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[00:00:07] Angela: Hello, and welcome back to Communicable, the podcast brought to you by CMI communications, ESCMID's, open Access journal, covering infectious diseases and clinical microbiology.

[00:00:16] Angela: My name is Angela Huttner. I'm an infectious disease doctor at the Geneva University Hospital in Switzerland, and editor in chief of CMI Comms. I'm joined by my co-host, Erin McCreary, fellow editor at CMI Comms and Director of Infectious Diseases Improvement and Clinical Research Innovation at UPMC in Pittsburgh, USA.

[00:00:36] Erin: Hey Angela. So happy to be back with you and our esteemed guest today to discuss the long anticipated release of the 2025 IDSA complicated UTI guidelines. And so this is something that has truly been challenging for clinicians for decades, and even today when we read literature and we look at patient populations and we say, what exactly do we mean by complicated, uncomplicated, how was that defined in the study?

[00:01:00] Erin: And it's been really all across the board. And now we have more clear marching orders from the release of these guidance documents. So we're very, very excited. first, let me introduce our very first guest, Dr. Barbara Trautner who' s an MD PhD and the co-chief of the Division of Infectious Diseases at Washington University in St. Louis. She's affiliated with the Houston VA Medical Center and the St.

[00:01:22] Erin: Louis VA Medical Center as well. Dr. Trotter's work is focused on urinary tract infections and antibiotic stewardship. Dr. Trautner is very passionate about animals, even the very smallest ones, like bacteria. And so she's a champion of using antibiotics only when needed. Dr. Trautner, welcome to Communicable.

Thank you.

[00:01:40] Angela: Second guest is Professor Valéry Lavergne, Canadian Infectious Disease and Medical Microbiology specialist affiliated with the Division of Medical Microbiology and Infection Control at Vancouver General Hospital and University of British Columbia in Vancouver, Canada. since 2017, Valéry has worked as a guideline methodologist for the Infectious Disease Society of America.

Hi everyone. Thank you very much for having me here, and it's a pleasure to meet you.

[00:02:07] Erin: you, Angela, you were also an author and you're hosting today, but I think it's so, so important that you're a part of this discussion. And really I'm honored to be with all three of you to discuss this tremendous effort.

[00:02:19] Erin: But before we get started, as our communicable listeners know, we like to begin with a get to know you type of question. And Angela and I just had the opportunity to meet in Rome, Italy for the CMI comms editors meeting. and so I've been dreaming of pasta and gelato ever since I got back,

so we have to ask and kick this episode off with what is your favorite food? Or you can also tell us a story of the best restaurant you've been to in one of your travels. Barbara, do you wanna go first?

[00:02:44] Barbara: Sure, but I'm gonna go with favorite restaurant.

[00:02:46] Barbara: in Houston. And it's a Cuban restaurant that's family run. And so the current owner is my age, but I used to go there in high school when his dad was running it and Awesome. I mean, they're, black beans. They're vieja, they're fried plantains.

[00:03:03] Barbara: We have them cater every event, including, one of the parties leading up to my daughter's wedding. They call it Maison, like the table,

[00:03:10] Angela: Yeah. I love that two families grow together and yeah, it's beautiful.

[00:03:15] Angela: Little longevity there.

Valéry,

[00:03:18] Valery: from my side, I think I'm gonna have to go with a specific dish, which is a pizza that you can find in Curry Village in Yosemite Valley. And the pizza is absolutely awesome, but usually when I eat it, I've been like four or five days into the wilderness eating, dehydrated food, being super hungry, super hot.

[00:03:37] Valery: So that pizza is absolutely amazing every time, with a big lemonade and like ice cube, like you cannot believe Ice cube is like such a beauty thing when you come from the wilderness. So that would be my favorite dish.

[00:03:50] Erin: You know what's so funny? This is the most American thing I'm ever gonna say. like, ice is only a thing we do in America routinely, right? Like when you go out to eat in Europe, they do not bring you ice. And so when I come home, the thing I want the most is like a big glass of ice water.

[00:04:05] Angela: Turning to these glorious guidelines. Barbara, let's go back to the beginning.

[00:04:10] Angela: Can you share with us, what was sort of the genesis of this update? when was it decided that it needed to be done? Of course, we all know the last standing guideline was from 2010. It obviously needed to be done, but when was it, decided, okay, we need to do this. And when did you and Valéry come on board?

[00:04:26] Barbara: It's gonna go way back. in 2018, IDSA put out a call for people who wanted to work on the guidelines. since I live under a rock, I didn't see it, but Nico Cortez Penfield forwarded to me and said, you'd be really good at this.

[00:04:39] Barbara: Why don't you volunteer for the panel? and I was pretty excited So like, the bottom line is and I submitted that and I got accepted and then was, co-chair, with Valéry and I didn't know how that was gonna go.

IDSA had just gone to making sure that there was rigorous methodology that had happened in the middle of a previous guideline we were working on. So IDSA wanted to make sure that Valéry and I met up front and were really clear that we were partners in this and we were gonna follow the methodology.

[00:05:06] Barbara: I was like, I don't know who this person's gonna be. So we meet at ID week of probably 2018. It was just like we were so ready to work together. It was like a meeting of the minds and the right personalities and very complimentary skills, she won't let me say things that I wanna say just because I feel like saying them if there's no actual evidence behind them. And that's a good thing to have on your guidelines. co-chair, situation.

[00:05:29] Angela: Yeah.

[00:05:30] Erin: That's really neat. So they connected y'all two. And then, did you at that time know all the rest of your author group too? Did you get a hand in selecting them or IDSA picked the author pool from all the applications and then asked if you guys wanted to co-chair the process?

[00:05:44] Valery: so initially, like Barbara said, there was a shift that happened at IDSA where we tried to have great methodologists involved in more and more guidelines.

[00:05:51] Valery: And that's how, this guideline is so important that we wanted to have a co-chair as a methodologist as well. So I'm not gonna talk about any expertise, like Barbara said, we have different, strengths and limitation, the expertise is Barbara. But, the process, basically what happened is that there was a call, for panelists and, there was a lot of submission.

[00:06:10] Valery: We review, the cvs, the. People that wanted to participate as a panelist and then, they had to fill the COI format that. It's a very rigorous process. after, looking at all the, potential participant, we had to submit a list and the SPGC, which is the Standard Practice Guideline, committee, needed to prove, all the panelists and then it went to the board for final approval.

[00:06:32] Valery: So it's a very rigorous process to make sure that we have, diversity and, from different geographical, sites, gender, different type of practice, and also different type of specialties. So that's why we do have infectious disease, but we also have hospitalists. We have emergency, medicine, physician.

[00:06:51] Valery: We have a gynecologist that were obstetric specialists that were involved as well. so we try to have as much representativeness as possible.

[00:07:00] Erin: It's such an honor to be a part of it, but it's a lot of work that you volunteer for, right.

[00:07:03] Erin: Years of your life writing this document. So when you put your name in the hat and you're like, I wanna do this, what was your main goal in starting this? What were you hoping to answer with this particular document on complicated UTI? Did you have a personal favorite PICO?

[00:07:16] Barbara: Let me just say a little bit about the selection process.

[00:07:18] Barbara: IDSA had thought it was important to not just go back to the prior panels, but to open things up and make it more inclusive. So that's why Valéry and I were choosing among a panel of people that wrote in and volunteered, for this, because it is time to get different perspectives on this. our original thought was to update the uncomplicated UTI guidelines from 2010 Calpana Gupta.

[00:07:41] Barbara: The lead author is one of my mentors and friends. I thought we were probably going to start with updating that. I mean, that was our plan, but when we wrote out our clinical questions, we decided to start with complicated UTI, the questions that we'd written around that rather than uncomplicated UTI, because there were no guidelines at all for complicated UTI, which meant that men in postpartum or postmenopausal women weren't covered by any set of guidelines.

[00:08:13] Barbara: And we thought we would address that first. We just didn't know it would take so long. we got the whole panel chosen by sometime in 2019, and then everyone had to get trained in grade and we kind of got up to speed and then, you know, what happened right after 2019. And so nobody did anything very productive other than we did some of the literature reviews between 2020 and 2022, but no one really had bandwidth to dig into writing the guidelines.

we had the new definition though, but I don't wanna, jump ahead, but I think before COVID came, we did have the new definition, which to me was super exciting. And I think we had all the PICO questions. At least you're

[00:08:54] Barbara: right. We had to write the framework and write the PICO questions and to write the questions.

we don't have to call 'em PICO just to write the clinical questions that we wanted to answer. We had to decide what the population was that we're going to address. And so that's where we got into complicated versus uncomplicated. And then what constitutes complicated versus uncomplicated?

[00:09:14] Valery: And then after we kind of assess all the clinical question that we really wanted to answer, there's also a process where we decided to make the panel vote on which one should be prioritized to be answered first. ' cause we cannot answer all the question unfortunately.

[00:09:28] Valery: We need to choose. And that's how we ended up with the three PICOs that you see. And there's a fourth one on imaging that is, hopefully, coming this fall. that's how we ended up with those specific questions for complicated UTI.

[00:09:41] Angela: Valéry, can you actually define PICO for some of our listeners? Because we have a lot of clinicians, we have, a,

[00:09:46] Angela: Diverse population of listeners.

[00:09:48] Valery: So a PICO question is basically a clinical question that we wanna answer.

[00:09:52] Valery: p stands for population. So like Barbara said, we have to make sure which type of disease we're talking about. Is it complicated versus [00:10:00] uncomplicated? Are we talking about male women, which age? So everything that is very specific to a subpopulation that we wanna address, I is for intervention. C is for the comparator.

[00:10:10] Valery: So sometimes the intervention versus the comparator could be different agent, or different duration or, for example, continuing oral, iv, parenteral therapy versus, transitioning to oral. So these are different comparison that we can look at. and O is for outcome. So, basically outcome, what we do is we assess, which one are important for the patient, which we call usually patient important outcomes.

[00:10:34] Valery: And again, this is another process where we look at which one are the most important for patient at the end of the day, and we rank them for, the importance. sometimes, like, let's say mortality is critical, for decision making. but let's say having a minor rash, might not be considered important, for the assessment of our comparison.

perhaps one of the biggest headlines to come out of this new document is that updated definition of complicated versus uncomplicated UTI. So can you remind our listeners what was complicated UTI before and , why did we choose, the new definition?

[00:11:12] Barbara: It's interesting because this is, I agree. It's one of the big headlines. This part is not grounded in evidence. Like we didn't do a literature search on this because we're redoing the definition. So there's no literature search possible on that topic.

[00:11:29] Barbara: We simply aligned with clinical practice in our definitions. If you. Think about how clinicians decide to treat someone with UTI, whether or not the infection is still in the bladder or beyond the bladder is one of the most important deciding factors in how you're going to manage that.

[00:11:48] Barbara: And so we made uncomplicated UTI is confined to the bladder and complicated UTI is beyond the bladder because that affects everything. what antibiotic would be the appropriate choice? What's the setting for the treatment? Maybe how long you need to treat is impacted by that as well. So we didn't do anything revolutionary.

[00:12:07] Barbara: Like if you looked in up to date or if you look at the, European Urologic Association guidelines, they're all really saying this same thing. It's just that we differ so much from the FDA guidance on how you design a clinical trial about UTI, that I think it shook people up of it.

[00:12:23] Angela: Yeah. this new definition is so intuitive.

[00:12:26] Angela: I think as clinicians, we've always wanted it to be like this, right? Like, cystitis is not, terribly complicated. it's still a localized infection. whereas anything outside the bladder does become a systemic disease. it changes your antibiotic options. we've been working with this clinically for so long, so it's nice that a guideline caught up to that.

Valéry as the anchor and the methodologist behind this. How did you feel the big headline around the whole document being probably the least evidence-based?

[00:12:57] Valery: Well, actually this is probably one of the most important piece to start with 'cause right, the thing that, you know, if you wanna look at the evidence and interpret it correctly, you need to define your population.

and that's good that it came early in the process., 'cause When we read a paper, when we look at RCT is the population that we look at in that evidence, is it corresponding to our definition? And the whole guideline is based on these definitions.

[00:13:21] Valery: So there's a practical aspect to it, as Barbara said. But at the same time, for us to make sure to really assess the evidence appropriately, we need those definitions. So That was a really critical step, to be able to implement as a starting point.

[00:13:35] Barbara: We felt strongly about, in the definitions is they need to be applicable at the point of care to the general practitioner.

this idea that if you have a urologic abnormality, it's a complicated UTI. Okay. First of all, what is a urologic abnormality? Would that be a grade two cystocele? Would it be benign prostate hypertrophy? If so, how much and how is the person at the point of care going to know that the person has a cystocele or has some reflux of the urine, or BPH, how do they know if you have a small non obstructing stone?

[00:14:04] Barbara: So we're just like, if you can't see it at the point of care, it's not in the classification. On the other hand, you can see a nephrostomy tube. That would be complicated,

[00:14:13] Erin: to your point, it helps more people on the care team better understand what exactly is going on, and then we can all collaborate to make better patient-centered decisions around what treatment is necessary.

[00:14:22] Erin: So moving into that, and I think, Valéry, you made the point, so, well, you have to define this population first. You guys defined it, so now let's treat it, and that's kind of the next step of this document is, you guys as an author group introduced a four step approach to therapy, which in general, I really like, we like checklist medicine, right?

[00:14:40] Erin: People function better under this. And you say, number one, you need to assess severity of illness, two risk factors for drug resistance in the infecting pathogen. Three patient specific considerations. And then four, whether the patient has sepsis or not. And if they have sepsis, you'd take into consideration more your antibiogram and what your empiric agent is.

[00:15:02] Erin: You have a smaller window to get it wrong, right? The likelihood of having active therapy on board becomes more important, the sicker the patient is. So you guys stated that if you have sepsis, then you can choose from a third or fourth generation cephalosporin. A carbapenem or piperacillin tazobactam or a fluoroquinolone.

[00:15:20] Erin: And then if you're not septic carbapenems are not an option anymore, but those other drugs are so a fluoroquinolone, pip tazo, or cephalosporins as are empiric IV therapy options. Although, you guys said if the patient's not septic, you can also potentially start with the oral route, which is a bit of a change, from most guidance, including pyelo that would say you gotta get at least one dose iv, which came kind of from nowhere.

[00:15:44] Erin: And then, you could potentially go to oral. But we'll come back to the oral transition. But can you describe for our listeners why you as an author panel decided on this four step approach and how you landed on those drug classes as your empiric options?

[00:15:59] Barbara: as you might well imagine, we had lots of trials to work with, many new drugs come to market under the approval for UTI. A lot of the new gram negative drugs.

[00:16:09] Barbara: So we had, really a wealth of different trials to look at and review. Well, they were all designed as non-inferiority trials according to the FDA guidance. So what you get is you get a whole bunch of trials that say Drug A is not inferior to drug B. But what Valéry Astutely noticed over time is the drug, called drug A, the old drug, and drug B would be the new drug, right?

[00:16:31] Barbara: So at the start of our literature review period, there'd be a drug A and a drug B. Well, like 10 years later in our literature review period, drug B would now be the old drug. A drug C would be the new drug, right? And we noticed that the drugs were becoming less effective, over time due to rising resistance.

[00:16:49] Barbara: And so we thought, you know, if we just recommend specific drugs, our stuff is gonna be outdated before we can even get around to updating it. So that we needed a process to choose rather than a specific antibiotic recommendation. So that's why we wrote the four steps.

[00:17:06] Erin: Oh, I like that. That's really insightful.

[00:17:07] Erin: Thanks for that background. Was there conversation on, and I know later in the document we talk about the data supporting antibiograms, but what if I work at like a community hospital and like rural Montana that has like never seen a drug resistant organism ever or what have you, and say my institutional antibiogram, my e coli susceptibility to cefuroxime is a hundred percent.

[00:17:29] Erin: I mean, in that setting, even if a patient comes in with sepsis, could they use that or are you saying, Nope, everyone has to go broader for this initial encounter. And I guess related, my question is, did your group talk about the most common causes of UTI, which of course e coli up there, but then, in enterococcus is not an insignificant player in UTI and you know, some of these empiric.

[00:17:51] Erin: Have in vitro activity against enterococcus, some don't. So was there any dialogue around that in picking these agents? Or was it strictly limited to like, which drugs have been studied in RCTs for UTI?

[00:18:03] Barbara: Oh, there was a ton of dialogue around that. In fact, when I speak about these guidelines, I like to give people insider tips because that's where you're gonna find our discussions.

just take the whole document and search for implementation issues or taking it to the bedside. And that's where we record the discussion that the panel would have about, well, what if it isn't e coli? How would you know that? Or what if you don't know what organism the patient has?

[00:18:28] Barbara: How do you apply the antibiogram? So you can find our thinking in that clinical question. One, if you search under implementation issues or taking it to the bedside.

[00:18:36] Erin: Love that you included that section. So that's really insightful. So read beyond the executive summary and really dig into the author's thoughts in those sections of the document.

[00:18:44] Barbara: Yeah. Just go to clinical question one and search for those. It's called implementation issues. there's not as much thought into it. There weren't as many controversial things in the other two questions. So it's mainly in question one.

I have to confirm. I love That this four step approach was sort of formalized officialized, I guess. we're doing it of course, in clinical practice, right? These four things we are always doing we are always assessing the patient's severity. We're always thinking about the host risk factors, et cetera. But this is just a very nice way of formalizing it, of saying, okay, you know, take a moment, you know, do this systematically.

[00:19:18] Angela: It creates that framework. for people who may not be as experienced, we're all ID people, right? But the people who will most consume, let's say this document, are not ID specialists. that's why we're building it. So. it's just really nice that it's sort of this permission structure to, take the time, do this, be systematic about it.

[00:19:37] Angela: And I think it will probably be useful for other infections. Right. we should be doing this all the time, not just for UTI. .

[00:19:44] Barbara: You

[00:19:44] Barbara: asked about small town, no resistance, septic patient. Would you start with cefuroxime, a non septic? I think, yeah, you can give it a try, but septic, I don't think we were feeling comfortable with the oral beta-lactams.

[00:20:00] that didn't come up in our evidence base as starting. Yeah. With the septic patient ceftriaxone though, that's why Ceftriaxone is still in there among the preferred 'cause there are a lot of settings where there's not a lot of resistance to ceftriaxone. Yeah. And we know it works well for pyelonephritis based on evidence-based trials that are for the most part earlier than our review period.

[00:20:19] Barbara: But we do have a section, another insider tip on the clinical question one, which is very long. If you wanna know about a specific antibiotic, just search for that name. There's a section on ceftriaxone, there's a section on fluoroquinolones, there's a section on cefiderocol phosphomycin. Just search and read the like three paragraphs about that particular antibiotics, use in uti.

[00:20:39] Barbara: I.

Yeah, absolutely. And I apologize. I was definitely thinking IV cefuroxime, but the point is super well taken so you either way, , I represent a pretty large, hospital system and what we struggle with is we have one order set for you present to the emergency department with suspected polynephritis. There's one order set but I have 37 hospitals and , their local resistance patterns are, quite different. And so. The dream would be for it to be dynamic based on the institution.

[00:21:03] Erin: Here's your empiric drug here with your local antibiogram, and here's your empiric drug here with yours. 'cause I span a very wide geographic footprint in my health system. So just things we've been thinking about as we go to operationalize these guidelines. So I appreciate the insight

[00:21:17] Barbara: if you're going to operationalize it.

[00:21:19] Barbara: Is there any way to build in some of the four steps, like knowing the patient's prior urine culture mm-hmm. Is the most important factor to guide your choice.

[00:21:27] Erin: Absolutely. That's another question we wanted to bring up is really looking at the patient in front of you, they're gonna declare themselves first and foremost.

[00:21:35] Erin: And that patient specific information is always going to be superior to a general population based guidance document. or guideline. I think you guys say, if I remember correctly, the lookback period for patient specific cultures, you defined as a median of three to six months. There's also a caveat in here about avoiding fluoroquinolones if a patient has received a fluoroquinolone in the last 12 months.

[00:22:00] Erin: I will tell you in clinical practice, we get this question every single day. How far back are cultures relevant and what is recent drug exposure to be worried about, okay, you've already failed or been exposed to that. Now it maybe has the propensity to be more resistant. And so can you tell me a little bit more about how the authors came to these timeframes of this median three to six months is relevant and then this.

[00:22:24] Erin: Fluoroquinolone exposure in a year. And were there any other time cutoffs that were entertained or discussed?

I can give a little bit of background on what we did exactly to at least, start drawing these conclusion at that four step we basically went to the literature and we search for all risk factors of resistance, that we can identify for the last 25 years or so.

[00:22:46] Valery: and we looked at cities that were really specifically looking at the complicated UTI or at least included some patient that had complicated UTI. we really avoided the uncomplicated UTI, population as much as possible. we identified. All the risk factor that were coming up in multivariate analysis.

[00:23:04] Valery: there's caveat to all these decisions, but these are judgment that we made. we, try to identify those that are risk factors that were, considered significant and they were reported in multiple papers with a significant findings. So, that's how we, came up with prior exposure to antibiotics.

We had, a signal for, trimethoprim Sulfamethoxazole and for fluoroquinolone. For Septra, or bactrim. It was like a weak signal as opposed to fluoroquinolone, that was a, really stronger signal. What we can tell is that all these studies, unfortunately, uh, report different time and they're all observational studies, so we have to live with what the evidence is providing us.

[00:23:41] Valery: So we try to provide what seems to be the more frequent timeline that was reported. But people need to have their clinical judgment and say, well, the closest you are to an event, the more likely it is. we can see in all the tables that we present in the guideline that odds ratio are higher when well exposure to fluoroquinolone is, more recent than when it's back in time.

[00:24:02] Valery: Same thing for prior urine culture. We did a similar strategy and the same thing we had up to six years sometimes of prior culture or some other studies were shorter time. And again, the clinician needs to use this judgment where, If you have, a more recent culture or repeated culture, or a negative in culture in the meantime these can influence your decision of what is significant.

there is no precise timeline, unfortunately. So we try to give some advice on what seemed to be the most useful for clinician. but Barbara, I don't know if you have a little bit more input on the timing, but I think it was really hard for us to, be more precise than what we did.

[00:24:39] Barbara: Valéry explained it well.

[00:24:41] Barbara: I have a slide that I use when I'm presenting the guidelines. It just shows why we came up with these different timings. It's because that's what the duration was, that people went back in different studies and it was a different duration for some risk factors than it was for others. And fluoroquinolones, the most commonly chosen duration, I think was 12 months.

I think the bottom line is the resistance mutations are essentially archived in organisms, in our guts. And so I think if you've ever had resistance in a culture, it's fairly likely you still have a resistant organism somewhere. However, if you have more recent cultures in a series that shows susceptibility treat based on the more recent culture, and we definitely have a dose relationship between how recent a culture is and how likely it is to predict resistance to a specific antibiotic or susceptibility to a specific antibiotic.

[00:25:33] Barbara: I have a slide on that too, and it just shows that as the time interval shortens that urine culture is more predictive.

[00:25:39] Barbara: But also keep in mind that. Everyone chose different risk factors to study, you know, and a lot of people decided they wanted to study fluoroquinolones far more so than any other antibiotic. And so right fluoroquinolones comes out as a strong risk factor. 'cause it showed up in so many studies. But I think that's just because people weren't all that interested in looking at like, if you had ceftriaxone resistance in your urine, where you still resistant to ceftriaxone.

[00:26:00] Erin: Well, we love to hate fluoroquinolones in the stewardship world. Right? I don't hate them as much as most pharmacists, and I think they do have a role. actually, Angela, I'm gonna ask you a question.

I know you're hosting, but as a, physician who runs a UTI clinic and also an author on this document. we have been taught that fluoroquinolones are evil and avoid them for uncomplicated UTI at all costs, which we agree with, right? We have a lot of reasonable options for uncomplicated UTI, but for complicated, here they are first line, right?

[00:26:27] Erin: Even in patients with sepsis. And so Talk to me about that as a, guidance author and, looking at the evidence as a clinician. I mean, is this the infection where fluoroquinolones it's a good drug still?

I would say I have this love hate relationship with quinolones. I mean, they're really such great drugs.

when you need them, of course, when you have a target, But they can be so detrimental to everything on the sides of that target, , anything that's, sort of around that target. And that's the real problem.

I fully support, sparing, quinolones for, uncomplicated UTI nowadays we really need to find other solutions. There's just very little reason to use quinolones for an uncomplicated UTI, much as possible, obviously, I mean, allergy and, when they need to be used, they should be used.

[00:27:13] Angela: But for very short durations, for complicated UTI, those certainly for pyelonephritis and of course in men prostatitis, which we did not address in this guideline, but which is a reality we have to deal with every day. they are so valuable, like this precious golden, double edged sword. They are so good, but they are so dangerous to your intestinal microbiota. they can hurt you later. that's why I try to avoid them.

I'm happy to talk about this. I'm old. So fluoroquinolones were like the big deal when I was a medical student, they were good for everything.

[00:27:50] Barbara: I mean, mycobacteria, UTI, they still are pneumonia. They were fantastic. Everyone in the ICU back then, ID doctors could be the ICU attending too, at least at my medical school. our attending had every single person on a fluoroquinolone and they were working. I mean, tissue penetration is fantastic.

[00:28:07] Barbara: They resolve the urinary symptoms rapidly. So what I wrote in the guideline draft, Fluoroquinolone were at one time humanity's best defenses against urinary tract infection. Let us learn from this example and prevent loss of other drug classes that can be used to treat complicated UTI. they got cut out because they decided it was too emotional.

[00:28:26] Erin: Oh, that is beautiful. I don't think that's too emotional. I think it's great. I should have

[00:28:30] Angela: been your editor. I would've loved it. We would've kept that in.

That's why we podcast. That content comes here.

So seeing the fall of fluoroquinolones is such a sobering lesson. seeing that they have essentially lost so much effectiveness because of rising resistance, because of overuse is one of the sadder things I've seen happen in medicine.

[00:28:50] Barbara: we wanted to keep 'em in the guidelines. There's a lot of evidence. I mean, fluoroquinolones, were brought to market with a ton of UTI registration trials and all sorts of different durations and formulations. So lots of evidence about how well they work and they do work well when you've got a urinate organism that's susceptible and the bug is in the tissue somewhere.

[00:29:10] Barbara: but there's so much resistance to them, and then they do have the side effects. So anyway, that's why they're still in the guidelines and why I think it's a very sad and cautionary tale. What happened with fluoroquinolones. I will say, though, I can give a little note of happiness here because I'm in a country where we are religious about sparing fluoroquinolones.

[00:29:29] Angela: especially in hospital settings, we try very hard not to use quinolones inside hospitals because we know that the hospitals that do use a lot of quinolones end up having, higher resistance rates in general, more c diff, et cetera. and when you stop using quinolones to that degree, those resistance rates really do go down.

[00:29:48] Angela: Mm-hmm. So you can get them back, you can get their effectiveness back, by preserving them, putting them on the shelf by treating them as the precious thing that they are.

I mean, if I personally [00:30:00] have pyelonephritis, I want to be in the hospital, zero days, I don't want anything in my arm. I wanna go home on an oral antibiotic.

We don't want patients on IV antibiotics if they don't need to be. And so a fluoroquinolone, we have ample data to support that, that is an excellent choice. And I think I would take the known risks of fluoroquinolone exposure over having a line in me or being in the hospital. But that's my choice as a patient.

[00:30:24] Erin: And we'll come back to the patient perspective too, so you guys included oral step downs, fluoroquinolones, trimethoprim, sulfamethoxazole, good data, high oral bioavailability. These drugs work when the infecting pathogen is susceptible. So we have to be judicious with our antibiotics.

[00:30:38] Erin: But you also do include beta-lactams. And I know this is extremely controversial. I know there's RCTs enrolling right now to try to talk about this. We talk about it all the time. can you use a beta-lactam for e coli bacteremia for e coli pyelonephritis? Where did you guys land in the guidelines?

[00:30:53] Erin: So tell us what they say and then you can please pepper in your personal thoughts and experiences especially if it differs from the totality of the evidence.

[00:31:01] Barbara: I'm gonna channel my inner Cal Gupta. All right. do

[00:31:04] Erin: love Cal too. Yeah, she's amazing too. ,

[00:31:06] Barbara: She did a lot of those trials with uncomplicated UTI or her direct mentor at the time. Walt Sta did them and also some Mac Hooten. Let's give them all some shout and Stapleton.

when you looked at those old trials, it would be like a beta-lactam versus a trimeth m su methol or a beta-lactam versus a fluoroquinolone. The beta-lactam arm always did worse on uncomplicated cystitis, and so there's a reason to think they aren't as good, at resolving symptoms and preventing recurrent UTI.

[00:31:36] Barbara: As the others. There are many potential explanations, but that's just an observation from older clinical trials. Now, those were cystitis trials in women, whether it extrapolates now, it's hard to say. we didn't do a systematic review on this and Valéry and I can comment on it.

[00:31:51] Barbara: We did more of a narrative review on this topic, but there is a signal that the oral beta-lactams, particularly at lower doses, which were our prior standard doses, are not as good for UTI. But the problem is in all those different studies that we looked at, they were measuring different outcomes for what define success in UTI.

So that's why we can't come out and combine it and do some kind of meta-analysis. Valéry, do you wanna comment more on the oral beta lactam? Lack of evidence?

Well, like you said, we, didn't do a formal clinical question on this, that was a question that was raised during the, review process to have more information about that and the fact that we also have a restricted number of clinical question allowed to be answered, just for, workload purposes, at IDSA.

There's a subgroup, within our subgroup of complicated UTI that looked at all the evidence and it was basically all, observational studies and there were no RCTs really answering that question. So that's why we opted to at least comment on it. 'cause people really are.

[00:32:51] Valery: Worried about that and you want some sort of guidance. but hopefully we'll be able to do a formal systematic review, meta-analysis on that topic, and, maybe develop more, systematic recommendation on that.

[00:33:02] Erin: Yeah, in pharmacy land. we love a beta lactam, right?

[00:33:05] Erin: They're relatively safe compared to other agents. They're effective for all other infections. But yeah, if you really look at the urinary tract infection literature, beta lactams don't necessarily pan out and no one wants to talk about that. It's why in the uncomplicated UTI guidelines, the duration of therapy for beta-lactams is seven days and everything else is three, right?

[00:33:24] Erin: They just seem to have more micro recurrence Layered on top of that, I mean US cast in the United States the EUCAST, affiliate. They just came out with a really robust PKPD reanalysis of the oral beta lactams and there is no breakpoint because they are not efficacious.

I think increasingly when we try to look at step down therapy and we're looking at anything more than seven days and it's comparing beta-lactams to fluoroquinolones, there's no difference.

[00:33:48] Erin: 'cause you just don't need that long of a duration. for truly uncomplicated gram-negative bacteremia, it's like do we even need seven days? Do these last couple days of step down matter? And when you're finding there's quote no difference. Is it just because the infection's totally gone by day five, maybe even day three?

Who knows? Angela, what are your thoughts on, duration?

[00:34:07] Angela: Erin we've brought this up on a few episodes., We just did an episode on the balance trial. We were saying the same thing, for gram-negative infections, do we necessarily need such long durations?

and so yes, we have strong thoughts about that, which do require some additional, clinical trials to be confirmed. but yeah, I do wanna go back and, make one comment. On these oral beta-lactams, I think Barbara is absolutely right, those older trials.

[00:34:31] Angela: That show some inferiority. Those doses were really small. we've had a lot of creep up in our dosings in the way we dose oral beta-lactams. I would essentially never give anybody nowadays, like 625 milligrams of co-amox. We now give a gram to everybody, you know?

[00:34:54] Angela: I don't know what you're doing out, in the states, but, we are giving such higher doses, we know we're going off-label. it's not ideal. would love to have more evidence to do it, but clinically we have higher mics nowadays, so we're just giving higher doses.

I think it would be really nice to have a trial that's just testing, at baseline higher doses of oral beta lactams across all the classes. But back to durations. Yeah, so , we were pretty evidence-based I would say in these, recommendations where we get to give shorter durations if we are using quinolones, just as we had seen in the 2010 guideline.

[00:35:34] Angela: In the earlier guideline. Because that's where the data are, that's where the trials have been done. the quinolones really are so good with bioavailability, so you're getting more antibiotic to the site, and then once they get there, they're, super efficacious. I think there just wasn't too much doubt right.

[00:35:52] Angela: among all of us. really a sort of this balance you have to do with following evidence. , And yet. trying to address the very pressing issue of stewardship nowadays. we had sort of err on the side of okay, we gotta be evidence-based.

but I would personally have liked to see very short durations for any antibiotic choice. but We couldn't say five days if you're using, beta-lactams. because we don't have that evidence yet. That's my take on it. What do you two who actually led this guideline?

[00:36:21] Angela: what do you think?

Well, the only reason we can say five days is a number of drug companies did trials of were five days enough with the fluoroquinolones. Right, right. You need more trials like that to see if five days is enough. With, other drugs. We don't have that evidence base right now.

[00:36:41] Erin: and maybe for our listeners, can you recap where you guys landed on the duration recommendations?

[00:36:47] Barbara: I mean, it's just easiest to remember. Seven. for complicated UTI, uh, unless you are treating with a fluoroquinolone, particularly if it's pyelonephritis with, no known obstruction or something, five days is probably fine.

[00:36:59] Barbara: a lot of the trials were really healthy people though. we carved out. The statement of prostatitis. And the reason is there's a signal, I have a slide on this too, of trials that we stratified for men. We took out all the data that we could get specific to men in all these trials, thanks to Valéry and pursuing the authors across multiple nations in time zones to get the original data.

[00:37:22] Barbara: And you set up this table and you can range it from trials that looked for prostatitis and excluded it to trials that only included men with prostatitis and the effectiveness of the shorter course of therapy falls as you move down the list where there were more men with prostatitis in the trial.

[00:37:38] Barbara: So knowing that we are only fully convinced of two drugs getting into the prostate, which is fluoroquinolones and trimethoprim Sulfamethoxazole. I personally think there are a lot of other drugs that get in there, but there's not a lot of consensus on that, and so I would be particularly concerned about treating febrile men with UTI with a beta-lactam for shorter than seven days if no one had at least checked for prostatitis.

thank you for that. I wanna point out something else that I found really cool about durations, if I can, read you guys your own words for a second here? this, guideline there's also a section on the patient perspective and there's a section on the patient perspective specific to treatment duration.

[00:38:16] Erin: And you say there's little direct evidence addressing antibiotic duration in complicated UTI and patient wellbeing. Clinical cure with relief of symptoms was the most important outcome from a patient representative's perspective. the duration of antibiotics chosen should be sufficient to achieve clinical cure.

[00:38:33] Erin: Patients do not feel that a negative urine culture was necessarily a goal and patients lacked confidence in the accuracy of a urine culture at predicting urinary symptoms. But patients value avoiding recurrence of a symptomatic infection and they value not going to the hospital. So seems like a no brainer, but it's so cool to have it in the written word in the guideline.

[00:38:55] Erin: Can you guys talk to us a little bit about adding in this patient perspective and what your method to that was? Did you go out and interview patients? Was this a survey and, how did you land on this language?

gonna let Barbara talk a little bit more about the patient, representative, but just to give you a little bit of background on the methodology, when we're doing guideline, we're supposed obviously to look at the balance of benefit and harms.

[00:39:16] Valery: We're supposed to look also at other considerations such as stewardship, which is a big driver of all our question and, even the structure on how we categorize antibiotics. Initially, we looked at costs, we looked at resources, but we also need to look at patient values and preferences. And what does that mean?

earlier I talked a little bit about patient important outcomes, we have to take into account what is important for the patient. So that's a good example where clinical cure, I think we all agree on that, but, microbiological cure is not important for patient, but might have been important for FDA in the past.

that's one big difference between what is valued by the patient and what is valued by. Other institution or organization, The other thing is that we also need [00:40:00] to, ask them which other outcomes could be important and we might not find these outcomes in the evidence. For example, recurrence of infection was not something that we were able to find for any of those question.

[00:40:10] Valery: It was really rarely reported. There's a few papers here and there that included that outcome as important, but should probably be one of the main driver of decision making. We were not able to really assess that outcome, but it's important to acknowledge it, to be transparent about it. And the same thing for rehospitalization.

[00:40:27] Valery: so we can see that the evidence and what patient values are a little bit discordant. I think it was really important and it's part of the process to, listen to what, people with, UTI, think and value.

[00:40:38] Barbara: our patient representatives were volunteers.

[00:40:41] Barbara: IDSA puts out a call for volunteers, but they're going to be doing a lot of work. There's a lot of documents to read and comment on in meetings to attend. So the people who volunteer are those whose lives are most severely impacted by urinary tract infections. So you don't get the person who is hospitalized once for pyelonephritis postpartum, 15 years ago.

[00:41:03] Barbara: You get people who UTI is ruining their lives. and so we couldn't necessarily, find scientific evidence for all concerns. And so the patients representatives, drafted that section. I felt that, the best way to listen was to have their words, pretty close to verbatim. So I did some light editing, of that section.

we have to listen. I don't have a scientific explanation for chronic UTI that symptoms may be controlled by two years of IV antibiotics. I don't have a scientific explanation for that. I do know that we are failing to relieve our patient's pain and distress with our current therapies for UTI and so there's a lot of scope for improvement in that zone.

[00:41:46] Barbara: I think it's important to listen so we know what directions we should go in with future studies.

[00:41:52] Angela: Yeah, I think that's so well said. It's kind of humbling when you, do all this work and then you turn to the patient groups and you're like, oh. so there are decades of literature that didn't actually address, some of the outcomes that are, essentially the most important to the patients.

[00:42:05] Angela: and then these trials did spend a lot of time on Yeah, like Valéry says, microbiologic outcomes, which a patient doesn't feel, so, lots more to do.

[00:42:15] Erin: Yeah. In talking about Microbiological cure and what value it made me realize we have failed to mention the amino glycosides, and I feel like we would be remiss to end a complicated UTI podcast and not talk about amino glycosides.

[00:42:27] Erin: So, amino glycosides are awesome Urinary tract infection drugs in terms of. Microbiological cure, right? We have an RCT with PLA mycin showing superiority to miropenem in micro cure. But maybe that's something that the FDA cares about and not patients, or not clinicians, but you guys as an author group do put a lower priority, lower totality of evidence for the quote, older amino glycosides in the guideline document.

[00:42:52] Erin: We're talking tobramycin, gentamicin, amikacin, but globally aminoglycosides are used quite frequently still. we've gotten really on board with a single dose for cystitis and we have some observational publications of multi-dose, daily dosing for five to seven days for pyelo. Talk to me a little bit about the positioning of aminoglycosides and your review of the evidence there.

Every single trial has a signal towards kidney impairment with aminoglycosides, and they didn't measure ototoxicity, but it's there too, so. We have safer choices. I used to give a single dose of aminoglycosides, in our shock rooms in the ER when I was a medicine resident, staffing the shock rooms.

[00:43:30] Barbara: That was kind of our standard practice. And then I would see the patient admitted to the MICU and go into renal failure because they were in shock and I gave them dose of aminoglycosides. I don't know, maybe they were gonna go into renal failure. Anyway, this is all anecdotal, but I don't think they're totally safe drugs.

[00:43:43] Valery: you summarized it really well. Like when we classified those antibiotics in the first table, we were considering the balance of benefit and harms. And that's probably the only one that, except for all the stewardship issues where we had like a harm that we could basically measure in clinical trials.

[00:43:58] Valery: So, that's why that was put into the alternative option. But it doesn't mean that it cannot be used. but there's all the caveat that Barbara just mentioned and that was our concern.

[00:44:08] Erin: Perfect. Thank you for that. we know as clinicians like ooz nephrotoxicity, but it's so interesting to hear that you are very.

[00:44:14] Erin: Structured approach, to assessing and, and placing these agents. So thank you for that.

[00:44:19] Angela: in a setting where you have lots of antibiotic choice. you're gonna obviously choose the safest option, but there are now entire countries where, they do not have access yet, to the newer, very expensive antibiotics, the beta-lactam, beta-lactamase inhibitor combinations, and they are really reliant on amino glycosides, for, certainly cystitis, of course, but also pyelo.

So I, think One area that really would require further research is understanding which patients are gonna be at risk for nephrotoxicity. Because I think if you use them properly, not everybody would, have nephrotoxicity. And of course, also duration is a huge factor, right? I do think one dose is very different than five days of an amino glycoside.

[00:45:05] Angela: So figuring out who would be, safe to get a few days of an aminoglycoside. At least that's what I see clinically. It's very age related and probably very related to baseline creatinine clearance. but I think that's important future research. So this has been such a great discussion, but before we close, is there anything either of you want the listeners to know that we haven't specifically asked you about Barbara?

[00:45:33] Barbara: Yes. I wanna give a shout out to our reviewers because those poor souls, all three of them ended up reading 280 pages and commenting and going through multiple rounds with us. And then we also had reviews by representatives of different societies. And I'm thankful to them too, because that's what made these guidelines more practical and useful at the point of care was the extensive revision we got.

[00:45:58] Barbara: And then we also went up for public review. So all in all, I. Thank everyone who contributed to shaping the guidelines in that manner. I will say that our number of pages of our initial response review was 89. We got a lot of comments and the size of the Excel file with public comments with 1 million rows and 16,000 columns.

[00:46:17] Angela: I remember seeing that and my jaw dropped.

[00:46:21] Barbara: that's what made our guidelines stronger.

Wow.

And I wanna shout out to Barbara because she was really patient and she spent a lot of her time to make sure that we could review every comment, address every comment we answered, all the comments we did not ignore one comment.

[00:46:36] Valery: And, It made the document so much stronger and, really implementable.

[00:46:41] Erin: Wow. Thank you for your leadership and your patience too, but it just shows you how valuable the work is. So.

[00:46:46] Angela: I'm gonna take this opportunity to thank you two. I was the ESCMID representative on this guideline panel. That was my role. I didn't really know very many people on the panel in the beginning.

[00:46:59] Angela: I think the panel has about 20 people on it, and, you guys were very, very welcoming to me

[00:47:05] Angela: and, really the whole time just exemplifying absolutely beautiful leadership. total integrity, and this humanity. feel very lucky to have been able to be on that panel, and to watch you do this. Thank you so, so much.

[00:47:22] Barbara: Thank you. The feeling is mutual.

[00:47:24] Angela: thank you so much to our guests. Barbara Trautner in St. Louis, Missouri, USA, and Valéry Lavergne in Vancouver, Canada.

[00:47:32] Angela: And thank you for listening to communicable the CMI Comms podcast. This episode was hosted by Erin McCreary in Pittsburgh, Pennsylvania, USA, and myself, Angela Huttner in Geneva, Switzerland, both editors at CMI, comms ESCMID's Open Access Journal.

[00:47:48] Angela: This episode was edited and produced by Dr. Katie Hostetler, oy and peer reviewed by Dr. Maria Anna Flores of Santa Maria Local Health Unit, Lisbon. Portugal. Theme music was composed and conducted by Joseph McDade. This episode will be citable with a written summary referenced by A DOI in the next eight weeks.

[00:48:06] Angela: And any literature we've discussed today can be found in the show notes. You can subscribe to Communicable wherever you get your podcasts, or you can find it on ESCMID's website for the CMI COMMS Journal. Thanks for listening and helping CMI comms and ESCMID move the conversation in ID and clinical microbiology further along.