#98 – Uncomplicated UTIs: Getting Uncomfortable with Uncertainty

Hello and welcome to Breakpoints, the Society of Infectious Diseases Pharmacist Podcast. My name is Aaron McCreary and I'm a clinical assistant professor at the University of Pittsburgh School of Medicine and the Director of Infectious Diseases Improvement and Clinical Research Innovation at UPMC. I am joined today by three exceptional panelists to discuss uncomplicated urinary tract infections.

We're gonna go through everything from diagnosis to treatment. We have focused a lot in the antimicrobial stewardship space and in the infectious diseases space in the past decade, maybe even two decades. on asymptomatic bacteria, right? So the presence of bacteria in the urine without clinical symptoms of infection.

But in preparing for this episode and in reading a lot more about this recently for some other projects I was involved in, we realized there's very little out there about the actual treatment of a true urinary tract infection. So how do we handle our patients when they really Do have infection. We're so used to saying, don't give them antibiotics. Well, some people do need antibiotics or other modalities of treatment, and there's not a lot out there. And so

The Infectious Diseases Society of America guidelines were published in 2010. And I think we have a lot to discuss today in terms of the updates in this space. I mean, it's been almost 15 years. And where we're gonna go from here. So we're really excited for this conversation. I can't wait to introduce our panelists, but before I do, I'm sharing with our audience that this educational activity is supported by an independent medical education grant from G S K.

All right, and now I get to introduce our panelists. So first, Dr. Chris Sernich is faculty in the Division of Infectious Diseases within the Department of Medicine at the University of Wisconsin. He's also the chief of medicine and the hospital epidemiologist at the William S. Middleton Memorial Veterans Hospital and the Assistant Director of Infection Control at UW Hospitals and Clinics. He chairs the Shay Long Term Care Special Interest Group.

And it's a nursing home antibiotic stewardship toolkit development task. force. His research has a specific focus on improving antibiotic use in skilled nursing facilities. So Chris, welcome to Breakpoint. Thank you, Erin. Delighted to be here. This is one of the smartest podcasts I listened to. Thank you. We're very excited and thank you for the compliment. We try. But

Uh that's a good that's a good segue,'cause in the next I get to introduce one of my fellow co-hosts, Dr. Jeanette Bouchard. She's a board certified infectious diseases pharmacist practicing as a clinical pharmacist within the Duke Antimicrobial Stewardship Network, or Dayson.

Um so y'all know Jeanette, she is a fellow host of Breakpoints. She currently serves as the chair of the Breakpoints committee. And I just really need to say, like, Jeanette is like the glue that holds us all together. She runs a very impressively large ship that she steers.

every day. So we're so thankful for Jeanette's work with all of this. Um and most importantly, Jeanette is a huge Taylor Swift fan. But given Jeanette's significant antimicrobial stewardship role across many urban, academic and community hospitals. in the United States. We're really excited to have her today and her perspective on the stewardship component of uncomplicated UTI. So Jeanette, welcome to Breakpoint. Thank you. I'm excited to be here as I always am and thank you for the kind words.

It's a big ship, but it's a pretty ship and it's a fun ship, so I enjoy steering it. It's like a Disney cruise. Exactly. Breakpoints is like the Disney cruise of podcasts. Yeah, no COVID. No legionella. There's no Listeria or Legionella on our cruise ship. Yeah, no GI disease on this cruise ship. Jeanette's over there in the guest what's a guest login look like from the studio? It looks I've never I mean I feel weird to not have like a lot of control, to be honest.

Yeah, I've never seen the guests I don't know what it's like. Well anyway, okay, we digress. Um so last but certainly not least, we are joined by Doctor Angela Huttner, who is a premier infectious diseases physician and researcher in Geneva, Switzerland. She has a deep and rich history of training in clinical infectious diseases, patient care, research, and epidemiology, and she now primarily focuses on conducting clinical research.

But in a very cool thing, Dr. Hutner started a urinary tract infection clinic at her institution, and we're so excited to have her discuss this in more detail today. She's also led and designed several urinary tract infection clinical trials. Angela is also the newly appointed editor in chief of a new Eskemid CMI journal, which is called CMI Communications, which is officially launched.

So Angela, congrats on that role and welcome to Breakpoint. Thank you so much. I'm really thrilled to be here. Just like Chris. It's I'm I'm a fan. Yay, we're so excited you're here. Okay, team.

So let's get started and let's start with diagnosis because again, we talk a lot about asymptomatic bacteria, and it's like they have bacteria, they have no symptoms. I mean, admittedly, we don't really talk a lot about how to treat a UTI because it seems like an easy thing to do, but it it's actually quite complex. So, Chris, why don't you start us off? Let's talk about a urinalysis at the highest level, right? What are your feelings about a urinalysis? What is a urinalysis?

telling us, does it have a role in diagnosing a UTI? You know, I love UTI because it's kind of a microcosm of all the challenges that we face in medicine. You know, William Osler said that medicine is the science of uncertainty and the art of probability. And that's the crux is that we are challenged by uncertainty. As human beings, we're uncomfortable with uncertainty. We want to assign labels. We want to be able to say patient has X and unfortunately we're all too

likely to rely on tests to provide that uncertainty. And unfortunately, you know, I'd like to say that certainty in medicine is an illusion. And the urinalysis unfortunately is a big purveyor. of illusion. So if you wanted my opinion on the urinalysis at a high level is I think we would probably do just fine if it went away from UTI diagnosis.

That being said, it's a little bit more nuanced and I I think there is certainly some value to your analysis. So to kind of step back A urinalysis is a complex test. that we utilize for a variety of other clinical management

purposes, kidney function, liver function, diabetes. So when we look at a urinalysis for its role or ability to help us make a diagnosis of UTI, we're really kind of looking at three components: leukocyte esterase, or a white blood cell count, which will tell us whether or not there's puria present in the urinary tract, and then nitrites, which tell us in general that there is a organism there that's reducing nitrate to nitrite.

And in general, studies suggest that if you have pyuria plus nitrites, there's a reasonably high probability that you have bacteria. Unfortunately, that's all it can tell us. And conversely, if you don't have pyuria and you don't have nitrites in the urine, you can feel reasonably comfortable that the urine culture is going to be sterile. So this test has fairly good negative predictive value and so I don't wanna kind of throw the baby out with the bath water.

It can be useful for excluding the presence of bacteria and allowing you to move on to other causes of a patient's symptoms if you get that negative result.

The problem is that abnormalities in those components are extraordinarily prevalent. So there's an excellent study. by Tom Hooten that was published in CID a few years ago with his excellent cohort studies that their group has done. where they asked a cohort of women to collect urine every day, um, do leukocyte esterase testing at home. They also did additional testing on the samples that were collected.

twenty five percent of the days being monitored in this cohort of women, they were able to see pyria in premenopausal women, uh a population where you would think their urine's gonna be normal most of the time. So pyurine is highly prevalent in quote unquote a healthy population. And then as you get into more chronically ill populations, which I deal with clinically and academically, it becomes almost pervasive. And so it has no discriminatory value whatsoever.

Nitrites again are indicative of a nitrate reducing organism, but if you let the urine sit out exposed to air, it will naturally break down nitrates will break down to nitrites, and so you can get false positives. And again, we're we're talking about bacteria, which doesn't indicate necessarily an infection. Again, we say that having bacteria in the urine is abnormal, but Probably isn't. In fact,

studies suggest that there actually is a complex microbiome in the bladder from the earliest ages, and it's only with molecular tests that we're able to appreciate this. But when we look at the recovery of Europathogens like Europathogenic E. coli or proteus. colonization of the urinary tract actually becomes highly prevalent as we get older. And studies in long term care, which is where I spend most of my time

suggests that bacteria in females is as high as fifty percent. In males it's twenty-five percent. As soon as you introduce an indwelling urinary device, it's gonna go nearly a hundred percent. And so these tests are really not helping us, you know, when we're talking about fifty-fifty, no better than a coin flip. Um, it brings me back to my mantra that UTI is not a laboratory diagnosis, it's a clinical diagnosis. And again, the urinalysis can be helpful for excluding the UTI.

But its positive predictive value and populations I work with are no better than twenty percent. In young, healthier populations, it might be as good as fifty percent, but certainly no higher than that.

And so when you're looking at positive predictive values that low, you should never be using this test as a ruling for UTI. And I think that that's challenging for some people to understand. Yeah, thank you for that background. I think that's interesting because we know recently and there's been more data coming out by this to really

It really explain just how much information a your analysis gives us, which admittedly I had never thought about, especially in pharmacy school. A urinalysis gives you metabolic endocrine information about a patient. We're using it for an infectious diagnosis.

Our nephrology colleagues use it for a whole host of kidney disorders. We use it sometimes to rule out allergy to different medications, right? What type of allergic reaction could this be versus some other kind of kidney injury? That's a lot to ask of one simple little test or one complex test. and sometimes too much information can be detrimental. So, Angela, your thoughts on a your analysis. Love it, hate it.

Goldilocks it somewhere. Actually, I'm glad uh I'm here with Chris because this way you get very different views. No, I I actually I I mostly agree with Chris and I I'm very cognizant of our different populations. Because Chris, you're much more in the long term care facility uh milieu, whereas I with my outpatient clinic, I'm seeing certainly a lot of young women, premenopausal women.

I also see much older women than I see a lot of men as well. But I am definitely seeing more like this, you know, sort of archetype of the woman who has UTI after having sex, etcetera. So for me, the urinal systems is actually very helpful, like you say, to rule out. The UTI. So, first of course, we start with symptoms. Um, these patients can tell me what they're feeling exactly what their symptoms are.

And then the next step is really a urinalysis. However, it's not just a dipstick. I think the usefulness of a dipstick alone is very limited. You need nuance. The nitrites themselves don't actually help much, I think. I don't even look at that, honestly.

But the pyuria and an actual quantified pyuria is very helpful. Yeah, I think the dipstick that just doesn't you know, it's just quantitate sorry, qualitative and doesn't tell you how many white cells can be totally misleading because There's a big difference between fifteen white cells and, you know, seven hundred white cells. So I actually I still adhere to this. There are two reasons that a person with Classic UTI symptoms would not have white cells.

And if they don't have white cells, I would be very dubious about their diagnosis. And those two reasons, those two big exceptions, are having gotten a dose of antibiotic before that urinalysis was taken. I mean, we know one dose of ceftriaxone can sterilize urine and it can clear white cells very fast. So that would be the first reason that a negative urinalysis would s you know, where I would still entertain the diagnosis of UTI. And then the second one would be if somebody is um neutropina

which is very rare. Like they just don't have any white cells to to have them in their urine. Those are really the two big reasons.

And otherwise if somebody has symptoms but negative pyria, I really don't wanna go further. I don't wanna get a culture. I really wanna explore other diagnoses. So that's to me the use of a urinalysis. Maybe I shouldn't say urinalysis, maybe I should say like cytometry, you know, what in in it's a sediment. The white. I'm really counting the weight. I love how you said that I think

Hearing and repeating you guys it's a clinical diagnosis. So you're saying they have to have symptoms and then you look at the UA and if they have pyuria and symptoms, UTI, which I think Chris had echoed that too. And I think that aligns with the twenty ten definition as outlined by IDSA to some degree as well. It's so wonderful hearing you guys talk about this because it it is. You're using, you know, one, maybe two parts of this very comprehensive test.

And so I think it's really interesting and intriguing. I've seen some presentations from UTI experts over the past few years at major conferences about this. And I've been thinking a lot of the work I do is you quality improvement operational work across a a lot of hospitals in a big system about how can we take care of patients better by empowering

Clinicians to make better decisions. And I haven't done it yet. It's like on my list, but I think some kind of initiative in looking at different reporting of different parts. of a urinalysis based on the indication for the urinalysis may really improve UTI diagnosis. And so I it's it's a great discussion. I have to ask you, Angela, though, because Jeanette's gonna laugh at me. She's already smirking. She already knows what I'm gonna say. Um

Is there a is there a I don't know why I'm laughing so hard, but is there a Pyuria threshold? Because this is Hot see you're laughing too. See? Because if you have ever sat on If you've ever sat in any meeting ever for epidemiology, infection prevention, hospital quality, stewardship, ID care, whatever.

We have all talked about this as it relates to reflex urine cultures, as it relates to diagnostic thresholds, as it relates to contamination. Like is there a white blood cell count where you can say Throw it away. Definitely a a UTI. Absolutely culture this. Like, is there an operating threshold? Do we have any data behind that? I just saw a manuscript on this and I can't remember if it was a man I think it was a manuscript that was just submitted to CMI Commons.

Uh they all go through me and then I do like a first pass. Yeah, and I yeah, I think that's in the perfect line. Data kind. But uh yeah, and they literally were asking this question. Yeah, yeah. Well we'll see. We'll have to evaluate it. But um they were asking this question and I'm not gonna

get into specifics but uh beyond that, manufacturer? I'm not aware. Chris, I don't know if you're aware of like actually quantifying thresholds. Okay, go. Please go. Yeah, so there's a couple of studies out there, the ones that I'm most familiar with are from Dan Morgan's group, who's done a lot of work on diagnostic stewardship and They looked at just inching up the white cell threshold from greater than five to greater than ten, which is a really minor difference.

And they found a substantial drop in urine cultures, reflexing. I've heard people go as high as the threshold should be greater than a hundred. And what we're doing there with raising that threshold or combining it with another, you know, so there's studies that have combined a white cell threshold greater than five plus a nitrite. before you reflex to urine culture.

They all show that you enhance the specificity of this test and you probably modestly reduce its sensitivity, which I'm not gonna get into receiver operator curves, but what you're trying to do is maximize that area under the curve. And I think most labs have their white cell threshold.

calibrated far too low. And I I think most labs probably need to up it up a little bit. I'm not sure what the actual threshold should be, whether it's ten, twenty five, fifty or even a hundred, I I think that this is an area that does merit some additional investigation and certainly with reflex culturing kind of becoming

uh a really important stewardship tool. I think there does need to be a lot more work devoted to kind of better understanding where labs should be setting these thresholds. Yeah. Reflex urine cultures are one of our biggest stewardship interventions, I think, that you use at hospitals. And that is such a nuanced question of what is the threshold. So we're using this reflex urine culture to help create better culturing

across the institution, but we don't actually know the thresholds we're supposed to be using in order to get that result. But if you go to any institution that doesn't have a reflex culture, they're probably talking about bringing the reflex in in order to help with contamination rates.

and not treating asymptomatic bacteria. So it's really interesting that we don't have a whole lot of data surrounding that. It was kind of a trick question. I know I'm I'm a mean, mean host, but there isn't. So I well I was at least to my knowledge, which

I guess will maybe be improved one day soon with with new data coming out in the space. But there is not a guideline recommended threshold yet. But I do know that across many, many institutions and hospitals that I've worked with, this constantly comes up and

people are trying to figure out their own specific threshold, but it's not something that there is a reference for, to my knowledge. But Jeanette, you You chimed in and I want to hear more'cause you work with the whole network of of hospitals of varying size. in different socioeconomic regions of the United States with different patient populations. So anything that stands out to you in terms of urine culturing UA diagnostic initiatives.

Um that have been successful and any insights you can guide on implementation for our audience?

Yeah. So uh within the Dayson network, we do have a toolkit that we give to a lot of our community hospitals that walks them through looking at what their current reflex criteria are and then also looking at what your contamination or what kind of mixed floor comes out. And we have this really awesome Excel spreadsheet that we give to our institutions that they can put all of the data in and kind of find out the negative predictive value, positive predictive value of different reflex criteria.

Um, so I think that is a really great toolkit that we give to institutions so that way they can adjust to their reflex criteria for what is working within their institution and what is going to create the best results that they want. And that's probably one of the best tools that I have seen. Johns Hopkins also has a great urine reflex slash urine culture toolkit. It focuses a lot on education with nurses, which I think is another key step to this, right? So nurses are often

in in the grand scheme of things, right? So they're the ones at the patient's bedside. being like, oh, this patient has a UTI, you should order a urine culture or urinalysis. And so they're kind of a a an in person reflex for us. And so working on education at that front line, I think, is another probably better way to fix a lot of inappropriate culturing and especially inside the hospital or in rehab facilities, things like that.

And then the last thing I probably would think about is just really leaning in on the negative predictive value of UAs, I think, inside the hospital, at least in in the United States. you hear a lot of, oh, the the UA is positive. Oh, there's something positive on the UA, it's the UTI, and that's the wrong train of thought. And really honing in on the education of looking at white blood cells, if it's zero, then we're

pretty sure there's probably no UTI there and we don't need to treat it. And so initiatives where you can really hone in on that fact. So at my previous institution, we did a really cool intervention with our callback nurse. Where All of the cultures that came back. for our callback nurse to call and give antibiotics to these patients who had left the emergency department. We had them look at the UA and if their white blood cell count on the UA was zero.

Then they weren't call they w they didn't even look at the chart anymore. They weren't calling the patient back even if something grew because that's probably just bacteria that's in there that's not really consistent with an infection. And so then once they looked at that, then they would go into the chart and look at symptoms in the emergency department chart. And if the patient did not have symptoms

they wouldn't call back an a prescription for that patient either. And if they were unsure, they would call the patient and see how they were doing. And if the patient was doing fine, we didn't call back an antibiotic. So um it actually decreased our antibiotics. prescriptions a lot after we had that algorithm. And the nurses loved it. It wasn't that much extra work. They they had to call all the time anyway, so

Yeah. I love that. Imagine letting the patient tell you what's up with them and giving letting the patient tell you the diagnosis a lot of the time. I know, but that's a lot of the work Angela does, which we're gonna move into because I I think it's really fascinating and we're gonna get into her UTI clinic, which is so cool. But yes, thank you all of that for that conversation. I do since I do transplant ID, I feel like I would be remiss to not

make the comment that the exception to these are if you've gotten previous antibiotics or if you're neutropenic. And I I sometimes feel like a really mean preceptor'cause my students or residents will say there's no pyuria and I'll be like Are there any white blood cells anywhere in this patient? And then they're like, Oh, missed that, you know. And it's but it's an important thing.

It's an important thing to look at. It's probably I I focus on that population a lot, which I do think is so cool. We all have very different patient populations we take care of and those are different things to look at in diagnosing uncomplicated and complicated UTI.

But let's talk about the definitions and so we've talked a lot about diagnosis. You're gonna give your patient a diagnosis, you're gonna give them a word, right? That's gonna tell them what's what they have. And that is really powerful. I think naming things, naming emotions, we could get a whole whole side train on productive communication. But naming things is very powerful. And so there's a lot of conversation in the literature.

conferences recently about this UTI continuum. So we were raised in a very binary society. You have symptoms or you don't. You have a UTI or you have asymptomatic bacteria. And it's probably more nuanced than that, as all things in medicine are. There's a lot of gray.

And so terms like LUTS, which is lower urinary tract symptoms or other urological symptoms, and then this bus term is evolving, bacteria of unclear significance. There's a really nice article recently published in the Journal of Urology.

Which is a friendly reminder too to those of us in the infectious diseases space to be keeping a peripheral eye on our partners and colleagues journals because that's where if you're trying to if you're trying to have an initiative with your urologist, maybe read their literature, right? To know what they're reading and seeing. So this was in the Journal of Urology, and it was called Proposing the Continuum of UTI for a nuanced approach to diagnosis and management of UTI.

And as always, we'll put these citations in our show notes. You guys can pull these articles later. But they propose basically extending this definition from no UTI, which would be no symptoms, negative UA. Asymptomatic bacteria, no symptoms, positive UA. Well oh my God, I hate myself. I said positive UA. No symptoms, bacteria and the urine, okay, specific. And then or UTI. And they added these two new categories of LUTS and bus. And then

Related. So that's a really great paper. And then also related, Angela, you recently wrote an editorial in CMI titled Urinary Tract Infection from Intellectual Dead End to an Exciting New Frontier. Just so provoking. It's so provocative. That's the article title I need for U T I's in my life right now. I know. It's definitely gonna we're gonna play on it and make it the title of this episode for sure. But I wanna read a couple of sentences she wrote'cause they're beautiful. So I quote, Angela.

Not long after launching our hospital's urinary tract infection clinic, I learned two truths. The first is that everyone gets a UTI. And if they haven't, they just haven't lived long enough, which Chris is probably laughing'cause that's true, as we advance in age, UTIs become quite common and prevalent. But the second truth is, given the pervasiveness and perpetuality of UTI, what we in the medical community know about it is next to nothing. And physicians love to hate UTI.

I love you. I love that you put this out into the literature. I think this is fantastic because it's true. And I really this has just opened my eyes in the last couple of months when I've been reading about this topic a lot. It's like, dang, there's really just not a lot about true infection and how to treat it or how to manage patients that have really life altering symptoms. Like they don't feel good, but we're just telling them

You're not, or we're just giving them antibiotics and they're not getting better, right? Okay. So, Angela, tell us all about your UTI clinic. How do these nuanced definitions show up? And You know, just just go. I'm so excited to learn. Oh, well, thank you so much. I love to talk about it because yeah, it's a busy part of my life. Um

So I started this UTI clinic, I think six or seven years ago, simply because number one, there was a need. Everyone does love to hate UTI. Physicians hate it. Patients hate it, of course. And the urologists do their best, but they are surgeons, right? So there was a need. But also having done a couple of trials in the UTI domain,

People in my institution started to think that I was like the clinical expert in UTI, and I really wasn't. So I needed to learn about it myself. So I asked my boss, can I start a UTI clinic? And he was perfectly happy for me to do that. So I never advertised this clinic. I, you know, don't get a lot of c I wish I had more clinical time. I never advertised it. And it is

like booming all the time because physicians love to hate UTI. So, um yeah, so and I do insist on actually getting an enti and I don't know if you can do this stateside, but I insist on getting an hour for the first visit that I conduct with a patient. So because there is a lot to talk about, a lot to listen to and a lot to talk about. And I often don't need to see them twice actually. So if I can get that one hour and we can just

discuss everything. That in itself I think is a very valuable intervention. the genesis of the clinic. How did people find out about it? Oh, okay. Well so number one they're the urologists, right? Like they're perf they're just so happy to to have someone to send these patients to. Um and actually what I do is I so my patient my sorry, my clinic is weekly. Um I I do it for an afternoon. Well, it's really more of a full day. Um

'Cause there's lots of spillover. Every week. But then one day of the month, so one week of the month, I do it with a urologist. I have a urologist with me and it's like double teaming. Yeah. And uh I don't know if you can do this in the States. um, you know, all this time spent with doctors, but our patients love it because and I really I use that that week for those patients who have structural abnormalities or whatever, you know, where we really need to have a multidisciplinary approach.

Um so yeah, who feeds my my clinic? It's definitely the urologist, but it's really a lot of primary care doctors in town. They they really are often lost or they say they're lost and they really want help and so they send the patient you know, um often it's just once to me and I go over things with the patient and then and then we

we work out a strategy together and then I can later on I can con you know, the the doctor can contact me if there are issues or the patient of course. And so often I don't need to keep seeing follow ups. I I actually I kind of t I kind of don't have enough time to see a lot of follow ups, um, because there are so many

This is why I wrote in that article, I think everyone gets a UTI because I am pretty sure I've seen the entire city of Geneva like in my clinic. They just keep coming. All these new patients.

So I don't have a lot of time for follow up. But I work with uh private care doctors, so it's good. Yeah, I I s suspect every institution if they establish a UTI clinic would have no problem booking it up um a hundred percent in week. weeks. I think it's so amazing because it it we're we're focusing to on complicated UTI and I think I I mean I work predominantly inpatient. I think most of us do.

Although we're all starting to except for you, Angela, of course, but I think we're all really tasked with transitions of care, how burdensome this info pa is for patients, how much we want to keep patients out of the hospital and learning more of these primary care practices.

And, you know, young, healthy patients get infections. And we don't talk about that enough and how to optimally treat and manage those. So, Angela, can you shed a little bit of light on the history of The definition of uncomplicated UTI versus complicated and then some of the work you're doing now redefining these definitions and some of your work with national organizations to improve our guidelines and to update our guidelines.

Yes, it can. I would give you one caveat. I actually do quite a bit of inpatient work as well. I do a lot of inpatient call and that actually also feeds my clinic because a a lot of the patients are follow ups after being discharged from the hospital and the doctor's a little worried and they just want someone to check on the the patient after her renal abscess you know, to make sure everything's going well or or the prostatitis patient, you know, who needs Just a good check afterwards.

So it it it it can be very cross populational, I guess. But yes, it is true that many of my patients are sort of the more like classic, you know, youngish female who has recurrent UTI and gets very frustrated because ha she has to go to multiple doctors and

UTIs often happen on the weekend and she has to go through all the hoops, right? She has to get the culture, wait for the culture. Well, first wait for the appointment, then wait for the culture, wait for the doctor to get back to her and tell her whether she has a UTI or not. because the doctor is using these cutoffs that are in some places very old fashioned.

Those patients end up loving me because I don't do that to them. So what we do here, and I think this is happening in the US as well, we are doing more and more this um strategy that we call pill in the pocket. where for women this is really for women, we don't do this with men. So for women who get recurrent UTI and know their symptoms and that's a very key thing. It's um so Paul Little and and and

his group have done a lot of work actually on looking at the positive predictive value of uh classic UTI symptoms. And really women know when they're having a UTI. Their ability to diagnose themselves is very good.

So you really just like you say Erin, you really just have to listen to the patient. And often, you know, they'll be honest. They'll say, well, you know, maybe this is a little bit of a vaginosis or of a a yeast infection. But they really know when it's a UTI. So you start with the symptoms.

And if I need to treat someone acutely, if they're really having symptoms right in front of me, then yes, I'll do the urinalysis. Especially if it's the first time I've seen that. I'll do a urinalysis reniculture, if positive. Um, and and we'll document, you know, the E. coli that it's probably going to be. Um but then for as a strategy for recurrent UTI, um, we

recommend nitrofrentine in the pocket. Meaning, um, I write a prescription for the nitrofrentine. I ask I tell her, and this okay, this I presented this once at a conference and I think Twitter wasn't so happy. because I actually there's one little key step that I do not really have data for. So what I will tell her if she is a in an immunocompetent woman who doesn't get pylone nephritides, recurrent pylone nephritidities. I will say, look, at the very first symptoms, drink a lot of water.

Um and I don't have data for this. Like I don't think anyone's done an R C T like drinking water for acute UTI, not for prevention. Like uh you know, we have one of an R C T for that, but for acute UTI drink a lot of water, we do not have However, I have like hundreds of patients who tell me if I just drink a whole lot at the very first symptoms, I can sometimes clear it.

So I do tell them, yeah. So this is totally not evidence-based, but I do tell them: look, if you're feeling okay, if it's like, you know, if you're in a good space. Go ahead and just drink a lot of water and see what happens before you take that nitrofrontine that's in your pocket. And they can do that.

for, you know, a cup a couple of days at most. This is essentially the delayed treatment strategy where you give the prescription um and then you ask them to, you know, yeah, drink lots of water But take ibuprofen, for example, um, and just see if it'll pass. Um I don't love to push the ibuprofen.

because I don't wanna mask horrible symptoms, you know. Um, I don't wanna yeah, so I I really push more like drink water and see if it gets better. And after twenty four to forty eight hours, if you if you're not feeling better, Give yourself a course of nitroforentine. Um, and but I explained to them, and this is where I need my hour with them, you know. I explained to them I would never do this with any other antibiotic.

you know, I I would not feel comfortable with that. I am a good steward. I'm an ID doctor. Um but nitroferontoin has this these two beautiful traits. Number one, E. coli, which causes, you know, probably ninety percent of UTI in this specific population. E. coli does not easily become resistant to nitrofrenti. I don't think anyone really understands why. Nitro has multiple mechanisms of action. I think it's very hard for E. coli. It's not like a point mutation. Um but at any rate

We've been tracking this in Switzerland for years. We have a national database that tracks like all the real pretty much really a lot of laboratories uh participate in this. Um and since 2010, um, where we've been using Nitro first line, right? According to our Swiss guidelines, according to IDSA guidelines. Um, our consumption of nitro is like through the roof and yet our E. coli

only one percent of our E. coli strains are resistant to nitro. So there we have that. And then we have this other beautiful thing about nitro, which is that it doesn't seem to have a lot of um collateral effect on the gut. Um there was a study done by my colleagues um in here in Geneva. Um called the Saturn study and they actually looked at um

th th they asked patients who were taking nitrofrontine for their UTIs. They said, Look, can we have your can we collect your stool for the next three months? And they did metagenomic analyses on the on the the resistal. um i the intestinal resistome and they could not uh find much effect at all with nitroferentoin. So because of those two factors, I feel pretty okay with

sending someone off with that I've seen only once in my life, um, sending her off with a prescription for nitrofrentoin and saying, You take it when you feel like you really need it. Um, just yeah. And one thing I do which I think um you you probably don't do in the States, um, and it I don't think it was part of the twenty ten guideline. Um, I give nitro three times a day. I do the uh a hundred milligrams, but three times a day. I feel that it's more effective.

Um, we know that it's a time dependent antibiotic. It's uh yeah, Johan Mouton from uh the Netherlands uh did some nice um basically time kill curves, um, looking at uh nitrofrenti nitroferentines activity against E. coli in particular. And we do know that it's time dependent for E. coli. So basically because of that and because we know it's not like the greatest drug ever, uh for that reason I push it a little and I make sure that to give three times a day. I tell my patients, look it

Like it's not the rules race, right? It's not gonna be Cipro, it's not gonna be Cotriamoxazol, it's not gonna it's it's not as effective as those two drugs. But it's like a good fiat, you know, or it's like a good stretch, I don't know. Like it'll still get you the mail. Yeah.

slower. Yeah. Like it'll still work. And it's yeah. But yeah. And they totally point A to point B. Yeah. It's a tra right. Everything is a trade off, right? And they get it. Like this is why I need an hour because I have to tell my patients about Rolls Rice.

It was fantastic. Yeah. It was the greatest thing ever, never felt cooler. Did you take a picture with it? I hope so. Of course I have photos. Yeah. Of course. They will die with me. But it was fantastic. Um I loved it. And you were saying, Erin, that the your analysis comes with so many data points on it. And and one thing that's actually quite important is the specific

gravity, um, because you can see how diluted they are, right? Which makes a difference, if I may add. That finally I said there were two exceptions to having no white cells in the urine, right? Having had an antibiotic or being neutropenic. But there is one new thing that I have seen now twice this year. And I I think it's like massive dilution of urine because now we're telling women drink, drink is I'm telling women, drink, drink, drink, you know, at your first symptoms.

And I have now seen a couple of cases where there are very few white cells, um, but she's having very classic symptoms and then the urine culture grows out like ten to the two of E. Our lab can do, you know, just a hundred, a hundred, you know, and the dilution of it. Yeah. So so and you see the the specific gravity is very, very

But Chris, you will not see that in a nursing line home because all those people are pretty hydrated. And we're sorry. Routine to see a ten thirty uh uh fairly frequently on a specific We're coming to talk about the nursing homes, Chris. But that's so interesting because I I don't know. I do feel like as a society we drink a lot of water now'cause like Stanley cups are very popular. Like my but uh I mean we've just like actually Commercialized drinking.

It's which is great. I mean, dehydration is the enemy. I my carry my emotional support awala water bottle everywhere. I like literally if I leave it at home, I like have a bad, bad, bad day. So I drink a ton of water too, but that's that's fascinating, the dilutional effect. Um

Okay, but Chris I do wanna come to you and I wanna ask'cause I wanna Talk a little bit more about definitions of uncomplicated versus complicated Because so the European Urology Association recently came out with really long guidelines about they're really nicely done. It's like I think they're like two hundred pages or something like that.

So again, urology, your society, but they talk uh all encompassing. But there's two pages in there on complicated UTI and I think there's like one page on uncomplicated UTI. But what interested me is about in the uncomplicated UTI box, they are basically defining complicated as this is harder to take care of. Whereas traditionally we've said complicated is an anatomical nature of being pilo or perhaps having associated um uh

Oh my god, I just lost the word for when you have bugs in your blood. Bacteremia. Oh you know, when you have I did say that was a smart podcast, didn't I say that? I retract my comment. Oh my god, I literally couldn't think of it. I was like it's not Eric, you're doing so well. And you had to read the two hundred page guidelines. Oh my god. That's called blood, Aaron. Okay. Oh my gosh. Sorry. Focus. Thumb. Wow, I truly I was like, it's not bacteria. What is it? Anyway, okay. Bacteremia.

Wow. Okay. But then and then uncomplicated, you know, focused on cystitis. But in this guidance, which is it's really and I poured through EskMID all these societies. So really since the twenty ten IDSA, there's nothing out there other than now these urological ones, which are great. Um but they said that if you have a history of a drug resistant organism

Such as an ESBL, which we know pre COVID, we made tremendous strides in AMR across the world. And the C D C in particular put out a report that said we've really, you know, KPC essentially went away with the advent of novel beta lactamase inhibitors, all these tremendous gains in AMR except community acquired ESBLs, right? Which is largely transmission from nursing homes.

from urinary sources, ESB L E. coli. And this is a huge problem because you don't want to put a pick in someone to give them outpatient carbopenums or IV therapy. We want oral effective options for ESB L E. coli. Because we don't live in Switzerland and so although we wish we did.

So I thought this was fascinating because I don't necessarily think having a certain resistance pattern makes your infection more complicated if you have an active agent. If you don't have an active agent, then yeah, that's tough. But if you have an effective active agent,

It doesn't really matter the resistance pattern. If it's just castitis, it's uncomplicated and I could treat you for five days or so. So um Chris, what do you think about that? Because your population is is definitely going to be more prone to have resistance. But they could still have just the sitis. They could have so how do you define uncomplicated versus complicated? Yeah, I I think, you know, as we were talking before, I've

tried to s stay away from the terms complicated, uncomplicated. Again, they have some utility, but I think the way that they were being applied historically, if you have complicated automatically, you're kind of locking your patient into a long duration of therapy, I think is a mistake. And so I think guidelines focusing more on the challenges of antibiotic choice and and using that.

stratification of complicated versus uncomplicated has some utility, but I get really uncomfortable with the idea of locking in duration of therapy based on your patients complicated or uncomplicated. I think that that probably was a mistake. So I think The direction that the guidelines are are moving in to kind of focusing on antibiotic choice is is useful. I find the anatomic location stratification probably

more useful i i in this discussion. You know, are we dealing with a bladder confined infection or do we have something that's outside the bladder because it really does limit what your agents can use. I mean drugs like nitroferon and phosamycin go off the list as soon as you say this infection may be outside the bladder. I I think that

Clearly resistance, which in my patient population, that's the norm, uh, not the exception. You know, Angela mentioned ninety percent of her community dwelling uh females have E. coli.

that proportion is probably closer to fifty percent in in long term care populations in organisms like Proteus, Morganella, uh klebsiella um become much more predominant and they have intrinsic uh uh resistance profiles that really take a drug like nitroferontoin off the table and and so we're doing an antibiogram study

in nursing homes and when we kind of look at empiric antibiotic choice just based on susceptibility profile, a drug like nitroferentoin has the lowest probability of spectrum coverage in this population compared to a drug like I hate to say it, acquittalone actually performs better than nitroferentoin as far as probability of coverage just because of the profile in organisms that are causing UTI. So anatomic for me is useful for determining which drugs are available to me.

And then I think clearly probability of resistance plays a huge role in empiric antibiotic choice. And I think we're at a point now, unless you have a very well defined patient like Angela spends the time to kind of characterize what's their history. what's their microbial profile and in the population she's dealing with, when they get UTIs, they tend to get UTIs with the same organism. It's unusual to see

organism switching. However, in my population, you see organism evolution as the norm rather than the exception. And so in my population I think it's not tenable to empirically treat. You have to get a urine culture when you're treating a a a frail older adult, particularly an institutionalized older adult, because the likelihood that you're gonna have

the same organism that was there three months ago actually becomes quite quite low. So these patient populations play a big role in and that also isn't kind of reflected in the terms complicated, uncomplicated it's so I think these simplifications Have some utility, but they also have limitations. And I think we have to kind of understand what are the specific types of decisions we're trying to make.

with these decisions. And so from the perspective of what are my drugs available to me or that I should be using based on the syndrome, that clearly matters. And for me the the anatomical bladder can find outside the bladder is probably the most useful. And then which patient populations you're dealing with are going to

influence the probability that I've got uh a resistance profile that I need to factor into my empiric decision making is kind of the way that I approach it, if that makes some sense. Yeah.

Angela, anything to add to that? Well, actually, Chris, you are right on target because I was telling you all before that uh the IDSA has not come out yet with the new guideline, but it will soon. and I have the the privilege and the honor of being the S comid representative on this guideline. So I'll tell you that the good news is that definition of complicated versus uncomplicated is gonna get a lot

Simbler and it's gonna follow exactly what you're saying, Chris. So an uncomplicated UTI will be very much an infection that's confined to the bladder. Whereas complicated will be an infection that appears to be extending beyond the bladder. And like you say, the anatomic location already determines what you can give, what you can't give. in terms of antibiotics. Um, so that's already a huge help.

So yeah, things will get a lot simpler, I hope, uh, because um I always thought it was a bit counterintuitive to say pylonephritis is simple. Um Yeah, so I think now it's gonna get easier. Essentially what is already out there is the up-to-date definition. That's that the up to date.

chapters are written by Count Gupta and she's on the guideline and she was I think first author of the twenty ten guideline. So it's i very much aligned with what you're already reading on up to date, if anybody wants to have a look. But I think it will be published by the end of this.

the new idea. We look forward to that. New guidelines. Yes. Covid was not e nice to us. We all had a we all had we were a little sidetracked. It's nice to be getting back into the other things. Um And so speaking of so let that's a nice way to kind of close out here as we move into our last segment of the challenges and the opportunities in the treatment landscape. And again, we're focusing on uncomplicated UTI today.

We haven't had a drug in the United States specifically FDA approved for uncomplicated UTI in in twenty years or so. And now we have two that are cl one close and one that just got approved, which is interesting. And so very briefly I'll I'll bring these up. So Um piv masillinum, which I'll admit this, I I try to stay very on top of the literature. If you're listening and you're like, I've never heard that drug before and I'm an American, you're not alone. I found out about this.

Coincidentally, I again I've been doing some work in the UTI space recently. So I've been reading a lot and I was like, oh, this drug, it's in the 2010 guidelines, right? It's like recommended, but we've never had it in the United States. So you've ignored it. It got FDA approved like last week while we were at ECMID and um

I did not know the company was was going through the FDA process and was submitting this. So this admittedly was a surprise for me, a pleasant surprise that we have a new U UTI antibiotic. It's the first U UTI again in almost 20 years. And so th that is recently FDA approved. Yo your team should look at this. I don't know, Jeanette, did your

Did you folks know anything about this coming through the states other than it's the drug you ignored in the twenty ten guidelines?'Cause you didn't have it. Yeah, I was like, that sounds familiar. Why do I was oh it's in the it's in the guidelines. Yeah, no, we I haven't even had any questions from any of my sites. About it. on top of it, like if something gets FBA approved, they're like, Can you tell me about that?

So I haven't even had that. Yeah. So it's it's actually a pro drug. The active drug is the amethystillium in it and it's It does have in vitro activity against ESBL E. coli and other things. We've talked a lot about the need for oral ESBL drugs, so that's exciting. somewhat unique mechanism of action. It's not exactly a beta lactam, but it does have some P B P inhibitory effects. So it's it's an interesting antibiotic. I admittedly need to read and learn a lot more about it, but

Listeners should note that is FDA approved if you're practicing in the states, it's something that may come to your PT committee soon. Um I'll be interested to see where we position this again, oral effective options.

for ESBLs are important, but we have to, as always, as pharmacists, be careful that the in vitro data correlate to the PKPD and the clinical data. I think there's some dosing questions on this drug. I think there's some duration questions on this drug. So I'll be interested to see how that plays out.

And then our second drug, which is in the pipeline, and recently heard from the company that they plan to be submitting soon, uh so soon submission to the FDA for a U UTI designation is jepocyto jepotitocin.

I think that's how you pronounce it. These are both very hard for me. If you listen to breakpoints, you know I'm not good at pronouncing drugs. So let's just say it fast and confidently, Jepotitosin. Uh and this is cool because this is a new antibiotics. We like new mechanisms. So it's a first in class antibiotic. It works.

selectively by interacting with DNA gyrase and topoisomerase four, but it binds to different sites, a different mechanism of action. They're studying it for U UTI and gonorrhea. urogenital gonorrhea. So that's also a global need. And this was studied for U UTI and the Eagle Two and the Eagle Three trials, which are which are both published. You can read those data. I think interesting data that compared it to standard of care nitroferantoin.

Non-inferior, but some GI concerns that kind of played out in those data. But again, in vitro activity against ESBL, a highly bioavailable oral agent. I think these are needs. And so I'm going to ask you guys, my esteemed panelists, For UTI, taking those pipeline agents out and looking at what's currently in our Armamaterium.

It's like it's so funny, right?'Cause we're like, we have all these antibiotics and they're fine. It's like, oh they have each I just give'em an antibiotic. But like actually when you really when you really talk about it, we have nitrofrantine, which is great if it's in vitroactive, phosphomycin, we can talk about. Trimethobrim sulfamethoxazole resistance is pretty prevalent.

Beta lactams are very plagued in the UTI space, which is interesting. Beta lactams seem to just consistently be associated with microbiological recurrence. You have to give them for longer durations. And then fluoroquolone. So um, Jeanette, what's your thoughts on this across your hospitals, across the patients you take care of? What do you think about our current UTI, U UTI options? And really, what do you think the greatest need is for a good UUTI drug?

I think our our current options are like you said. they're old and overused at this point. I mean, we haven't had anything new in in twenty some odd years and so

I think nitroferenton is a great drug and I I do push it whenever I can, especially given the antibiograms in some of my institutions. Because I have different sites, I do have to look at what is happening around their areas because they can be pretty drastically different. Um And some of my nitroferintoin does have lower susceptibilities to E. coli.

But I do find physicians do not necessarily like to use it for some reason. And I don't know if it's because it's a tried and true and they're like, this surely doesn't work anymore. But I do like to push that. Bactrum or sulfamethoxyl trimethoperm does have its issues with more heart failure patients. So if you have heart failure patients coming in, it has drug interactions in those specific patients. And so it does have these areas where it can become a problem. And then like you said,

the resistance is an issue. So if you've used it before, if you use it prevalently in a s in an area, it can have pretty low susceptibilities. I think what we really need is oral. Um, and so we have our one time aminoglycoside that we can use in our hospitals for our resistance, right? That has become more prevalent over the years and we're convincing providers that it's safe um and effective.

But oral would be great because not everyone feels comfortable giving a one time amino glycoside. And so, like you said, our beta lactams are. decent options if there's not resistance. So ESPL obviously fatal actives are for the most part out for orals. But having shorter courses, so three, five days for anyone who's like a young female who is going to be taking these drugs. No one wants to take a drug for two weeks. No one wants to take a drug for ten days.

I barely can take myself a method. So I'll drive out the print for three days. So um we want short course, orally available, and then works for resistance. So ESBL is becoming so prevalent in the community. Um, it's a prime culprit for a lot of our U U T I's that are coming in from outpatient arena, inpatient arena, rehab. So we want ESBL coverage. And w probably even more, we probably want C R E coverage in a lot of these because those are our patients that end up coming to the hospital.

um, because they can't get home health or end up on IVs. And so those are I think the n areas that are major gaps, which is why I think these two drugs aren't are coming up on approval because they do fill a lot of those gaps. And hopefully they work out. Yeah.

Chris, what do your patients need? They're complicated, uncomplicated, right? They are challenging because as I said, resistance is the norm, not the exception. I have to admit that I'm still a huge team beta lactam, uh and and I know you have to give'em longer uh to achieve similar outcomes, but The patient populations I'm dealing with are already taking a lot of medications, so this is just one more. And their pill burden is already high to begin with. Um

certainly if they're institutionalized they have med assistance and so that's less of of a barrier to entry. Um certainly I think we also have options in the institutional settings for injectable that also make it easier. Nobody's gonna be signing up for amino glycosides in my patient population. Even a single dose really gives the geriatricians a heart attack when I Propose that.

Um TMP sulfa, really hard drug, even if resistance wasn't an issue because chronic kidney disease, co-administration of ACE ARBs. and then layer on the amylorite effect of of trimethoprim and you've got a recipe for for hyperkalemia, which is not insignificant, so I think you have to be really careful.

uh with that drug. So I I keep on coming back to the beta-lactams. I think mesillanam is uh gonna be really interesting. I guess I have logistical concerns about how quickly we'll actually see susceptibility panels make it into

the US that allow us to really utilize this drug effectively. Um And uh you know, I I hate to say it, you know, a an oral carapenemum, uh, which, you know, is kind of a sign of the apocalypse, on one hand, is still a a very useful drug to keep in the back of our mind and and I think there's still a lot about phosphomycin. that we need to know more about and we need better susceptibility panel data because it's not a slam dunk with phosphomycin and we're often kind of guessing

whether phosphomycin is still active. So I think we we need better laboratory support to use some of these drugs as effectively as I think they could be used.

So that's clearly a need in my population. But like I said, I think the cephalosporns can still be a very useful drug in this population and you have to get creative. Um uh a lot of time. A non-sachet format formulation would be great too. Like let's not make sachets anymore. Yeah, phosphom phosphomycin is weird and Angela has actually brought to us

Some of the very few R C T data in recent years on optimal treatment for uncomplicated UTI. So she was of course the lead author on the phosphomycin verse nitropharantoin trial in twenty eighteen, was published in JAMA. So Angela, you see a lot of these uncomplicated patients. What do your patients need?

Then tell us a little bit about these treatment options. I mean, you know very well and thank you for generating good comparative effectiveness data for at least two of our options. But what are your thoughts on U UTI treatment? Thank you very much. Uh uh so yes, in the outpatient space it's true we have it a little bit easier, right? Uh because it's mostly E. coli and nitrofrontin looks, you know, like I was saying, very, very sensitive to

um Equoli is very sensitive to nitro, but we also have renal transplant patients, you know, whom Klebsiella loves, right? And then you lose the nitro. So so nitro sadly is not enough. It's just not. Oh, and by the way, I think I just found out that I've been pronouncing nitroferentoin all wrong in English. But uh it's ha using nitroferentoin. I say nitroferentoin. I say nitroferentoin.

Okay. Yeah. I guess I pronounce every letter. Yeah. Oh, okay. So there's just a good car I I I was gonna say nitro. Yeah. Okay, good. Okay, okay. Um so anyway, so I think um yeah. The the results of the study that we published disappointed me, even though we did have um a superiority hypothesis for the Nitro because there were some old data that the FDA had that phosmycin in a single dose format was really not very effective.

So that um informed this hypothesis that we had, which that's the only time I think in my life that the results of a trial actually mirrored exactly what our hypothesis was. We said nitro would be very superior to fuso and it really was, especially in the subset of patients treated with E. coli. So anyway, that being said, I actually still use phosphomycin. Sadly, I am one of those clinicians that easily goes off label with it. Most of the clinicians in my city

just tell patients preemptively, take a second dose. Um, you know, at forty eight hours, take a second sachet. And I have to admit I do that as well, even though I would love not to, because we don't There are some retrospective safety data on that. Actually I think there's even a prospective study from China that did look at multiple doses of phosphomycin.

But um it's not a bad drug, phosphomycin. Everyone thinks I hate phosphomycin and I wanna destroy it because of that child. It's not a bad drug. It's just a PK issue, I think, really. It's just one single dose is just not enough. Depending on the woman, there's a lot of um interpatient variability in in urinary concentrations for I don't know. I'm

The half life is long, but it's Oh, I'm gonna say sorry, go ahead. It might be a bad drug. I don't know. I this is the problem. We could talk oh my god, we could talk for another hour on this. But I I love this conversation because actually so your trial, I was like, Well, why would phospho fail?

You know, and then out of Chicago they did some really nice data in this. CLSI has looked at this from a breakpoint standpoint as is UCAS. And I think the whole n the fact that phospho needs G six P to be activated and there's not G six P in human urine. That really has changed my school of thought for a long time. We just wrote about this in CID in that. the in vivo MICs are actually probably much higher.

And and Chris, I loved your point because I'm a big ops girl. Like I love data and ID and science, but If you can't implement it, if you can't put it in practice to to help patients, it doesn't matter, right? We talk about this with, I mean, totally off topic, but we talk about this with lanasolid therapeutic drug monitoring. Probably a best practice, probably avoids toxicity. But how am I going to give a dose of 450 milligrams when it comes as a 600 milligram tablet that's hard to break?

I I can't. And so the operational piece is so important. And so regulatory bodies working with clinical labs and and hospitals and and institutions and clinics to get new drugs on susceptibility panels to have access to susceptibility testing so that we can actually use them is is really important. I think the phosphosusceptibility testing is very interesting.

But I think the summary and the punchline is that we have a lot of agents right now for U UTI. A lot of them are very old. We've used them for a long time. And so I think there's a a lot honestly like I'll call it a lack of respect for U UTI because people are like, uh, whatever. Pick your poison, like dealer's choice, whatever. There's all these drugs. But as we've talked about, all of the available drugs have something that's not perfect about them.

Resistance is increasing. And so yeah, I would echo oral agents, ESBL active for especially for more complex populations, you know, minimal side effects, minimal drug interactions. This is really the holy, holy grail. And then short course, right? We want not to take something for forever. I would just add to that sort of how we would all define the ideal U U T I drug. I would really add it's twenty twenty four. I would really add the also we need to have a criterion of

what are the effects on the gut microbiota on the resistome, let's say. I really think that this should almost be in the target product profile of these and it's not discussed a lot. It's not even an outcome in a lot of the uh phase three trials. But we have to really think about this. Um, it has to be part of the discussion early on. Absolutely. Thank you for that.

All right, the time has come, breakpoints faithful for the I feel nerdy segment of the podcast. I feel nerdy is meant to be a safe and place and a closing segment for our panelists to nerd out over their favorite ID topics, quirks, and fun facts. So for today's I feel nerdy, can you all please share? And we kind of talked about this, but more globally, what you think your biggest

Biggest unmet need in uncomplicated UTI care is and why. So we just kind of went through treatment round robin, but stepping back, so if it's diagnosis, what have you, what's the biggest unmet need in uncomplicated? UTI care and Angela, do you wanna go first? Sure. So I'm gonna take the viewpoint of my outpatient population to contrast a bit with Chris, I think. I would say we need prevention. And I think because it's

nearly a single pathogen disease in the outpatients almost, right? If you have immunocompetent patients, etcetera. i i i it it's so often e.cole, we need a vaccine. We really need a vaccine. There is one in development. I was very happy to be able to test it in Switzerland and the first in human phase one trial.

Um that was a really cool trial because it was first in humans, so we had to have safety and immunogenicity as our primary outcomes. But it was you it was like recurrent UTI, so we could look at the incidence of actual recurrent infections in this very healthy population as well. So that vaccine was made in Switzerland. Very proud of that. And then it was bought by Johnson Johnson, uh Jansen, uh, which is

Full disclosure, I'm an unpaid member of their steering committee because of my experience with this vaccine in the very early phase of development. So I know it's in phase three uh right now. It's a conjugate vaccine, so it it seems to be quite immunogenic. Um, but I I hope it works. I mean I I'm obviously I have is some bias because I worked with it and I really think the world could use a good E. coli vaccine.

But um that I think a lot of people are pinning their hopes on that vaccine. And then beyond that, actual treatment, I I would really love to see more clinical development, more research uh and development. of non antibiotic approaches. Barbara Trouner has done some really interesting work with bacterial replacement therapy, you know, like finding a way. Right, back to thank you, back to bacterial interference and

Um, you know, now she's working a lot on phage therapy. You know, there have to be other alternatives. We are hitting the wall with antibiotics. Um lactobacilli, a lot of good work done with lactobacilli, but it's

It's never really quite funded enough. So these trials are often very small. They don't have enough statistical power. So there's still so many unknowns. So I I really would hope to see more work done in non antibiotic approaches. Awesome. Thank you so much. That's fascinating. Chris. What's our biggest unmet need? The unmet need is is that CLSI and the FDI can't get on the same page. Um now they're gonna get rid of lab develop tests.

Uh so you know the the thing that blows my mind is that surrogate marker of whether you can use oral second and third generation cephalosporins is cephazolid. which blew my mind when I first kind of saw that. Now whether or not that is accurate or not, or appropriate from the clinical application, I think is an open question, but the FDA is saying they disagree with that as the surrogate.

marker and as a result, labs are not running appropriate secondary surrogates. So if I have cefazolin resistant, that means a drug like cephyroxine, cephadoxine, um are off the table according to CLSI, but labs are non then not running an appropriate second level surrogate. So until we have better non beta lacteum drugs for treatment. I would love to see CLSI and FDA get on the same page and have appropriate laboratory reporting.

to allow me to make better decisions of about, you know, whether I can use a second or third generation or ocephalosporin for treatment in these patients where we see cephalin resistance quite commonly. And I can't even get with many labs an uncomplicated UTI breakpoint reported out for Sabaslin'cause they're only using the systemic, you know, two four eight rather than the sixteen thirty two.

Um, which is is what CLSI is recommending. So I would love to to see some research. That is so true. It's a struggle and I I'm sure you guys saw the ruling. The FDA is getting rid of lab develop tests, which is well meaning, I'm sure, but it will destroy the micro community. I mean, it'll be very, very challenging. So we'll see how that un unfolds.

Okay, Jeanette, last but not least. I'm trying to think of an I feel nerdy that doesn't involve any of the things that were just mentioned because the cephazolin thing really does irk me a lot. Um it I will say in practice I like your general hospitalist does not know that information. So they see ceftriaxone susceptible and they're like great, sepodoxime. So or ceftonir for the most part, most of the time actually.

To be honest, that's what happens is it sept tracks on the circle. They're like Seftonir and then they send'em home. So definitely not happening in practice. And then they and then they come back to the hospital because they Because they got sent home on Septonir. 'Ca'cause it might not actually be a mission to get rid of that drug. It's the cheapest one though, so that's why they prescribe it. Yeah. It's fine. It's PK is like is has a half life of like four minutes. Terrible.

Good good stuff. Good stuff. The ideal antibiotic. They will if you miss your patient and you want them to come back, give them ceftonir. Ugh. Well if our goal is to adversely impact the resistome without actually improving the bunch of third generation civil sports.

Oh man. But yeah. This is why single single dose amino glycosides. I've said it before. I'll say it. I mean, in the hospital it is I think our best option, especially in transitions of care. Just give them the the one time dose and and send them out. But I I do think diagnostic uncertainty is one of the biggest unmet needs and it's one of the cruxes that kind of pins stewardship teams against

your general clinician because they're in front of the patient and they're like, I don't know if they have symptoms. They can't describe the symptoms. the UA is quote unquote positive and stewardship teams are calling it asymptomatic bacteria, but frontline clinicians are like, My patient is sick and so what am I gonna do about it? And so any way we can improve diagnostics and create some sort of certainty around those to make it a little bit easier, especially in some of those more

unique populations that can't necessarily like Chris's populations, for instance, who may not be able to describe their symptoms to you, or they always have symptoms. And so what are you gonna do with that? I think that was one of the really great things about Sinali's paper is when you ask a provider, Should we treat A ASB? they'll say of course not. They don't think they're treating ASCII.

when we come in and say you're treating ASB and and so I actually have to admit that I initially rolled my eyes when I saw the graphic from her paper in my Twitter feed. I'm like, great, we're making something that's already complicated more complicated, but When you cone into it, I actually really liked that stratification. And when you look at the impact it has two thirds of the ASBs move into this back to you of uncertain significance. And I think focusing on how do we better manage

Uncertainty is part of where we need to focus. So in our nursing home interventions, we're using a lot of Delayed action. protocols that follow clinical trajectory, which I still, you know, across all aspects of medicine, that is your best diagnostic test is patient clinical trajectory. And it's hard because it means you have to monitor the patient.

over various time points and it's probably why Angela's taking this very detailed history to better understand, you know, what has been the sequencing of events to confirm that indeed this patient has UTI. So we spend a lot of time saying, get comfortable with uncertainty and here's how you manage uncertainty, rather than kind of giving the illusion of certainty, which I think is the mistake that we make in medicine, saying, Well,

Are they gonna die if we do nothing right now? I is the basic premise that I start with. And if the answer is no, then I've got time to be wrong. Let's give it another day or two. And if they self resolve, great, we're done. if they progress, you're gonna be there, you're gonna be able to sweep in. Now that's not feasible with transitions of care and that's a really

difficult issue where you're handing off a patient from one setting to another. And so we haven't cracked that nut, but in the nursing home we do a lot of behavioral approaches to try to better manage uncertainty because I think it's a false goal to say that we're gonna have certainty. We just won't. Uh we have to get compliments. I mean patients believe they're doctors. When you give them a diagnosis, they really hold on to that. And so then if you change it later that's

That's uncomfortable as well. If you say, We're really not sure, but we're on this journey with you, I think they really appreciate that um and are in tune with with their symptoms. So This was a fantastic discussion, guys. Thank you so much. I think we've transcended everything in uncomplicated UTI from diagnosis to treatment.

uh what we have, where we're going, and I cannot thank you guys enough for for how rich and valuable this discussion was. I loved it. It was a fun, fun time. And with that, thank you for listening to Breakpoints, the Society of Infectious Diseases Pharmacist podcast. This educational activity is supported by an independent medical education grant from GSK. I have been your host, Aaron McCreary.

And Breakpoints was created by Julie Angusto, Aaron McCreary and Jason Pogue. This episode was produced by Jeanette Bouchard and Megan Clatt, edited by Nick Torney and peer reviewed by Jenny Thomas and Jeff Butler. Your fabulous panelists today one last time were Angela Huttner, Chris Cernic, and Jeanette Bouchard.

I am the executive producer of Breakpoints. Our theme song was recorded by SIDP member Steve Smoke. And you can subscribe to Breakpoints on Apple Podcasts, Spotify, or wherever you get your podcast. Thank you for listening and helping SIDP achieve our vision of safe and effective antimicrobials for now and the future.