The Plot (and Sputum) Thickens: Encountering Carbapenem Resistance in Critically lll Patients

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We're going to talk first about reassessing carbapenemases and the antibiotic fear of CRE.

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Case: Patient in a Nursing Home With a Tracheostomy

And I'll start with a case, a patient that I took care of. This patient was admitted from a nursing home after having a witness seizure that lasted roughly 2 minutes. Was treated with cepra, EEG showed diffuse slowing.

You can see the vital signs there, relatively stable, good SAT. The patient had been hospitalized 3 and 7 months earlier with the trach in place for what was thought to be tracheobronchitis and was treated with antibiotics including vancomycin and meropenem during those hospitalizations. In addition, received other antibiotics at the nursing facility.

And our plan at the hospital was just to discharge this person after about 48 hours of observation and having seizure meds started.

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Case (cont’d): Hospital Day 3

The chest X-ray, which you saw before, looked relatively clear. However, on hospital Day 3, we have this new chest x-ray, and it appears that there is some infiltrate in the right lower lobe and on the left side. The patient also now has secretions coming out of the trach. They're purulent. The patient also has more labored breathing.

You can see the SaO₂ has dropped while on 10 liters. The vital signs suggest that the patient is somewhat unstable. Blood pressure is down, respiratory rate is up, temperature is up.

So the patient is transferred from the trach floor. We happen to have a trach floor at our institution, and they go to the ICU. The patient gets a cuffed trach at that particular point, is placed on a ventilator. And then the house staff, along with the fellow, start antibiotics. In this particular case, vancomycin 1.5 g, and meropenem 1 g given IV. And a tracheal aspirate is sent off after the trach has changed for multiplex PCR testing.

And we happen to use the BioFire test at Barnes-Jewish Hospital.

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Rapid Multiplex PCR Testing: BioFire FilmArray Pneumonia Panel

So going forward here, this is the BioFire. You're all very familiar with it. It's a multiplex PCR allowing for the detection of multiple bacteria, as well as viruses, atypical bacteria, and resistance genes.

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Rapid Multiplex PCR Testing: Unyvero Lower Respiratory Tract (LRT) BAL Application

There's also the Unyvero, which is another very similar multiplex PCR. Again, looking at a number of different resistance genes, bacteria. This one also allows pneumocystis to be detected.

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Case (cont’d): Multiplex PCR Results

And so it's sent to the lab. The tracheal aspirate is sent to the lab. And after 6 hours, we get a call, actually a call, and it comes up on the computer, Klebsiella pneumoniae, and the resistance gene that's detected is NDM.

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Poll 3: Patient's condition worsens with need for 100% FiO₂ and addition of vasopressin. What do you do now? (Is this vHAP or sCAP?)

So this patient's condition worsens with need for 100% FiO₂. They're on the ventilator. They need vasopressors at this particular point. So the question is, what do you do now? And so, you know, you could debate, is this a hospital-acquired pneumonia that now requires ventilation, or is it someone who comes in from the community? We're not going to debate that point, but we need to come up with a regimen to treat this person. So, would you:

1. Continue the current regimen, which was vancomycin and meropenem;
2. Give 1 dose of IV tobramycin;
3. Switch the vancomycin to linezolid;
4. Switch the meropenem to ceftaz-avi and aztreonam; or
5. Add nebulized colistin.

So these are choices, and we're going to pick 1 of these.

And so, continue the regimen, 3%, probably a good place to start; IV tobra, 14%; switch vanco to linezolid, 5%; 74% picked ceftaz-avi + aztreonam; and 2% wanted to go with inhaled colistin.

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Considerations for Antibiotic Selection

Okay. So, really, it's a matter of looking at the picture here in terms of this particular case, and in general, when making decisions about antibiotic selection, one needs to get some information about organisms.

We can get that more quickly now with some of the multiplex testing. We need to understand the site of the infection. Obviously, pneumonia being different from urinary tract infections in terms of the potential drug delivery aspects, as well as pathogens and susceptibilities, the prevalent resistance mechanisms in your institutions and in your community, and other patient-specific factors, like in this case, the trach and the patient having received multiple prior courses of broad-spectrum antibiotics.

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2024 IDSA Recommendations: Antibiotic Escalation in CRE Isolates Based on Rapid Genomic Testing Results

And these are actually the 2024 IDSA recommendations that they put forth on using antibiotics for particularly resistant organisms based on the presence of specific carbapenemases. And so you can see for KPC, which is a Class A carbapenemase, you're likely to have resistance to multiple areas here: penicillin, cephalosporins, carbapenems, and aztreonam. IDSA recommends ceftazidime/avibactam, meropenem/vaborbactam, or imi-rel.

Those would be the 3 choices. There are alternatives that are there: cefiderocol, tigecycline, eravacycline. Problems with the latter 2, being tetracycline derivatives, are that the registration trial suggested some problems with the treatment of urinary tract infections and bloodstream infections, so you would probably avoid those in those particular circumstances.

When you get the Class B, and that's the case for our particular patient here because they had an isolated NDM carbapenemase, that's NDM, VIM, and IMP, really what IDSA recommends here are ceftazidime/avibactam and aztreonam or cefiderocol. Those are really the 2 agents there for that particular class of resistance. Again, tigecycline, eravacycline, one would consider, but avoid if you had a UTI or a bloodstream infection.

For OXA-48, where we can see this in various pathogens, Acinetobacter Pseudomonas, again, you have a broad spectrum resistance. Drug of choice here by IDSA is really ceftazidime/avibactam based on its overall activity, and then cefiderocol would be an alternative.

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Case (cont'd): Further Treatment and Outcomes

Just continuing here, in this particular case, our patient was switched from meropenem to ceftazidime/avibactam and aztreonam once we identified that the patient had NDM. It had an essentially severe pneumonia that we had documented. Disc diffusion results returned 36 hours later, and these are the results.

So, 1 of the key points here is that we got information relatively quickly with the multiplex PCR. You can see the disconnect here almost more than 24 hours since, or delay, if you will, if you were waiting on just the disc diffusion or the micro lab to get back to you. And we can see resistance to ceftazidime, meropenem, colistin was susceptible, amikacin was intermediate, ceftaz/avi was resistant. So, that's really key here.

You know, we're dealing with the NDM. We're dealing with an organism that will be resistant to aztreonam, or excuse me, to ceftazidime-avibactam, but the addition of aztreonam confers susceptibility, and then ceftolozane/tazobactam was resistant as well. When we made the switch in this particular case, although it took a while, this patient did recover, and after about 3 weeks in the ICU was eventually able to get back to their long-term acute care setting.

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CRE Resistance Mechanisms

So, mechanisms of resistance. Again, this is really sort of the breakdown. You know, we need to be aware, and Ryan will talk more about this, that we sort of focus on carbapenemases, and we've already talked about the 3 classes of carbapenemases that are listed here for you, but also keep in mind many pathogens can have a phenotype of carbapenem resistance without actually having a carbapenemase, case in point being Pseudomonas in the United States, either because of high-level expression of ESBL or ampC, plus the deletion or modification of a porin channel.

So, one has to understand that even if one comes back with a negative result on the multiplex PCR, particularly for Pseudomonas, one can still have a phenotype that is carbapenem resistant.

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US Carbapenemases: Rise in NDM and OXA-48–like

Now, focusing specifically on NDM, the data suggests, and those of you from New York and other places where you're seeing a lot more of this, this is an increasing and escalating problem throughout the U.S. These are just data from 1 proprietary database in the United States from 74 medical centers, and you can see what's happened here from 2019 to 2021, and when you look at the metallo-beta-lactamases in the middle here, which would include NDM, VIM, and IMP, the numbers are going up, and they're significantly going up.

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US Carbapenemases: The Continued Increase of NDM

More importantly, if you look at data from the CDC, one can see that their resistance lab has seen almost a 500% increase in the numbers over a relatively short period of time, roughly 4 years. And in New York City, and those of you from New York can hopefully confirm this, NDM has surpassed KPC as being the most common carbapenemase in 2024.

So we're seeing, as we have seen over the last decades, changes in the spectrum of organisms, and more importantly, their resistance elements.

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Carbapenemase-Producing Enterobacterales: FDA-Approved New β-Lactam/β-Lactamase Inhibitors

This is just a review for you looking at carbapenemase-producing the enterobacterialis, and really, you know, the antibiotics that would confer activity here.

When we're talking about cefiderocol, you can see it covers across the board. Ceftaz-avi primarily for KPC and OXA-48, ceftaz/avi plus aztreonam across the board. And then you are left with the antibiotics that primarily are going to be treating KPC, which is imi-rel and meropenem/vaborbactam.

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Ceftazidime/Avibactam + Aztreonam for MBLs

Again, the combination, which is the newest combination that we have here, although prior to this drug being released, we were sort of doing it on our own by combining 2 different antibiotics.

Ceftaz/avibactam + aztreonam for metallo-beta-lactamases. There are a number of studies now. They tend to be more smaller case series, if you will, and a lot of them come from Europe. And these are a couple of studies here from Europe, 1 in the US, that make the point that when you look at these antibiotics and the ability to treat relative to alternatives, the use of ceftaz/avibactam + aztreonam achieves higher rates of clinical cure, if you will. So there are advantages in using this for this particular type of an organism.

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Ceftazidime/Avibactam + Aztreonam for MBLs: Additional Considerations

Now, there are some additional considerations here when you're dealing with the metallo-beta-lactamases.

Based on results from surveillance studies in general, more than 90% of these will be susceptible. And you need to be aware that many of your labs may not be reporting susceptibility results for these particular organisms to you. So if you're using a microarray and you identify an NDM in the respiratory tract, one has to make a decision at that point.

And it's really a little bit of a leap of faith in terms of picking a drug that you think is going to be active against it. And we've already talked about the antibiotics that are most likely to be active against it in this particular case, which would be ceftaz/avibactam + aztreonam, or cefiderocol.

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Cefiderocol for MBLs

Cefiderocol for the metallos, again, there are some studies here.

Just to summarize them, if you focus in the graph down in the corner here, it's important to understand that the drug can work with these particular organisms. There's the CREDIBLE study as well as a nosocomial pneumonia study that was done. The issue is that when you look at overall cure rates here, the cefiderocol cure rates were in the rate of about 30%, and the mortality was roughly 30%. And the ceftaz/avibactam + aztreonam mortality was roughly 22%. They did better than some of the comparator regimens. So overall, those are the drugs that seem to be most active against this class of organisms.

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Cefiderocol for MBLs: Additional Considerations

Cefiderocol, some additional considerations, I mean, it's been looked at in systematic reviews now and meta-analyses, taking into account a number of different studies. The cefiderocol non‑susceptibility rate for metallos was about 13%. So it tells us that the majority of these organisms will be covered.

So we have these 2 antibiotics now that we can use for this class of resistance, which is escalating in the United States. And again, there is an issue with susceptibility from your microlab. If they're using, sort of, disk diffusion methods, they really need to have the Mueller Hinton Broth in order to, because, you know, when you talk about cefiderocol, it requires iron, sort of, you know, what's the Greek horse, the Trojan horse, the Trojan horse approach in order to get its way into the bacteria.

So the lab has to have the capability for testing for this in terms of its susceptibility. And you can see resistance, just like you can with ceftaz/avibactam + aztreonam. It's uncommon, and it has to do with mutations of the penicillin-binding 3 protein.

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Tetracycline Derivatives for CRE

Tetracycline derivatives. I've already covered this. Not to go through it in detail. These drugs have been around for a while. They can be effective. The problem is when you look at the registration trials, they didn't do as well with urinary tract infections as well as bloodstream infections.

So one just needs to be careful with their use, given that we have alternatives, and the alternatives which I've already discussed.

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Take-home Points: CRE

So there are a couple of take-home points. I think, you know, the number 1 is that CRE is not KPC, okay?

CRE really refers to the broader group of organisms, the Enterobacteriaceae, that will have resistance to carbapenems, whereas KPC really speaks to a specific carbapenemase gene. And so, you know, we're talking about a Class A gene for KPC. And those antibiotics that we would consider based on IDSA recommendations, ceftaz/avibactam, meropenem/vaborbactam, or imipenem/cilastatin/relebactam.

For the metallos, where we have NDM, VIM, and IMP, NDM being the 1 that's really sort of raising its head in the United States, ceftazidime/avibactam + aztreonam, or cefiderocol. And finally, for OXA-48, IDSA really recommends ceftazidime/avibactam.

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Posttest 1: A rapid diagnostic test for a critically ill patient with severe pneumonia detects Klebsiella pneumoniae and the NDM resistance gene in sputum and blood. If following IDSA, what would you recommend?

So now we're going to go back to those questions that we asked before. We're going to go through them again. So this is the first 1. A rapid diagnostic test in a critically ill patient identifies NDM resistance in a Kleb specimen in sputum and blood. So what are you going to select for treatment based on IDSA? And the choices are:

1. Ceftazidime/avibactam;
2. Meropenem/vaborbactam;
3. Imipenem/cilastatin/relebactam; and
4. Cefiderocol.

So we'll make a choice here.

Let's see. Okay. So you can see here we've got the pre and the post. And so ceftazidime/avibactam, 33% to 44%; meropenem/vabor, 38% to 4%; Imipenem/relebactam, 11% to 8%. And really the biggest change was going to cefiderocol, 20% to 42%. And so that's 1 of the 2 agents here that would be effective.

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As I mentioned, the other 1 being ceftazidime/avibactam. But it has to have aztreonam added to it in order to confer susceptibility and overcome the resistance from NDM. And that's really sort of the rationale behind using these agents in terms of treating these types of resistance patterns.

Just so I have an idea in my own mind, how many people, if you could just raise your hand, if you've seen a patient in your institution or heard of 1 with NDM resistance? Okay. Maybe 25‑30 people.

Okay, great. All right. Good.

Questions and Answers

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Questions and answers? No. Okay.

DTR-P. aeruginosa: Pathways to Overcoming Diverse Resistance Profiles

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And now we're going to move forward, and it's really my pleasure to invite Ryan Shields here, who really has done tremendous work in this particular area of antimicrobial resistance and stewardship.

Ryan Shields (University of Pittsburgh): Well, good afternoon, everyone. It's a pleasure to be here, and I'm excited to talk to you about what we've learned in the last few years about how to manage some of these difficult-to-treat gram-negative infections. And we'll start with a pathogen that everybody in this room is familiar with, and that being Pseudomonas aeruginosa.

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Case: Patient in a Nursing Home With History of COPD With Frequent Exacerbations

So let me also start with a common scenario that many of you are seeing in your intensive care units. You've got an elderly patient coming in from a nursing home with a history of COPD and frequent exacerbations, coming to you again with cough and shortness of breath. And you've noted in their prior history that they've been treated for Pseudomonas aeruginosa in the past.

And importantly, for the previous treatment, several beta-lactams, including meropenem, cefepime, and aztreo. The patient also has now ARDS, leukocytosis, and is hypoxic with 84% on room air.

Subsequently, this patient gets intubated and sent into your ICU, and BAL samples are sent for culture. And again, you're using a lower respiratory tract multiplex PCR for testing.

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Case (cont’d): Multiplex PCR Results

So Dr Kollef has gone through how that's really helpful for Enterobacteriaceae, but what we know about Pseudomonas aeruginosa is that identifying carbapenemase genes is far less common in the United States. As you can see from the figure on the right-hand side of the screen here, less than 2% of carbapenem-resistant Pseudomonas in the United States harbor carbapenemase genes.

This stands in contrast to what we see with the epidemiology at other places globally. But in the US, we don't really anticipate to see genes like NDM or KPC amongst Pseudomonas in many of our hospitals. We also don't expect to see ESBL genes, like CTX-M, for example.

So we may be able to identify Pseudomonas early, but we really can't predict susceptibility testing based on the presence or absence of resistance genes, unlike what we can with Enterobacteriales.

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Case (cont’d): Considerations for Treatment

So often what we rely on in patients like this is their prior microbiology. And in this particular scenario, this patient is giving us a very important clue that they have been previously colonized or infected with a resistant Pseudomonas strain, as you can see on the slide here.

Now, notably, this particular isolate is resistant to all the traditional anti-pseudomonal beta-lactams you've become accustomed to using. Meropenem, cefepime, piperacillin/tazobactam are all demonstrating high-level resistance in this case.

So this may be spurring a number of questions that you're either asking yourself or discussing with trainees on rounds. What would you empirically want to start for a patient like this with a history of resistant organisms? Is there a role for combination therapy? Our pretest answers suggested many of you think that is yes. They've used ceftazidime/avibactam and tobramycin was the most popular answer for a case like this. And then where, if any at all, do the novel beta-lactams fit into this equation? And most notably here, you see 2 of them, ceftazidime/avibactam and ceftolozane/tazobactam reported as susceptible.

So we'll try to work through some of these considerations.

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Definitions: MDR vs DTR P. aeruginosa

Now, before I do, you've probably noticed something we like to do in infectious diseases is give everything an abbreviation, and we talk about MDR and DTR and KPC and CRE, and we have a tendency of throwing these acronyms around interchangeably. But for the purposes of this presentation, I want to very deliberately define MDR as being nonsusceptible to at least 1 agent in 3 or more classes, but the category we're going to talk about today is difficult to treat, or DTR, which is a relatively new acronym that essentially represents to you that the isolate is resistant or nonsusceptible to all the traditional agents, much like the case example we have today.

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Mechanisms of β-Lactam Resistance: DTR-P. aeruginosa

So, 1 of the things that's really shifted significantly in the last decade in our field of infectious diseases and antimicrobial resistance is we now very much target underlying mechanisms of resistance. Rather than reported susceptibilities or the pathogen themselves, many of these new antibiotics really specifically target mechanisms of resistance, and Dr Kollef showed you some excellent examples of that.

Now, Pseudomonas aeruginosa is a bit more difficult to target 1 precise mechanism of resistance because oftentimes in Pseudomonas, we're dealing with organisms that are highly complex. They have very large genomes, including large accessory genomes that allows the organism to adapt in the presence of stressors like antibiotics. And there are a number of both intrinsic and acquired mechanisms of antibiotic resistance for Pseudomonas.

The 3 that are most important to know for beta-lactams is number 1, beta-lactamases. Pseudomonas on their chromosome have an ampC cephalosporinase that can be derepressed or overexpressed to make more enzyme. We also see that Pseudomonas has a number of efflux systems.

One of the most common that's constitutively expressed or expressed at baseline is the MexAB‑OprM tripartate efflux system, which can also be overexpressed and cause higher-level resistance to beta-lactams. And then finally, porin regulation. OprD is the major porin in Pseudomonas. And when we see downregulation of those porins, it makes it increasingly hard for antibiotics to get into the periplasmic space where we know our beta-lactams have their mechanism of action.

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Effect of Resistance Mechanism on Susceptibility to Antipseudomonal Drugs

Now, as this relates to our traditional beta-lactam antibiotics, 1 of the things I want you to take away from this slide is notice that how each of these mechanisms has a differential impact on each of the agents we're talking about. There's some excellent examples here and maybe some things that we've taken for granted over the years.

For example, imipenem and meropenem, 2 carbapenems, we often think of, well, carbapenem resistance is caused by the same mechanisms. But that's absolutely not true in Pseudomonas. In fact, imipenem is not a substrate for efflux whatsoever where meropenem is, and meropenem is very incredibly stable against ampC and Pseudomonas, where imipenem can be hydrolyzed.

So there are some inherent differences, and the key to know here is that resistance to 1 beta-lactam does not predict resistance to another beta-lactam in Pseudomonas. Unlike a Klebsiella that has NDM where you'd anticipate all of your beta-lactams to be resistant, you have a very different scenario with Pseudomonas.

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2024 IDSA Guidance: DTR-P. aeruginosa

So when we reference then the IDSA guidelines, this is 1 of the reasons why we differentiate DTR. We're really talking about the most resistant strains where you're not using your traditional beta-lactams. And outside of the urinary tract, what these guidelines will suggest to us is you have 3 preferred options, those being ceftolozane/tazobactam, ceftazidime/avibactam or imipenem/relebactam.

Now, much like you, I often find recommendations like this to be a bit confusing. They're telling me 3 drugs should be preferred, but when would I know when I should pick 1 over another? And that's something I want to help you disentangle during the presentation today.

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Ceftolozane/Tazobactam for DTR-P. aeruginosa

So let's start with ceftolozane/tazobactam.

Brand name is Zerbaxa, something that you guys have been familiar with using in your intensive care units. It's hard to believe that this is a new antibiotic that has now been available in our hospitals for over a decade. And over the course of that decade, we've learned a lot about ceftolozane/tazobactam through real-world evidence.

So much so that we have several meta-analyses now that have compared the efficacy of ceftolozane/tazobactam to what we used to use prior to ceftolozane/tazobactam being available, and that was largely aminoglycoside or polymyxin-based combinations. And what the genesis of those data suggests to us is that Pseudomonas aeruginosa DTR, when it's treated with ceftolozane/tazobactam, as compared to aminoglycosides or polymyxins, you see higher clinical cure rates, greater microbiologic eradication, and certainly something we know about beta-lactams compared to polymyxins, much less nephrotoxicity or acute kidney injury. So the overwhelming data are compelling, and this is why ceftolozane/tazobactam is 1 of the preferred options.

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Ceftazidime/Avibactam for CR-P. aeruginosa

You can see synonymous data with ceftazidime/avibactam. Again, when you're comparing to polymyxins, beta-lactams generally look good, particularly if they're testing susceptible in vitro. We see lower 30-day mortality rates in a small study, single-center study from China, and a larger multi-center study from Saudi Arabia showed, again, higher clinical cure rates, similar mortality, but lower incidence of acute kidney injury for patients treated with ceftazidime/avibactam.

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CACTUS: Ceftazidime/Avibactam vs Ceftolozane/Tazobactam for MDR P. aeruginosa in US

That's great, and so we know that both of those agents should be preferred instead of polymyxins, but what about comparing them to each other? One of the things we haven't done a good job with in infectious disease is doing comparative effectiveness studies for preferred treatment options. And so this is a study that we did that was published earlier this year called the CACTUS study.

This was a multicenter study across 28 centers in the United States, and we powered the study to enroll a total of 420 patients, with our underlying hypothesis being that ceftolozane/tazobactam would actually result in higher efficacy compared to ceftazidime/avibactam. And the reason we made that hypothesis is that we know that ceftolozane gets into the lungs or has higher penetration into the epithelial lining fluid than ceftazidime/avibactam. Moreover, the MICs, or minimum inhibitory concentrations, tend to be lower for ceftolozane/tazobactam than ceftazidime/avibactam, and those are 2 really important pieces of information in this calculation we like to do when we look at PK/PD target attainment, particularly in the lungs.

So we hypothesized in this study ceftolozane/tazobactam would be better, and we powered the study to test that hypothesis, which is something really important in real-world observational studies. Very rarely are they powered to be hypothesis testing.

The second thing that we did that was really important about this study is if you're thinking back to your local facilities, you maybe have a stewardship program or a hospital formulary that guides you to preferentially use 1 of these 2 agents.

And in fact, each of our institutions probably has a little bit different approach to this same problem. Because of that, what we did is we matched patients 1-to-1 within each institution. So for every patient that received ceftolozane/tazobactam, they were matched to a patient that received ceftazidime/avibactam at the same hospital.

We also matched patients by key determinants of outcomes, those being severity of illness, time to treatment initiation, and site of infection. We only included patients with pneumonia or bloodstream infections in this study, essentially excluding patients with urinary tract infections or intra-abdominal infections. Everybody received at least 48 hours of 1 of the 2 antibiotics, and our primary outcome was a composite of clinical success at 30 days, which we defined as survival, resolving signs and symptoms of the infection, and not having a recurrent infection within that 30 days.

So as you move on to the baseline characteristics that you see on the right-hand side, 1 of the things that was most reassuring to us as investigators is the patients in this study were incredibly well matched. If you have the opportunity to read this study, you'll see in table 1 that all the underlying diseases, baseline demographics, severity of illness are almost identical between these 2 cohorts of patients, suggesting that our design to match patients within each institution worked really, really well.

The other thing that was reassuring in this study is that these were the kinds of patients we were used to taking care of in our local hospitals. They were critically ill: 80% in the ICU, 70% were on the ventilator, 40% were receiving vasopressors. So this truly does represent, then, a real-world ICU population infected with multidrug-resistant Pseudomonas.

[00:34:49]

CACTUS: Clinical Outcomes

So what did we find? Well, we found, in fact, that ceftolozane/tazobactam did indeed manifest in higher rates of clinical success compared to ceftazidime/avibactam. And what was really driving that clinical success at 30 days was not mortality. It was actually lower rates of recurrent infections.

More specifically, what we saw, as you move to the bottom left of the slide there, clinical success was significantly higher for patients with pneumonia and not necessarily those with bloodstream infections. And remember, this is analogous with our underlying hypothesis, that if ceftolozane/tazobactam was going to be better, it would be better because it penetrated the lungs at a higher rate. And indeed, the pneumonia cohort is where we saw the greatest benefit of ceftolozane/tazobactam.

We saw no differences in mortality, but important differences in clinical success across a number of interesting subgroups that are listed on the slide.

[00:35:45]

Case (cont’d): 1 Wk After Discharge

So, the patient that we've talked about today was indeed successfully treated with ceftolozane/tazobactam, and she was discharged from the ICU. But what happens so often with many of these kinds of patients is they end up coming back to us. And now they're even more treatment-experienced. We've now used ceftolozane/tazobactam for 2 weeks. The patient's readmitted to their ICU, and now the team's asking, what do we do next?

[00:36:07]

Imipenem/Relebactam for P. aeruginosa

Well, that's where I start thinking about some of the other antibiotics you've heard about today. imipenem/relebactam, for example, is a newer antimicrobial that has in vitro activity against Pseudomonas, but has somewhat limited and concerning clinical data behind it. In the RESTORE-IMI 1 trial, this was compared to colistin-based regimens, and overall, it did better than colistin.

Similar to what we've seen with ceftolozane/tazobactam or ceftaz/avi, the newer beta-lactams are almost certainly superior to colistin or polymyxins. And indeed, we saw lower rates of acute kidney injury. But there seems to be a dearth of real-world available evidence for Pseudomonas specifically.

In the HAP/VAP registration trial, where imipenem/relebactam was compared to piperacillin/tazobactam, there were numeric trends in favor of piperacillin/tazobactam and not in favor of imipenem/relebactam. So we have to learn more about this antibiotic in real-world studies. And another study we just published called the MIRAGE study started to capture some of this evidence.

What was notable about studying imipenem/relebactam in the United States is, number 1, it's very infrequently used in the United States, we found. But in the scenarios in which it's used, it was typically used after patients, much like our case today, had been previously treated with ceftolozane/tazobactam, and this was a recurrent infection. Indeed, 54% of patients in our study had received other novel beta-lactams prior to receiving imipenem/relebactam, suggesting that the drug is likely being positioned for recurrent infections in most of those scenarios, which is personally how we position this drug at my university, the University of Pittsburgh Medical Center.

[00:37:51]

Cefiderocol for P. aeruginosa

And then what about cefiderocol? Well, many of you may remember the CREDIBLE-CR trial, which compared cefiderocol to best available therapy for carbapenem-resistant pathogens. Well, there was a Pseudomonas cohort within that trial, and there was no difference in all-cause mortality when you compared cefiderocol to best available therapy for carbapenem-resistant Pseudomonas.

We also have some registry-level observational data from the PROVE registry that is a growing repository of clinical evidence, suggesting that many of these isolates do indeed retain in vitro susceptibility to cefiderocol, and clinical cure rates are 65% in 30-day mortality, just south of 20%. So another potential treatment option, but this in the IDSA guidelines is reserved as an alternative recommendation, largely because of these CREDIBLE-CR findings of higher mortality for patients that were co-infected with Acinetobacter specifically.

[00:38:50]

Considerations for Combination Therapies

Well, what about combination therapy? This is something that has been kind of come in and out of vogue over the years, and really, 1 of the things that's changed most significantly about combination therapy is we used to use combination therapy for Pseudomonas out of desperation, because we were using inferior antimicrobials, like polymixins or aminoglycosides, and oftentimes when you're using inferior drugs, you tend to combine them to reassure ourselves that we're doing something that's beneficial for the patients.

But now we have a number of new novel beta-lactams, as we've just explained, that are very well-tolerated. Well, what about the aminoglycoside specifically that's changing this pendulum a little bit? Well, the CLSI has recently evaluated all the clinical susceptibility breakpoints for aminoglycosides, and turns out at the doses we've been using for several years, they don't actually reach their pharmacokinetic and pharmacodynamic targets, particularly in the lungs.

These are antibiotics we know don't penetrate the lungs well, and when you look at the MICs in relation to our exposures, many times we don't even cover the susceptibility breakpoints. Accordingly, amikacin and gentamicin have largely been removed as anti-pseudomonal agents for systemic infections, and thus tobramycin is the only agent that reasonably achieves those pharmacodynamic targets. But again, there's a lot of reservations around using tobramycin, particularly in combination therapy, which is why the IDSA says there's no evidence to support the use of combination therapy for Pseudomonas.

[00:40:19]

Take-home Points: DTR-P. aeruginosa

So what are our take-home points for DTR Pseudomonas specifically? Hopefully, I've shown you a little bit about resistance and how complex it is in Pseudomonas, and this idea that we really can't predict susceptibility from 1 beta-lactam to another because of these underlying mechanisms of resistance. In my clinical practice, because of our CACTUS study and other real-world evidence, we're prioritizing ceftolozane/tazobactam for DTR Pseudomonas. We're using ceftazidime/avibactam if it's the only 1 that's reported susceptible for us, but generally speaking, is our alternative agent. Imipenem/relebactam is then the next in line for us. If we are unable to use ceftolozane/tazobactam or ceftazidime/avibactam, we'll test imipenem/relebactam. And cefiderocol, we've positioned essentially for metallo-beta-lactamase-producing Pseudomonas, which at this point are uncommon in the United States. But again, as Dr Kollef has shown us, NDM are rising in enterobacteriales, and it wouldn't be surprising to see them rising in other organisms like Pseudomonas in the future. So an important caveat, that cefiderocol is the only 1 of these available options that has activity against MBLs specifically.

[00:41:28]

Posttest 2: Assuming susceptibility, based on available data, what would you recommend for a critically ill patient with nosocomial pneumonia caused by difficult-to-treat resistant Pseudomonas aeruginosa?

So let's go back to the question Dr Kollef asked in the beginning. Assuming susceptibility and knowing what you know now, what would you recommend for a critically ill patient that has nosocomial pneumonia caused by difficult-to-treat-resistant Pseudomonas? The same options are available to you. You could pick:

1. Ceftolozane/tazobactam;
2. Imipenem/relebactam;
3. Ceftazidime/avibactam + tobramycin; or
4. Cefiderocol.

I'll give you a minute just to weigh in there. Okay, fantastic. We certainly have been influential in your responses, which we appreciate. Ceftolozane/tazobactam is how I would answer that question as well. We have some evidence, and hopefully that you were able to appreciate that evidence today.

[00:42:28]

So here's the underlying rationale. Even though all 3 of these agents are recommended as preferred treatment options, we know we have different weights of evidence for each of them. And the strongest evidence does support ceftolozane/tazobactam over imipenem/relebactam and cefiderocol for sure.

And then answer C, the combination therapy is not recommended. And that's the main reason why answer A is the most accurate answer in this particular scenario.

Questions and Answers

[00:42:56]

Okay, I'm going to keep going through here. Maybe we'll take questions at the very end.

Modern S. maltophilia Management: Current Concepts for Best Outcomes

[00:43:02]

Let's talk briefly now about a pathogen that is starting to gain a lot of attention. And many of you may also see this in your chronically ventilated patients, Stenotrophomonas maltophilia.

[00:43:14]

Case: Patient Who Recently Received an Allogeneic Hematopoietic Cell Transplant

So we'll wrap up talking briefly about Stenotrophomonas and give you kind of a classic case example here. This is a patient with an allogeneic stem cell transplant coming in neutropenic, and they have now a new ventilator-associated pneumonia. Respiratory cultures are only identifying Stenotrophomonas maltophilia. No other pathogens are present. And so I think a common question we ask ourselves is, well, is this really a pathogen? Is it something sticking to the ET tube? Or do we need to aggressively manage this with antimicrobials?

Now, the host is really relevant here is you have a neutropenic stem cell transplant patient certainly at risk for hemorrhagic pneumonia caused by Stenotrophomonas, which has been reported in the literature. And so this would be the kind of patient we'd probably err on the side of treating. And I think most of you would agree with that, particularly if Stenotrophomonas was the only thing we found in our respiratory cultures.

[00:44:06]

S. maltophilia: Mechanisms of Resistance

Really briefly about Stenotrophomonas, what makes this bug such a nuance is all the factors you see listed on the screen here. This is a bug that's equipped with a number of intrinsic underlying mechanisms of antibiotic resistance.

It has 2 chromosomally encoded beta-lactamases, L1 and L2. Most notably, L1 is a metallo-beta-lactamase. The combination of these 2 really mitigates the activity of all beta-lactams.

Besides some of the options we'll talk about today, it makes a lot of efflux pumps. It has a methyltransferase, which means all aminoglycosides are intrinsically resistant. So already knowing that you're treating Stenotrophomonas, you feel a bit handcuffed because you don't have many treatment options available to you because of its mechanisms of resistance.

[00:44:52]

S. maltophilia: Challenges to Treatment

Now, if you are looking into your literature, or maybe your microbiology laboratory is reporting some of these options to you, you'll really see summaries about 4 agents that are now recommended with variable weight, those being trimethoprim/sulfamethoxazole, levofloxacin, minocycline, and cefiderocol. In fact, these are the only 4 agents that CLSI has adopted susceptibility breakpoints for.

In reviewing these breakpoints and trying to update the most recent evidence, what has become eminently clear is there's not a lot of good or high-quality evidence for the management of Stenotrophomonas whatsoever. We've largely relied on observational studies, and I'm going to show you in a minute an observational study that you may not have known it, but you've probably put some stock into in your clinical practice.

[00:45:38]

How Did TMP/SMX Become A Frontline Therapy?

So when you look at those treatment options, many of you, like myself, have probably taught your trainees over the years that Bactrim or trimethoprim/sulfamethoxazole is really the drug of choice for Stenotrophomonas. In fact, many of us have done this for several decades.

And in preparing this presentation and looking into this, we start to wind the clock back. Where do we start with as Bactrim being the frontline agent for Stenotrophomonas? We can go back to the 1970s, where at that point Pseudomonas maltophilia was reported to have high levels of resistance to aminoglycosides, which we now understand why, and high levels of resistance to beta-lactams.

And so Bactrim became, well, 1 of the few options that would test susceptible. But the clinical evidence that supports Bactrim being a frontline agent for Stenotrophomonas originates with a single case series of 3 patients. That's right.

We've taught all of our trainees to use Bactrim, largely originated from a case series of 3 patients, all that had endocarditis due to Stenotrophomonas, and all of which received Bactrim in combination with other antimicrobials, as you can see on the slide. Now, all 3 of these patients survived their endocarditis, which was a feat in the 1970s, of course, but that is the basis of the evidence for Bactrim for Stenotrophomonas. So when I say we don't have a lot of high-quality evidence for this particular drug–drug combination, this is the kind of evidence that we're talking about.

[00:47:08]

Is It Time to Rethink TMP/SMX as a Frontline Therapy?

So what has happened in a more contemporary study is we said, well, if there's not a lot of clinical evidence to support Bactrim for Stenotrophomonas, what can we generate from a laboratory perspective? Well, when we start looking at Bactrim in a laboratory setting, as it turns out, even with using humanized dosing of 20 mg/kg, you actually can't kill Stenotrophomonas in a test tube with Bactrim. You're like, well, maybe it's just the drug's not working in the particular media, and so you can see in this study they used an E. coli strain as a control, and Bactrim killed E. coli very well, but Bactrim did not kill Stenotrophomonas in a test tube. So, okay, that's really not all that reassuring.

[00:47:48]

Levofloxacin vs TMP/SMX for S. maltophilia

So what about the clinical evidence that's available? Unfortunately, the best evidence we have comes from an administrative database. Many of you are familiar with the Premier or Pink AI database, and they took observational data from that database of over 1,500 patients that had Stenotrophomonas isolated in either blood or respiratory cultures, and they compared patients who received Bactrim or levofloxacin.

And here is the forest plot of that study. Now, mind you, these patients did not have clinically defined pneumonia per se. They just had positive respiratory cultures, but you can see that the outcomes favored levofloxacin for patients with respiratory cultures specifically where there was no difference in bloodstream infections.

So the accumulating evidence suggests maybe we do need to rethink this idea that Bactrim should be our first-line agent for Stenotrophomonas, and, of course, many of you are well familiar with the limitations of fluoroquinolones.

[00:48:44]

Cefiderocol for S. maltophilia

What are our alternatives? Well, cefiderocol, it turns out, and several large surveillance studies has excellent rates of in vitro susceptibility.

You see greater than 98% of all Stenotrophomonas are reported as susceptible at an MIC ≤1. We also have animal model data. The figure on your left is showing you in a neutropenic mouse model that you see significant reductions in log CFUs in a thigh compared to ceftazidime or controls.

And then on the right-hand side of your slide, you see a neutropenic rabbit model where 8 rabbits in each of those arms were treated with humanized dosing of either cefiderocol or Bactrim compared to control, and you see significantly higher rates of survival for those rabbits that received cefiderocol.

[00:49:30]

Comparative in Vitro Activity Against S. maltophilia

So where does this leave us if you're putting it all together and looking at the available treatment options at your institution? Well, we've done this at my institution.

These are 371 consecutive patients with Stenotrophomonas. Here's our reported susceptibility rates. These were generated by Broth microdilution in triplicate, and you see very high rates for 3 options, those being aztreonam/avibactam, cefiderocol, and Bactrim, where you see lower rates of susceptibility for levofloxacin or minocycline.

[00:49:59]

2024 IDSA Guidance: S. maltophilia

So when you put this all together, then, now you have some rationale to understand why the IDSA is taking kind of a unique stance in how we should be treating Stenotrophomonas. Their stance is you need to use combination therapy. And this goes back to what we talked about with Pseudomonas before.

We don't feel like we have a preferred monotherapy. As clinicians, we have this tendency to use combinations because we're not sure if any individual component of that combination is all that effective. And that is indeed what IDSA is recommending now for Stenotrophomonas is to use any 2 of the following you see in the blue box there, those being cefiderocol, minocycline, Bactrim, or levofloxacin, or alternatively use the combination of ceftazidine/avibactam + aztreonam, because remember Stenotrophomonas is a metallo-beta-lactamase-producing organism, much like what you learned about with NDM earlier today.

[00:50:51]

Take-home Points: S. maltophilia

So our take-home points with Stenotrophomonas. We all recognize in this room it's a very difficult pathogen to distinguish colonization vs infection. But in the right host, it certainly does warrant treatment. And what treatment you're going to do largely depends on maybe your local clinical practice, your clinical experience. But if following the guidelines, really it doesn't recommend any therapy as monotherapy and now strongly prefers combination therapy for everyone.

[00:51:18]

Posttest 3: If following IDSA guidance, what would you recommend for a patient hospitalized in the ICU with nosocomial pneumonia, where Stenotrophomonas maltophilia is isolated from a blood culture?

So, final posttest question for you then. If we were indeed following the IDSA guidance, what would you recommend for a hospitalized patient in your ICU with nosocomial pneumonia caused by Stenotrophomonas maltophilia who also has a positive blood culture? Your options here are:

1. Trimethoprim/sulfamethoxazole;
2. Minocycline
3. Ceftazidime;
4. Ceftazidime/avibactam; or
5. The combination of ceftazidime/avibactam + aztreonam.

And we'll give you a minute to weigh in.

All righty, wonderful. So as many of you see at the very bottom, you're able to recognize that combination therapy is now recommended by the IDSA.

[00:52:14]

88% of you correctly identifying ceftazidime/avibactam + aztreonam.

So at this point now, we have an opportunity, I believe, for some questions and answers. So I'd certainly welcome anybody in the audience here locally to please stand up if you have a burning question. We'd be more than delighted to field that for you.

And I know we have a few questions online as well here that Dr Kollef has in front of him. So do you want to start with maybe an online question?

Q&A

Dr Kollef: I think we'll go with the online questions first. And the first one is dealing with the case that I presented. And the question is, what about adding colistin in the critically ill patient with NDM infection? Other than the risk of nephrotoxicity, why not use colistin? And at least from my stance on that, the problem with IV colistin is it doesn't penetrate well into the lung. And we really don't have good data for treating pneumonia cases with it.

One might argue using it as an inhaled adjunctive therapy in addition to some IV treatment. But the problem there, again, is, you know, we're administering an inhaled drug. It has to be administered properly. We still don't have good randomized control trials of its efficacy. So I think from that standpoint, it would not be a viable option.

I don't know if you have a different take on that, Ryan?

Ryan Shields: No, I totally agree. You're unnecessarily increasing the risk of toxicity with no really well-defined benefit for efficacy in that scenario.

Dr Kollef: Then there was a question from, let's see, combination therapy for steno, which I think you've already addressed. So we'll skip that one. Could trimethoprim-sulfa be a better initial option due to its wider coverage in a patient with an allogeneic bone transplant, apart from bone marrow suppression?

So I guess they're getting at, you know, if you're not sure what the pathogen is, you know, and they might have PCP neocardia or something else going on, why not just use that as an empiric drug? I don't think they're specifically asking about Stenotrophomonas.

I guess my take on it is with a bone marrow transplant patient, you really want to know what's going on. So in that type of a situation, it would be ideal to get cultures and ideally use multiplex PCR, both in blood as well as in the respiratory tract, and really try to identify the presence of the organism and resistance elements and then treat in a directed manner. I don't think there's a role for using Bactrim as an empiric drug for someone with a serious infection in that setting.

Ryan Shields: Yeah, I agree as well. And I'm trying to think of the clinical scenarios in which I would empirically cover for Stenotrophomonas. And I really can't think of any.

Because number one, the pathogen is relatively infrequent. So covering for it empirically, you know, in the best-case scenario, you're going to be right a very small proportion of time. But number 2 is we're not even all that positive that Bactrim empirically would add benefit, given what we know now about the observational data. And then, particularly in this host, the additive myelosuppression would be really kind of, I think, a contraindication to overprescribing Bactrim without knowing the pathogen.

Dr Kollef: Another question online from the online audience. Where does avibactam/aztreonam fit? I think we've already covered that to some extent in terms of really focusing on the increasing rates of NDM resistance in the Enterobacterialis population. So that would clearly be one area.

I guess in Pseudomonas, what would you add, Brian?

Ryan Shields: Yeah, so I think a couple of interesting points there. We've largely talked today about the combination of ceftazidime/avibactam + aztreonam. And Dr Kollef alluded to this during his presentation, we've kind of been doing this for a few years now. It is notable that the more precise combination of aztreonam/avibactam has now been cleared by the FDA. It's becoming available in many of our hospitals.

The dosing is a little bit different. There's a loading dose, and then every-6-hour administration. But it prevents the pharmacy from having to try to coadminister 2 antibiotics at the same time. So that's something you may be hearing about in your local P&T committees.

One of the things that's really, really important to know about aztreonam/avibactam for Pseudomonas, we've talked a lot about MBLs today, but for Pseudomonas, it's just not a potent in vitro anti-pseudomonal agent.

And the reason for that is aztreonam is not a great anti-pseudomonal on its own. And avibactam doesn't really overcome the beta-lactamases or carbapenemases like we've talked about with others, because the underlying mechanism of aztreonam resistance is largely efflux-mediated as well as ampC. So you don't overcome resistance in Pseudomonas with aztreonam/avibactam.

So it's unfortunately not going to be one that you'll see prioritized in future guidelines for Pseudomonas specifically.

Dr Kollef: Okay, we have a question here. What is the typical duration of therapy for these infections? And what I would say to that is that, you know, we've really moved over the 40 years that I've been practicing to trying to use the shortest course of effective antibiotics, assuming that we're giving the right drug for the pathogen at the right dose in order to achieve drug levels at the site of infection.

So for pneumonia, the current data would suggest a 7-day course is adequate. Now, having said that, if one's dealing with a highly resistant organism and the initial several days one was treating ineffectively, meaning the drug was not active against the bug, then one would have to think about starting that 7-day clock from that new point in time. But in general, for uncomplicated gram-negative pneumonias in the ICU setting, no empyema, no secondary bacteremia, a 7-day course would be appropriate.

Ryan Shields: I totally agree. In fact, I think it's shifted so much so that we used to, in stewardship practices, try to identify patients we could treat for 7 days. I actually think it's the inverse now. We try to identify patients who actually warrant treatment longer than 7 days, at least in our local practices.

Dr Kollef: Let's see. Those are the online questions. How about from the audience here? Does anyone have a question that they'd like to ask? Yeah, yeah, please.

Speaker: Thanks very much. I was very interested in Stenotrophomonas. I kind of think of it as a grumbler in the ICU setting. So why not go ahead with, you know, separate something like immunosafety rather than, you know, running the risk of increasing the resistance to some of our other anti-inflammatory therapies?

Ryan Shields: Yeah, that's a great question. And just repeating that for the online audience, the question is around Stenotrophomonas. And why not maybe use an agent like minocycline where you can kind of spare the activity of some of these other agents for Stenotrophomonas?

And of course, I agree. It's often very difficult to know if it's truly pathogenic in these patients. And at least in Pittsburgh, we often see it as part of several respiratory pathogens, and it tends to be the one we ignore the most often.

A few points about minocycline specifically for Steno. The breakpoints have recently changed for minocycline. And so what historically may have looked at as a very active drug for Stenotrophomonas, with the shift in the breakpoints, probably about 60-70% of isolates now are categorized as susceptible. Whereas with the older breakpoints, it was over 90%. So there's a shift there as well.

Secondly, with minocycline, of course, it has excellent lung penetration, gets into bones really well. Not an agent that I typically rely on, if I do see a secondary bloodstream infection, tend to try to use beta-lactam combinations in those settings if we can. I will say what often happens, again, just speaking in my clinical practice, when we're hedging our bets and not sure if Stenotrophomonas is problematic, sometimes we'll do something like this, is add minocycline and see if their oxygenation improves and they're getting better. If so, then maybe we think Stenotrophomonas was causative.

But typically, it's those gray scenarios where, like, well, it couldn't hurt to add it for a few days to see if they get better. And that's kind of how we've used it locally.

Dr Kollef, is there anything you want to add about minocycline?

Dr Kollef: No. Any other questions from anyone? If not, I'm just going thank everyone for attending this afternoon and hope that you enjoy the rest of the conference. And if you have any questions that you want to ask us personally, please feel free to come up.

Thank you again.

[END OF TRANSCRIPT]