#132 – Complicated UTIs: What’s Crystal Clear & What’s Still Cloudy

Introducing Guests and Today's UTI Guideline Discussion Hello and welcome to Breakpoints, the Society of Infectious Diseases Pharmacist Podcast. My name is Whitney Buckle and I'm an infectious diseases pharmacist and the System Antimicrobial Stewardship Program Manager for Intermountain Health based out of Salt Lake City, UT. Today I have two amazing guests here to discuss the updated Complicated Urinary Tract Infection Clinical Guidelines for Treatment and Management from the Infectious Diseases Society of America, which were published in July 2025. At ID Week this past October, there's an excellent session #194 titled What's New in Urinary Tract Infection? Whereas Zachary Nelson and Barbara Trottner artfully presented back and forth a compare and contrast of the updated IDSA guidelines with the Wiki Guidelines for the Prevention, Diagnosis, and Management of Urinary Tract Infections in Pediatric and Adults, published in JAMA Network Open, November 2024. That session brought into light a number of the controversies that arose during the IDSA guideline development and public comment period, many of which we'd like to dive into today. First, let me introduce our guests. I'm sincerely honored to be hosting our two panelists today, Doctors Kyle Molina and Dana Bowers. Doctor Kyle Molina is an infectious diseases and stewardship pharmacist at Scripps Health in San Diego, CA. His research interests include long acting lycoglycopeptide, real world use of novel therapeutics to combat antimicrobial resistance, and antimicrobial pharmacokinetics and pharmacodynamics. Kyle, welcome to Break Point. Speaker 2 Thanks Whitney, Happy to be here. Speaker 1 Next up, Doctor Dana Bowers is an associate professor and infectious diseases specialist at Washington State University College of Pharmacy in Yakima, WA. Her current research interests include gram negative resistance, pharmacokinetics, pharmacodynamics, and the behavior economics of antimicrobial stewardship. Dana, we're thrilled to have you join us today. Speaker 3 Thank you, Whitney. I'm so happy to be here. Speaker 1 In order to best break this topic down for our listeners, let me go over the general outline of today's podcast. We'll start with a discussion of the key recommendations from these two UTI guidelines, and throughout we'll weave in discussions on how an ID pharmacist and antimicrobial stewardship might implement these guidelines in clinical practice, particularly oral options for complicated urinary tract infections, the role of the antibiogram, and unique considerations for catheter associated urinary tract infections. Then we'll wrap up with a rapid fire overview of some of the new drugs in town for the treatment of UTI. We've got a lot to cover in this episode and I'm ready to get started. Clarifying Complicated UTI Definitions and Clinician Education Kyle, could you start us off with a quick overview of the new definitions for Complicated and uncomplicated? Speaker 2 Absolutely. This is one of the bigger changes we see in the 2025 IDSA guidelines and it really changes how we categorize patients compared to older guidelines that are focused primarily on uncomplicated UTI. So to start, in the past, uncomplicated UTI was actually a fairly narrow box and essentially only applied to healthy premenopausal non pregnant women without history of urologic abnormalities. So under those rules, everyone else including men, patients with diabetes, anyone with an immunocompromising condition was really defaulted into this complicated bucket regardless of severity of illness or sight of infection. The 2025 guidelines really emphasize the differentiation of complicated from uncomplicated based on observable factors rather than requiring a more advanced urologic workup. So when we take a look at what this looks like, uncomplicated UTI is described as an infection confined solely to the bladder. And crucially, this means that patients with well controlled diabetes, men, those with urologic abnormalities or immunocompromised who present with lower urinary tract symptoms and no systemic symptoms can now be classified as having an uncomplicated UTI. Complicated UTI, on the other hand, is defined as patients with likely infection extending beyond the bladder with presenting symptoms including fever, chills, rigors, hemodynamic stability, flank pain, among other systemic signs and symptoms. This classification includes patients with structural and functional urologic abnormalities, again that extend beyond the bladder or put patients at very high risk of having extension beyond the bladder. Notably, it includes Papa nephritis and old catheter associated UTI, which I think we'll come back to here in a moment. So for pharmacists and stewards listening, this is a major practice change. You might see a male or a diabetic patient with simple cystitis uncomplicated UTI under these new IDSA classifications and so you wouldn't need to automatically reach to treat them with antibiotics we typically reserve for complicated UTI. When you look at these guidelines in the context of other guidelines, this approach is actually very consistent with some of the European guidelines that differentiate infection by classifying infection as either localized versus systemic. And notably, the Wiki guidelines take a different stance here all together with the use of terms uncomplicated and complicated. They argue that the terms complicated and uncomplicated are really vague and lack a standardized definition across the literature. So that group actually recommends we stop using those terms all together and use more syndromic based location based definition such as cystitis or pyelonephritis rather than these broad kind of vague definitions. Speaker 1 Thank you, Kyle. That's an amazing overview and I do think it's moving in the right direction. We can talk about the terminology, but it's at least nice now that uncomplicated better aligns with cystitis, right? And complicated better aligns with pyelonephritis. Dana, any perspective you'd like to add about how to educate to this big practice change? Speaker 3 Yes, thank you, Itanya. I would love to discuss that. In an ideal world, an educational update to clinicians about any updated guidelines or guideline changes, new guidelines, etcetera should be tailored to the specific audience and delivered in a manner that is going to be most effective. People who are part of antimicrobial stewardship teams hopefully have a good idea of what is going to be most effective for their audience. I think a good place to start is just providing education that this update has occurred. Focusing on the new recommendations and the definitions is a very good place to start. What I like from the IDSA is they have a specific slide that has the old classifications and the new classifications on a single slide. I think that this is a good visual and it includes a definition in a really straightforward manner. And this is a good place to start with education. And then after you've made awareness of these guidelines and the changes, then you can work in more specific antimicrobial stewardship recommendations on how to implement these and then also highlighting the recommendations for empiric therapy. Speaker 1 Yeah, great point. A picture can sometimes be worth 1000 words, right? And I think having that graphic is an excellent thing to include in slides. IDSA's Four-Step Empiric Therapy Selection Approach All right, Kyle Ordina, now that we've clarified the new classifications for uncomplicated and complicated UTI's or cystitis and Pylo, could you introduce us to IDSA's recommended four step approach for selecting empiric antibiotic therapy in patients with complicated UTI? Speaker 2 Yeah, I'm happy to walk through this. So I think this is another really big change and we see this across guidelines moving from recommendations that are are something to the effect of thou shalt use ceftriaxone in in this patient for every patient at this time really to tailoring guidelines to your institutional needs to patient specific factors and to local resistance, which we know most antimicrobial stewardship and ID practice is really quite local. So when we look at the IDSA approach that they have introduced, it relies on four factors. The four steps are assessing the patient's severity of illness and largely this means assessing the presence of sepsis, septic shock or no sepsis. Next assessing risk factors for resistance. And so this is evaluating the likelihood that a patient has a resistant pathogen using some strong risk factors like previous resistant urine cultures or recent antibiotic exposure. Next, patient specific consideration should be accounted for. This includes allergies and contraindications, physiological factors like patients, renal function, drug and interactions, ability to tolerate oral medications and maybe the site of care, whether this patient is should be treated with IV or oral medications. And then finally, consideration of the local antibiogram for selected patients. And I think a big change here is actually the use of antibiogram really that is reserved for patients with sepsis and septic shock with varying thresholds. And so I think we'll get more into this here in a moment, but it is a step towards using antibiograms in in patients with high risk of a severe outcome and actually moving against using potentially the antibiogram in patients who are at low risk of a severe outcome. And so I think this framework, if you can apply this for your institution and for your patients individually, you might end up with very different antimicrobial choices. Then again, A1 size fits all recommendation that could come from a guideline. Speaker 1 Yeah, that's a great overview and I do appreciate this, this concept of tailoring to your local reality and that these guidelines are supporting that. Dana, anything you'd like to add? Speaker 3 To reiterate, the importance of the evaluation of risk factors for resistant organisms and when we think about empiric therapy selection, we should be thinking about what makes sense for this specific patient based on their history. It's important that this is included in the guidelines as it represents A framework. This is not a one-size-fits-all approach when we are deciding empiric therapy for these patients. Empiric Antibiotic Choices for Septic Complicated UTIs All right, now let's hone it into patients with sepsis due to complicated UTI. We're talking about different patient populations, how we treat them differently. Let's start with sepsis. So IDSA recommends starting with 3rd or 4th generation cephalosporins, carbapenems, piprosilentasobactam or fluoroquinolones rather than newer agents or aminoglycoside. That's a lot of option. What do you actually recommend as empiric therapy to treat pyelonephritis? Dana, let's start with you. Speaker 3 I feel fortunate to have worked in places where there isn't a lot of extended spectrum betalectinase producing interactor eyes, and thankfully we can still lean on ceftriaxone as the workhorse for many infections. For a complicated UTI in a patient with sepsis, I like ceftriaxone for many reasons. We know that ceftriaxone works in pyelonephritis. It was in the previous IDASAUTI guidelines for the treatment of pyelonephritis and it has a long established history in this disease process. So we know that it works. Where I have at least personally encountered a little bit of resistance to using ceftriaxone is in the patients who present with sepsis. And I think that providers that I've worked with have felt they need to be overly aggressive in treating these patients with sepsis. And I understand that it can be worrisome when patients present, they present really sick. It's easier and maybe perhaps more comforting to reach for a broader spectrum agent or a bigger gun such as a carbapenem. It's also important to keep in mind that sepsis is a host response. It doesn't necessarily mean that this patient has a multidrug resistant Organism. This is another good place to lean in to patient specific risk factors for multidrug resistant organisms and your local antibiogram for support. Anything about the most common Organism across the board, it's probably going to be E coli. And then at your particular institution, if E coli is still relatively susceptible, then perhaps ceftriaxone is going to be just fine in someone who doesn't have any specific risk factors for increased drug resistance. When we think about E coli is the most likely Organism and you retain good susceptibility for it, then it doesn't make as much sense to include something with anaerobic activity such as a carbapenem or piptasol. Those just don't make as much sense. This brings me around to the other option that you mentioned in the guidelines, which are the fluoroquinolones. And I personally as a stewardship pharmacist, I'm not super excited to use the fluoroquinolones when we can use other options since at my institution ceftriaxone works pretty well. I like to learn more on ceftriaxone over the other options such as a carbapenem, Piper Sol and tasoactam or the fluoroquinolones. Speaker 1 Thanks, Dina. I do feel like we are all W coasters here on this call. It's a a unique experience. We don't have as much East Coast representation here today, but I think it does really tailored to your local reality. And that can be because you're on the East versus the West Coast, but also if you're in a more urban versus a rural setting. Kyle, what do you recommend as empiric treatment for pyelonephritis in your septic patient? Yeah, I think. Speaker 2 As a W coaster, our ESPN rates are also really not that high down in San Diego and so we are able to use Ceftrax and effectively for most of our patients. So that really is our workhorse agent. When we're talking about patients with maybe history of ESPLI think potentially using peptazo or irdapenem is a reasonable choice. But again, we really try to make sure patients have adequate risk or clear recent history of ESPL before using those agents. Speaker 1 Agreed. Thanks, Kyle. OK, now let's move to the outpatient setting. Empiric Treatment Options for Outpatient Complicated UTIs What about treatment options for our complicated UTI patient who presents to the Ed with urinary burning urgency, has a fever and there's concerns for pyelonephritis, but they're not sick enough to be admitted. What's your go to agent in that situation? So. Speaker 2 I think it's nice if your patient is really still in the office to start with an initial dose of IV antibiotics when possible. So if you're able to get them, a dose of ceftriaxone or maybe even a dose of an aminoglycoside that really could buy you the 1st 24 hours and potentially bred you slightly till you have antimicrobial susceptibilities. I think one of the challenges with treatment on the outpatient side is resistance and or pharmacokinetic concerns with some of our options. Fluoroquinolones and sulfamysoxyltramethoprim really have great evidence for their efficacy in complicated UTI pyelonephritis. However, we see rates of resistance nationally for both agents somewhere between 20 and 40%. And so using these empirically does always feel like a great choice. Alternatively, we have our beta lactam agents and the relationship I think with those drugs for complicated UTI, especially when you think there's a little bit more systemic in involvement, is quite complicated. There's emerging PK data that does give clinicians some pause. So with that, we tend to lean towards using a fluoroquinolone actually just because of the demonstrated efficacy in some of these clinical trials. The guidelines are actually very interesting in how they approach risk stratification with the antibiogram for empiric therapy. So essentially these guidelines really emphasize the fact that for non septic patients, you should really consider the antibiogram less in a way. So it's better to be less sensitive for resistance than those with sepsis and septic shock. And so that allows you to potentially use options that appear a little bit more resistant on your antibiogram. Sorry in advance Dana for pulling the fluoroquinolone gun. I know. Speaker 1 Nobody, no, no antimicrobial stewardship that I know loves to pull the fluoroquinolone card, but I think sometimes there's reasons that it makes sense to you. Do you know what's your recommendation for those complicated UTI outpatients? I do. Speaker 3 Trimethoprim sulfa here, this is one of the places where a fluoroquinolone could be used and could be used really well. So it's not that I dislike fluoroquinolones for every single thing. Pyelonephritis definitely could be a place in the outpatient setting where fluoroquinolones come into place. The caveats here in the nuances of recommending trimethoprim sulfa of course are going to depend on your local antibiogram rates, your resistance rates, patients, and then of course any individual patient specific risk factors. Because as a general statement, I do trimethoprim sulfa here. So I I. Speaker 1 Don't hear anybody in the beta lactam camp here. Maybe ceftriaxone, but not a oral beta lactam. Speaker 2 I, I think we'll, we'll dig into a little bit of that, but at least my take on some of the literature is that there is just not a lot of evidence for upfront use and there are concerning signals here and there about their overall efficacy, their ability to really eradicate organisms. And so it gives me a little bit of pause. Speaker 1 That's a great way to put it. All right. Critically Assessing the Role and Limitations of Antibiograms Before we move into that section, I already want to touch one more thing that you both have highlighted here and that's about the role of the antibiogram. So part of College of American Pathologists or CAP accreditation. For many of our microbiology laboratories, they require producing an annual antibiogram. Most often these are put together by a stewards or at least distributed by antimicrobial steward. There's some controversy around their role. So Dana, what's the role of antibiograms according to the updated IDSA guidelines? How does that compare to how you use antibiograms in your practice? Speaker 3 As Kyle previously mentioned, the current CUTI guidelines include antibiogram assessment as the last of their four step approach in choosing empiric therapy. They also mentioned that the clinical outcomes with using antibiogram to guide prescribing for individual patients is uncertain. The guidelines suggest when you're using antibiogram, there's some caveats. That the antibiogram needs to be local, within the same healthcare facility. It needs to be recent, within the last 12 months and then relevant, which is based on organisms from a similar patient population. The guidelines recommend a threshold of 90% or greater in patients who are presenting with sepsis with shock and then a patients with sepsis without shock. They have the consideration for an antibiogram if you have a threshold of greater than or equal to 80% of the organisms are susceptible. Probably most importantly, the guidelines highlight the uncertainty for guiding antibiotic choices when the Organism itself is unknown. As an ID pharmacist, I have a complicated relationship with antibiograms, which is well described in an editorial by Conan McDougal where he challenges us to rethink the antibiogram and question its underlying assumptions. After I read this article, I felt extremely validated in my feelings, my complicated feelings with antibiograms. One of the assumptions that Conin has us question are what can the antibiogram help us do? Can they help us answer the right question and are they providing the correct answer? Where antibiogram work the best is when we know what specific Organism we are dealing with, we just don't know its specific susceptibility. And these assumptions are aren't always present with traditional or standard antibiograms because they tend to pool data together from various patient locations such as ICU, the General Medical floor or even including outpatients and some of these pooled antibiograms. And that is not going to be always helpful if you are able and you have access to enhanced antibiograms, The type that I'm most familiar with or have created are ones that are location specific and syndrome specific. And these types of antibiograms along with stay specific or incidence weighted antibiograms, these tend to be more helpful than standard antibiograms alone. I recognize that these enhanced antibiograms are not always feasible to create or not even available at many institutions. If you're going to use an antibiogram, it all boils down to knowing what information your antibiogram provides and what are the limitations of that specific antibiogram. Yeah, I. Speaker 2 Totally agree with Dana here. I think the main issue seems to be that we're trying to generalize very aggregated data that's very high level to individual patients. But when we look across the literature, if you're able to target very specific populations within an antibiogram, whether it be syndrome specific, unit specific community acquired versus nosicomial, whether it be transplant specific antibiograms, even these enhancements often improve the predictive capacity of of the antibiograms really telling you that this aggregated data is not appropriate to apply to all of your patients. With that said, there are interesting studies and in particular study published in in CID this past year looking at the predictive of ability in a large VA data set finding really poor discrimination of most antibiotics upon individual patients and so there are real issues with conventional antibiogram. Alternatively, some have looked at risk factor models to actually predict risk of resistance rather than purely relying on an antibiogram. And one study published this past year by some of our SIDP members, Sam Aiken and Jason Pogue really showed that compared to an antibiogram using a more syndromic unit based risk factor approach that incorporated history of resistance within a year and previous antibiotic use actually outperformed the antibiogram. And so I think this really highlights the role that we as stewardship pharmacists have in finding that information and making the clinical decisions to choose antimicrobial therapy. All of these, I think, have issues with sensitivity and specificity. And in particular, this is very challenging to do with some of our lower prevalence pathogens like CRE, where restoring really just does not work well because of the low prevalence. But with that said, I think what we're seeing is more publications on some of these machine learning approaches to really narrow in risk factors and to do this in a more automated built into the EHR fashion. So I expect that much of this prediction of resistance will actually move towards that in the future. Speaker 3 When considering these enhanced antibiogram, they are great, they provide us this additional information. We can really tailor them to our specific patients. But it also reminds me of the smaller institutions who perhaps don't have access to these enhancements in their antibiogram data. And so in that case, what is best for those specific institutions? Is it better for them to use an antibiogram, knowing that perhaps this is not the most perfect tool? Or is it better for them to just broadly prescribe antimicrobials across the board without using or incorporating that antibiogram data? It's just something to think about and we talked a lot about how these tools are available and these enhancements are great. We also need to keep in mind in specific resource limited settings, these might not always be applicable. And so we have to use the best information that we have. Speaker 1 Those are all excellent points. I think that the antibiogram is a tool, but it's not a perfect tool. So we need to understand what those limitations are. One thing that I think about all the time is that they don't cover all the patients that get empiric antibiotics that then don't have susceptibilities. It's only those patients with positive cultures. And that's just one additional limitation. But I do think that there's value. We have some hospitals within the Intermountain health system that have not seen a Pseudomonas in the last year or have only seen three. So do they need to empirically cover for Pseudomonas? They don't and we base that on the anabiogram. So I think sometimes that's really helpful. Kyle, it's an excellent point about machine learning. Maybe this is the way to leverage use of an anabiogram tool within a bigger picture with the various factors and this is just one of them. And that could be really exciting. Classifying and Treating Catheter-Associated Urinary Tract Infections All right. Speaking of transplant or unique population, one thing we haven't touched on with this definition is catheter associated urinary tract infections, which is a unique niche here. So the new IDSA guidelines include patients with urinary catheters in the complicated UTI bucket. Why do you think that is and what challenges does that create? Speaker 2 Yeah. So these guidelines really do classify catheter associated UTI patients as complicated. And recall that I had mentioned that the classifications were really meant to be easy to use for clinicians in factors that they could observe at the point of classification. And the guidelines really mentioned that patients with long term indwelling catheter stents are percutaneous and nephrostomy tubes and symptoms related to UTI are at high risk of extension of the infection beyond the bladder. However, the guidelines do acknowledge that there are a subset of patients with catheter associated UTI without systemic symptoms that may be treated as uncomplicated UTI. The challenge I think is parsing out those patients at the onset of therapy when maybe you don't have a lot of information. And these classifications are really quite oversimplified I think for clinical use. But there are important patient populations you can think about that might be more likely to have an uncomplicated UTI. So think of some of your patients with short term catheter use, maybe post surgery. Some of these patients really have not had time to have infection extension beyond the bladder. And we've seen data previously where treatments for uncomplicated UTI seems to work just fine for these patients. Some other issues or populations that think about it with increasing risks are those with super pubic casts or functional issues. These are really a much higher risk population for infection extension. And in particular, patients in this population have functional issues like oh urinal reflex, which actually places them at high risk of having a functional reason for extension beyond the bladder. Finally, those with long term indwelling cats probably on the highest risk very often have UTI's, recurrent UTI's and extension beyond the bladder. And so I think it's important to think about the different types of catheterized patients, the different risk factors these patients have, if you're going to differentiate these patients as uncomplicated versus complicated, which is a little bit different than the guideline approach. Speaker 1 Yeah, thanks, Kyle. I think this was definitely a controversial area of the guidelines. And I think one of the implications too is about what treatment options, for example, nitrofurantoin is something that we do not use in a complicated infection that is beyond the bladder, but would be appropriate for something like cystitis. I don't know, Dana, if you wanted to add anything more to this Coddy discussion. Speaker 3 Adding Kati to the definitions makes it easier in one way, but tends to, for lack of a better word, complicate the issue a little bit more because as Kyle mentioned, not all catheters are the same. When people are reading these guidelines and implementing these guidelines that look and read what did the idea say mean when they were talking about these different type of catheter associated UTI's? As Kyle mentioned, in patients who perhaps have not had a catheter placed for too long or they lack systemic symptoms, then those patients maybe could be treated as simple cystitis. However, when these catheters are in place for longer, there's also this bladder colonization that we need to consider. There's some evidence to suggest that Kodi may be classified as complicated UTI in patients without that confirm progression. But I think that we also just need to look at those risk factors. And when patients don't have those risk factors, they don't have confirmed systemic disease, then we can treat them as uncomplicated UTI. It's understanding the details that are included in the guidelines and what was meant as an initial simplification perhaps encourages more teasing out of individual specific patients. Yeah, and if. Speaker 1 There's one thing that ID pharmacists are great at. It's the nuance, right? So this is like overall probably works most of the time, but we appreciate that there's always exceptions. Okay, before we move on from treatment and dive into duration, we hinted at this earlier. The Controversial Role of Oral Beta-Lactams in UTI Treatment One last area of controversy and it's a big one, beta lactams in the treatment of urinary tract infection. So this discussion could probably take hours, which we don't have. So we'll try our best to summarize. Dana, let's start with you this time. You're right, Whitney. Speaker 3 I think that this could take hours to discuss completely and people tend to have very strong feelings about it. I'd just like to update the audience that there's a few members of SIDP. Myself and Kyle are included. We're working on a paper that discusses some of these nuances of the complicated UTI guidelines. We're going to provide some additional context and further discussion around some of the treatment recommendations. We also hope to cover the previous discussion point on CODIS being classified as complicated Utis, navigation of antibiograms and also the oral beta lactams. I don't think it's a surprise to anyone in this audience that historically beta lactam agents have been viewed to be less efficacious than first line treatments for UTI sort of in general. However, amid growing concerns of increased antimicrobial resistance to the first line agents, there's been this renewed interest in using the oral cephalosporins for the treatment of complicated UTI. Regarding pharmacokinetic data, one of the concerns that's been raised is related to the poor bioavailability of these oral beta lactams. While bioavailability is one piece of the puzzle, it's not everything in itself. Oral sulfosporins don't have great bioavailability. This is not super shocking to this audience. However, despite this poor oral bioavailability, we still use them in clinical practice. There was an observational study that was published in March 2025, and this reflects how these agents are used in clinical practice. This was a study that took place at 11 different emergency departments, and it compared patients who received an oral Cephalosporin versus either a fluoroquinolone or trimethoprim sulfa, and these are patients who had pyelonephritis. Their primary outcome was treatment failure, and they found no significant difference between the cephalosporins, which was 17.2%, and the combined group of fluoroquinolones and trimethoprim sulfa, which was 22.5%. The authors concluded that the cephalosporins were not associated with treatment failure and it's important to note that 60% of patients in the Cephalosporin group and 47% of the patients in the combined fluoroquinolone trimethoprim sulfa group received an IV antibiotic in the emergency department prior to discharge. This also can be a controversial topic for providers, whether we need to give patients IV dose of antibiotics before they go out the door and so separate of how one may feel personally about the need for IV antibiotics before discharge. This happens often in clinical practice and I like this paper because it reflects real world practice and it brought up that we need to reconsider the cephalosporins, especially when others may be limited based on their resistance rates. So even though cephalosporins don't have great bioavailability, people use them in the real world and probably will still continue to use them. We need more information and more literature that supports the clinical, real use of these agents. Yeah, I. Speaker 2 Totally agree with data here. To circle back to some of the PKPD, there's really been a shift toward beta. Lactams don't work. Wait, it's just a low bioavailable agents that don't work. If we use the high bioavailable agents, then we should be fine. But the PK is actually much more complicated than that in that we're not looking at just high quote UN quote high concentrations, right. We're trying to optimize exposures to the PKPD target of interest at the site of infection. And in particular, this takes into account the MIC distribution of the pathogens or suspected pathogen that we are trying to treat. So to talk about cephalexin, which I think many clinicians feel good about because it's bioavailability is about 90%, has high renal excretion as unchanged drug of about 90%. If you look at the PK data, it's actually a little bit more mixed, especially when you're looking at this for more systemic infections, infection outside of uncomplicated urinary tracts. So last year, US CAS had presented some updated PKPD analysis of cephalexins at doses ranging between 500 and 1000 milligrams Q6, finding high target attainment of targets and plasma associated with bacterial stasis, but only up to isolates with MI CS of two. And the problem with this, of course, is that the MIC distributions for cephalexin are such that most isolates are at an MIC of four or above. The MIC 50 is 8 for E coli. And so when you look at doses that would be required to hit a 4816, there's been some work done suggesting you'd need something like 1500 milligram Q6, which is really unlikely to be tolerable for many of our patients. And so when we're assessing the use of any of these cephalosporins, we really need to take into account all of these factors and likely a target attainment relative to your MIC distributions. Speaker 1 Yeah, I think those are all great points. The interest in these beta lactams is in those settings where we have higher Bactrim, higher fluoroquinolone resistance or you want to avoid those toxicities and you want to put somebody on IV, you want an oral option. And I think we have some good negative bacteremia data right about step down therapy to beta lactams. And even if there may be an increase risk of recurrence, absolute risk of recurrence is relatively low, which makes some people feel pretty comfortable. But there definitely are challenges, limitations with these and they're dosed really frequently, which can be an issue with adherence. So when we try to push doses, are they tolerable, but also are they going to take those really high doses that we're recommending? I think those all come up in these discussions and I think data your points will take in. We'll probably still continue to see patients who get fatal actins for complicated Utis. And so maybe that's just an area for more research and more understanding to figure out what we can do in this patient population. Speaker 2 Yeah. I might just add that when we look at what the guidelines actually recommend in terms of beta lactams, they do really recommend many of the beta lactams that we're talking about, cephydoxin, CEFTA, buten, cephyroxin, But cephalexin and augmentin are actually called out as being potentially less effective than other regimens given some studies have shown some worse outcomes there. And so it highlights the point that we do need to be a little bit careful about our actual selection of a beta lactam overall. Speaker 3 I have to highlight from the previous study that I was discussing about the oral cephalosporins that were being used, the most common one that was used in that particular study was cephalexin, although the doses were not consistent across patients. There's a variety of different doses so that the topic for itself, but then also ceftinir was commonly used. Speaker 2 Yeah, I totally agree. The challenge really is just the lack of clinical data with these specific agents. And if we had comparative data, we might be having a very different conversation about beta lactams. Speaker 3 So that's a. Speaker 1 Shout out to our listeners to consider research in this topic and that we can host your research on a future Breakpoint episode. All right, let's move on from treatment into duration of therapy. New Guidelines for Shorter Antibiotic Durations in cUTI Kyle, do you want to take this? Speaker 2 Yeah, happy to take this one. The complicated UTI guidelines recommend shorter durations of antibiotic therapy for most patients showing clinical improvement on effective treatment. And so this was a big win for antimicrobial stewards out there who are focused on shortening antimicrobial durations to as short as possible while still maintaining efficacy. So some differences in duration that are recommended for patients with complicated UTI without bacteremia, they do recommend five to seven days of therapy if using a fluoroquinolone or seven days of therapy if using a non fluoroquinolone option. In those with bacteremia, 7 days is recommended over 14 days as long as clinical improvement is a cheap and I think we've seen a number of large studies evaluate this population with gram negative bacteremia showing that seven days is adequate for the vast majority of patients in true clinical improvement is achieved. Finally, they do point out men with febrile bacteremia UTI in whom acute bacterial prostatitis is suspected. They do note that these patients may benefit from a longer treatment duration, although evidence to guide the optimal treatment duration in this subgroup is overall lacking and we should really treat these patients in a different bucket than some of our other patients. But overall, I think again, this is a real win for antimicrobial stewards having recommendations for shorter treatment durations. Speaker 1 Yeah, I think it's exciting. I always thought it was really confusing before where the treatment duration was different based on which drug you were using and which had a study. And I think it's not only shorter, it's also simplified, which is much appreciated. It's a good call out, Kyle, about men. One of the things that we didn't mention the beginning, but it's worth mentioning here is that these complicated UTI guidelines specifically exclude prostatitis. And so there was a good discussion at ID Week about are we actually doing exams to assess for prostatitis in these patients. We probably should be doing more of that. That way we can exclude and focus on urinary tract infection, but that may be one of the pieces that's complicating that decision For those acute febrile men. What's the presence, potential presence of prostatitis in that population? Dana, anything you want to add on duration? Speaker 3 I was so excited to see the durations of therapy in these guidelines. It adds to the growing information that we have that shorter courses of antimicrobials are safe and efficacious. Of course, you need to keep in mind the caveats that individuals do not fall into the subpopulation of higher risk for treatment failure or complications, but as a general statement that shorter courses can be used, these shorter courses and durations of therapy give us confidence in complicated UTI with gram negative bacteria. I also consider this a huge win for antimicrobial stewardship. Agreed. Speaker 1 Thank you both so much for this insightful discussion. I really enjoyed our conversation today about these guideline updates and there's a lot of things our listeners could take back to educate their providers and their pharmacists at their institution. Many of the points that we've made today will be included in an upcoming publication from SADP and Insights, SADP publication for the treatment of urinary tract infections. Rapid Fire: Pivmecillinam for Uncomplicated UTIs Now, of course, there's a limitation of all guidelines in that data are always being published. And uniquely enough, we have several newly approved drugs for the treatment of urinary tract infection, some for complicated UTI, some for uncomplicated UTI, but not complicated UTI, and we'll get into that. Let's do a quick rapid fire discussion of these new agents to wrap up today. We'll cover the FDA indication, mechanism of action, dosing, and a little commentary about the pros and cons of each agent. Speaker 3 Let's start with PIV mesalinem. PIV mesalinem was approved in the United States in 2024 for uncomplicated UTI. I'd like to highlight that this has been used outside of the United States for over 40 years and just recently approved in the United States. It's a beta lactam. Like the other beta lactams, it binds to penicillin binding proteins, but unlike other beta lactams, it has high specificity for PBB. 2, the dose of 185 milligrams PO is actually equal to 200 milligrams of the PIV miscellaneum hydrochloride. This can be a little bit confusing, especially when you compare it to dosing outside of the United States, which has a dose of 400 milligrams of PIV mesalinem hydrochloride. The frequency is every 8 hours for a duration of three to seven days. There is not an established pediatric dose within the United States, so it's not approved for Pediatrics with the FDA. But outside of the United States, it has been used in Pediatrics that are greater than six years old and greater than 40 kilos. This also doesn't require a renal dose adjustment, which is nice. Some of the pros is this unique target for penicillin binding protein 2 and this is another agent that we can use if we need it has a long established history of clinical use for this indication, albeit outside the United States. Many studies of PIV micellenum report no or mild adverse effects and if they do have adverse effects, they tend to be GI effects. A unique adverse effect that's associated with pivicillinum is carnitine deficiency, and this has to do with the way that it is metabolized. Prolonged administration can result in carnitine deficiency and defects in fatty acid oxidation. And if you're wondering what this looks like symptoms of hypoglycemia, muscle aches, fatigue or confusion, the good news is that there haven't been any clinical effects that have been associated with decreased carnitine with short courses of penicillin M. However, if individuals have a history of primary, secondary carnitine deficiency that would be inborn errors and metabolism, then you're not going to want to use this medication as it's contraindicated. Lastly, I want to highlight that this medication is not indicated for complicated UTI, which when we think about how is this going to fit into where it's going to be used, that could impact its overall use. Speaker 2 Yeah, I think this is a really exciting new drug to have available. There's a ton of clinical experience given how long it's been available in parts of Europe. And when you look at susceptibilities, it really targets more than 95% of E coli, more than 98% of the SPL producing E coli in US based surveillance. So I think it gives us a real nice option for uncomplicated UTI duty SPL producing pathogens. Speaker 1 Agreed. I think that this one's exciting, especially with that unique mechanism of action and the experience that we have with this being a great option outside the US. Finally, we got it in the US. It's great. All right. Gepotidacin: A Novel Topoisomerase Inhibitor for uUTI Next up, Kyle, can you take Geppo Titus in? Yeah, I'd love. Speaker 2 To so hepatitis N was approved in March of 2025. This is an oral antibiotic that's approved for the treatment of uncomplicated urinary tract infection. And actually more recently JEPO received approval for treatment of uncomplicated urogenital gonorrhea and those with limited treatment options. And so it's an interesting drug in that it can treat both of those. So Jeppo is the first agent in a new class of topoisomerase inhibitors. So specifically inhibits topoisomerase type 2 with pretty broad spectrum activity against gram positive and gram negative organisms. It's actually very similar to chloroquinolone both based on the mechanism and based on the spectrum of activity. But importantly, because the mechanism is sufficiently different, it actually overcomes many of the traditional fluoroquinolone resistance mechanisms. The drug is dosed at 1500 milligrams twice daily for five days and notably comes as 750 milligram tablets. Some warnings that I think are important to point out is that JEPA carries risk of QT prolongation and is a SIP 3A4 substrate. And so you may need to think about drug interactions and some cardiac comorbidities. And then it's also notable that this is another drug that's approved for uncomplicated UTI and not complicated UTI. And this is really based on some prior PK data showing that really high doses of the drug would need to be used to achieve more systemic type concentrations. And those concentrations are actually associated with pretty high risk of QT prolongation. So just really a less safe dose to use. And so the company really stuck to using this for uncomplicated urinary tract infections. That's a great. Speaker 1 Summary, Kyle And I think the biggest thing from my coverage of Jeppo for gonorrhea is just tolerability. So that's going to be a question with probably all of these agents. What's the GI tolerability of some of these new uncomplicated UTI treatments? But still really nice to have some oral options. It is unfortunate some of these won't ever be indicated for complicated UTII, think PIV. My Selenium has maybe some data in pyelonephritis Dana or some interest. But for shepatitis in this agent is really going to be limited to uncomplicated UTI and gonorrhea, which brings me to the next one that also is going to be limited to uncomplicated UTI. Dana, do you want to take Solupanum next? Sulopenem: An Oral Carbapenem for Uncomplicated UTIs Sulopenem Edodroxyl probenicid is indicated for the treatment of uncomplicated UTI in adult women with limited or no alternate oral treatment options. Sulopenem edodroxyl is a thiopenem Ester pro drug that's hydrolyzed to sulopenem upon oral administration. The reason that it needs probenicid is to increase or boost its systemic exposure. Sulopenem inhibits bacterial cell while synthesis by binding to the penicillin binding proteins. Dosing is 1 tablet which contains 500 milligrams of the zalopenem pro drug and 500 milligrams of probenicid and its dose 1 tablet every 12 hours for five days. And based on oral bioavailability studies, the pro drug bioavailability has shown to increase when administered with food or probenicid to reduce its tubular secretion. Hence the recommendations to administer it with food and in combination with probenicid. This drug is great. It is active against the neurobacterialis in the presence of certain beta lactamases, I think NFCCTXM, TEM or Chevs. And it's also reassuring to know that we have additional options at our disposal for these types of organisms. A limitation of the clinical trials for uncomplicated lower urinary tract infection is there exclusion of essentially all patients who traditionally would be considered to have risk factors for these infections. So they excluded these patients. And if these patients were somehow still included, then there was a very small minority of patients who had organisms with ESPL phenotypes in both trials. We just need more information and experience with resistant infections to feel comfortable to recommend this drug in the majority of patients. A few coins are that in its label. It's not indicated for complicated urinary tract infections or it's not indicated a step down treatment after intravenous antimicrobial therapy for complicated UTI. This is because it failed to meet its endpoints for complicated UTI in the trial. And this was the SHR 2 trial. This is a phase three trial where patients were randomized either to receive a solupenem 4 once daily for at least five days followed by oral solupenem twice daily to complete a 7 to 10 day course of treatment. Or they could have received erdipenem 4 once daily for at least five days followed by ciprofloxacin or amoxiclav twice daily. Their primary endpoint was overall clinical and microbiological response on day 21 in the micro modified intent to treat population. These findings showed that the trial failed to demonstrate non inferiority that I had a responder rate of 67.8% for solupanem at the test of cure visit compared to 73.9% for irdapenem. The authors believe that these results were contributed by the high rates of asymptomatic bacteria that were present in the solupedem arm. I personally haven't seen this drug being used too much yet, but whenever we have of course new antimicrobials, the antimicrobial stewardship program, especially within the outpatient setting, need to carefully evaluate where this drug might best be used. Speaker 2 Yeah. And I think the trial in complicated UTI really brings up an interesting point about the FDA required UTI outcomes as a composite of clinical and microbiologic cure at Test of cure. So I don't know how many of our ID stewardship friends are getting test of cure cultures, but I certainly have never seen that done. And so I think there is a a reason to be skeptical that's a clinically relevant endpoint. On the flip side, the FDA has published data looking at 13 trials that were submitted to it, essentially showing that there's an association between lack of microbiologic cure and late relapse. And this is particularly in in some patients with risk factors like older patients or patients with diabetes. And so I think that's their continued justification for using some of these endpoints to not allow drug approval. And unfortunately, this is again another drug that's going to be confined to the use of uncomplicated urinary tract infection, but does look really good against some fairly resistant fluoroquinolone not susceptible and ESPL subgroups. So I think a really nice option to have. Speaker 3 Yes. Thanks for bringing this up, Kyle. I do not see people do test of cure in clinical practice. We don't have patients come back in for another urine culture if their symptoms have resolved. For one thing, it's unnecessary because the patient is no longer symptomatic. And then also we might find something that we didn't mean to find and this contributes to inappropriate testing for asymptomatic bacteriuria, which raises some additional concerns. I appreciate appreciate this point specifically made in the ideas say C UTI guidelines. It says something along the lines of collection of a urine culture and a now asymptomatic patient is discouraged in clinical practice and that is because treatment of asymptomatic bacteria does not prevent urinary tract infection and may predispose subsequent recurrent UTI. This is an important part to make. So when we were looking at these clinical trials, that doesn't reflect what is done clinically nor should be done clinically. Speaker 1 All great points. It's exciting that there are so many new drugs in this space and that like maybe we can re evaluate some of these old practices. We just talked about solupenem. Now we'll bring. That brings us to another penum, Kyle, How about Tebi Penum? Tebipenem: An Oral Carbapenem for Complicated UTIs Yeah, Tebopenem. Speaker 2 Is another Penum class antimicrobial and it's actually been available in Japan for over a decade, but originally was indicated for pediatric respiratory and ear infections in a slightly different formulation. So the drug in the US has been reformulated into a prodrug hydrobromide salt and that improves the bioavailability, lets it be put into tablets. So as a beta lactam, its mechanism is binding of penicillin binding proteins and the drug spectrum of activity appears quite similar to erdopenem overall. So noticeably fails to cover some of our important non fermentors, Pseudomonas, Acinetobacter and it's not going to be the step down of the drug for those pathogens. The drug isn't quite FDA approved yet and has a little bit of a complicated history there. Suffice to say that there was some new data presented at ID Week this year, the PIVOT PO trial which looked at patients with complicated UTI including pyelonephritis. The trial was actually stopped early for efficacy with tebapenem achieving a 59% overall success rate compared to 60% in those treated with imipenem. And so tebapenem at this dose of 600 milligrams Q6, which was a little bit higher of a dose than the initial tebapenem trial for complicated urinary tract infection is what it's expected to be approved at. So I think tebapenem will be a pretty nice tool for complicated UTI, seeing as most of the drugs we've talked about so far are uncomplicated UTI and particularly enterobacterialities with ESPL and AMP C as a tool that we can implement in our health systems. This could help us discharge our patients who have limited treatment options. So that there it is really a ton of interest in using this as our oral transitional. I will note that there's really not a ton of data to use this as oral step down in Graham negative BSI. Originally there was a trial plan for this that got cancelled when the drug changed hands, so I think that'd be a very interesting research area for the future to see if we're able to use this as a step down agent. I completely agree with you. Having carbapenems, oral carbapenems out in the world is a scary prospect. And we know that despite all the nuances we're describing, the drug will likely be used in places where maybe it shouldn't be. And so that really emphasizes stewardship's role in kind of monitoring use actively, particularly in these outpatient settings that we don't typically look at. Yeah, agreed. Speaker 1 If this is something that stewardship program should probably monitor and I do think too that this might be a really exciting option for oral step down therapy. I'm trying to remember from the Pivot PO trial. I think that they did include. Some patients with bacteremia, it was just a minority of that population. So we need a little bit more evidence, but it may be a really important niche. IV Fosfomycin: A New Intravenous Option for Complicated UTIs All right, last but not least, we also have the recent FDA approval of intravenous fosfomycin. So we've been talking all about oral agents. What about a new IV agent for UTI? Dana, let's wrap up the section with you, I feel like. Speaker 3 We've been talking about getting this drug approved for years and IV phosphomycin was approved in the US in October of 2025 for the treatment of complicated UTI in adults. It is dosed at 6 grams IV every 8 hours as a one hour infusion and the FDA approval was based on the results of a Phase 2-3 zoo's trial which found that IV phosphomycin was non inferior to Piperasil and Tasobactim in hospitalized patients with complicated UTI. They also found that it was generally well tolerated and points were clinical cure and microbiological eradication at the test of cure visit and this was achieved in 63.5% of patients on IV phospho and 55.6% of patients receiving piperasol and tasobactam. The mechanism of action for phosphomycin. It inhibits bacterial cell wall synthesis in a unique fashion. It results in bacteriocytal activity in the urine. It also decreases bacterial adherence to uroepithelial cells and alters leukocyte function and can penetrate biofilms, which I think is super cool. The data for biofilm associated infections with four phosphomyosin is really interesting, particularly in bone and joint infections. And I realize we're not talking about that today, but this is something where once this drug is entered into the market, we could see it in these types of infections. And I anticipate now that it's approved in the US, we will start to see it in other uses that could expand its potential utility. The formulation has a high sodium content, which may contribute to congestive heart failure type of symptoms in patients who are at risk. You also need to monitor electrolytes. It can cause hyponatremia, hypokalemia, hypomagnesemia, and then hypophosphatemia, but also because of the sodium content, you'll need to be careful if you administer this with other sodium containing drugs. And then of course continue to monitor the serum electrolytes closely during treatment. There's also neutropenia such as agranulocytosis that's included as an adverse effect that could be potentially problematic depending on your patient population. The pros with phosphomycin, it generally does not exhibit cross resistance with other classes of antimicrobials which include the beta lactams and aminoglycosides. And it's pretty safe separate from the sodium load that it can have. But it has generally GI effects and headaches associated with IV phosphomycin, which are similar to the PO form. Overall, pretty excited that this is available. We'll need to review and follow how it's being used now that it is available in the United States. Speaker 2 Yeah, I think each vial has close to 2 grams of sodium in it. And so it's really going to be something we need to watch for many of our patients, particularly those with cardiac comorbidities and pre-existing electrolyte abnormalities. I think one thing to point out, as many people may be more familiar with the existing phosphomycin oral formulation months or intermittently if you're using it off the label, this formulation is dosed at 6 grams every eight hour. And so we're using IV infusions with doses that are much higher to target some of these pathogens. So this will be really interesting to see how this drug develops and we'll have to educate folks that if they've started on. Speaker 1 IV phosphomycin, we would not want them to step down to the oral phosphomycin sachet because just the dosing is different and the indication would not be for complicated UTI. That was a whirlwind. I learned a ton that was amazing. I think these are going to be really fun to watch and see what we use and how this changes our practice and urinary tract infection moving forward. Anticipating Biggest Changes in cUTI Treatment by 2026 Last, but most certainly not. Speaker 3 Least we'll pivot to our segment. Speaker 1 Called I Feel Nerdy, I Feel Nerdy is meant to be a safe place for our panelists to nerd out over their favorite ID topics, quirks, and fun facts. For today's edition, I would love to know what do you think will be the biggest change at your institution in the treatment of complicated UTI in 2026? Yeah, we've actually already updated. Speaker 2 Some of our guidance at scripts to incorporate elements of this guidance and I think the classifications are certainly important and guiding therapy and so implemented a lot of what the IDSA has said about these classifications. And then in addition, we've actually implemented some guidance related to our patient populations without sepsis and the ability to be a little bit less sensitive in our recommendations for treatment of antimicrobial therapy, knowing that some portion of our patients may be receiving therapy that's less active to start, but knowing that we have room to get that a little bit more. And so I think this is a nice way to steward antibiotics patients who are really at low risk of a severe outcome. I'm really excited about the duration of therapy. Speaker 3 That will be a big change and a big shift towards shorter courses of antimicrobials. I'd also like to encourage the listeners out there to make sure that your teams are aware that these guidelines are now available. I was discussing this with emergency medicine provider who was unaware that these guidelines had recently come out. And it's our job to educate people on new guidelines, getting the put out there that there's these new definitions and how that will expand into empiric treatment recommendations that are tailored to your specific institution. Thank you, both. Yeah, I think there's a lot of changes with these guidelines in terms. Speaker 1 Of classification, agent selection, duration, lots of education opportunities. Wrapping Up: Thanks and Podcast Information Thank you both so much for being on this podcast today. Thank you for being authors on the SIDP Insights paper, which I am so excited that to come out this year as well. I wanted to sneak in a big thank you to Kelly Cronesburg. Speaker 2 And Ventita Wong for leading our SIDP Insights paper, and you can expect that to be submitted for publication here shortly. Well, I can't thank both of you enough for joining us on Breakpoints. Speaker 1 I know I've certainly learned things from our conversation. I appreciate your time today. I'm looking forward to that publication that you mentioned from SADP Insights and all the impact that we can make with urinary tract infection moving forward. Thank you so much. Thanks for having us. Yes, thank. Speaker 2 You so much for the. Speaker 3 Opportunity and it was my pleasure and sorry again about the fluoroquin I was Dana. Speaker 2 With that, thank you for listening to Breakpoints, the SADP. Speaker 1 Podcast I have been your host Whitney Buckle, and our featured speakers have been Kyle Molina and Dana Bowers. A huge thank you to both of them for sharing their time and expertise with us. Breakpoints was created by Julianne Justo, Aaron McCreary and Jason Pogue. This episode was produced by Megan Clatt and Lacey Warden. It was edited by Katie Lambert and peer reviewed by Joey Cone and Julianne Justo. The executive producer at Breakpoints is Lisa Dubcow, and our theme song was recorded by SADP member Steve Smoke. You can subscribe to Breakpoints on Apple Cast, Spotify, and wherever you get your podcasts. If you'd like to support us further, please consider writing a review on your favorite podcast platform for us during this episode with a friend. Thank you, dear listener, for your ongoing support of our podcast and helping SADP achieve our vision of safe and effective antimicrobials for now and the future.