Dietary Supplements To Prevent Recurrent UTI: The Evidence

good morning everyone we'll get started this morning it's my pleasure this morning to introduce Chris as she's previously presented with us but she's our urogynecology fellow and the topic this morning is going to be supplements and supplements focused on lower urinary tract infection thanks to studies so I want to thank you for attending this talk it's a decidedly non-surgical topic and so I'm grateful for your interest just a brief outline I'll be talking about just very briefly the epidemiology of your lower urinary tract infections and the pathophysiology as it relates to the use of dietary supplements I'll then talk about supplements including definitions and some of the Food and Drug Administration guidelines and then talking in depth about cranberry and probiotics and then touching on some of the other supplements that may be less familiar to you and then finally discussing the recommended recommendations if any that we can give to our patients regarding prophylaxis of urinary tract infections with dietary supplements so you are probably all familiar with greetings publications in 2005 looking at some of the economical costs of urinary tract infections and the estimated annual cost in both men and women is approximately three and a half billion u.s. dollars which is a huge economic burden let alone the morbidity that it causes to our patients we also know that females are more susceptible to lower urinary tract infections than men in the order of about fifty to one and that'll their lifetime risk of a single urinary affection episode in women is approximately 50% so moving on to the pathophysiology yura pathogenic organisms predominantly in coli colonized the peri urethral tissue and then ascends up the urethra into the normally sterile bladder and studies have shown that Ecola causes the majority of these your new tract infections in the adult population the first step in terms of causing infection is adherents of the pathogenic organisms to the uro epithelial cells and this bacterial adhesions facilitated by embryo which other proteinaceous fibers on the bacterial cell wall ecoli exhibit either type 1 or type P or P type fimbria type 1 if embryo bind to Manos like receptors which will become more relevant as the talk progresses and then pick the P type embryo bind to different receptors on the uro epithelial cell wall so this is just a schematic diagram of how infection occurs the e.coli attached to the surface of the epithelial cell and then by process involving secretory lies ohm's they invade the cell where they form by replication large biofilm like intracellular bacterial communities and this provides some protection against the action of antibiotics at some point in time the bacteria then flux out of the intracellular bacterial communities as some of them adopting these filamentous morphologies which allows them to actually avoid engulfment by the neutrophils and then the cycle is repeated so why are we interested in supplements the risk of recurrence within a year of the index case particularly in the female population is almost close to 50% and this is in the presence of appropriate antibiotic therapy as well as negative post treatment cultures and this is probably where those intracellular bacterial communities play a role we also know that antibiotic prophylaxis works either on a low dose continuous basis or post-coital II in the female population but there is the problem of emerging antibiotic resistance particularly for the trimethoprim ins sulfamethoxazole antibiotics as well as the fluoroquinolones this emerging resistance makes non-antibiotic alternatives to prophylaxis attractive but we need to keep in mind that we need to approach these alternative alternative prophylactic treatments with the same scientific rigor that we apply to traditional preventative macomb procedures so what is a supplement according to Health Canada it can be pretty much anything so it can be a plant and algae bacterium fungus can be vitamins amino acids essential fatty acids minerals or probiotics and that they need to supplement the diet and this definition varies quite significantly from country to country the Food and Drug Administration presented the dietary supplement health and education Act in 1994 basically stating that they had very little role in terms of reviewing the safety and efficacy of these dietary supplements and that it was largely the manufacturers responsibility to ensure that dietary supplements were safe before they were marketed and then other than the manufacturers responsibility to ensure safety there was really no rule that limited the serving size or the amount of any nutrient in the dietary supplements and the FDA aren't required to review or approve this prior to the manufacturer marketing the product however in June of this year the FDA will put into place a good manufacturing practice for dietary supplements trying to standardize the way in which dietary supplements are actually produced and also mandating reporting to the FDA of any serious dietary supplement related adverse events which is probably long overdue the other reason that we're into should be interested in dietary supplements is that it's not infrequent that when you ask patients whether they're taking anything that they will actually state that they're on some form of herbal preparation that they've received from the natural health store and most of the time they don't have it with them if they do you might be lucky to actually be able to read the contents but you may be completely unaware of what those ingredients are apart from the fact that many of our patients may be wasting their money we also need to be aware of what they're taking because of the potential adverse effects that these supplements may have on the patient's health and also we need to be aware of how they interact with the sort of standard pharmaceuticals that we may want to prescribe to our patients so now we're going to talk about various supplements I love this slide it basically depicts the harvesting process of cranberries and this is a cranberry bog in Richmond and the way that how cranberries are harvested is that they're grown in the fields and then the fields are flooded the bushes are beaten by a machine and then the berries because they're largely air-filled they float to the surface of the water and then are harvested by hand that way vaccinium macro carbon is the chemical other biological name for cranberry it's also known as American cranberry it's been historically used for many medical disorders and then since about the 1800s has been documented for use in the treatment of bladder disorders it's a huge industry so for 2008 Ocean Spray posted earnings of 1.9 billion u.s. dollars 90 percent of the world's annual production comes from the states and then approximately 10 percent from Canada most of the berries are used for juice initial studies looking at the role of cranberry in urinary tract health focused on the potential role for urinary acidification Queenie Cassidy's the precursor of hippo ricasso which is a known bacteriostatic agent but it also lowers pH one of the earlier studies published in the late 70s showed that there was a significant bacteriostatic effect of cranberry related to urinary pH but it required the ingestion of large amounts of essentially pure cranberry juice which is given it's low pH of 2.5 is almost unpalatable and then subsequent studies didn't reproduce these results so now it's generally accepted that iourney acidification isn't the major factor that's responsible for it and our cranberries effects subsequent to that studies have looked at the anti adherents properties of cranberry so basic science studies have shown and he adherence properties and then these have been translated to human studies following these studies then the search was on for what was the actual compound in cranberry that produced these results one of the components of cran B that's been investigated is fructose it inhibits the type 1 which is a menos specific receptors fimbriated ecoli in vitro but there haven't been any in vivo studies to support this use subsequent to that in the last two decades the focus now has been on the proanthocyanidins and these are derived from the skin of the cranberry prior no cyanide ins a flavonoid compounds that occur in ten enriched foods and they're conjugated dimers and trimers of the anthocyanidins the PA C's that come from cranberry is special in that they exhibit these eight hyped linkages and these give the cranberry PA C's superior anti adherence properties compared to the PA CS that are found in other things such as apples grapes and green tea they inhibit in adhesion of PF embryo to de colo but they also inhibit adhesion of other gram-negative bacteria and they do this by either competitively binding to the FEM RIA and this is a non reversible binding or they reduce the adhesion capabilities by altering the PF embryo and it's been shown that they actually shorten the FEM bre on the e-coli unfortunately in cranberry PA sea levels are related to pH temperature and light and so studies have shown that the PA see content degrades significantly with rising temperature and also with exposure to light and this has an impact in terms of how we deliver PA CS to our patients with respect to the pharmacokinetics of PA CS I haven't been well studied in the in the human population but the studies that we do have show that pkuran EPA C concentrations are seen at about 3 to 6 hours after ingestion and usually excretion is completed by 12 hours so this provides the rationale for the twice daily dosing of cranberry products only a small amount is actually excreted into the urine there's also being colonic excretion exhibited and this raises the potential role for selection of non-pathogenic Ecola in the gut as well cranberry can be provided in pure juice and as I mentioned pure juice is very acidic so it usually has to be diluted and sweetened cranberry juice cocktail can be bought in the supermarket it's most commonly around twenty five to twenty five seven percent concentrated and it's sweetened either artificially or with natural sugar and then it can also be presented in the form of tablets and capsules so now we move on to the evidence the Cochrane systematic reviews published their review in 2008 which is an update from their 2004 of you may identified ten randomized control trials seven looked at juice versus placebo water two was studying the tablet form versus placebo and then one study which was doctor studies study looked at juice tablets and placebo only four out of the 10 studies were actually included in a meta-analysis the other six studies weren't included because of methodological issues or lack of available data but only one of those six that were excluded from the meta-analysis reported significant results with respect to symptomatic UTIs so of the four that was included in the meta-analysis a significantly decreased risk of UTI incidents over a 12-month period was noted and this was a 34% risk reduction women who had had previous year new tract infections had a greater risk reduction than those other populations such as men older women and patients with neurogenic bladder subsequent to that review there have been three other randomized control trials published and I'll go through these the first one was a randomized control trial using research-grade cranberry juice cocktail at a concentration of 27 percent versus placebo and they used a multi dose regime initially they used once-daily versus three times a day dosing but due to compliance issues they had to drop this down to twice daily dosing the study was looking at pregnant women who were recruited in the first or early second trimester and their primary outcome was either asymptomatic bacteriuria or a symptomatic urinary tract infection they did not show a significant reduction in UTI risk however unfortunately despite the excellent study design they were only able to achieve a 61% can and this was largely due to dropouts secondary to GI upsets in in this pregnant population so they ended up being underpowered to show any difference in UTI incidents the next study was a randomized control trial looking at the capsule form of cranberry versus low-dose prophylactic trimethoprim for six months these were women who were classified as older women with recurrent me urinary tract infections and the primary outcomes were antibiotic treated you a new tract infection and time to that UTI they found actually an increased risk for urinary tract infection in the cranberry treated group but this was not statistically significant and their time to UTI was not different between the two groups so the authors concluded given that they were adequately powered that they felt based on this study that cranberry was equivalent or as effective as trimethoprim in terms of prophylaxis but this was not designed as an equivalent study so I'm not sure how relevant those findings are then last study is in a completely different population so these were spinal cord injured men who had bladder emptying by various techniques and the design was across over trial looking at cranberry captioning versus placebo their primary outcome with symptomatic urinary tract infection and in fact they did find a statistically significant decrease in UTI incidence in the cranberry treated group over that complete 12-month treatment period there are many limitations to the currently published literature it's very difficult to compare results between studies because there's no universally accepted standard method of quantifying the POCs in these commercially produced cranberry products and there's currently no requirement to state what the PA C content is so when the NIH we're looking at developing research grade cranberry juice and cranberry cranberry tablets they actually tested some of the commercially available products and found that the cranberry tablets varied significantly in terms of their PA C content from being quite similar to pure juice to having essentially undetectable levels there's also been no objective measure of adherence to treatment such as measuring the urinary output of PA C's there's been no systematic evaluation of the frequency of dose administration or the dose response relationship and each study uses different outcomes and different definitions for urinary tract infection with respect to colony count and what constitutes a symptomatic urinary tract infection the studies vary in duration of follow-up and a lot of them have higher withdrawal rates secondary to the GI symptoms so apart from GI upset there are very few adverse events published in the literature there has been some concern about the interaction of cranberry with warfarin as cranberry has been shown to inhibit the activity of one of the cytochrome p450 ISO enzymes there have been case reports detailing increased I&R in patients who have been taking cranberry products concurrently but subsequent to those case reports two randomized control trials didn't support that so currently in the absence of definitive evidence patients who are on both cranberry and INR should be monitored carefully with respect to their iron ours there was also some concern about stone formation in patients who take lots of cranberry products due to the high levels of oxalate there are conflicting results in the literature these are very small studies in the order of five to twenty patients and as you can see in one study they noted an increased urinary excretion of oxalate but also an increase in the stone inhibitors magnesium and potassium and then in another study it appeared that cranberry was potentially protective for stone formation so now I'd like to talk about probiotics what are they they're live microorganisms which confer a health benefit to the host that can be either bacteria or yeast and they're often found in dairy products or probiotic fortified foods they can also be found in freeze-dried form so in tablets capsules or powders I'll be speaking put on basically about lactobacilli which are anaerobic gram positive bacteria and they are the predominant bacteria that are found in the general floor of healthy premenopausal women you may be aware of some of the lactobacilli that marketed for intestinal health but for obvious reasons I'll just be talking about the highlighted ones because they are the ones that have been shown in studies to benefit urogenital health how might they work in terms of preventing urinary tract infection well the lactobacillus cell produces a many different products by product so the bio surfactants are thought to inhibit adhesion the acids and the hydrogen peroxide inhibit growth and the co a group co egg so in co aggregation molecules blocked the spread of the pathogens they've also been shown to competitively bind to vaginal epithelial cells and compete for the nutrients women with the history of recurrent urinary tract infections have altered virginal flooring that they've been shown to have reduced presence of lactobacillus species and they've also been shown to have prolonged vaginal colonization with the Euro pathogens predominantly the e.coli so theoretically we could use probiotics to return the abnormal flora to normal vaginal flora thereby inhibiting overgrowth of the Europe pathogens preventing Perryville colonization with these euro pathogens and thereby hopefully preventing recurrent urinary tract infections so what's the evidence there isn't a lot most of the studies have focused on this combination of lactobacillus species they've been shown to once again adhere competitively to the vaginal epithelial cells to have bacteriostatic properties and the lactobacillus momentum produces these surface active proteins which also prevent adhesion for these probiotics to be clinically effective we need to be able to change the vaginal flora irrespective of the route of administration so both oral and vaginal administration has been shown to result in conversion of abnormal to normal vaginal flora and this change has been shown to persist weeks after administration of the probiotic these were the only randomized control trials that I was able to find looking at this particular combination of lactobacilli so the first one was a randomized controlled trial of lactobacillus rhamnosus and ferment 'm given vaginally on a weekly basis versus lactobacillus growth factor for a period of 12 months in 55 premenopausal women the primary outcome was Ti incidents the the study didn't find any difference between the two groups but there was a significant difference for both groups in terms of reduction in UTI incidents from before the study was started to at the end of the study period the next study looked at both antibiotic treatment and then probiotic prophylaxis so this was a randomized control trial of North locsin or septa for three days to treat a culture proven urinary tract infection and then the use of the probiotic for John Lee versus placebo they looked at pre menopausal women who had a urinary tract infection and their primary outcome was bacterial eradication for the antibiotic phase of the study and then UTI recurrence for the probiotic phase of the study they didn't find any difference between the antibiotic groups so they believe that both antibiotics were effective in treating the infection and that there was no significant difference in the recurrent UTI right between the probiotic versus placebo but as you can see the absolute percentages are quite different and it's likely that this study was underpowered to actually show a difference and in the last study I've just put in there for completeness sake but it didn't find a statistically significant result and the author's themselves commented that the strain that they had used had not actually been demonstrated to inhibit in e.coli in vivo sorry in vitro so I'm not exactly sure why they chose that particular preparation their next probiotic that I wanted to talk about is L Chris partes and the reason I'm talking about is not because it has a lot of literature but supporting its use currently but it is one of the preparations that are currently involved in a randomized control trial so this has been shown to strongly adhere to vaginal epithelial cells once again and lowers the pH of the vaginal environment and this is the only study that I've been able to find with respect to this particular probiotic and was published in 2006 and this was a before-and-after study of nine women with a history of recurrent urinary tract infection and they were given this vagina preparation twice a week for one year and they found a statistically significant difference in the UTI incidents through five UT ARS per patient year prior to the study to 1.3 per patient year following the study adverse events of probiotics are very rare they relate primarily to systemic infection in immunocompromised patients so now just very briefly talking about the various other supplements that are often found in the preparations that your patients may be on oversea is also named bearberry the active component is in the leaves and they contain our beautified the beauty side is ingested and hydrolyzed in the gut to hydroquinone which is then glucuronidation in the liver and this hydroquinone blue quran ID is then excreted in the urine where it's the active ingredient and it's been shown to have increased the hydrophobicity of e.coli thereby decreasing the bacteria's ability to adhere to the uro theal cells it's also shown to have antimicrobial activity against other bacteria and yeasts there was a randomized control trial of 57 women with recurrent urinary tract infections and this was published in 1993 which may account for its unusual study design they used over E which is a preparation of our butan in a standardized doses dandelion and patients took these three times a day basis for one month but interestingly they had a follow-up at 6 and 12 months and they found a statistically significant difference in urinary tract infection rate and there were no reported side effects of the oversee in this population there are however concerns about the long term use of oversee and that relates to the hydroquinone metabolite apart from causing various adverse events with respect to excessive doses there are concerns about long term use and mutagenicity and carcinogenicity as well as its interaction with some of the cytochrome p450 ISO enzymes there also has been one case report in the literature of bullseye maculopathy related to long-term use forskolin is another common supplement it's extracted from coleus forskohlii there have been basic science studies which show that they elevate cyclic a MP and it may have a role in decreasing the secretory lysosomal process that actually allows the bacteria to invade the epithelial cells there haven't been any randomized control trials in humans to support its use a juniper berries contain two pen IDEs which have been shown in animal studies to have antimicrobial and diuretic properties but there aren't any human clinical trials to support its use golden rod is a native plant in North America there's been one double-blind randomized control trial which essentially shows that it acts as a diuretic by increasing urine flow the mechanisms of which are still undetermined it's contraindicated in patients who have renal impairment and a lot of these products don't actually have that as a warning on them and d-mannose is the last supplement that I'll be discussing it's a natural sugar it competitively blocks adhesion of the e.coli by binding to those menno's specific receptors there's a lot of literature in vivo and in animal model models sorry Envy in vitro and in animal models but there aren't any human randomized control trials so now I'd like to talk about current trials and and where research is heading in terms of the dietary supplements so with respect to cranberry currently the NIH and the National Center for Complementary and alternative medicine are funding studies specifically addressing the limitations of the current available literature so there is certainly quality control of the product they have developed a research grade cranberry juice which has a standardized amount of PA CS the juice is delivered to the patients in packaging that protects it from light the patients are instructed to keep it in the fridge and in those circumstances the PA CS are shown to retain relatively stable levels for a period of about four weeks there are also studies that are looking at dose response so that we can get an idea of what the adequate dose is for prevention of urinary tract infections there's also documentation of compliance by quantifying the urinary pocs and tracking of symptomatic urinary tract infections and also looking at the specific virulence factors associated with the bacteria that cause urinary tract infections so when you look at the clinical trials website and put in Cranberry and you're in fact infection you come up with this list of current trials that are underway these are all randomized control trials and the one that I've highlighted at the top is the one that dr. stutters is involved in at the moment it's nearing completion in terms of patient recruitment and hopefully data collection will be completed by the end of next year is that right dr. status or this year yeah and as you can see you know most of the data that I've presented today is focused on women but a lot of these studies are looking not only at pre menopausal women but postmenopausal women men children and those with neurogenic bladder so hopefully once we start seeing the results of these studies we'll have a lot more to go on in terms of recommending one way or the other whether these products should be used and once again when you put in probiotics and you take an infection this is what you come up with on the clinical trials website so once again there are a number of randomized control trials looking at probiotics and recurrent urinary tract infections so what can we conclude from this well with respect to cranberry we've noted that there are very few high quality studies available to guide our recommendations there are conflicting results regarding the efficacy of the commercial cranberry products in UTI prevention and this is largely due to the fact that we don't know what the content of these in of these cranberry products are with respect to their PA CS there's no consensus as to whether juice is better than capsules but some of the basic science studies suggests that pure cranberry juice provides adequate amounts of PA CS in as little as 240 Mills and is probably the most cost effective way of obtaining the PA CS has it been estimated that the cost is approximately three to four dollars per day so at this point in time if you ask dr. stutters what she recommends to her patients she'll say that you dilute the cranberry juice maybe in a concentration of one to four and drink 60 mils twice a day and that's probably the best that we can do at this point in time and with respect to probiotics we need to be aware and we need to make our patients aware that there are specific probiotics for genitourinary health that drinking a bottle of your call today is not going to help them with respect to their recurrent UTIs or their bacterial vaginosis unfortunately in Canada we don't have access to the most commonly studied probiotic combination I did do a google search and it is possible to buy these products online but at the moment there's no commercial product that you can just walk into a pharmacy or an actual health store and buy this particular preparation that's been scientifically studied for those of you who are interested there are some useful resources which I found useful in terms of researching this area the National Center for Complementary and alternative medicine website is excellent it's actually a US federal government agency for research on complementary and alternative medicines and it forms one of the 27 Institute's that make up the NIH the office of dietary supplements is also a part of the NIH it came into existence in the mid 90s and its mandate is to promote research into the benefits of dietary supplements and basically to disseminate that info motion and then the Health Canada website has an excellent section on natural health products where they alphabetically list all the licensed health products available in Canada and I also have a series of monographs on these yep and that's questions

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