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You’re in the Know Podcast: Applying the Latest Advances in Complicated UTI to Practice

Introduction

Dr. Colgan: So we're going to talk about some latest advances in complicated UTI to primary care practice.

Faculty and Disclosures

And my name is Richard Colgan. I'm from Department of Family and Community Medicine at the University of Maryland School of Medicine. And Dr. Christopher Smith, you'll meet in just a moment. Infectious Disease Physician from Chase Brexton Health Care. Clinical Assistant Professor, Shock Trauma Center, University of Maryland Medical Center, Baltimore, Maryland.

We're going to talk about some of the latest advances in the complicated UTI world. Assess the burden of complicated UTIs on patients and the health care system, look at some evidence-based strategies for selecting empiric antibiotics for patients with complicated UTIs, and tailor definitive antibiotic therapy for complicated UTIs, incorporating oral agents when appropriate.

The Burden of cUTI

So let's - let's dive into this topic a little bit and talk about the burden of complicated UTI and antimicrobial resistance. A topic that's near and dear to your heart. You live it, you work it. You're - you're dealing with it every single week, I'm sure. Close to three million cases of complicated UTIs in the US yearly are seen. Because of these cases, it leads to an extended length of stay during their hospital stay. And with that comes increased morbidity and mortality.

For non-catheter associated complicated UTIs mortality, percent of 2.78%, a bit higher if they have a catheter. The length of stay is approximately seven days for complicated UTIs when they don't have a catheter, and almost eight days when they do have a catheter. And if anybody cares about the money, it costs more money to be in the hospital for a non-catheter-associated complicated UTI. Even more so if they have a catheter. And the total costs are high as well.

Financial Burden of Antimicrobial Resistance

So financial burden of antimicrobial resistance. You know, the cost for Cipro 500 bid for a seven-day course when you don't - when you exclude those who are hospitalized, you know, it's about $5.20. If you're going to put somebody on ceftriaxone in the outpatient setting for a complicated UTI, 2 grams a day, $66 - $67, ertapenem 1 gram a day, $168, and if you go up to ceftazidime avibactam, that's a $10,500 tab in the outpatient setting. So the - the point being is that the impact, as we all know, of antimicrobial resistance is huge.

Global Impact of Antimicrobial Resistance: 2019

Even as far back as six odd years ago - this is close to seven years ago from Lancet - but looking at the global impact of antimicrobial resistance. And I kind of - I thought it was interesting. I guess the first couple of organisms, E. coli and Staph aureus, as far as global impact for antimicrobial resistance. And I was interested to see how - how many other pathogens down the - down the line also confer a problem with antimicrobial resistance, all the way to Pseudomonas and Salmonella and Group A Strep, and even Salmonella enterica serotype and non-typhoidal salmonella. So, almost five million deaths are associated with bacterial antimicrobial resistance, including about 1.27 - 1.27 million deaths attributed to bacterial antimicrobial resistance. So, this is a big player not just for us here in the US, but across the globe.

Resistance Among Gram-Negative Uropathogens Is Rising

Resistance amongst gram-negative uropathogens is rising. No surprise to anybody in this room. This increases the burden of caring for those with complicated UTI. Extended-spectrum beta-lactamase-producing uropathogens now represent 20% of complicated UTIs. You know, I'm thinking back to the days, in my earlier days of practice, when you know, ciprofloxacin fluoroquinolones first came out, were first used, and they had the resistance rate of like, you know, 2% in Canada with a study that was done way back then.

It's just amazing what's happened. Of course, the more you use any one drug, the greater the likelihood of resistance over time. And these infections with multidrug-resistant organisms are associated with delays in effective therapy, often needs for IV antibiotics thereafter. Limited treatment options, cost more money, toxicity, and, unfortunately, a higher rate of treatment failure. So, resistance among gram-negative uropathogens matters.

Defining cUTI: Major Change in IDSA Guidelines

IDSA came out with new guidelines for complicated UTIs.

But complicated UTI now includes any infection beyond the bladder in a woman or a man. But before it used to be a differentiated between male or female. No longer is there such differentiation. And the new classifications is sites that are uncomplicated UTI, which I assume you see hardly any of, I would think. An uncomplicated UTI is an infection confined just to the bladder in an afebrile woman or man. Whereas complicated UTI, the focus of our talk here means an infection that's beyond the bladder in women or in men.

So, for example, pyelonephritis, febrile or bacteremic UTI, and catheter-associated UTI are included in this group because most of the studies to date have been with this grouping. And so, catheter, you might say, why is that included? But if the patient has a catheter in them, they're considered to have a complicated UTI. If you're deciding that they do have a UTI.

Diagnosing cUTI

So, how do you diagnose a complicated UTI? It's - it's by their clinical symptomatology largely. It's their symptoms. It's the history and physical exam, clinical symptoms drive that diagnosis. Yes, you would expect to see pyuria in your patient. But this - this finding is non-specific. Yes, you would expect to see bacteriuria in your patient, but this also is non-specific.

However, the caveat being is that if anybody is going to look to designate somebody as having a urinary tract infection and there's not bacteriuria or pyuria, then maybe you should rethink the diagnosis or be extra careful because that's not common, typical, or mainstream. So, this - that's for UTIs in general.

Now, for an uncomplicated UTI, as I mentioned, that denotes an infection that's confined solely to the bladder in a male or a female. A complicated UTI, as I said just now, is an infection extending beyond the bladder. There is typically systemic signs, fevers, rigors, sepsis, bacteremia. If they have a catheter and you're saying they have an infection, then that's a complicated UTI.

If it's pyelonephritis, flank pain, CVA tenderness, consistent imaging to denote that. So, this is the new classifications of complicated UTIs by the IDSA. So, we now have Dr. Christopher Smith, an actual member, I am certain, of the Infectious Disease Society of America, who's going to walk us through some of the more in-depth, detailed and difficult nuances of this topic. Dr. Smith.

Dr. Smith: Thanks, Dr. Colgan. Again, I'm Christopher Smith. I'm an infectious disease physician coming down from Baltimore. Dr. Colgan definitely was a little bit too humble there. He failed to mention that he is on the guideline panel that introduced this. I am the new kid on the block, comparatively. I do not have the same history or eminence. But I did wear my favorite bow tie, so you can trust my ID bona fides. So just so everyone feels confident in what they're going to hear today. So, now we're moving into some case-based learning and diving into more of the complexities of antibiotic management of complicated UTIs.

 Patient Case 1: Choosing Empiric Therapy

We're going to start with a pretty classic case that I am sure we have all ended up being consulted on in the hospital. We've got a 72-year-old gentleman admitted with several days of acute onset dysuria, urgency, and flank pain. He's got a past medical history of prostate hypertrophy, type 2 diabetes, and chronic kidney disease. He also has a prior hospitalization for UTI eight months ago. We're going to say, for the purposes of our questioning, that we don't know what he was treated with or what his pathogen was at that time.

He is febrile. He's borderline hypertensive, a little tachycardic. His initial urinalysis shows some pyuria and positive nitrites. His labs are also notable for a moderate leukocytosis and an AKI with a serum creatinine bump. And we do have some imaging in this gentleman, a CT abdomen and pelvis, which shows no obstruction and no abscess.

Poll 3

So, we'll start with our first question. What consideration is most important when selecting empiric therapy for this patient? 90% say risk of resistant pathogens. I agree those first three options his age, history of diabetes and absence of bacteremia have no real impact on either our choice of antibiotic or duration based on current guidelines, but we are certainly concerned with this presentation of a high-risk of resistant pathogens with that history.

Empiric Antibiotic Selection: A 4-Step Process

The new IDSA guidelines on complicated UTI have introduced a four-step process for assessing patients and choosing empiric therapy. It starts with an assessment of the severity of illness. Is this a well person, ambulatory, seeing you in outpatient clinic? Are they hospitalized, ill but not septic? Hospitalized and septic. Septic shock with multisystem organ failure. We can kind of have a bunch of different batches for folks.

Then we think about what are their risk factors for antimicrobial resistance. Do we have a documented history of a multidrug-resistant organism? Some good things about living in an electronic medical record world, some of them now have a - do a better job of flagging histories of MDROs. Some not so much. But it's helpful whenever we can get that clear history. Were they - did they have a health care system exposure within the past year? And, in particular, do we know of treatment for urinary tract infection within the past year? Are there patient specific - specific factors history of allergies, adverse effects of certain antibiotics that we're considering, drug-drug interactions? And finally, looking at the local antibiogram data, specifically in cases of patients with sepsis or septic shock, which is where the use of antibiograms to guide empiric therapy has actually been validated.

Poll 4

Next question, which empiric antibiotic regimen is most appropriate for this patient based on what we know about them? All right. Most of us thought C, IV pip-tazo, which I agree with. I think, thinking back to our clinical scenario, that gentleman met SIRS criteria. He was febrile, leukocytosis, a little bit hypotensive, tachycardic. There was concerned for infection, concern for sepsis. I think overall, starting with IV Zosyn makes sense in him.

Initial Selection of Empiric Antibiotics

And the newest guidelines have broken down that choice of selection of empiric antibiotics into kind of three categories, based on that for step selection process and that - that patient differentiation.

I'm actually going to start with our kind of well patients, without sepsis, oral therapy is appropriate. In this case, our preferred choice would be fluoroquinolones or Bactrim trimethoprim sulfamethoxazole. And that's because both of those are well studied, high oral bioavailability, high urinary concentration, and penetration into renal tissues. Our backup alternatives here are Augmentin or oral cephalosporins.

I do want to point out a couple of caveats there. A, all of those are - are less well studied in terms of their clinical effectiveness than either fluoroquinolones or Bactrim. Slightly less oral bioavailability. Augmentin does have really strong urinary availability. However, particularly when it comes to the cephalosporins, I want to put my ID vote out there that everyone should be avoiding cefdinir these days if you're not already. It is a terrible drug, particularly for urinary tract infections. It has poor bioavailability, poor urinary penetration. And we now actually have a really strong study that came out this past year, looking at a comparison of cefdinir versus cephalexin in uncomplicated urinary tract infections in women that showed a significantly lower clinical cure rates or effectiveness. So, if you ask any ID physician, they will tell you that it's among their least favorite antibiotic. So, if you're considering an oral cephalosporin, I'd point you in a different direction there.

Moving up to patients without sepsis who are hospitalized, indicated for IV therapy. Our preferred options are third or fourth gen cephalosporins, ceftriaxone, cefepime, pip-tazo, and fluoroquinolones, with alternatives being the carbapenems and these newer agents, newer beta-lactam beta-lactamase inhibitor combinations or aminoglycosides.

And then in patients like ours, with concern for sepsis with or without septic shock. Again, the preferred agent is that third or fourth gen cephalosporin, carbapenems within the preferred category, Zosyn, and fluoroquinolones. This is where there is a caveat within the guidelines that we need to be thinking hard about carbapenems as our first line here, due to the rising rates of extended-spectrum beta-lactamase within the population and the concerns for resistance there.

Poll 5

Question five: What do you recommend for definitive therapy? We're going to assume that we have definitive therapy. We are - we are susceptible to all of the options that we're given. Most everyone said de-escalate to oral Bactrim, which I agree with. In this case, he is - we're assuming that we have susceptibility. He's doing clinically well. He's appropriate for de-escalation. Bactrim is a great option in that case. And what if Bactrim is not an option?

Poll 6

What if this patient were allergic to sulfonamide antibiotics? What is our backup plan? Levofloxacin, ceftriaxone, amoxiclav or Bactrim? In this case, I think that the levofloxacin is perfectly reasonable. The Augmentin is also, I think, an option in this case as well based on our susceptibilities.

Approach to Selecting Definitive Therapy

So, the approach to selecting definitive therapy, we would want to be tailoring to definitive therapy as soon as possible based on the culture susceptibilities, with strong consideration at this point for stewardship, once we're beyond that empiric coverage period. We want to have as narrow a spectrum of activity as possible, taking into account the cost, toxicity, and route of administration.

And whenever you do come upon a multidrug-resistant organism, in general, it's important to understand that multidrug-resistant organisms are not necessarily more virulent. They do not require a longer duration of therapy. They do not require IV therapy. There's been no clinical evidence that that - that is different here. But they often impact the choice of therapy because we want to ensure that we have an agent that will cover that resistance.

It is acceptable to transition to oral therapy if the patient is clinically improving. In general, if they are afebrile for 24 to 48 hours, they're hemodynamically stable symptoms are resolving. And most importantly, they can tolerate oral therapy without nausea or vomiting.

And if they are not clinically improving, we need to extend the workup beyond just extending the duration of antibiotic therapy. We need to think about what we're missing. We'll discuss that a little bit more later.

Novel Treatments for cUTI

These are typically not the antibiotics that you all are going to be pulling out immediately, but it's good to have some familiarity with them. Most of these are novel beta-lactam, beta-lactamase inhibitor combinations that on your formularies are largely going to be restricted to ID approval.

So, first up we've got ceftazidime, avibactam and ceftolozane, tazobactam, meropenem, vaborbactam, imipenem, relebactam, all of those. So, the first two are beta-lactam beta-lactamase inhibitor. Second two are carbapenem and beta-lactamase inhibitor, which can work for against carbapenemases. Cefepime-enmetazobactam, I can't even say that one yet because it's not generally available. And then Plazomicin, those two have FDA approval for complicated UTIs. But honestly, I'm not seeing them commercially very available yet or on formularies. Potentially with the cefepime-enmetazobactam coming in the near future. Plazomicin, I'm not sure where that's going to necessarily have a role. That's been approved for a few years, but has not become clinically prevalent or relevant really yet. That's a novel once daily dosed aminoglycoside.

Cefiderocol definitely comes into play nowadays with complicated infections and multidrug-resistant organisms. This is a cephalosporin with a novel mechanism of action that hijacks the iron transport system of bacteria in order to avoid resistance and be able to act on some of these resistant organisms, particularly carbapenemase-producing bacteria and Acinetobacter. There are some interesting questions about the barrier of resistance of cefiderocol in clinical practice, and we definitely have some concerns about that within ID world, but it is a nice tool for us to have often as kind of our last line treatment.

Pipeline Agents for cUTI: Combinations With Cefepime

In the pipeline, we have a couple of IV agents coming that are both combinations with cefepime. We've got cefepime zidebactam and cefepime taniborbactam, both of which have completed some trials, are being evaluated by the FDA, but not yet clinically available.

Pipeline Agents for cUTI: An Oral Carbapenem Option?

And then, what's most exciting and potentially interesting, and what is clearly coming potentially within the next year, is an oral carbapenem option. So, this is specifically looking at an option for complicated UTI caused by ESBL-producing gram-negative pathogens. Most exciting from the ID standpoint for use in step-down therapy, particularly saving people from having to go home with an IV on IV ertapenem therapy for ESBL infections.

Also, potentially useful in outpatient management, although every ID doctor you speak to is a little tremulous about this, and certainly wants all of us to be thinking about antimicrobial stewardship as much as possible in that outpatient setting, and truly only using a carbapenem in the setting of a known or highly suspected ESBL resistant organism where we are lacking other options for treatment.

The first of these oral carbapenems is sulopenem, which has been FDA-approved for uncomplicated UTIs. It does not have an approval for - for complicated UTIs at this point. That was based on some trial data comparing to ertapenem and showing non-inferiority. Tebipenem, on the other hand, has been studied and submitted specifically for the treatment of complicated UTIs. It now has multiple Phase 3 trials, actually. The latest, this PIVOT-PO trial which was just being published currently, compared tebipenem with imipenem cilastatin in adults with complicated UTI and pyelonephritis, showed non-inferiority. The trial was actually stopped early for meeting the primary endpoint. It is with the FDA currently, and we are anticipating potential approval and availability even sometime this year.

So, that's going to be a really interesting space for treatment of complicated UTIs and figuring out where we are fitting this in between primary care, infectious disease, urology, on - on taking care of our patients, particularly those with a known history of recurrent ESBL pathogens.

Poll 7

A couple more questions for us. If this patient had prostatitis, how long should they be treated with antibiotics? A little bit of a trick question here. I would say if this were concerns for an acute prostatitis, I absolutely agree. A two-week course would be appropriate. If this is one of my patients that I am concerned about recurrent UTIs and a chronic prostatitis picture, then we're looking at a longer four to six-week course.

Duration of Therapy

Looking at duration of therapy. In general, within ID world, the dogma these days, which I hope you've heard, is shorter is better. We're getting more and more evidence across the board in different infectious syndromes that shorter courses of antibiotics are non-inferior and have lower adverse effect profiles, if we can limit the exposure to potential agents. With complicated UTI, with or without bacteremia, we are now recommending seven days. So, we're going by the calendar count here.

With fluoroquinolones that can go down even potentially to one hand. Five days is reasonable, but generally speaking, you're not going to be docked by - by any ID physician for aiming for seven days, in that case with clinical improvement.

Certain subpopulations certainly need individualized durations and were excluded from the - the complicated UTI guideline update. Prostatitis, epididymitis, orchitis all were separate from that. Certainly, considerations of indwelling stents, obstructive infected stones, percutaneous nephrostomy tubes, that's all outside of the realm of this guidance. And that needs a little bit more individualized consideration.

What If the Patient Is Not Clinically Improving?

Patients who are not clinically improving, despite effective therapy, need further evaluation, not just prolongation of treatment. What does that mean? We need to evaluate the antibiotic itself and the drug-bug interaction there. Do we have a - an antibiotic that is active against that pathogen? It is - is it appropriate for reaching therapeutic levels in the target tissue that we're aiming for?

Do we have source control, most importantly? Are there any urinary obstructions that need to be relieved? Are there any abscesses that we have not found at this point? If we do not have imaging, we should be getting imaging to be looking for any other source of infection. Or reassessing our complicated UTI diagnosis. Is there something else going on here that is explaining our persistent symptoms?

Patient Case 2: Interpreting Susceptibility Results

Moving on to another case in order to explore a little bit more about susceptibility. And we've now got a 59-year-old man with type 2 diabetes and neurogenic bladder, recurring UTIs. He's admitted with fever, rigors and left flank pain. He started empirically on IV Zosyn. His blood cultures come back negative. He's clinically improving. He's doing well, and his subsequent culture grows a Kleb pneumo with the following susceptibility results. It is resistant to ceftriaxone. Susceptible to pip-tazo. Resistant to ciprofloxacin. Susceptible to meropenem and susceptible to ceftazidime avibactam.

Poll 8

Based on susceptibility results and the clinical scenario, which is the most appropriate definitive antibiotic therapy for this patient?

So, there's a little bit of ambiguity in guidelines here. Particularly, whenever it comes to any ESBL infection that is systemic, that is outside the urinary tract, including bacteremias. We have higher concern for the clinical efficacy of pip-tazo in that case. And a switch to meropenem would be absolutely appropriate. There is some wiggle room, however, and a separate IDSA guideline for the treatment of gram-negative infections or resistant gram-negative infections.

In the case where we have an ESBL infection isolated to the urinary tract, no associated bacteremia, the patient is responding to empiric Zosyn and doing well, it is actually acceptable to finish therapy on Zosyn in that specific case. So, in this situation, it's a little bit of grey area that we don't have perfect clinical evidence on.

And then I think we are opening to questions. Yes.

Speaker: Many hospitals antibiograms test against aminoglycosides and are overwhelmingly effective. What's the role of aminoglycosides in these patient populations?

Dr. Smith: I think the question was in general, aminoglycosides have held up in terms of susceptibility even in these ESBL organisms or in some of our resistant pathogens. So, what's the role here? Personally, and I think that this is general consensus among infectious disease physicians, we love aminoglycosides whenever it comes to uncomplicated UTIs, and single dose aminoglycoside as treatment, including for resistant organisms. I use that all the time.

It is a little bit trickier whenever it comes to complicated UTIs and a requirement for an extended course, because then you're coming up against all of the potential toxicities of aminoglycosides, in particular nephrotoxicity and ototoxicity, which we all remain quite concerned about.

And there is less direct evidence for aminoglycosides in complicated UTI. The - the clinical evidence that we do have is ancient at this point comparatively. And in that case, we do have better up-to-date clinical evidence and profile for some of these novel agents that I think we're turning to. But it does remain quite attractive in that - that uncomplicated, resistant, uropathogen situation.

Dr. Colgan: Chris, there was a study, I think, looking at the value of biograms in hospitals and how accurate things are. Do you have any like - like caveats when you review a biogram for which you say, you know, be careful about this or about that? Can you give us any comments on your - your interpretation of biograms?

Dr. Smith: You're really going to call me out like that as an ID doctor. I'm going to have to say antibiograms, while we love them, they're colorful, they're beautiful, they're great, they are not as clinically validated in their utility as we would like them to be.

And truly, the reason why the IDSA guidelines only listed, or had a specific caveat for that consideration of the clinical antibiogram, only for patients with sepsis or septic shock, because that's the only situation where we have actually had some clinical evidence of an impact of being guided by that in empiric decisions in those more severe cases.

There is less evidence and even potentially some contrary evidence in terms of relying on antibiograms for less severe outpatient clinical management and empiric antibiotic choices. So, really, that's - that's pretty exclusive to that - that severe hospitalized high acuity patient that we are most dependent on it.

Dr. Colgan: Thank you. Well, thank you very much for joining us, Dr. Christopher Smith from the IDSA society and hopefully making you aware of some new nuances with the topic of complicated UTIs. And we're grateful for your attention.