Thank you for that introduction, Dr. Mazur, and it's an honor and privilege to be here on the panel with such esteemed colleagues. And so I'm going to spend the next few minutes talking about our treatment options relative to antifungals. And so with that, I have no disclosures, unfortunately. Relative to our objectives, we heard from Dr. Jakob and Dr. Sweeney to talk about epidemiology and diagnosis, and I'll try to provide some context in terms of how we can initiate, when and how do we initiate antifungal therapies. And so Talia did an excellent job highlighting kind of the risk factors associated with the development of fungal infections. I only provide this slide here to highlight that just about all of our patients have some risk factor for a fungal infection. So it's probably easier to identify a patient who's not at risk, as opposed to a patient who is at risk. And so as Dr. Mazur had mentioned, there has been an evolving number of antifungal options that are available. Classically, Amphotericin B has been kind of the workhorse relative to antifungal options. But fortunately, we've seen an expansion in terms of available options, including chinocandins and extended spectrum triazoles. And so I'll spend the next few minutes reviewing the pharmacology between the common antifungals that are used in critically ill patients, and then we'll discuss common therapeutic challenges that are frequently encountered specific to critically ill patients. And so Amphotericin B, probably well known to most of us in this room, acts through binding agrosterol. It is a broad, has broad fungicidal activity, and it works at the cell membrane of fungi. And that's important to note. And I'll try to highlight where they work, because when we talk about combination therapy later, that's going to be an important distinction that we need to understand. In terms of Amphotericin B, certainly it is useful in immunocompromised patients. And as we talked about immunocompromised patients, that could be from cancer, that can be from solid organ transplant, or it can be related to biologics that we use for rheumatologic diseases. Also, Amphotericin B, we talked a little bit about the resistance associated with different antifungals. Amphotericin B remains a useful option in many instances when we talk about resistant fungi. In terms of its adverse effects, typically and classically, it's known for its nephrotoxicity. Less common when we use its liposomal form, which I would venture to say, I think if we took a poll of the audience, most folks, when they use Amphotericin B, now use the liposomal formulations. When we talk about using these agents, and you see some of the treatment dosing and considerations here, it's important to note that deoxycholate, which is the classic, classical older version of Amphotericin B, can be used for other delivery mechanisms, including inhalation, intrathecal, or intravitreal administration. For liposomal type of administration, you see the dosing, it's a little bit different. And for both agents, we would consider using IV hydration and premeds if we're concerned about an infusion reaction with the administration of Amphotericin B. With respect to echinocandins, these and how it differs from Amphotericin B is that it acts on the cell wall, the fungi cell wall. So it has fungicide activity against candida and fungostatic activity against molds. It is only available in an IV formulation. Generally speaking, echinocandins have relatively few side effects. One is hepatotoxicity, but that's generally a rare phenomenon, as well as infusion-related reactions have been described. When we talk about echinocandins, one of their benefits relative to azoles that we'll talk about in a moment is that they have minimal drug interactions. And so when we talk about looking at managing therapy in patients who are solid organ transplant patients that are on multiple immunosuppressing agents, we certainly echinocandins offer a benefit here. You see some of the dosing listed here. I want to highlight one particular one that is a very recent one that folks may not be familiar with. It's Rezafungin. It was approved in the United States in March of this, of 2023, excuse me, and it's indicated for treatment of invasive candidiasis and candidemia. What's unique about this particular agent, it's extremely long half-life relative to the others. Its half-life is about 133 hours as compared to, for instance, mycofungin, where it's about 15 hours. And so that allows for it to be extended in terms of how often it's given. It is given Q7 days as opposed to daily treatment with some of the other echinocandins. And so that may represent an opportunity if we're talking about discharge or things of that sort for patients who may need longer courses of therapy. Generally speaking, echinocandins are highly protein-bound and have relatively low penetration into the CSF. So if you're thinking CSF involvement, echinocandins probably are not the agents that you want to choose. You'll probably want to use one of the other agents like amphotericin B or azoles that we'll talk about in a moment. So with respect to those azoles I mentioned, here they work primarily by inhibiting cyrochrome P450-dependent demethylation, excuse me, and this acts in the fungi cell membrane. And so it has a lot of activity against candida species and varieties of mold. The benefit here is that it is available in an IV and PO option in many instances. In terms of adverse effects, primarily associated with this are hepatotoxicity. It can cause some adrenal suppression. So think about that if you have a patient that is in septic shock. And then also has QT prolongation as well. The major take-home point as a pharmacist, I would be derelict of duty if I don't highlight the drug interactions here that are associated with triazoles. They interact with not only fungi, cytochrome P450 enzymes, but also human cytochrome P450 enzymes as well. And so specifically and concerning critically ill patients, you can expect to see some interaction for drugs that are commonly used in critically ill patients, including things like fentanyl, midazolam, phenytoin, quetiapine, and warfarin. And then from when we talk about patients who are immunosuppressed can interact with cyclosporine and tacrolimus, as well as serolimus. Also you can expect to see some interactions as well with rifampin and clopidogrel in terms of drug interactions. So you certainly want to be mindful. And at this point, if you have, if you're using these azoles, you certainly want to make sure that your clinical pharmacist has had opportunity to review for any drug interactions. In terms of the options here, really we're thinking about posyconazole, voriconazole, and isovuconazole. You see the dosing listed there. I won't read it for you, but it's there for your reference. I do want to highlight a couple of things, though. When we talk about posyconazole, the PO and the IV, or excuse me, the PO formulations themselves are not interchangeable. There's an intermediate as well as an extended release formulation. So just be mindful of that. With the intermediate, immediate release, excuse me, formulation, that should be taken with a full meal to optimize oral bioavailability. When we talk about voriconazole, you see the dosing listed there. I do want to highlight that when we talk about using voriconazole, there has been some recent emerging literature that looked at population pharmacokinetics and suggested that you may need lower loading doses in patients with liver dysfunction, but that hasn't been validated in large RCTs. That's more with modeling data. And then lastly, isovuconazole, it definitely is something that when we look at it, it is associated with lower levels when we talk about obese patients. So something to be mindful of when we encounter those patients who may need a dose adjustment. And so for the next few minutes, I'm going to highlight both empiric and definitive treatment. For the scope of this presentation, I won't talk about prophylaxis. And so what are some of those considerations one may think of? When we talk about critically ill patients, it's going to be important to understand when we're considering fungal infection, the immune status of the patient. So we talked about how immunocompromised patients may be at increased risk for certain types of fungi and molds. And so understanding that history of the patient is going to be important for us to identify which pathogens do we need to be concerned about up front. Also, Dr. Salini highlighted some patient-specific factors when we talk about understanding the history of the present illness that maybe can help guide the considerations of what pathogens we're most concerned about. So for instance, if we understand that the patient has recently went to a motocross race, certainly that is important in terms of your consideration of what pathogens are important. And then also clinical conditions. So when we talk about critically ill patients, obviously we know that there can be a spectrum of how patients present. And so if a patient is presenting in a more critically ill condition, then that may make us be more aggressive with our choice of antifungal therapy. Also, the choice of combination therapy. We'll talk about when and which agents. And then in the next few slides, we'll talk about dosing considerations in a critically ill patient, specifically thinking about drug interactions, therapeutic drug monitoring, as well as obesity. And so empirically, when we're talking about candida infections, acanocandins kind of remain that first-line treatment option. In many instances, if a patient is showing improvement after five days, it is feasible to consider switching to oral azole therapy, depending on the pathogen that grows out. Talia mentioned earlier about the changing resistant patterns about candida. So you want to make sure that we're being cognizant there if we are going to transition to oral azole. When we talk about azoles, you certainly are going to be important if we're thinking of deep penetrating infections. So for instance, azoles are recommended for if there's ocular involvement, because acanocandins themselves don't penetrate well to the eye. And then certainly, if we're concerned about co-infection with aspergillus, azoles may be an option here. Also, when we talk about empiric coverage for candida, amphotericin B usually has a limited role here for empiric coverage. But again, if there are other considerations relative to a patient, maybe having CNS involvement could be something to consider. In terms of invasive mold infections, amphotericin B remains really the standard of care, at least initially, for empiric coverage. And any time you're thinking of an unidentified mold infection in immunocompromised patients, certainly amphotericin B rises to the top of that list, typically, again, the lipid formulation being used most often. You also may consider amphotericin B in a patient who's previously been on azole therapy, because of concern for the development of resistance. Voriconazole can be an option if we think aspergillus is a causative pathogen for a particular patient. Amphotericins usually aren't used here, but can be used if we think about patients that are intolerant to other therapies. So I've talked about being able to talk about antifungal therapies. I just really want to highlight here that there's a lack of high-quality data to support use here, but it is recommended in the context of salvage therapy and non-responsive therapies or those with breakthrough symptoms. I do want to highlight that the caveat or the exception to this is when we're talking about cryptococcus disease and thinking about dual coverage there, and that's typically amphotericin B and flu cytosine. But in the context of outside of crypto, combination antifungal therapy is not recommended for most patients, is usually reserved for patients with salvage therapy. But the number of patients that may present in that scenario is upward to 30 to 50 percent of patients. You may want to be thinking about it if you have a patient who's not responding. Typically speaking, you're going to use differing mechanism of action. So instance, here I'm talking about cell wall versus cell membrane. And so the combination is an echinocandon or an azole or an echinocandon or amphotericin B. We wouldn't use amphotericin B or azoles together for their potential for antagonism. I did want to highlight a particular study that was done a few years ago, but it compared monotherapy with voriconazole with combination therapy of voriconazole plus anadulafunzine in patients with invasive aspergillus. And they found no difference in terms of six-week mortality. You see the numeric difference there, but it didn't reach statistical significance. In a post hoc analysis, however, when they looked at patients with an optical positive galactoman result, that there was a statistically significant difference. So if you have those available, those diagnostic tools available to you, they represent potentially this could be something to look at. When we talk about dosing considerations really briefly, I'll say from a dosing standpoint, antifungals are chronically overdosed in the ICU. And a lot of this is due to what we know about pharmacokinetic and pharmacodynamic changes that happen in critical illness. So for instance, we know that in critically ill patients, they have an increased volume of distribution in many instances. And so that leads to a need for higher dose. If you use normal doses in that setting, you will end up seeing decreased serum concentrations. Also augmented renal clearance is something that happens quite frequently in critically ill patients. And so we need to be thoughtful there in terms of dosing. That itself underdosing can lead to treatment failure, resistance, and certainly worse outcomes. I briefly highlight here just how common it is for patients to fail to achieve therapeutic targets quite high, almost a third in fluconazole, and about a third when we talk about isofuconazole. Obesity also contributes to underdosing and can be associated with some of the same PKPD changes that we highlighted earlier. So some of the recommendations are in terms of dosing, picking the right weight matters. And so for voriconazole or posiconazole, it's recommended to dose on lean body weight. And for echinocandidins, it's recommended that in obesity to consider increasing the dose by 20 to 50%. Really briefly highlighting drug interactions, again, primarily azole antifungals. They're all strong inhibitors of CYP3A4. And that's the primary pathway for most drugs that are metabolized through the liver. TDM or therapeutic drug monitoring is becoming increasingly common. On the right, I highlight some situations when one may consider therapeutic drug monitoring. Some of this is also contextual, context-dependent, because if your institution doesn't have it or if it's a send-out, that becomes less of an option. But typically speaking, you may want to consider it if someone's obese or there's significant drug interactions, or you may want to consider it in patients on renal replacement therapy, particularly thinking about azoles and monitoring their serum levels. Really briefly, and this is just a summary of those recommendations here. And so with that, I just want to provide an overall summary that empiric choice of antifungals is guided by patient-specific factors, including clinical condition, immune status, as well as concomitant therapies and patient history. Azoles themselves are important but have multiple drug interactions, but we can effectively use them, but we just need to be mindful of the drug interactions. The evidence for combination therapy is weak, but certainly may be considered in certain circumstances. And then when we talk about antifungals themselves, we need to be cognizant of dosing and tend to dose aggressive in critically ill patients. So with that, I will yield the floor back to my friend, Dr. Sweeney, to close us out and walk us through the case.

antifungal therapies

critically ill patients

Amphotericin B

echinocandins

azoles