Dr Colgan: Thanks for having me. I appreciate it. And this is a interesting topic, and it's a timely one, a complicated issue. These urinary tract infections and the burden of antimicrobial resistance is not foreign to any of you, I'm sure. It's exciting. We've got people from all over the world, United States and multiple countries on today's call. So, I hope you're enjoying this as much as we are.

[00:05:35]

Defining cUTI: Major Change in IDSA Guidelines

Next slide shows some breaking news, you know, cutting news, that you may not have heard. They just were published by the IDSA. And that is the fact that from a task force that was led by Dr Barbara Trautner and Dr Nicolás Penfield, who you'll hear from in just a few moments, the guidelines for treating urinary tract infections have been changed to better define what constitutes a complicated urinary tract infection. The verbiage has changed. The guidelines have changed. In the old world order, it was a male with a urinary tract infection that was considered a complicated UTI. Not any longer. A complicated UTI now includes any infection beyond the bladder in a woman or a man. That's new. Several populations are not specifically addressed in these guidelines. These guidelines don't incorporate information or studies of those who suffer from prostatitis, epididymitis, orchitis, or indwelling catheters. But the new guidelines, reiterate, or rather, declare that an uncomplicated UTI is an infection that's confined just to the bladder in an afebrile woman or man. That's perhaps the biggest take home point I can tell you as far as definition of terms. This is new. And having heard this, this may change the way that you voted earlier on in the pre-poll that you did before the onset of this call. A complicated UTI is defined as an infection beyond the bladder in a woman or a man, such as those suffering from pyelonephritis, febrile associated, or bacteremic urinary tract infection, or catheter associated UTIs.

[00:07:21]

Global Impact of Antimicrobial Resistance: 2019

And this slide is interesting. Since we have participants from all over the world, this slide looks at the global impact of antimicrobial resistance done in 2019. And I'm sure no surprise to most anybody on this call is that the - the leading offender is identified here as Escherichia coli, followed by some of the other well-known players, Staphylococcus aureus, Klebsiella pneumoniae, Strep pneumoniae. And I found it interesting that towards the other end of the spectrum, you had organisms such as Shigella, Serratia, as other pathogens, Salmonella. They're also involved in this estimated, nearly 5 million deaths associated with bacterial antimicrobial resistance, including about 1.3 million deaths attributed to bacterial antimicrobial resistance.

[00:08:15]

Resistance Among Gram-Negative Uropathogens Is Rising

Resistance among gram negative uropathogens is rising. Antimicrobial resistance compounds the burden of complicated UTI. Our patients are suffering from this. You've seen this, I'm sure week in and week out in your practice of medicine. These extended spectrum beta-lactamase producing uropathogens now constitute about 20% of the complicated urinary tract infections. It's rising. The more you use any 1 antibiotic, the greater the risk of antimicrobial infection. Infections with multidrug-resistant organisms are associated with delays in therapy, a need for more IV antibiotics, limited treatment options, excess costs and toxicity, and, oh yeah, this leads to a higher rate of treatment failure. Not good. Not what we want.

[00:09:09]

IDSA Gram-Negative Resistance Categories: 2023

On this slide, it looks rather busy. But let me break this down for you a little bit. There are now several different antibiotic resistant phenotypes circulating among the gram negative uropathogens in the United States, and the optimal empiric treatment can vary substantially based upon which of these your individual patient is at risk of having. For example, the extended beta-lactamase producing enterobacterales are typically susceptible to carbapenems, whereas Streptococcus pneumoniae is intrinsically resistant to carbapenems. A general practitioner like myself does not need to have all of these resistance types memorized. The point is, is that resistance is a complex topic, and if you find yourself unsure as to what to do with a multidrug resistant uropathogen, don't hesitate to call an ID specialist or a pharmacy specialist where you work.

[00:10:05]

Carbapenem-Resistant Enterobacterales Resistance

And the next slide also looks a bit busy, but let me break it down for you a little bit. Here's a specific example. Some of those nuances that I just mentioned. For gram negative bacteria resistant to carbapenems, there are some mechanisms that confer only low level resistance and for which optimizing the carbapenem dosing, excuse me, might be adequate. On the other hand, bacteria that produce carbapenemase enzymes that have high level of resistance for which dose optimization really isn't an option. And then to complicate matters further, different types of carbapenem enzymes produce different resistance profiles.

So, for example, the KPC carbapenemase that you see here, which is currently the most common in the United States, generally still leaves the bacteria susceptible to ceftazidime avibactam, whereas the less common metallo-beta-lactamases also confer ceftaz avibactam resistance. So again, the take home point here is that if you see a uropathogen with a susceptibility report full of ARs, don't hesitate to pick up the phone and call for help, as antibiotic choice can get very complicated. And with that, I'll turn this over to Dr Nicolás Cortés-Penfield.

Dr Nicolás Cortés-Penfield: Thank you so much, and thank you all for joining. So, I'm Nicolás Cortés-Penfield. Along with Dr Colgan, I was 1 of the panelists on the developing the IDSA guidelines. And I'm going to talk a little bit about kind of the specific recommendations, and we'll walk through a couple of illustrative cases.

[00:11:44]

Patient Case

So, let's start by considering a 54 year old woman who presents to clinic with dysuria and increased urinary urgency. She's not received antibiotics in the past year. Has normal renal function. No drug allergies. Her vital signs include blood pressure of 110/78. A heart rate of heart rate of 90 beats a minute, a temperature of 100.8 Fahrenheit, and an O2 saturation of 98%. Urine and blood cultures are obtained and sent to the lab for analysis. So, while they're pending, we decide to start empiric antibiotic therapy.

[00:12:39]

Diagnosing cUTI:

Okay, so let's first talk about the diagnosis of a UTI. And the main thing I want to emphasize here is that the UTI is not something that is diagnosed by urine studies, or any type of laboratory testing. Diagnosis of UTI is something that you yourself make based on, you know, obtaining a history and physical examination of the patient. It really hinges on the presence of characteristic clinical signs and symptoms. And yes, pyuria should be there. Bacteria should be there. If these things are absent, you should reconsider the diagnosis. But these things alone are nonspecific and so they don't make the diagnosis.

And then once we've decided a patient has UTI, you know, the first sort of pathway is do we think it's complicated or uncomplicated? And I won't reiterate what Dr Colgan already told you, but, you know, the main point is, do we think that the person has 1 of these more severe phenotypes that suggests it’s an infection extending beyond the bladder. I want to specifically call out catheter associated UTI here. Some of you may have been thinking, well, how is how is CAUTI necessarily infection beyond the bladder? That doesn't make a ton of sense. And 1 of the reasons we included it, besides the fact that it's been included historically in definitions of complicated UTI, in - in study designs for, you know, getting antibiotics approved for complicated UTI, but true catheter associated UTI, that is not merely a misdiagnosis based on laboratory findings, frequently involves systemic symptoms; fever, rigors, you know, derangements of vital signs that indicate sepsis. And so, you know, if a patient doesn't have these things that indicate infection beyond the bladder, we should really, you know, be careful in labeling them with CAUTI and convince ourselves that we're not simply treating an abnormal urinalysis.

[00:14:54]

Empiric Antibiotic Selection: A 4-Step Process

So, we recommend choosing antibiotics through this systematic 4-step process. One is assessing the severity of illness. Essentially this is: does your patient have sepsis with or without shock? Are they or are they not in sepsis? Assessing specific evidence based risk factors for antimicrobial resistance. And there are really 2 here. One is to review recent urine and blood cultures that have been positive for uropathogens and looking at the susceptibility of those uropathogens. You know, and if the patient has a history of infection with uropathogens that are resistant to a certain drug, we probably shouldn't be using that drug as empiric therapy.

And then the second is to look at the patient's history of fluoroquinolone exposure, specifically within the past year. Don't necessarily need to worry about well, they've got, you know, trimethoprim sulfa 6 months ago or oh, they got ceftriaxone last month. So I can't use those 2 drugs. Because the evidence that prior receipt of those other antibiotics predicts current resistance is actually pretty weak. But that's not the case for fluoroquinolones. There is a really robust body of evidence at this point that suggests that prior fluoroquinolone exposure, is a major risk factor for fluoroquinolone resistance in a current episode of infection.

The third thing we want you to look at is those patient-specific factors. And this is honestly just us saying we can't do your jobs for you. You are the physicians or nurse practitioners or physician's assistants. You are the clinicians at the bedside who have to apply your expertise to consider what factors specific to that individual patient scenario. You know, for example, perhaps their history of chronic kidney disease makes an aminoglycoside not a preferred choice for treating their UTI. Perhaps their recurrent episodes of C. difficile infection should cause us to hesitate when picking a third generation cephalosporin or other, you know, broad spectrum beta-lactam associated with C. difficile infection.

So, you kind of have to—you know, we can't design essentially what we're saying, an algorithm that is big enough or complex enough to replace your expertise and your own ability to kind of assess these clinical decisions. And then last but not least, specifically for patients who present with sepsis, with or without shock, we suggest you look at your local antibiogram, presuming you have a, you know, local, actively updated and relevant antibiogram, and ensure that whatever drug you're picking for empiric therapy has at least 80% for patients without shock, or 90% for patients with shock susceptibility for the most likely uropathogens.

And we - we kind of restricted this recommendation only to patients presenting in sepsis, with or without shock. Because interestingly, the data demonstrating whether or not using an antibiogram improves our choice of antibiotics and more importantly, improves patients ultimate clinical outcomes. It's not that good. In fact, there are studies of antibiogram uses specifically in urinary tract infections that suggest that the main thing that these things that using antibiograms may be causing us to do is perhaps prescribe overly broad therapy.

Like they may actually, perversely, be hindering rather than supporting antimicrobial stewardship. And so, while we weren't ready to let go of that idea entirely, we said, well, why don't we restrict it to the patients for whom the margin of error is narrowest? Which is these patients who are presenting with more severe forms of UTI and in critical illness.

[00:18:47]

Initial Selection of Empiric Antibiotics

Okay. So, when we look at that first step, so the degree of severity that the patient presents with, defines what go in the 2, you know, pools of antibiotics, we want you to consider. Which are the preferred antibiotics, the drugs we'd like you to use if you can, and the alternative antibiotics, which are the drugs that you should be looking at if none of the preferred options are appropriate in this particular scenario.

The real difference here is where carbapenems go. So, we list carbapenems as a preferred option for patients who present with sepsis, and we list them as an alternative option for patients who present without sepsis. And this is largely, again, due to stewardship considerations vs margin of error. We know that the risk of mortality or serious morbidity with a complicated UTI in a patient who presents with no signs of sepsis is very, very low. And so, we really prioritize stewardship in that, you know, noncritically ill outpatient patient population.

Whereas folks who are presenting with sepsis or septic shock, our emphasis is really on ensuring the patient receives appropriate empiric antibiotic therapy. And we'll mention that we did also provide some, you know, potential choices for a patient with complicated UTI who doesn't have sepsis, in whom you want to do oral therapy from the outset. This would be most relevant for our outpatient and emergency department colleagues. I will say that, you know, the quality of evidence of some of these options is a little bit lower. Fluoroquinolones and trimethoprim sulfa are probably the 2 best studied choices. However, the study supporting those are a little bit older. But I think if you look at among the options that we have today to treat with oral therapy for a complicated UTI, these are probably kind of our best bets.

[00:20:50]

Poll 3

So, let's start with a question. Going back to our case here. Which of the following would you choose for empiric therapy for this patient? Would you choose:

A. IV meropenem

B. Trimethoprim/sulfa

C. Levofloxacin; or

D. Cefepime.

All right. So, I have kind of a range of options here. You know, the patient we described to you is someone who does have some evidence of complicated UTI. So they - she has some fever, evidence of systemic infection, but was otherwise hemodynamically stable, not acutely ill. Someone it would be reasonable to either discharge from the ED or from clinic with those urine cultures pending, some empiric antibiotic therapy, and a plan for close follow up.

And so, you know, I saw the preponderance of folks picked either trimethoprim sulfa or levofloxacin. And I actually think either 1 of those options would be reasonable. If we had given you a history of recent use of a fluoroquinolone, that would really make trimethoprim sulfa the preferred choice over levofloxacin.

[00:22:28]

Patient Case, continued

Let's keep going. So, you know, we try to discharge her with some empiric oral therapy, but unfortunately over the next 3 days her condition worsens. She returns to the ED with flank pain, continued urinary urgency, and burning on urination. Her vital signs include a blood pressure of 120/86. Heart rate 90 beats per minute. Temperature now 101.8 Fahrenheit, and oxygen saturation of 98%. Again, urine and blood cultures are obtained and sent to the lab for analysis.

[00:23:06]

Poll 4

And a couple of days later, her urine sample returns positive for ESBL or extended spectrum beta-lactamase producing E. coli. Which of the following would you choose for definitive therapy?

A. IV piperacillin/tazobactam

B. IV meropenem;

C. Oral/ciprofloxacin; or

D. Oral cefuroxime.

Okay, again, a range of answers here. So, you know, for a patient who has evidence of systemic illness due to an ESBL producing E. coli, I personally would lean on B, meropenem as a carbapenem, so it has retains very good activity, for the ESBL producing uropathogens would be a great option here. I think among the remaining choices, D is probably the most clearly inappropriate. You know, unfortunately, that ESBL beta-lactamase enzyme would destroy and inactivate cefuroxime. Piperacillin/tazobactam is a little bit more of a controversial choice. There are some studies suggesting, specifically in urinary infections, you may be able to achieve enough of the drug to eradicate an ESBL producing organism.

But, you know, piperacillin/tazobactam can be inactivated by that beta-lactamase, and in a patient who's having progressive illness and evidence of systemic illness, I'd just be a little bit more cautious about picking that one. And then C, ciprofloxacin, you know, we didn't give you specifically the fluoroquinolone and susceptibilities of this isolate. And without knowing that, I guess the thing I would caution you is the majority of ESBL producing organisms, by the time they've developed that degree of resistance, they're also fluoroquinolone resistant. However, if you had a, you know, a proven susceptible isolate, that might also be a reasonable choice.

[00:25:29]

Approach to Selecting Definitive Therapy

So, let's talk about switching to the definitive therapy. First off, you don't have to, you know, wait for a minimum duration of, you know, of IV therapy or a minimum duration of empiric therapy. Once you have the targeted susceptibility results of the pathogen causing your patient's urinary tract infection, you can go ahead and switch them to whatever you think is optimal based on antibiotic stewardship and also considering factors like cost, the toxicity profile of that drug vs the alternatives and the route of administration. Again, generally, we would prefer an oral route of administration over an IV route in a patient who's clinically improving due to the lower cost and improved safety profile. One more call out, you know, for managing extensively drug resistant infections, please don't hesitate to give your local ID specialist or ID pharmacist a call. Having a more resistant pathogen doesn't necessarily mean that you can't switch to an oral agent, or that you necessarily need to treat for a longer treatment duration.  

But it, very often, has an impact on what is the optimal antibiotic choice. And that's something that ID specialists would be delighted to help you out with. I guess I've just hinted at this, but 1 of the main recommendations in this new guideline is a recommendation to switch to oral agents quickly, rather than give prolonged IV therapy in patients who are both clinically improving. Clinically improving means they're either afebrile or their fever curve is trending down. They are haemodynamically stable, and they don't have any uncontrolled source of infection. Meaning, besides giving them antibiotics, there's not another procedure that we need to do to them acutely to get them stabilized and ready to leave the hospital.

Of course, that patient also needs to be able to take oral agents. So, if they're still having intractable nausea and vomiting, or if it's a patient who, for example, has had extensive small bowel resection and can't take oral medications generally, of course, the IV formulation would be preferred in those cases. And the other thing I want to call out is that, you know, if a patient's been on antibiotics for several days for urinary tract infection and they're not clinically improving, I don't want your answer to be, well, then I'll just give them IV therapy and I'll give them 2 weeks instead of 1 week. Because really, if a patient isn't having an appropriately prompt response, we should be concerned about either some uncontrolled source of infection or whether or not we have the correct diagnosis.

[00:28:14]

Novel Treatments for cUTI

I want to mention briefly some of the novel treatments for complicated UTI. These are all drugs that have been approved specifically for complicated UTI. You can see the key trials on which their approvals are based, and their specific roles kind of within the menagerie of - of highly resistant gram negative pathogens. These drugs are generally in the alternative antibiotic pools in our algorithm. That is not due to, you know, inferior clinical efficacy. They work just as well as our preferred agents. That is mostly based on antibiotic stewardship, you know, kind of principles, wanting to prefer more narrow spectrum agents. And then also, frankly, wanting to prefer agents that are less costly, and agents in whom there's broader experience with their safety, and whom the toxicity profile is, you know, perhaps better defined.

[00:29:17]

Pipeline Agents for cUTI: Combinations With Cefepime

There are a couple of pipeline agents that may have complicated UTI approvals very soon. Both of these are combinations of an old drug, cefepime, with a novel beta-lactamase inhibitor. So, zidebactam and taniborbactam that substantially increase the kind of spectrum of activity for some of these more highly resistant gram negatives and specifically the carbon carbapenemase producing organisms. So, cefepime zidebactam, recently completed a phase III trial looking at complicated UTI and pyelonephritis, and has a drug application accepted at the FDA. Cefepime/taniborbactam has a completed trial. Also has that application submitted. Although the FDA has asked them to submit some further data.

[00:30:14]

Pipeline Agents for cUTI: An Oral Carbapenem Option?

Other, you know, other agents that may be available in the near future are oral carbapenems. There’s sulopenem, which is already approved for uncomplicated UTI, although does not currently have a complicated UTI labeling. This is a carbapenem with both IV and oral formulations. And then, tebipenem is not yet approved, but is under review by the FDA after a positive phase III result for complicated UTI. Just 1 thing I want to mention here is, we're going to have to collectively, you know, as a medical community, be very judicious in how we use these drugs. Having an oral formulation means anyone can prescribe a carbapenem now. And quite frankly, it being more difficult and more costly to prescribe carbapenems is probably an important reason that they've retained activity over the years. And so, if we are not careful, we may lose what is, you know, currently our default choice for empiric therapy for patients who are presenting with critical illness and suspected gram negative infection. So, this is a drug that, you know, we're going to have to work together to use wisely.

[00:31:41]

Duration of Therapy

Let's move on to duration of therapy. So, for most patients, and this is again a new IDSA guideline recommendation, for most patients with complicated UTI with or without bacteremia, as long as they are clinically improving on effective therapy, we recommend 7 days of antibiotics total rather than a longer course. And there is adequate clinical trial data to support as few as 5 days if you are using a fluoroquinolone. There are certain subpopulations within complicated UTI that I think deserve an asterisk to that statement. So specifically, there are a couple of clinical trials that have been done in men with suspected acute bacterial prostatitis, suggesting that, perhaps, outcomes are better with a longer course, more like 10-14 days vs 7 days. Even that is itself a little bit of a complicated statement. Because, you know, the difference in outcome that were observed in these 2 trials. And by the way, if you want to go look it up, it's the PROSTASHORT [?] Trial and the [?] Trial.

But the real difference in clinical outcome wasn't clinical per se, it wasn't symptom improvement. Men improved their symptoms just as well if they got shorter, long course therapy, but they had more persistent bacteria. And so, there's a concern that, you know, maybe that might be a risk factor for late relapse of infection or progression to chronic bacterial prostatitis. So, I guess what I would say is for the large majority of folks, 7 days should be adequate as long as they're clinically improving. And for men in whom there are specific signs and symptoms that suggest acute bacterial prostatitis, perhaps we should be a little bit more cautious.

And then I mentioned again, you know, I don't want you to walk away from this with the idea that the oral switch and short duration recommendations are for folks who are clinically improving, and therefore, if someone is taking a while to get better, I should just give them a long course of IV antibiotics and that will fix everything. I really encourage you to take a systematic approach to trying to troubleshoot why a patient who is not having an appropriate response to complicated UTI treatment might not be having that good response.

[00:34:01]

What If the Patient Is Not Clinically Improving?

And there are, you know, when I'm called about this as an ID consultant, I really break these down into 3 buckets. One is, are they on the right antibiotic, or did we pick the right drug and are we using an appropriate dose? Honestly, this is mostly not the issue. My general medicine colleagues are very good at picking appropriate antibiotics. The things that are more often the issue is, you know, the patient has some occult source of infection that needs to be removed. We have to do something beyond just give them antibiotics. We have to find their urinary obstruction and relieve it. We have to drain the abscess. We have to do some imaging. Or, you know, maybe they don't have a complicated UTI at all.

Maybe they have a - another type of infection in, you know, and an anatomically regional space. Maybe they have a vertebral infection, retroperitoneal infection, deep pelvic abscess or other intraabdominal infection, that, again, needs a source control procedure to - to get better. Or they now have some noninfectious mimic. And so, the classic 1 here would be you put a patient on a penicillin to treat their infection, and after a few days, they stopped having fever because their infection—because that's been treated—and now they're having fever because they're having drug fever related to the penicillin.

[00:35:29]

Patient Case

So, let's go back to cases. So let's consider a 58 year old woman with neurogenic bladder and a urinary catheter who develops fever and dysuria, and who's culture of the urine grows Pseudomonas aeruginosa that's resistant to ciprofloxacin, meropenem, and piperacillin - piperacillin tazobactam.

[00:35:54]

Poll 5

Which of the following would be the best choice for definitive therapy of that patient's infection? Would it be:

A. Ceftolozane-tazobactam

B. Ceftriaxone;

C. Oral nitrofurantoin; or

D. Oral amoxicillin-clavulanate.

Okay. Great. So, the majority has it. And this I would say is of our questions, the 1 that has the clearest cut right answer. So, I told you this patient's uropathogen is pseudomonas. And so, pseudomonas is intrinsically resistant to a number of antibiotics, both oral and IV, including all of the non-pseudomonal beta-lactams like ceftriaxone and amoxicillin clavulanate, as well as nitrofurantoin.

Typically, for pseudomonal urinary tract infection, you'd probably want to start with an oral ciprofloxacin, perhaps cefepime meropenem, or piperacillin tazobactam if it was fluoroquinolone resistant. I told you that this patient's isolate is resistant to those options, and so you'd be left with 1 of our newer regimens like ceftolozane tazobactam, which generally has very good activity for difficult to treat pseudomonas.

[00:37:44]

Patient Case for Discussion: Interpreting Susceptibility Results

And we can consider another case here. This is a 67 year old gentleman with benign prostatic hyperplasia and an indwelling urinary catheter. And he's being admitted with fever, dysuria, and flank pain. He started empirically on IV piperacillin tazobactam. Blood cultures are obtained and negative. He's now clinically improving and his urine cultures have grown Klebsiella pneumoniae with the following susceptibility results: resistant to ceftriaxone, susceptible to piperacillin tazobactam, resistant to ciprofloxacin, susceptible to meropenem, and susceptible to ceftazidime avibactam.

I'll show you this antimicrobial susceptibility here. Okay.

[00:39:14]

Poll 6

All right. Great. Review these options here. So, I think we had substantial proportions of folks wanting to either continue piperacillin/tazobactam because the isolate is susceptible or switch to meropenem to ensure reliable treatment of a likely ESBL producing organism. And I think these 2 would be kind of the best options. Again, a little bit more controversial to treat an ESBL producing uropathogen with piperacillin tazobactam. Although here I suppose you could argue, well, the patient's been on that and they're clearly clinically improving from that.

I think switching to ceftazidime avibactam to minimize carbapenem exposure probably makes a little bit less sense just because you have more narrow spectrum options. And then de-escalating to an oral ciprofloxacin would be a less preferred choice due to that organism being resistant. And I'll hand it back over to my colleague, Dr Colgan.

[00:40:21]

Posttest 1

Dr Colgan: Okay. So, if following - let's see, yeah, if following evidence-based practice for a patient with a complicated UTI, when is it appropriate to transition from IV to oral definitive antibiotic therapy?

A. Appropriate if the duration is extended;

B. Appropriate if the patient is clinically improving;

C. Appropriate if the drug achieves high urinary concentrations; or

D. Not recommended for patients who present with sepsis - with sepsis.

So, B is - well, before we get to that. So, good. So, it looks like the majority of you, 80 odd percent, thought it was appropriate if the patient is clinically improving and a few picked other options. And that's exactly what we were thinking. It is appropriate to transition to oral therapy, as long as the patient is clinically improving and they can take their medication. So, good job. The majority got that just right. Thank you.

[00:41:34]

Posttest 2

Question number 2. Did you want to read that, Nico?

Dr Cortés-Penfield: Absolutely. So, if following the 4-step process in the IDSA guidelines, what would you recommend as outpatient treatment for a 42 year old with fever and flank pain from a suspected complicated UTI, no current medications or allergies, and a history of uncomplicated UTI 3 months ago treated with ciprofloxacin?

Great looks like - so it looks like the majority of folks opted for bactrim, which I think is perfectly reasonable choice. With, you know, kind of minorities of folks going for the options here. Bactrim would be for certainly a preferred option, particularly for someone who we were trying to manage with empiric oral therapy outside of the hospital system. Amoxicillin could be an alternate oral option, but would be less preferred than trimethoprim sulfa due to the kind of lower body of evidence. I would avoid a fluoroquinolone, given the patient has recently received that. That's a pretty strong predictor of resistance in the current uropathogen. And then ceftriaxone, I think, would be most reasonable in a patient who perhaps was having severe enough illness that they needed to be hospitalized. I probably wouldn't go to the expense and burden of arranging outpatient IV antimicrobial therapy if trimethoprim sulfa, amoxicillin, clavulanate were options. Because those would also be, you know, kind of very reasonable treatment approaches.

[00:43:40]

Q&A Session

Dr Colgan: Great. I think we've come to our question and answer session.

Dr Cortés-Penfield: Sure. So, why don't we start at the top here. So, are there any new antibiotics available for the treatment of severe urinary tract infection in immunocompromised patients? So, I discussed a little bit of the pipeline agents that are coming out for complicated urinary tract infections. There was also a, you know, a very old drug that was recently, given labeling in the US. It's been used all around the world for quite a while. But pivmecillinam is now available here in the US. I don't know that, you know, unfortunately, none of these drugs have specific FDA labeling or have had specific clinical trials or other well done studies showing superior efficacy in immunocompromised patients in general. And if you're someone who takes care of immunocompromised patients, you're probably very familiar that, you know, in general, the quality of evidence for treating these folks infections is much, much more limited than for the general public. And many immunocompromised specialists are sort of forced to extrapolate from data in the general population. And, Richard, do you have anything to add to that?

Dr Colgan: No, I agree. I agree fully.

Dr Cortés-Penfield: Yeah. And then what diagnostic procedures, besides classical methods can speed up the culture, result in identifying the causative agent of infection, and are they available to us? That's an interesting question. There are some new, you know, rapid culture based methods that have had data published on them. I think they're more clinically validated PCR-based systems and blood cultures. There are commercially available PCR tests that will - that can be done on urine. I think the problem is that those tests have not been clinically validated. I'll say, unfortunately, I've now encountered many providers who've received sort of like direct to physician marketing, sort of trying to bypass getting a lab approved as part of, you know, an institutional organization. And going directly to the physician or clinician consumer and saying, "Hey, you can run our test and get a result, you know, from your patient's urine." And I think the problem with that is urine is not like blood. Urine is not sterile. And without clinical validation studies being done, my concern is that that might really drive kind of overdiagnosis and overtreatment.

Let's see, why would you not use nitrofurantoin? I think this is referring to that previous question about the drug resistant pseudomonas. So nitrofurantoin is a wonderful drug, but unfortunately doesn't have pseudomonal activity. The other thing I'd call out for nitrofurantoin, again, a wonderful drug that I use a ton for uncomplicated UTI, but it doesn't achieve particularly good levels in renal tissue or in blood. And so in a patient with a complicated UTI and someone in whom you're concerned, they may have or be developing systemic infection, it might not be the most reliable choice. But for an uncomplicated UTI for infection that's clearly confined to the bladder, it can be a wonderful option.

I have a patient with neurogenic bladder and diabetes who's having frequent recurrent UTIs. In the past year, they've all been ESBL E. coli. Would oral carbapenems be a viable option if available? Can't use nitrofurantoin due to chronic kidney disease. So, you know and an oral carbapenem is probably going to be active against an ESBL producing organism. It would be the carbapenemases where you might run into trouble with oral carbapenems. What I'd say is this kind of getting at that risk statement, I was - I was talking about. Where if we - if we use long courses of oral carbapenems, if we try, you know, oral carbapenem suppression or prophylaxis, there's a pretty substantial risk, I think, that patient may then be colonized with a carbapenemase producing organism. And then, you know, when they develop true complicated UTI and bacteremia, it's with 1 of these awful bugs and they're at much greater risk of prolonged hospitalization and death.

Folks who have spinal cord injuries and recurrent urinary tract infections are just really tough to deal with that. And I wish I had a magic bullet for you. I mean, it's often difficult to make the diagnosis because of their neurogenic injury limiting their ability to perceive urinary symptoms. So, honestly, sometimes the first objective evidence of infection that you have is sepsis, bacteremia, fever. Another option you might consider would be methenamine, which is sort of more of an antiseptic than an antibiotic and now has a couple of clinical trials suggesting that it works about as well as antibiotic prophylaxis for preventing recurrent UTI.

Dr Colgan: I might add here in, I agree that, you know, it's difficult to diagnose UTIs and know those with neurogenic bladder. I do remember from being on the catheter associated UTI guidelines years ago, that at least some symptoms that we may be helpful to us is increased spasticity on the part of the patient, thermoregulatory dysfunction diaphoresis on the forehead and thirdly, you know, patients who have a neurogenic bladder and have a UTI, they have a sense of disease that they remember from past urinary tract infections. I don't know—what do you think of that, Nico? Does that help a little bit?

Dr Cortés-Penfield: Yeah, I think - I think those are also great considerations. Again, it's kind of like the immunocompromised folks. This is a really underserved patient population where the quality of data that we have is much more limited. But I agree, you know, when I'm assessing one of these patients, I do ask them about things like diaphoresis, spasticity, autonomic dysfunction, and these can be more subtle clues.

Dr Colgan: Yeah.

Dr Cortés-Penfield: It looks like - looks like the next question, Nico, kind of segues nicely with the last one you just had in what types of complicated UTI scenarios would you consider an oral carbapenem only for definitive therapy, or would you consider as empiric therapy if the patient had a MDRO history?

Dr Cortés-Penfield: You know, I would really prefer that oral carbapenems only be used for definitive therapy and only when other options are not reasonable. You know, if a patient has an ESBL E. coli causing a complicated UTI and it's susceptible to trimethoprim sulfa, or ciprofloxacin like, please use those instead. Yes, you can use these drugs. And yes, they should work for complicated UTIs and uncomplicated UTIs. Just remember that, when you know your patients or or your loved ones are admitted to the hospital in gram negative sepsis, the ICU team is probably going to be reaching for a carbapenem as empiric therapy. And so, you know, for the benefit of all of our patients and our whole community, we need to be really judicious users of this drug, or we're going to lose kind of our - our workhorse drugs for critically ill patients.

When adding to formulary, what types of criteria for use of restrictions would you consider for the carbapenems? I think it's that thing I just said. I mean, and I don't—I'm not on my hospital's antimicrobial stewardship team. And so to some extent, I don't really make those decisions and consider them a little bit above my pay grade. But I would really prefer they be used with input from an ID specialist, be that a physician or a pharmacist. And that we make sure that what we're doing is the right thing, both for the patient and for the hospital system and community.

Dr Colgan: If if I may take the next question, When, if ever would you use nitrofurantoin for a urinary tract infection? So I think, you know, an answer for that would be when you diagnose an uncomplicated UTI, remember, that is 1 of the 3 choices by the IDSA guidelines that are over 10 years old now for uncomplicated UTIs, but namely nitrofurantoin, trim/sulfa or fosfomycin as first line therapy. A little asterisk here is that also in those guidelines, they mentioned pivmecillinam, but when those guidelines came out more than 10 years ago. Pivmecillinam was not available in the US, but now it is available in the US.

Dr Cortés-Penfield: I'll jump 1 question down because I see someone also asked when would you recommend fosfomycin? And my answer is essentially the same as for nitrofurantoin. Again, fosfomycin, whether or not it achieves adequate renal or prostatic tissue levels is not clear. Probably doesn't achieve adequate blood levels, and so we should probably avoid it in folks in whom we're worried about infection beyond the bladder. However, for uncomplicated UTI, it is a wonderful option.  

What's a good resource for antibiotic selection for specific pathogens? Wrote really interesting question. I don't know that there is a ton of data that suggests 1 antibiotic class is particularly good for individual uropathogens. I would say if you look at the antibiotic vs antibiotic head-to-head clinical trials in general, they're mostly designed as non-inferiority trials. And they by and large show that everything works as well as everything else.

And so really, our choice of antibiotic is based on what are our options based on susceptibilities or likely susceptibilities based on those risk factors? And then what are all the other things we think about when we're choosing a drug for a patient, besides, will it do its job? So you know, the toxicity profile, the cost, the pill burden, all of that good stuff.

Dr Colgan: Nico, if I could follow that up with a wonderment myself. On our last call, you talked a little bit about the local biograms from hospitals. Can you give us your thoughts on that? I mean, in the old days we thought that, you know, looking up the data from the local hospital’s biogram could be very helpful. But were you suggesting that maybe there it's less clear or less helpful?

Dr Cortés-Penfield: Yeah. There. So actually, while this guideline was being developed, there was a really large study in the VA system of antibiograms and whether or not they correlated with, you know, improved empiric antibiotic decision making. And it was depressingly negative. And I do think some of that is probably influenced by, the quality of the antibiograms. Are they being done specifically in the facility when you're operating? Because if not, if it's like a regional or like, you know, if it's a 12 hospital system's antibiogram, that may be less relevant. Are you considering whether or not your patient fits in that box? You know someone who's just returned from a 2 week trip to the Middle East and is coming to you with a UTI, may have different bugs than someone who hasn't left the city in the past decade.

And so I think there are some caveats, but in general, the most recent studies have been actually a little unencouraging.

Dr Colgan: Interesting.

Dr Cortés-Penfield: Antibiotic choice for pseudomonal uncomplicated UTI with recent exposure to fluoroquinolones. Man, that's a tough choice. I think that if the patient doesn't have susceptibility to fluoroquinolone, you're stuck with IV therapy. And so, if you truly believe that this patient just has, you know, pseudomonal cystitis in the outpatient setting, you might set down the IDSA guidelines and say, "Well, I'm going to give you ciprofloxacin because it's the only oral agent that I have, and I'll follow your cultures and let you know if I have to call you back and put you on IV antibiotics in a day or so." That's probably what I would do in real life. But yeah, just because pseudomonas has 1 oral option makes it a little bit more complicated.

Do externally draining catheters like urethral catheter nephrostomy tube need to be changed upon initiation of antibiotics? And do internal stents need to be changed? That is a great question. I mean, the traditional teaching was that you would exchange a urinary catheter whenever you're seeing someone for infection. And you’d ideally do that before you obtained urine cultures so that you're culturing what's actually in the bladder, not just on the catheter wall.

But I don't know that that has actually been studied. I'm not aware of any, like, comparative outcomes data to tell us, is this simply a thing that we believe because we were, you know, taught it from generations past? Or is this something that we know to be true and good evidence based medicine? I don't know, Dr Colgan, if you have any other thoughts?

Dr Colgan: No, I agree fully.

Dr Cortés-Penfield: Yeah. The question of stents. I often get this question with folks who present with urinary obstruction and a ureteral stent is placed as part of relieving that. And then the question is, do they need to be on antibiotics until the stent is removed? And this really gets to be an issue when you know our urology colleagues, you know, who are very busy and in whom this is - they don't consider this to be like an emergent procedure, are going to book that as an outpatient procedure 2 or 3 months later.

And again, I don't know that there is an evidence based answer. I have seen some preliminary non-published data that suggests that if you get this stents out promptly, it probably doesn't make a difference. But I can't point you towards a peer reviewed answer for that.

What do you do for elderly female patients with recurrent UTIs week after week? This is an excellent question. First, I convinced myself that they're actually having recurrent UTIs, and I'm not fixating on repeated abnormal urine studies. Second, I try all the things that are, you know, free and easy to do. Teach them about double voiding. If they're having urinary retention, increase fluid intake. Make sure that they're voiding after intercourse. If they - if you have access to topical or intravaginal estrogen, that can do wonders for recurrent UTI, specifically in postmenopausal women. And then my 2 kind of last resort options in terms of preference would be methenamine hippurate or some sort of antibiotic prophylaxis.

Dr Colgan: Are cranberry extracts totally off the - off the shelf now, Nico?

Dr Cortés-Penfield: You know, I thought and was taught that they were bogus and actually our peer UTI guidelines developers, the Wiki Guidelines group actually did a review of all the randomized controlled trials of cranberry products. And they found that, as long as you are using a product with above a certain dose of the active ingredient that blocks that p-fimbriae, that there actually is some evidence for benefit. So, for the longest time, I have been thinking and teaching that - that was all kind of hogwash, and actually it seems that there may be something to it.

Dr Colgan: Yeah, I remember reading that from Kal Gupta's work that cranberry extracts may be better, less sugar involved, and you can get as much as the impact from cranberry extracts.

Dr Cortés-Penfield: Yeah. Is an option to use several doses of oral fosfomycin for uncomplicated or complicated UTI? For uncomplicated UTI? Absolutely. For complicated UTI, it's not in our guidelines. We did not find enough supporting data. There is 1 observational, retrospective study out of the University of California system I'm aware of that suggested maybe fosfomycin was okay for complicated UTI. But that was also used as step down therapy in folks discharged after a couple of days of IV antibiotics. So, I'm not sure what to believe. I guess I'll simply say it is not part of the IDSA's algorithm.

Can you speak on your approach to diagnosing UTI in paraplegic patients? I think we kind of talked about that. It is quite difficult, but there are some of those subtle symptoms that you can think of.

I usually use cephalexin as a first line agent. Is bactrim more appropriate if clinically appropriate? That's a great question. I think for uncomplicated UTI cephalexin is a wonderful choice. Oral beta lactam certainly can. They are listed among the alternative options in complicated UTI. The body of evidence for them isn't as robust, but I think a lot depends on what E coli is still susceptible to in your area. And, if the answer is cephalexin is a better bet than trimethoprim/sulfa, and you prefer cephalexin for that reason, I think that makes total sense.

Can you comment on the utility of a single IM dose of aminoglycoside? Yes. Limited data suggests it is effective and could be another alternative option for trying to treat UTI outside of the hospital. Most of that data was for patients with uncomplicated UTI. But it could be, you know, again, not the thing that I would reach for first, but in a specific scenario where you're trying to prevent hospitalization in someone who might not need it, that could be a reasonable option.

Dr Colgan: And I think - I think Kal Gupta mentioned that in the uncomplicated UTI guidelines more than 10 years ago. I'll also add that in addition, in those guidelines, it mentions not just immuno glycosides, but also IM 1 gram of ceftriaxone could be an alternative for those where I think the rates of resistance is felt to be greater than 10%.

Dr Cortés-Penfield: Yeah. How do you diagnose UTI in someone with neurogenic bladder? I think we talked about that a little bit. For patients with a chronic indwelling catheter that can't be removed, no specific guideline about catheter exchange frequency when stable. How often do we change the Foley to prevent CAUTI? That's a great question that I don't know has a evidence-based answer for you. I wish I could tell you clearly what the right answer was.  

With the change of definition, several new agents are approved for uncomplicated UTI. With the new definition, are you concerned with broad inappropriate use due to confusion and definitions? I am always concerned about inappropriate use of broad spectrum antimicrobials. I mean, honestly, my hope is that the newer definitions are clearer than the old ones. I mean, previously we had a very fixed, narrow definition of uncomplicated UTIs, like cystitis in a healthy woman who's not pregnant and everything else is complicated.  

And I think that may be included a lot of folks that didn't need to be included in complicated. Again, I think my hope is that we've, the sort of 3 bullet system like UTI with fever, sepsis, systemic infection, CAUTI, and pyelonephritis is easy for folks to keep in their brains. But I suppose we shall see.

In the context of stewardship, several mentions of meropenem is there advocacy and guidelines for a narrow agent? So the actual guidelines simply recommend carbapenems and specifically call out ertapenem as an option. And yes, certainly, the main uropathogen in all forms of UTI is E. coli, and meropenem is not strictly needed for that. You don't need the anti-pseudomonal activity and ertapenem can be a great choice.

Bioavailability of oral agents with quinolones when choosing outpatient discharge. Good question. So, I think what you're getting at is, there are some studies that suggest that oral fluoroquinolones or trimethoprim/sulfa, which are considered highly bioavailable, may be more effective than oral beta lactams, which are low, generally considered low bioavailability for UTI.  

The data on this is a little conflicting and nuanced. I will say there is a table that has specific dosing recommendations in the guideline. My kind of read on the totality of that data is that, if you're going to use an oral beta-lactam, you should probably give the highest tolerated dose, particularly for complicated UTI where you're worried about is there systemic infection? Is there renal infection or bloodstream infection? But, you know, high dose oral beta-lactams, at least in observational studies, seem to work just as well as these other classes.

Afebrile 95 year old with valve prolapse and recurrent UTI. What would be the drug of choice? It would depend putting in patient, as AFib isn't a concern. It would depend on if it was complicated or uncomplicated, and it would depend on what the uropathogen and susceptibilities report suggests. I would say, I am always more cautious about trimethoprim/sulfa, and fluoroquinolones in folks at the extremes of age, and particularly when they have chronic kidney disease. Quinolones can make elderly folks loopy, and bactrim can really do a number on - on folks who have baseline renal impairment, which many folks at advanced stage do.

Dr Colgan: I'll take the next 1, if that's okay. Cranberry plus D-mannose, is that more effective than cranberry alone? So, what I understand is that when it comes to preventing urinary tract infections, the combination of cranberry and D-mannose is often considered more effective than just cranberry alone because they target bacteria in 2 different ways, 2 complementary ways, and there was some recent clinical studies done in 2024 and 2025 that looked at that, as they have - having a synergistic effect, the 2 together.

Dr Cortés-Penfield: I've been recommending cleansing foam to minimize skin bacteria, and helping to prevent recurrent UTIs. That's interesting. I think that's been more studied for preventing recurrent soft tissue infections and staphylococcal infections. I don't know of any data for UTI prevention, but that's interesting.

Can you speak on why gepotidacin is approved for uncomplicated, not complicated UTI? I do not know the answer to that. I don't have that on deck. Richard, any chance you do?

Dr Colgan: No, I don't know the answer. I don't know if there are studies that showed improvement. I don't know if they could prove that it was indicated for complicated vs uncomplicated. That's what comes to my mind, but I'm not certain about that. I think we have to wrap up our questions, if I'm not mistaken. From what I'm hearing from our organizers, do you have anything else to add, Nico?

Dr Cortés-Penfield: I do not, except thank you guys so much for your attention and all of the wonderful questions and for joining us today.

Dr Colgan: Thank you as well.

[END OF TRANSCRIPT]