Complicated UTIs: What’s Crystal Clear & What’s Still Cloudy

[Music] 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, Utah. 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 was an excellent session number 194 titled "What's New in Urinary Tract Infection?" where Zachary Nelson and Barbara Trotner are fully presented back and forth the compare and contrast of the updated IDSA guidelines with the Wiki guidelines for the prevention, diagnosis and management of urinary tract infections and pediatric and adults. Publish and Jammon Network opened 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, Dr. Skial Malina and Dana Bowers. Dr. Skial Malina is an infectious diseases and stewardship pharmacist at Scripps Health in San Diego, California. His research interests include long-acting, glycopeptide, real-world use of novel therapeutics to combat antimicrobial resistance, and antimicrobial pharmacokinetics and pharmacodynamics. Kyle, welcome to Breakpoint. Thanks Whitney, happy to be here. Next up, Dr. Dana Bowers is an associate professor and infectious diseases specialist at Washington State University, College of Pharmacy, and Yakima, Washington. Her current research interests include Graham Negative Resistance, pharmacokinetics, pharmacodynamics, and the behavior economics of antimicrobial stewardship. Dana, we're thrilled to have you join us today. Thank you Whitney. I'm so happy to be here. 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 anti-biogram, and you need 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. Kyle, could you start us off with a quick overview of the new definitions for complicated and uncomplicated? 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. To start, in the past, uncomplicated UTI was actually fairly narrow box and essentially only applied to healthy pre-manipausal non-pregnant women without history of urologic abnormalities. 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. When we take a look at what this looks like, uncomplicated UTI is described as an infection can find 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, riggers, hemodynamics, 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 palinofritis and all catheter associated UTI, which I think will 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 complicate and uncomplicated are really vague and lack a standardized definition across the literature. So that group actually recommends we stop using those terms altogether and use more syndromic based location based definition, such as cystitis or palinofritis rather than these broad kind of vague definitions. 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 rate and complicated better aligns with palinofritis. Dana, any perspective you'd like to add about how to educate to this big practice change? Yes, thank you, Whitney. I would love to discuss that in an ideal world and educational update to clinicians about any updated guidelines or guideline changes, new guidelines, etc. 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. Yeah, great points. A picture can sometimes be worth a thousand words, right? And I think having that graphic is an excellent thing to include in slides. All right, Kyler, Dean, now that we've clarified the new classifications for uncomplicated and complicated UTIs or Sistitis and Pilo. Could you introduce us to IDSA's recommended four step approach for selecting empiric antibiotic therapy in patients with complicated UTI? 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 something to the effect of thou shalt use seftraxone in this patient for every patient at this time, really to tailoring guidelines to your institutional needs to patient specific factors into 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 contrainocations, physiological factors like patients' renal function, drug interactions, ability to tolerate oral medications. And maybe the site of care, whether this patient should be treated with IV or oral medications. And then finally, consideration of the local anti-biogram for selected patients. And I think a big change here is actually the use of anti-biograms, really that is reserved for patients with sepsis 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 any biograms in patients with high risk of a severe outcome. And actually moving against using potentially the end. anti-biogram in patients who are at low risk of a severe outcome. 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, a one-size-fits-all recommendation that could come from a guideline. Yeah, that's a great overview. And I do appreciate this concept of tailoring to your local reality and that these guidelines are supporting that. Dana, anything you'd like to add? 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 in empiric therapy for these patients. 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 third or fourth-generation sephalus borin, carbopenams, purposyl and tasobactam, or fluoroquinolones, rather than newer agents, or amino glycoside. That's a lot of option. Would you actually recommend as empiric therapy to treat pylonofritus? Dana, let's start with you. I feel fortunate to have worked in places where there isn't a lot of extended spectrum beta-actamase producing interactrials. And thankfully, we can still lean on sephtriaxone as the workhorse for many infections. For a complicated UTI in a patient with sepsis, I like sephtriaxone for many reasons. We know that sephtriaxone works in pylonofritus. It was in the previous IDSA UTI guidelines for the treatment of pylonofritus 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 sephtriaxone, is in the patients who present with sepsis. And I think that providers that I've worked with have felt that 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 spectra of agent or a bigger gun such as a carbopenum. It's also important to keep in mind that sepsis is a host response. It doesn't necessarily mean that this patient has a multi-drug-resistant organism. This is another good place to lean in to patient-specific risk factors for multi-drug-resistant organisms and your local anabiotogram for support. When you think 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 sephtriaxone 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 carbopenum or pipteso. 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. I personally, as a stewardship pharmacist, I'm not super excited to use the fluoroquinolones when we can use other options since I, my institution, sephtriaxone works pretty well. I like to lean more on sephtriaxone over the other options such as a carbopenum, pipteso and tasobactam or the fluoroquinolones. Thanks, Tina. I do feel like we are all West coasters here on this call. It's a unique experience. We don't have as much East Coast representation here today, but I think it does really tailor 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 an empiric treatment for pile and a frightest in your septic patient? As a West Coaster, RESBL rates are also really not that high down in San Diego. And so we are able to use sephtriaxone effectively for most of our patients. So that really is our workhorse agent. When we're talking about patients with maybe history of ESBL, I think potentially using pipteso or erta-pendum as a reasonable choice. But again, we really try to make sure patients have adequate risk or clear recent history ESBL before using those agents. Agreed. Thanks, Kyle. Okay. Now let's move to the outpatient setting. What about treatment options for our convocated UTI patient who presents to the ED with urinary burning urgency, has a fever and there's concerns for pile and a frightest, but they're not sick enough to be admitted. What's your go to EJ in that situation? So 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 sephtriaxone or maybe even a dose of an amine glycoside, that really could buy you the first 24 hours and potentially bread you slightly till you have any microbial susceptibilities. I think one of the challenges with treatment on the outpatient side is resistance and/or pharmacokinetic concerns with some of our options, floorquinolones and so-filmas oxytrymethbrim really have great evidence for their efficacy in complicated UTI, pylon or fridaz. However, we see rates of resistance nationally for both agents somewhere between 20 and 40 percent 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 involvement is quite complicated. There's emerging PK data that don't give clinicians some pause. So with that, we tend to lean towards using a floorquinolone 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 anobiogram for empiric therapy. So essentially, these guidelines really emphasize the fact that for non-septic patients, you should really consider the antibiotic 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 anobiogram. Sorry, in advanced data for pulling the floorquinolone gun. I know, nobody, no, no antimicrobial stewardship that I know loves to pull the floorquinolone 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 trimethyprims-solpha here. This is one of the places where a floorquinolone could be used and could be used really well. So it's not that I dislike floorquinolones for every single thing. Pylonephragus definitely could be a place in the outpatient setting where floorquinolones come into place. The caveats here in the nuances of recommending trimethyprims-solpha, of course, are great to depend on your local anobiogram rates, your resistance rates, and your patients. And then, of course, any individual patient-specific risk factors, but as a general statement, I do trimethyprims-solpha here. So I don't hear anybody in the beta-lactam camp here. Maybe sephteraxone, but not a oral beta-lactam? I think we'll dig into a little bit of that, but at least my take on some of the literature is that there's 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. That's a great way to put it. All right, before we move into that section, are you want to touch one more thing that you both have highlighted here? And that's about the role of the anti-biogram. So part of the College of American Pathologists or CAP, accreditation for many of our microbiology laboratories, they require producing an anulanta biogram. Most often, these are put together by a steward, or at least distributed by antimicrobial steward. There's some controversy around their role. So Dina, what's the role of antibiotics according to the updated IDSA guidelines? How does that compare to how you use anti-biograms in your practice? As Kyle previously mentioned, the current CUTI guidelines include antibiotic assessment as the last of their four step approach in choosing empiric therapy. They also mention that the clinical outcomes with using antibiotics to guide prescribing for individual patients is uncertain. The guidelines suggest when you're using antibiotics, there's some caveats. That the antibiotic needs to be local within the same health care 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 in patients with sepsis without shock, they have the consideration for an anabhyogram. 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 anabhyograms, which is well described in an editorial by Conan McDougal, where he challenges us to rethink the anabhyogram and question its underlying assumptions. After I read this article, I felt extremely validated in my feelings, my complicated feelings with anabhyograms. One of the assumptions that Conan has us question are, "What can the anabhyogram help us do? Can they help us answer the right question? And are they providing the correct answer?" Where anabhyograms 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 aren't always present with traditional or standard anabhyograms because they tend to pool data together from various patient locations, such as ICU, the general medical floor, or even including outpatients in some of these pooled anabhyograms. And that is not going to be always helpful. If you are able and you have access to enhanced anabhyograms, the type that I must familiar with or have created are ones that are location specific and syndrome specific. And these types of anabhyograms along with state specific or incidence weighted anabhyograms, these tend to be more helpful than standard anabhyograms alone. I recognize that these enhanced anabhyograms are not always feasible to create or not even available at many institutions. If you are going to use an anabhyogram, it all boils down to knowing what information your anabhyogram provides and what are the limitations of that specific anabhyogram. Yeah, I 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 of individual patients. But when we look across the literature, if you're able to target very specific populations within an anabhyogram, whether it be syndrome specific, unit specific, community acquired versus nose acomial, whether it be transplant specific anabhyograms even, these enhanced populations often improve the predictive capacity of the anti-bhyograms, 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 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 anti-bhyogram. Alternatively, some have looked at risk factor models to actually predict risk of resistance rather than purely relying on an anti-bhyogram. One study published this past year by some of our SIDP members, Sam Aiken and Jason Pogue, really showed that compared to an anti-bhyogram using a more syndromic unit-based risk factor approach that incorporated history of resistance within a year and previous antibiotic use, actually outperformed the anti-bhyogram. And so I think this really highlights the role that we on stewardship pharmacists have in finding that information and making the clinical decisions to choose anti-microbial 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 risk storing 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 towards that in the future. When considering these enhanced anti-bhyograms, 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 anti-bhyogram data. And so in that case, what is best for those specific institutions? Is it better for them to use an anti-bhyogram 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 anti-bhyogram data? It's just something to think about. And we talk 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. Those are all excellent points. I think that the anti-bhyogram 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 those 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 Inter-Mountain 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 anti-bhyogram. 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 anti-bhyogram tool within this bigger picture with the various factors. And this is just one of them. And that could be really exciting. 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? Yeah. So these guidelines really do classify catheter associated UTI patients as complicated. And recall that I 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 mention that patients with long-term indwelling catheterists or percutaneous and ifrostomy tubes and symptoms related to UTI aren't 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 oversimplifying, 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 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 catheter functional issues. These are really a much higher risk population for infection extension in particular patients. In this population, have functional issues like how 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 acats probably in the highest risk very often have UTIs, recurrent UTIs, 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. 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, nitroferanto and it's 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, Dean, if you wanted to add anything more to this CAUTI discussion. Adding CAUTI 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, they look and read what did the IDSA mean when they were talking about these different type of catheters, associated UTIs? 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 CAUTI may be classified as complicated UTI in patients without that confirmed 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 there's one thing that IDFermis is so 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, one last area of controversy and it's a big one, beta lactams and 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. I think that this could take hours to discuss completely and people tend to have very strong feelings about it. It just like to update the audience that there's a few members of SIDPs, myself and Kyler, included were 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 Coddies being classified as complicated UTIs, Navigation of Antibiotic Grams, 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 UTIs 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 sephalus boran 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 sephalus boran 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 sephalus boran versus either a flora-quinolone or trimethoprim sulfa. And these are patients who had pylonofritis. Their primary outcome was treatment failure, and they found no significant difference between the sephalus boran, which was 17.2 percent, and the combined group of flora-quinolones and trimethoprim sulfa, which was 22.5 percent. The authors concluded that the sephalus boran were not associated with treatment failure, and it's important to note that 60 percent of patients in the sephalus boran group and 47 percent of the patients in the combined flora-quinolone 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 an IV dose of antibiotics before they go out the door. And so, a 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 sephalus boran, especially when others may be limited based on their resistance rates. So even though sephalus boran 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 totally agree with data here. To circle back to some of the PKPD, there's really been a shift toward beta lactam's salt or weight. 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, clinical high concentrations, right? We're trying to optimize exposures to the PKPD target of interest at the side of infection. We want the MIC distribution of the pathogens or suspected pathogen that we are trying to treat. So to talk about sephalusin, 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 tracks. So last year, US cancer presented some updated PKPD analyses of sephalusins at doses ranging between 500 and 1000 milligrams, Q6 finding high target attainment of targets in plasma associated with bacterial stasis, but only up to isolates with MICs of two. And the problem with this, of course, is that the MIC distributions for sephalusin are such that most isolates are at an MIC of four or above. The MIC of 50 is eight for E. coli. And so when you look at doses that would be required to hit a four eight to 16, 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 sephalus boran, we really need to take into account all of these factors and likely a target attainment relative to your MIC distributions. Yeah, I think those are all great points. The interest in these beta lactams is in those settings where we have higher back drum, higher flu or quinoleon resistance, or you want to avoid those toxicities and you don't want to put somebody on IV. You want an oral option. And I think we have some good gram negative bacteria, mead data right about step down there, beta beta lactams. And even if there may be an increase risk of recurrence, absolute risk of recurrences relatively low, which makes some people feel pretty comfortable. But there definitely are challenges, limitations with these and their dose 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 Dana, your points will take in. We'll probably still continue to see patients who get beta lactams for complicated UTIs. And so maybe that's as an area for more research and more understanding to figure out what we can do in this patient population. Yeah, and I 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, cephodoxy, cephributin, cephuroxy, but cephalaxin and augumentin are actually called out as being potentially less effective in 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. I'm to highlight from the previous study that I was discussing about the oral cephalosporums that were being used. The most common one that was used in that particular study was cephalaxin, although the doses were not consistent across patients. There's a variety of different doses, so that the topic for itself, but then also septin ear was commonly used. Yeah, I totally agree. The challenge really is just a last. of clinical data with these specific agents. And if we had comparative data, we might be having a very different conversation about data like Dems. So that's a shout out to our listeners to consider research in this topic. And then we can host your research on a future and breakpoint episode. All right, let's move on from treatment into duration of therapy. Kyle, do you want to take this? 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 a microbial 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 fluoraquinolone or seven days of therapy if using a non-floraquinolone option. In those with bacteremia, seven days is recommended over 14 days as long as clinical improvement is a cheat. 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 bacterimek UTI in whom acute bacterioprostatitis 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. 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 at 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 prostacitis in these patients? We probably should be doing more of that that way we can exclude and focus on urinary tract infections. But that may be one of the pieces that's complicating that decision for those acute febral men. What's the presence, potential presence of prostatitis in that population? Dana, anything you want to add on duration? 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 in the year. I also consider this a huge win for antimicrobial stewardship. Agreed. 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 SIDP, an Insights SIDP publication for the treatment of urinary tract infections. 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. Dana, let's start with PIV miscellenam. PIV miscellenam 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 PBB2. The dose of 185 milligrams P.O. is actually equal to 200 milligrams of the PIV miscellenam 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 miscellenam hydrochloride. The frequency is every eight hours for a duration of three to seven days. There's not an established pediatric dose within the United States, so it's not approved for pediatric 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 too, 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 of the United States. Many studies of PIV miscellenam 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 PIV miscellenam 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 PIV miscellenam. However, if individuals have a history of primary, secondary, carnitine deficiency that would be inborn errors in 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. 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 SBL producing E. coli in US-based surveillance. And so I think it gives us a real nice option for uncomplicated UTI due to the SBL producing pathogens. Agreed. I think that this one's exciting, especially with that unique mechanism of action and the experience that we have with its being a great option outside the US. Finally, we got it in the US. It's great. All right, next up, Kyle, can you take Jeppo Titusin? Yeah, let's do it. So Jeppo Titusin 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, Jeppo received the approval for treatment of uncomplicated neurogenital gonorrhea in 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 grant positive and grant negative organisms. It's actually very similar to flora quinolones both with 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 flora quinolone resistance mechanisms. The drug is dose that 1500 milligrams twice daily for five days and notably comes as 750 grams tablets. Some warnings that I think are important to point out is that Jeppo carries risk of QT prolongation. It is a CIP-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 summary, Kyle. And I think the biggest thing from my coverage of Jeppo for gonorrhea is just tolerable. ability. 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 that some of these will ever be indicated for complicated UTI. I think PIV miscellanyum has maybe some data in Pylina Phritis, Dana or some interest for Chepotitisin. 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 like limited to uncomplicated UTI. Dana, do you want to take solupenum next? Psylopenum at a drug cell probenesid is indicated for the treatment of uncomplicated UTI in adult women with limited or no alternate oral treatment options. Psylopenum at a drug cell is a thio-penum estupro drug that's hydrolyzed to Psylopenum upon oral administration. The reason that it needs probenesid is to increase or boost its systemic exposure. Psylopenum inhibits bacterial cell wall synthesis by binding to the penicillin binding proteins. Dosing is one tablet, which contains 500 milligrams of the Psylopenum pro drug and 500 milligrams of probenesid. And it stows one tablet every 12 hours for five days. And based on oral bioballability studies, the pro drug bioballability has shown to increase when administered with food or probenesid to reduce its tubular secretion, hence the recommendations to administer it with food and in combination with probenesid. This drug is great. It is active against neurobacterialis in the presence of certain beta lactamases, so thinking of C, CTXM, TEM or Shevs. 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 their 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 ESBL 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 cons are that in its label, it's not indicated for complicated urinary tract infections or it's not indicated as step down treatment after intravenous antimicrobial therapy for complicated UTI. This is because it failed to meet its end points for complicated UTI in the trial. And this was the sure two trial. This is a phase three trial where patients were randomized either to receive a solute venom IV once daily for at least five days followed by oral solute venom twice daily to complete a seven to ten day course of treatment. Or they could have received urtepinum IV once daily for at least five days followed by cyprophloxicin or a moxclav 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-infurioreality. So that I had a responder rate of 67.8% for solute venom at the test of cure visit compared to 73.9% for urtepinum. The authors believe that these results were contributed by the high rates of asymptomatic bacteria that were present in the solute venom arm. I personally haven't seen this drug being used too much yet, but whenever we have of course new antimicrobials, the antimicrobials to your show program especially within the outpatient setting need to carefully evaluate where this drug might best be used. Yeah and I think the trial in complicated UTI really brings up an interesting point about the FDA required UTI outcomes as a compositive 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 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 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 end points 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 fluoroquine alone, not susceptible and ESBL subgroups. So I think a really nice option to have. 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. Or 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 bacteria, which raises some additional concerns. I appreciate this point specifically made in the IDSA CUTI guidelines. It says something along the lines of collection of a urine culture and 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're looking at these clinical trials, that doesn't reflect what is done clinically, nor should be done clinically. All great points. It's exciting that there are so many new drugs in this space and that like, maybe we can reevaluate some of these old practices. We just talked about solute venom. Now we'll bring that brings us to another venom. Kyle, how about tebby venom? Yeah, tebby venom is another venom class antimicrobial. And it's actually been available in Japan for over a decade. But originally it was indicated for pediatric respiratory and urine infections. And a slightly different formulation. So the drug in the US has been reformulated into a pro drug hydropromide salt. And that improves the biovaluability. Let's 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 urte venom. Overall, so noticeably fails to cover some of our important non fermenter pseudomonas aceneto backter. And it's not going to be the step down 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 pylon nephritis. The trial was actually stopped early for efficacy with tebapenum achieving a 59% overall success rate compared to 60% in those treated with immunopenum. And so tebapenum at this dose of 600 milligrams Q6, which was a little bit higher of a dose than the initial tebapenum trial for complicated urte tract infection, is what it's expected to be approved at. So I think tebapenum 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 enterobacterialis with ESBL and AMPC as a tool that we can implement in our health systems. This could help us discharge our patients who have limited treatment options. So 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 gram-native PSI. Originally there was a trial plan for this that got canceled 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. Completely agree with you having carbopenum, oral carbopenum's 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 a stewardship role in kind of monitoring use actively particularly in these outpatient settings that we don't typically look at. Yeah agree. This is something that stewardship programs 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. All right. Last but not least, we also have the recent FDA approval of intravenous phosphamysin. So we've been talking all about oral agents. What about a new IV agent for UTI? Dana, let's wrap up this section with you. I feel like we've been talking about getting this drug approved for years. An IV phosphamysin was approved in the U.S. 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 Zeus trial, which found that IV phosphamysin was non-affirurior to pepper cell and tasobactam and hospitalized patients with complicated UTI. They also found that it was generally well tolerated. Endpoints 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 pepper cell and tasobactam. The mechanism of action for phosphamysin, it inhibits bacterial cell wall synthesis and a unique fashion. It results in bacterial cytokine activity in the urine. It also decreases bacterial adherence to ureloyopathyleos cells and altars leukocyte function and can penetrate biofilms, which I think is super cool. The data for biofilm associated infections with IV phosphamysin is really interesting, particularly in bone-in joint infections. And I realize we're not talking about that today, but it is something where once the 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 U.S. 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 and patients who are at risk. You also need to monitor electrolytes. It can cause hyponitremia, hypokalemia, hypomegnesemia, and then hypophosphatemia. 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 agrenolocytosis, that's included as an adverse effect that could be potentially problematic, depending on your patient population. The pro is with phosphamiasin. It generally does not exhibit cross-resistance with other classes of antimicrobials, which include the beta lactams and amino glycocides. And it's pretty safe, separate from the sodium load that it can have. But it has generally GI effects and headaches, or associated with IV phosphamiasin, 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. Yeah, I think each vial has close to two 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 is many people may be more familiar with the existing phosphamiasin oral formulation that's dose at three grams, once or intermittently. If you're using it off label, this formulation is dose at six grams every eight hours. 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 IV phosphamiasin, we would not want them to step down to the oral phosphamiasin 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. Last, but most certainly not least, we'll pivot to our segment 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 some of our guidance at scripts to incorporate elements of this guidance. And I think the classifications are certainly important in 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 home. And so I think this is a nice way to steward antibiotics and patients who are really at low risk of severe outcome. I'm really excited about the duration of therapy 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 word out there that there's these new definitions and how that will expand into impaired 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 of classification, agent selection, duration, lots of education opportunities. 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 and Vantita Wong for leading our SIDP Insights paper and you can expect that to be submitted for publication here shortly. Well, I can thank both of you enough for joining us on breakpoints. 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 SIDP Insights and all the impact that we can make with your an air-entract infection. Moving forward, thank you so much. Thanks for having us. Yes, thank you so much for the opportunity and it was my pleasure. And sorry to get in about the floor when I was down. Well, with that, thank you for listening to Breakpoints, the SIDP 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 Jussle, Erin McLeary and Jason Pogue. This episode was produced by Megan Klatt and Lacey Warden. It was edited by Katie Lambert and peer reviewed by Joey Cohn and Julianne Justo. The executive producer at Breakpoints is Lisa Dubco and our theme song was recorded by SIDP member Steve Smoke. You can subscribe to Breakpoints on Apple, Casts, 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 SIDP achieve our vision of safe and effective antimicrobials for now and the future. [BLANK_AUDIO]