Great. Well, thank you. So I am sure most of the people in this audience deal with patients with recurrent UTIs in some way, shape, or form. And I have had an evolving thought process about how I manage this patient population over the last 20 years. The title of this is Bugs Versus Drugs. If we have time, I would love to talk about scenarios where I focus more on the bugs versus the drugs. But hopefully, we'll have some time for questions. Let's see if I can make this go. All right, those are my disclosures. So we're going to talk today in terms of my focus on where the microbiome may play a role. I'm going to talk today about recurrent UTIs. I do also have some thoughts about overactive bladder, but I'm going to hold those. You're a patient who thinks she has recurrent UTIs and diabetes and OIB. I have some thoughts about that, too. But when you talk to our primary care colleagues or people out in the community, you might talk about this concept. And they'll say, UTI, what's the big deal? Just treat with an antibiotic. It'll go away. But as you all know, because you're probably struggling with this patient population, for women who are getting this problem of repeated infections over and over, particularly at a monthly basis, it can be really problematic. There are times where in our surgical practice, this rears its head after slings, for example, even with normal voiding. There are certainly times where it may spike and become more of an issue for your patients. So I don't think any of the statistics here are that surprising to this audience. But about half of women will have a UTI in their lifetime. And if you have one, you have about a third, a 30% chance of having another one in about six months. Those statistics get substantially higher with aging. And we see our postmenopausal population, about a third of them will struggle with recurrent UTIs at some point. So I currently feel like we have a lot of problems with three aspects of recurrent UTI care. It's a big topic. But we have issues with how we diagnose UTIs. I don't think we're always very precise. I think we have some issues with treatment, in that we pretty much only have antibiotics. And there could be some other ways of treating UTIs in the future. And I think we have a lot of issues with prevention, particularly because I think there are ways we could optimize prevention. And I use the same tools you all use. I probably just use something slightly differently, because I've changed my style over time. So one of the reasons why I've changed my style over time is because I study the urinary microbiome in my research life. Now, how many of you here, I'm going to ask you all to raise your hands, because I'm doing low tech today. How many of you here think you have some bacteria in your bladder right now? Raise your hand. If you didn't raise your hand, you're behind the times. Everyone here should be raising their hand. We have all low levels of bacteria in our bladder all the time. How do we know this? Why is this not more pervasive knowledge? Well, first and foremost, in terms of the urinary microbiome, or the carpet of bacteria that live in our bladder at all times, there really wasn't discovered in women until 2012, where Linda Brubaker and Alan Wolfe and their colleagues at Loyola published what in that field is a sentinel study, really showing some conclusive evidence using suprapubic catheter aspirates, along with a whole bunch of other samples, to sort of debunk the naysayers who felt like bacteria that were being evaluated were coming from the urethra or other places. So we see that there is a urinary tract microbiome, and that has really kind of influenced several areas of how I think about recurrent UTIs. First step is in UTI diagnosis. How many of you think your current diagnostic algorithm of a UA and culture is 100% diagnostic all the time? I don't see a single hand in the audience raised, which I agree with you. So this is what we typically do in our offices. You have a patient who's coming in with symptoms. You get a urine sample. You get their urinalysis, their dipstick. You may get an intermediate result, or you may be following a person who's been having recurrent symptoms and be sending it off for a culture, even with a presumptively positive UA. And your standard urine culture is going to give you one of three results. It's going to give you a no growth, negative. It's going to give you growth of an organism with some CFU, that 100,000 threshold. We're going to ignore that for a while. We're just going to say some CFU, which I'm going to say a positive in the setting of a symptomatic individual. Or it's going to give you a mixed flora, which we have historically inferred as a negative. And I'm going to tell you right now, it's not a negative. Now, it can be a negative. It can also be a positive. Technically, it's indeterminate. And each laboratory that you work with, your clinical microlaboratory, has an algorithm or a protocol for how they report out their urine cultures. And so my lab's mixed flora might actually be different than your lab's mixed flora, than your lab's mixed flora. So that's just something that we, as clinicians, are not always privy to understanding that. But you can have low level pathogens in something that is reported out as a mixed flora result. So in microbiome conferences, this picture is pretty famous now. But the standard urine culture that we all rely upon for diagnostics pretty much is putting some urine onto a plate and letting it grow. Well, that test is an imperfect test for microbes. These two plates right next to each other are showing the same exact urine sample. That urine sample here is put under the standard clinical micro sort of protocol for how they run urine cultures in most of our hospitals and labs. That same sample was put onto another plate and run under slightly different conditions, different levels of CO2, so different atmospheric conditions, different nutrients, different growth time. And there's stuff on that plate. There's stuff that grows. Not only one thing, but several different morphologies here. So this is just an example of just to show you that a quote unquote negative culture test is just no growth using the conditions that were applied. And that may not necessarily mean that there are no bacteria there. That becomes important when we have patients with confusing symptoms. So you're run of the mill, standard patient, 20-year-old college student who had sex last night and has symptoms this morning, you may use your standard testing and be fine. But that's not the typical patient who's coming into our clinics. And in our clinics, many of us need some more precision for people who are having recurrent symptoms. I see a few smiles in the room, so I hope that I'm telling you something that you are believing in here. But who here uses a molecular diagnostic test in your practice at all? Raise your hand if you do. And I'm intentionally raising my hand because I do once in a while. So this is where I think we have some evolving science. And some of this is informed by what we're learning in our land of the microbiome research lab. If you are using molecular diagnostics, I hope that you understand the test and the report. We saw one example during lunch today of a molecular diagnostic option. There are several out there. They're different. Their reports are different. How you interpret them are different. I've had to learn many of these because I have a little local, I don't know, patients will find me because I study this. And so I've had to learn all the reports that I can find. But if you're sending one of these off, understand what you're looking for. Consider the microbiome. I do think it's relevant that not every positive test is always going to tell you that you have to treat a patient. You still have to come back to their symptoms, what you're dealing with. It's not simply just knee-jerk reacting to a test. And so realize that these tests, molecular diagnostics or urine culture, molecular diagnostics are not the holy grail that are going to solve every problem you have in terms of diagnostics, but they may be helpful in some scenarios. So what are the scenarios where I may use a molecular diagnostic? I don't use it in every patient. I'm going to tell you that right now. For me, I think about it in a couple of scenarios. In my younger patient population, I think about the fact that in that group, if they have UTIs, about 80% of the time it's E. coli, but 20% of the time it may not be. E. coli is a kind of bug that grows really well in standard urine culture conditions, but some of those other bugs may not. So if I have a young woman with recurrent symptoms, maybe even a little bit of recurrent pyuria, like 1 plus coming up on her UA, but generally mixed flora or no growth cultures, that is a patient where I might tell her, well, next time when you have symptoms, come to my office and we'll send off one of these tests, because I want to be really conclusive about whether or not I think there might be an infectious etiology here. It's almost a similar thing as some of my young patients, or any age, really, with IC, where I'm thinking about I might want to rule out the infectious side of things before I put somebody on an IC painful bladder syndrome pathway. Also, in our older adults, so our postmenopausal patients, now in this population, they are much more likely to have non-E. coli UTIs. So in any recurrent UTI population, non-E. coli goes up in terms of the proportion of bugs you're going to find. And again, some of those bugs are just less likely to grow out in our standard urine culture conditions. So in some of my older adult patients who are having recurrent pyuria, recurrent symptoms, maybe at times they might have improved with the course of Macrobit or some antibiotics, where you sort of get the clinical gestalt, like this could be a bit infectious, and getting repeated mixed flora or no growth. Now in this population, it tends to be much more mixed flora will be my results repeatedly. That might be the patient where I'll say the same thing. Until next time, let's send off this type of test to be a little bit more precise about what we're looking for. And there are instances in both of these scenarios where when I send off a molecular diagnostic, I might get different information than I might have had with a standard urine culture. So I reserve these tests for some of my patients with reheated symptoms where I'm trying to really ferret out what's going on. But again, part of that is because the standard urine culture is an imperfect test for microbes. And we as a physician community, and I'm going to say physicians because I'm now including ID and other people outside of our groups here, we have had this over-reliance on thinking culture is the gold standard here. And while it has been for what we had, there are many ways where even if you look in the literature over the last 20 years, the ways that we interpret urine culture is somewhat flawed. So I'm going to get off that bandwagon and move to something else about recurrent UTIs for a moment. So in terms of treatment, I'm not going to go into a lot of detail about this. Actually, think of all the areas between diagnosis, treatment, and prevention. Treatment is a place where I think we probably all are pretty, we have a handle on that. We kind of know how to treat an acute UTI. But what about prevention? I think this is a place where we have some room for improvement. If you look at the AUA guidelines right now, and you were to read their algorithm, it pretty much says prophylactic antibiotics, plus or minus vaginal estrogen, and maybe some other stuff. Maybe some probiotics or some supplements, maybe cranberry, those things. And they talk about the data behind those things. I do say I've had a preview of the, I was a peer reviewer for the update that's coming out. And I like the direction they're taking in their new update. But I still think that the algorithm is going to look very similar, because we don't have a lot of new data in support of other prevention options. So I do think we're sort of at the precipice of a paradigm shift. And I see this more coming from patients than our colleagues, which is that patients are looking online, on Instagram, TikTok, wherever they can go, to see how can they think about improving prevention, and how they prevent UTIs from continuing to happen. And I have started to think a lot more about this because of my research in the microbiome space. So in terms of what I have learned, I'm going to sort of segment this into what I've learned about aging and menopause in general, and then how I apply that to recurrent UTIs, and then how I have taken that information to change a little bit of the scripting of how I talk to my patients. I really think about local ecology when I talk to my patients. So in terms of aging and menopause, it is probably no shock to you that there are dramatic changes in the microbiome that happen at this life transition. And a lot of it is the story of lactobacilli. Lactobacilli are the dominant microbe in the human female vagina, but until the last decade, we didn't realize, are also the dominant constituent in the human female bladder, in the bladder microbiome. We do know that the vaginal and urinary microbes are interrelated. And in the vagina, for those of us with gynecologic background, we know that the lactobacilli are plentiful prior to menopause. They drop with the withdrawal of estrogen. And they can be recovered in the vaginal environment with estrogen therapy. And it should come as no big shock and surprise to you that if I change the word vagina to bladder, the same things apply. We are now seeing this from our studies of the microbiome that the same phenomenon are happening in the bladder, particularly with estrogen therapy. So this is a complicated, you know, researchy figure. I'm not gonna go too deep into it, but I'm just gonna orient you for a moment. This is a study that we have not yet published, but basically we surveyed pre-menopausal, post-menopausal women, and then post-menopausal women using vaginal estrogen, vaginal, for six weeks. And essentially, each bar, each standing up bar, is one patient's microbiome. You see different colors because each color represents a different type of bug, a different bacteria. And we purposefully sorted this by lactobacilli. So all the purples are lactobacilli. And this is just so visually you can get a sense of how much is there. So we see in the pre-menopausal women, first off, they're not all totally dominated by lactobacilli, but a lot of them really are. And a lot of them have a fair amount of it, like a fair number of these women have more than 25% of their microbiome hosting lactobacilli. In post-menopausal women, that drops off pretty significantly. And in post-menopausal women using vaginal estrogen, we see some recovery. I'm going to show you the same exact data, just simplified here. And this is quantifying it, where we see these are statistically significant differences that happen in lactobacilli with the post-menopausal transition, and then, again, with the addition of vaginal estrogen. And we see that this is a fairly unique phenomenon that's happening with that bug, different than other bugs. Gardnerella drops after menopause doesn't necessarily come back with estrogen. And we saw the same phenomenon with other bugs. So lactobacilli are special in their response to estrogen. And we kind of know that already. And how do I think about that, particularly when we're thinking about recurrent UTIs? Well, we all know that vaginal estrogen is part of our armamentarium of treatment for prevention, for kind of preventing future UTIs. And I think that part of how I incorporate that, and part of how I think about recurrent UTIs overall, has changed over the last decade. First of all, I think when we were all in medical school, we were taught that the dogma that UTIs were like the bad bug that escaped from the GI tract, and fought, and ascended through the urethra, and got into the bladder, the sterile environment, and they just took hold. And now we know that that's not really the truth of the matter. There are bugs around there all the time. There are low levels of E. coli in half of our bladders, probably, in this room. So there are bugs that are sitting there. They are kind of kept in check by immune mechanisms. And there are times where they bloom. There are times where they hide out in our cells, in the urethelium, in the vaginal epithelium. So there are reservoirs. And there are times where they just evade the immune system holding them at bay, and come out. And that's where we kind of see the symptoms of an infection. So when I think about that, that there are bugs there all the time, I think about, well, what are the ways that we keep them at bay, where our immune system helps? This may be why people who are immune suppressed, for some reason, have problems with UTIs. This may be a reason why I started to screen more heavily for Humira and some other TNF alpha inhibitors as part of the medications that people may be taking. Because that makes me think that person's going to be at higher risk of ongoing UTIs. And it also, kind of thinking about the mechanism, makes me think about local ecology when I'm treating people. So I think about what's happening within the microbiome. I'm trying to think about how it's associated with this woman's UTIs, and how might I tweak the therapies to boost or sort of re-up the plentiful, the healthful part of the microbiome while we're trying to keep bad stuff down. This is a study that we published, I think, in 2021 now. But this was a study where we basically did a lot of similar techniques as what I showed you before, but we were looking at patients with recurrent UTIs. And these are catheterized samples, so we're specifically looking at the microbiome of women who all were post-menopausal, all were using vaginal estrogen, so we really tried to control for those factors, and look at lactobacilli. And one of the things that I want you to see is, you probably, if you squint here, these kind of look similar to you. At least they do to me. And maybe there's a little bit less of that purple lactobacilli in this recurrent UTI group who are on antibiotics. But otherwise, they kind of all had them. And that was a bit of a surprise to me. I thought we were going to see some major differences, and we don't. But what we saw was more of this sort of shift, this subtle shift or trend from a more healthful state to a more negative state. A really important thing that kind of changed my clinical practice in recruiting for this trial, I'll tell you, when we were recruiting for this trial, we needed everyone to be on vaginal estrogen for six weeks before we wanted to sample them. And so, different than normal clinical practice, we arranged to give people free tubes of vaginal estrogen. We told them the importance of using it. And if you want to join this study, you've got to use it. And then we'll sample you. And we had all these recurrent UTI patients that we were recruiting who had had like maybe two UTIs. So I said, well, if she has her third, we're going to put her on prophylactic antibiotics. So I was thinking we were going to pretty easily recruit for that. I don't know if I can go back. We thought this group on antibiotics, we're going to be able to recruit super easily, because we see so many of these patients. And back at that time, we were using a lot more of those. When we told people about vaginal estrogen and talked to them about it differently and gave them tubes, we did not see people coming back with UTIs at the same frequency that we had been before. And that was a little bit of a light bulb moment for me, was the compliance aspect of this therapy that we give out all the time, that when patients understood why they were getting it and what the compliance meant, we all of a sudden saw that the condition was getting better. We had a really, really hard time recruiting for that last group. And in fact, we had to stop the study with fewer patients in this group than we had intended, where when we planned the study, we thought this was going to be the easiest group to recruit for. So in implementing that study, the results didn't tell me what I thought it was going to. But actually, it has changed how I think about and talk about estrogen with that population. The other thing it changed in terms of looking at the field is thinking about lactobacilli. We know that lactobacilli are the healthy bug, the healthy component of the microbiome. They're also not monolithic. There's like 147 species of them. And just like human beings, some are better suited to some functions than others. If you look at most commercial probiotics out there, they contain stuff that is not part of the human female microbiome. They contain lactobacillus rhamnosus and acidophilus, things that are easy to grow in the lab, things that were designed for the food industry. When we look at females, typically, the most healthful or plentiful one is lactobacillus crispatus. Crispatus and other lactobacilli use multiple mechanisms to counteract other organisms. They have different ways of essentially being the bullies in the room. So when we look at what's in the female urogenital tract, lactobacillus crispatus, as well as gastri, inners, and Jenseni, these are the ones that tend to come up over and over in vaginal and urinary microbiome studies. It is pretty hard to find those things in commercial probiotics. If you look, because I have looked, it's very difficult. I have a list of five that have lactobacillus crispatus, three oral, two vaginal. Happy to share that list with anybody who wants it. But that has also influenced sort of how I talk about probiotics with my patients. So when I'm talking with patients these days, different than 10 years ago or 20 years ago, I think a lot about ecology. I see patients all the time who are swirling and do need prophylactic antibiotics. I am happy to prescribe a prophylactic antibiotic to somebody who's getting monthly UTIs. But while I'm doing that, I'm also talking to them about how we're going to change the local ecology in the background over the next three or four months so that you can get off the prophylactic antibiotic. And how do I change the local ecology? Vaginal estrogen. I've totally changed how I prescribe it. If, different than atrophy and menopause or dyspareunia symptoms, if we're using it purely for UTI prevention, throw away the applicator. I do periurethral and vaginal opening. That's how I tell my patients to apply it. I tell them to apply a pea-sized amount every other day, sometimes every day. So some of the older adults who are very atrophic, I will do a daily application. But really, I talk to them about the why, that this is not for dryness. This is not for pain. This is because we're trying to boost up your healthy bacteria. When people understand that, I think they're much more compliant with that therapy. At the same time, if somebody wants to take a probiotic, and if they're post-menopausal, I tell them you have to have the vaginal estrogen with it. Lactobacilli are not going to stick around and stay if they don't have the nutrients that they want. If your home, if your heater broke in your home and it was winter, you would leave. It's that sort of analogy. You don't want to just be taking a probiotic without providing the hospitable environment. And again, for patients who are reluctant to use vaginal estrogen, some of these conversations and the way we've talked about it, also the fact that if they don't start it right away, I just kind of stay with them and we keep working on things. And I've had a large number of patients who will eventually start using it if other therapies don't work. But we talk about that quite a bit. So when you go to the AUA treatment algorithm, again, this is sort of what you see on prevention. You basically see antibiotics. We see vaginal estrogen therapy for peri and post-menopausal women without contraindications. I think there's very few contraindications. We've already heard how breast cancer may not be an absolute contraindication, and in fact, have many breast cancer survivors in my practice. And then we see this non-antibiotic prophylaxis area, cranberry behavior modification, and others. I do talk a lot about adding a lactobacillus crispatus probiotic if someone's going to take a probiotic. I do talk about some adjunctive things like D-mannose or cranberry. I do usually stage it, though. So if somebody is swirling in repeated culture-positive UTI situation, I do think we have to get them back to a point of stability before you move to supplements. So I'm typically starting a prophylactic antibiotic and priming the conversation for the next visit when we'll go off. If somebody is not in that swirling bad phase, then sometimes you can start with the non-antibiotic methods first. I think, basically, I've already talked to you about some of the lessons I've learned from our research lab. I really emphasize why vaginal estrogen is important for the microbiome. I do talk a lot about lactobacillus containing probiotics. But specifically, if you're going to take a probiotic, I try to have my patients take one with crispatus in it because I don't want them to waste their money. And I really do think about evidence-based practice when it comes to this patient population. I really focus on the fact that I only want to treat symptomatic UTIs. So making the diagnosis requires symptoms, pyuria, and a pathogen. I think about working hard to look for that pathogen if my typical testing is not showing it. If I have a patient who is not actually having symptoms but having positive tests, ASB, I still don't treat that. So I think I'm probably practicing in a very similar way as many of you. But I do think a lot about that local ecology in the background when we're getting people on a program. Essentially, based on our microbiome studies, I think about combining vaginal estrogen with a lactobacillus crispatus probiotic to change the local environment. And I use other aids like D-mannose and cranberry when I'm trying to get people off of antibiotics. I think we have a lot of clinical challenges in this space, timely diagnosis. How do we separate symptomatic UTI from ASB in a patient who also has urgency, frequency, and other LUTs? That's, I think, a tricky scenario that's hard for all of us. I do struggle with the precision of our urinary testing. And I really do think that there are hopefully going to be better ways in the future for us to prevent recurrences over time. And we have to get the word out to our colleagues because I do see a large number of patients who I think, why have they not been on vaginal estrogen or something all this time? So with that, I'm going to end. And I think.

urinary tract infections

urinary microbiome

molecular diagnostics

vaginal estrogen

lactobacillus crispatus

probiotics