used probiotics as they can survive the passage to the gut and form part of normal healthy intestinal flora. Saccharomyces boulardii and cereviciae are probiotic yeasts.

3 Common uses Reported uses for probiotics include: Acute infectious diarrhoea Travellers diarrhoea Antibiotic-associated diarrhoea Irritable bowel syndrome Inflammatory bowel disease (ulcerative colitis, pouchitis and Crohn s disease) Probiotics may help prevent traveller s diarrhoea and diarrhoea caused by antibiotics, and are used in the treatment of acute infectious diarrhoea. Lactobacillus rhamnosus GG and S. boulardii strains have been shown to be most effective for these conditions. There is also found some evidence to support use of S. boulardii probiotics in prevention of Clostridium difficile disease recurrences, giardiasis, human immunodeficiency virus-related diarrhoea. 1 Genitourinary infections Marketing claims for the use of oral probiotics in treating genitourinary infections such as vaginal thrush and urinary tract infections (UTIs) are not supported by evidence, 2 however they may be beneficial for the treatment of patients with recurrent bacterial vaginosis. 3 Healthy vaginal flora is heavily colonised by Lactobacillus. Lactobacillus produce lactic acid to maintain the acidic environment of the vagina and inhibit the growth of pathogens. Probiotics promoted for vaginal health contain Lactobacillus species such as L. acidophilus, L. rhamnosus, and L. reuteri. So if women want to have a therapeutic trial of probiotics, pharmacists should suggest a product that contains Lactobacillus strains. A 2004 Australian randomised controlled trial (RCT) of 235 women did not support use of oral or vaginal forms of Lactobacillus to prevent post-antibiotic vulvovaginitis, usually caused by Candida albicans. 4 In this trial participants administered an oral powder (containing L. rhamnosus and Bifidobacterium longum), a vaginal pessary containing (containing L. rhamnosus, L. delbrueckii, L. acidophilus, and Streptococcus thermophilus) or placebo during antibiotic therapy and for 4 days afterwards (10 days). Escherichia coli is the predominant pathogen in UTIs, with other pathogens such as Staphylococcus saprophyticus, E. faecalis, and occasionally gram negative bacteria Klebsiella pneumoniae and Proteus mirabilis. The results of studies of lactobacilli for the prophylaxis of recurrent UTIs in women are inconclusive. 2 Acute infectious diarrhoea Acute infectious diarrhoea is defined as more often than usual bowel movements lasting 10 to 14 days. Probiotics of proven efficacy in this condition include products containing Lactobacillus casei ssp. L. rhamnosus (GG) and S. boulardii. Probiotics appear to be a useful adjunct to rehydration therapy in treating acute, infectious diarrhoea in adults and children. 5 Use of probiotics with acute diarrhoea may reduce stool frequency and shorten the duration of symptoms by 30 hours. 5 There is mounting evidence for L. reuteri as an adjunct to rehydration therapy is efficacious in the treatment of acute diarrhoea reducing the frequency a and duration of symptoms in children. 6

4 However, more research is needed to inform the use of particular probiotic regimens in specific patient groups. Travellers diarrhoea Traveller s diarrhoea is usually a self-limiting condition that clears up after a few days. It is often caused by eating contaminated food or water/ice, so high risk foods such as raw fruits and vegetables, raw, rare or undercooked meats of any kind, seafood, dairy foods, food from street vendors and food from buffets should be avoided. Boil it, cook it, peel it or forget it E. coli is the most common aerobic commensal in vertebral gut; however some strains are pathogenic and cause severe bloody diarrhoea. Salmonella and Campylobacter appear to be increasing in importance in Asia. Therapeutic Guidelines does not recommend chemoprophylaxis for healthy travellers, including children. While there is evidence for prevention, use of probiotics for treatment of acute traveller s diarrhoea is not recommended. The most commonly used probiotics for traveller's diarrhoea protection are lactobacillus species and S. boulardii. 7 Pharmacists should recommend lyophilised products that are stable at room temperature for travellers. A meta-analysis of 12 studies concluded that probiotics prevent 85% of cases of traveller s diarrhoea, but there was inconsistency between studies, with variability across populations of travellers and destinations. 8 For example, in a study of S. boulardii, travellers to North Africa showed a benefit whereas travellers to South America did not. A recent double-blind, placebo-controlled trial of a synbiotic showed no difference between rates of traveller's diarrhoea between groups and no decrease in the use of antibiotics for treatment. 9 Antibiotic-associated diarrhoea Antibiotic treatment may disturb the balance of organisms that normally inhabit the gut, leading to diarrhoea in up to 44% of patients. 10 Antibiotic-associated diarrhoea (AAD) is usually a mild and self-limiting illness. Good evidence exists to support using probiotics with S. boulardii and L. rhamnosus GG to prevent antibiotic-associated diarrhoea, with emerging evidence for certain mixed strains that include L. casei or L. acidophilus. 11 A systematic review and meta-analysis of 63 trials found that probiotics were associated with a 42% reduction in the risk of diarrhoea. 12 The majority of trials used Lactobacillus based interventions alone or in combination with other genera such as Bifidobacterium. Sixteen studies used S. boulardii exclusively, which showed a pooled relative risk (RR) of The quality of the included trials was low, with most trials not showing a statistically significant advantage of probiotic use. The number needed to treat (NNT) to prevent one episode of antibiotic-associated diarrhoea was 13. A systematic review and meta-analysis of S. boulardii in adults found a significant therapeutic efficacy in the prevention of antibiotic-associated diarrhoea (RR = 0.47, 95% CI: , P < 0.001). 13 S. boulardii also reduces the risk of antibiotic-associated diarrhoea in children. 14 However, there is insufficient evidence to support routinely using probiotics for prevention of antibioticassociated diarrhoea. Because of the low incidence and generally mild severity of antibiotic associated diarrhoea in otherwise healthy people, routine use of probiotics in all people taking antibiotics to prevent antibioticassociated diarrhoea is not recommended. Routine use with antibiotics may be justified in frail patients in hospital

5 and possibly in children. 11 People who have previously had antibiotic associated diarrhoea may be offered probiotics when they are treated with antibiotics, regardless of setting, but probiotics should be avoided in people who are seriously immunocompromised. As probiotics seem more effective at higher doses, doses of at least 50 billion colony forming units (CFU) should be used; probiotics should be taken for the duration of antibiotic treatment and continued for a week thereafter. 11 When making recommendations to consumers, pharmacists should check the contents of various products as many of the popular products do not contain this dose. Clostridium difficile-associated diarrhoea Clostridium difficile is one particularly dangerous organism that may colonise the gut if the normal healthy balance has been disturbed with use of antibiotics. Infection with C. difficile causes diarrhoea and colitis, and less commonly toxic megacolon, colonic perforation and death. About a third of cases of antibiotic-associated diarrhoea are due to C. difficile. Clostridium difficile may be present in the guts of 5 percent of healthy adults, 15% to 70% of neonates 15 and over 50 percent of residents in aged care facilities. Although many antibiotics have been implicated, broad spectrum agents such as ampicillin, amoxycillin, third or fourth generation cephalosporins and clindamycin are most commonly implicated. Cumulative antibiotic exposure increases risk. Previously thought to be only associated with hospitals, C. difficile infection (CDI) can also be acquired in the community and in out-patient settings. 16 Symptoms, most notably, diarrhoea, can occur at any time during, or up to some months after, a course of antibiotics. CDI usually occurs 5 to 10 days after commencing antibiotic therapy, although symptoms have been described as early as 2 days and as late as 10 weeks after antibiotic treatment. 17 Clostridium difficile-related disease varies from asymptomatic infection, diarrhoea, colitis, and pseudo-membranous colitis to death. Current or previous (within 10 weeks) antimicrobial use is the major risk factor for C. difficile. Avoiding inappropriate antibiotic therapy prevents C. difficile in individual patients. 18 Other risk factors for C. difficileassociated diarrhoea (CDAD) include: 18 Use of proton pump inhibitors and H2-receptor antagonists Current or recent hospitalisation (within 2 months) Chemotherapy Older age Medical comorbidities Precious C. difficile infection, especially relapsed disease Use of diclofenac Proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) substantially raise the risk of CDI. 19 People with depression and depressive disorders are at an increased risk of CDI. 20 Certain antidepressants such as mirtazapine and fluoxetine may also increase risk of infection. 20 A recent Cochrane review (23 trials, 4213 participants) concluded that probiotics are both safe and effective for preventing CDAD. 21 In this systematic review probiotics reduced the risk of CDAD by 64% (2% vs 5.5%), preventing 35 episodes per 1000 patients treated.

6 Irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterised by intermittent abdominal pain or discomfort and accompanied by a change in bowel habit. Some patients report urgency of defecation and painless diarrhoea while others complain of constipation. The evidence from clinical trials and systematic reviews are largely supportive of the use of probiotics in IBS, but only for specific strains. 22 However, studies are often limited because the products studied are not a single species or strain but combinations. Most of the meta-analyses indicate a beneficial impact of probiotics on global symptoms, abdominal pain and flatulence, whereas the impact on bloating was equivocal. 22 There is moderate evidence for probiotics for the relief of overall symptoms in patients with diarrhoeapredominant irritable bowel syndrome (IBS); but there is less evidence with constipation-predominant IBS. 23,24 A multi-centre, randomized, double blind, controlled trial evaluated the effect of a probiotic vs non-probiotic dairy product on symptoms in IBS with a constipation element. 25 Seventy-six patients (43 active, 33 placebo) were randomized to consume dairy 'yoghurt' products which either did or did not contain active probiotics (Bifidobacterium animalis) twice daily and to complete a daily diary over 12 weeks. Significant improvements were reported for most outcomes in all trial participants in both the control and active arms; therefore this trial did not provide evidence for effectiveness of probiotics over placebo in IBS. Probiotics should be recommended as adjunctive therapy to routine care such as diet including a low FODMAP diet, exercise and stress management. 26 Adverse effects Probiotics appear to be safe and effective when used as an adjunct to antibiotics in immunocompetent patients, but should not be used in residents who are severely ill or immunocompromised due to the risk of probiotic sepsis. The most common adverse events include abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance (decreases with repeated use). Saccharomyces sp can cause constipation. A simple approach to minimising the most bothersome side effects (generally bloating and flatulence) is to start slowly, dosing every second day until bloating settles. Dose The strains contained in probiotic products vary considerably, often containing multiple species and in differing doses. The dose of probiotics is usually given as the number of colony forming units (CFU). A CFU is an estimate of viable bacterial or fungal numbers in a probiotic at the end of shelf-life. In general, at least 10 billion CFU is required; however, different probiotics have been shown to be effective at different levels. The high doses required is generally a reflection that probiotics are acid labile and the transient nature of the bacteria in the gut. Many only persist for up to 7 days and few actually colonise the bowel after oral administration. L. reuteri can persist longer and even colonise the bowel and perhaps requires lower dosing and thus less bloating.

7 Limitations Whilst some good evidence exists to use of probiotics in the prevention and treatment of various conditions, there are still questions on how different probiotics compare in safety and effectiveness. It is also uncertain what the best length of time to take them is. Effects of probiotics are strain- and disease-specific, so that benefits reported with one product may not apply to others. However if a global view is taken to the data, a general recommendation for patients interested in taking probiotics for bowel health would be that it probably does not matter what probiotic they take as long as the dose is optimal. It is also important to recognise that, in general, probiotics do not colonise the bowel to a great extent. Therefore after about a week they have been cleared from the bowel. Patients may need to keep taking probiotics to maintain benefit. Summary Many trials on probiotics are of poor quality and type of probiotic tested, study populations, and effect sizes varied widely between studies. It is hard to know the precise mix of micro-organisms that is likely to work best and the characteristics of patients most likely to benefit. More research is necessary to determine which probiotics are associated with the greatest efficacy. Working with consumers to construct a therapeutic trial will help identify the usefulness of a product, identify safety issues and avoid unnecessary ongoing expense if no benefit is gained. Probiotics may be useful in preventing and treating antibiotic-associated diarrhoea, in particular C. difficile infections, and in treating diarrhoea-predominant irritable bowel syndrome. Avoiding inappropriate antibiotic therapy and proton pump inhibitor use reduces to risk of C. difficile infection. The relative efficacy of probiotics may be strain specific. A more concentrated dose of probiotics generally gives better therapeutic results. Probiotics are usually well tolerated. Pharmacists should recommend probiotic brands from reputable manufacturers with procedures in place that ensure strain specificity during production. Cold chain should be maintained throughout the product lifecycle. Probiotic products containing microbes indicated as acid and bile stable are preferred.

8 MCQs Questions based on the above article: Select ONE alternative that best represents the correct answer to each of the following multiple choice questions 1. According to the best available evidence, which of the following conditions has the least evidence of efficacy for probiotics? a. Vaginal thrush b. Irritable bowel syndrome c. Antibiotic-associated diarrhoea d. Travellers diarrhoea 2. In which patients should probiotics not be used? a. Patients who are severely immunocompromised b. Children c. Patients taking antibiotics d. Patients with inflammatory bowel disease 3. All of the following are considered a risk factor for Clostridium difficile-associated diarrhoea, except: a. Recent use of antibiotics b. Recent hospitalisation c. Younger age d. Use of proton pump inhibitors 4. Which of the following is INCORRECT about Clostridium difficile infection? a. Probiotics are effective in preventing Clostridium difficile-associated diarrhoea b. Judicious use of antibiotics will reduce the incidence of Clostridium difficile infection c. Depression increases the risk Clostridium difficile infection d. Clostridium difficile infection is only acquired in hospitals 5. When considering the appropriateness of a product for a particular condition, which of the following aspects should be considered? a. Probiotics with multiple species may be better than those with a single specie b. Whether a specific strain was clinically studied for that condition c. Dose of specific strain d. All of the above

9 References 1 McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adults. World J Gastroenterol. 2010;16(18): Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clin Ther. 2008;30(3): Abad CL, Safdar N. The role of lactobacillus probiotics in the treatment or prevention of urogenital infections--a systematic review. J Chemother. 2009;21(3): Pirotta M, Gunn J, Chondros P, Grover S, O Malley P, Hurley S, et al. Effect of lactobacillus in preventing postantibiotic vulvovaginal candidiasis: a randomised controlled trial. BMJ 2004;329: Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010;(11): CD Francavilla R, Lionetti E, Castellaneta S, Ciruzzi F, Indrio F, Masciale A, et al. Randomised Clinical Trial: Lactobacillus reuteri DSM vs. Placebo in Children With Acute Diarrhoea. A Double-Blind Study Aliment Pharmacol Ther. 2012;36(4): DuPont HI, et al. Expert review of the evidence base for prevention of travelers' diarrhea. Journal of Travel Medicine 2009; 16: McFarland LW. Meta-analysis of probiotics for the prevention of traveler's diarrhea. Travel Medicine and Infectious Disease 2007; 5: Virk A, et al. A randomised, double blind, placebo-controlled trial of an oral symbiotic for prevention of travelers' diarrhea. Journal of Travel Medicine 2013; 20: Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granstrom G, Lagergren L, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001;47: Butler CC, Duncan D, Hood K. Does taking probiotics routinely with antibiotics prevent antibiotic associated diarrhoea? BMJ 2012;344:e Hempel S1, Newberry SJ, Maher AR, Wang Z, Miles JN, Shanman R, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;9;307(18): McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adults. World J Gastroenterol. 2010;16(18): Kotowska M, Albrecht P, Szajewska H. Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: a randomized double-blind placebo-controlled trial. Aliment Pharmacol Ther. 2005;21(5): Hamm L. Clostridium difficile. Pediatr Pharm. 2000;6(6). Available at [Accessed 3 March 2014]. 16 Chitnis AS, Holzbauer SM, Belflower RM, Winston LG, Bamberg WM, Lyons C, et al. Epidemiology of Community- Associated Clostridium difficile Infection, 2009 Through JAMA Intern Med. 2013;173(14): Cheng AC, Ferguson JK, Richards MJ, Robson JM, Gilbert GL, McGregor A. Australasian Society for Infectious Diseases guidelines for the diagnosis and treatment of Clostridium difficile infection. Med J Aust 2011;194: McFarlane M, Hajkowicz K. Controlling Clostridium difficile. Aust Prescr 2013;36: Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012;107: Rogers MA, Greene MT, Young VB, Saint S, Langa KM, Kao JY, et al. Depression, antidepressant medications, and risk of Clostridium difficile infection. BMC Med 2013;11: Goldenberg JZ, Ma SSY, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD

10 22 Whelan K, Quigley EM. Probiotics in the Management of Irritable Bowel Syndrome and Inflammatory Bowel Disease. Curr Opin Gastroenterol. 2013;29(2): Whelan K. Probiotics and prebiotics in the management of irritable bowel syndrome: a review of recent clinical trials and systematic reviews. Curr Opin Clin Nutr Metab Care 2011; 14: Hungin AP, Mulligan C, Pot B, Whorwell P, Agréus L, Fracasso P, et al; European Society for Primary Care Gastroenterology. Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice - an evidence-based international guide. Aliment Pharmacol Ther. 2013;38(8): Roberts LM, McCahon D, Holder R, Wilson S, Hobbs FD. A randomised controlled trial of a probiotic functional food in the management of irritable bowel syndrome. BMC Gastroenterol. 2013;13: McKenzie YA, Alder A, Anderson W et al. British Dietetic Association evidence-based guidelines for the dietary management of irritable bowel syndrome in adults. J Hum Nutr Diet 2012;25: