Activity Transcript

NOVEL THERAPEUTIC APPROACHES TO TREATMENT AND PREVENTION OF INVASIVE FUNGAL INFECTIONS

George R. Thompson, MD, FIDSA, FECMM: Hello, I'm Dr George Thompson from the University of California Davis Medical Center. I'm a professor of medicine with an appointment in the division of infectious diseases and the department of medical microbiology and immunology. Welcome to this program. It's titled "An Overlooked Cause of Preventable Deaths in the ICU: Invasive Fungal Infections."

In this section, I'll discuss novel therapeutic approaches to treatment and prevention of invasive fungal infections and discuss a little bit of the epidemiology of these infections, because it has changed over the last decade. We do have a number of new agents in current development that are going to be on the market within the next several years and their potential role in the treatment in the ICU setting will be discussed.

Treatment of invasive fungal infections is challenging as the number of existing antifungal therapeutic options is limited by drug-drug interactions, by toxicity to our patients, and the constraints in administration routes, and that is some of these agents are only available orally, which is very difficult mechanism to give to some of our ICU patients.

Really, despite the need for new antifungal drug options with either a narrower spectrum or even a broader spectrum in other cases, only a single agent in the antifungal class has been approved in over the last 20 years. A number of other therapies from new antifungal classes are in late stages of clinical development like I discussed, and we'll talk just a little bit about those.

Current antifungal therapies are hampered by significant variability in the pharmacokinetic properties. What I mean by that is the echinocandin class, we tend to give the same dose to all patients regardless of body weight, regardless of what else is going on with those patients, and maybe that's not the best dosing strategy to give those patients. We do dose adjust the azole class by patient body weight and other factors ongoing with those patients that may change the pharmacokinetics, but I think really some of the agents in development really fulfill a great need to really improve outcomes with some of the different pharmacokinetic aspects they have, as well as their spectrum of activity.

An important factor contributing to the relative ineffectiveness of existing antifungal drugs is the insufficient drug exposure at the site of infection, and sufficient penetration into infected tissue compartments is really a key requirement for efficacy of all these antimicrobial agents. To give an example of that, we have seen in patients with invasive candidiasis, the echinocandins don't reach the gallbladder well. You may say, "Well, why does that matter? Echinocandins, we don't usually need in the gallbladder. That's not a typical site for invasive candidiasis."

Well, there have been some papers that show that that's really a sequestered site where Candida can survive the kind of Candida exposure and really develop resistance. That's best described with Candida glabrata, so resistance after exposure to echinocandins in that particular pathogen.

The distribution process of most antifungal drugs is characterized by considerable variability among different target tissues. Drug penetration into areas of tissue infection may differ markedly from healthy tissue as a result of the altered tissue structure and permeability associated with tissue necrosis and/or fungal biofilm formation. So those are some different areas that existing antifungals are not going to be able to cure those particular structures if there's a biofilm in place. Any foreign body is going to have a biofilm on that. It's going to be very difficult to eradicate the infection. Some of the new agents may fortunately be able to eradicate biofilms.

Then again, some of these structures that either have impaired blood flow or necrotic tissue, really, it's not going to be able to get a good amount of drug into those tissue sites. So we do need to try to talk about that and what some of the strategies may be to optimize patient outcomes when you encounter those situations.

Then the accumulation of antifungals with different intracellular compartments also may influence their activity. That's been described a little bit with the echinocandins in a recent paper that came out just last week.

Let's talk just a little bit about drug toxicity within the ICU setting. Currently available antifungal agents do have cumulative toxicity. Again, a lot of these fungal infections we treat for a considerable amount of time so it tends to be weeks to months rather than just a few days. The triazole therapy class is really well known to have a number of side effects, particularly with sustained therapy or chronic therapy. So fluconazole, which we think of as fairly benign, with prolonged therapy does cause cheilitis, xerosis, and alopecia. You may say those really are not that clinically relevant, but patients really despise those side effects and 50% of them will discontinue the medication due to one of those 3 side effects.

Voriconazole, the toxicity is very well-known, but just to review, there's certainly hepatotoxicity in between 8% to 10% of patients. Ocular toxicity, photopsia -- so they get sort of a flashing light sensation. That occurs primarily with IV voriconazole and happens at about a third of patients. Then phototoxicity, voriconazole can be very difficult to give in an outpatient setting as a photosensitizer. It's also been associated with skin cancer with long-term use.

Then posaconazole and itraconazole, structurally very similar to one another, but have been associated with drug-induced hypertension with both of those drugs through an impairment of the cortisol synthesis pathway. All of these factors really come into play when we're deciding which one of these azoles to give, and certainly if we're going to have to give them for a prolonged amount of time.

Then moving forward a little bit, amphotericin formulations, they cause a lot of electrolyte toxicity. Renal toxicity is very well-known. The lipid formulations have improved that, but again, if we're going to use these for any amount of time, we do typically run into these different electrolyte derangements, whether renal tubular acidosis or potassium wasting or just frank renal toxicity.

The echinocandins, we really don't see a whole lot of toxicity. There can be some infusion reactions. There's certainly idiosyncratic drug reactions to this class, but overall, they're heavily used within the ICU setting. They're really our drug of choice for invasive candidiasis up front. We typically give them echinocandin until there's clinical improvement in their symptoms, clearance of their blood cultures. Then we might consider stepping those patients down to an azole for the duration of their invasive candidiasis treatment.

Well, in recent years, echinocandin resistance has emerged. We've seen that with Candida glabrata like I mentioned just a little bit earlier. Candida auris is certainly going to move across the country. It's already being seen in Europe and some other sites throughout the world, but that is going to be a big problem. Candida auris isolates, that's about 30% of those are going to be echinocandin-resistant, so a very tough group of organisms to treat. They can be pan-antifungal-resistant.

Then in recent years, we have seen more fluconazole resistance in Candida parapsilosis, and parapsilosis does have higher MICs to the echinocandins. As those reports continue to come out, our empiric antifungal strategies for invasive candidiasis may adapt depending on your local epidemiology and which pathogens you are seeing in your ICU.

We mentioned that echinocandins are really the first-line agent in the treatment of invasive candidiasis, but despite echinocandin therapy, we still see failures in almost a third of the patients up front. The reasons for failure are not fully elucidated. There's really a lot of host factors. These patients are very sick up front. That's really their major risk factor for candidiasis, of course. They're in the ICU. They have intravenous lines in. They're receiving TPN. A lot of them have had a recent surgery. All of those are risk factors for invasive candidiasis, but those are all risk factors for mortality even without invasive candidiasis. So failures certainly occur. It may not even be related to the drug. It may just be strictly host factors that we have a difficult time still in 2022 improving over time to really get their immune system back up to fighting off these infections.

The echinocandins really are reliant on concentration-dependent effects and the drug levels within a target tissue site. Currently available echinocandins and dosing strategies may be insufficient to eradicate Candida species or to prevent the development of resistance. I mentioned a little bit about the reports for Candida glabrata that may be hiding within the biliary system, allowing it to see very low doses of echinocandins and become resistant.

These sequestered sites, again, really are where there's probably subtherapeutic echinocandin concentrations. Failure has been reported in echinocandin-resistant organisms with FKS mutations. These are mutations within the target site for the echinocandin gene. What that means is they have polymorphisms within these 2 FKS regions. There's FKS1 and FKS2. When they develop a polymorphism in that, they produce a drug target that's aberrant. So the echinocandin does not bind and inhibit growth and target killing of the organism. This has really been seen in Candida albicans, Candida glabrata, and seen in a number of other Candida species, but those are fortunately much rarer.

Since we talked about exposure really is key for development of resistance for a lot of these Candida species, the role of antimicrobial stewardship has really moved up to the forefront of our day-to-day activity in infectious disease. We really try to minimize the amount of antifungals used. Again, the number of antifungals used in your hospital are going to directly correlate with the amount of resistance that you are seeing. Taking patients off antifungals that they may not need not only decreases toxicity and exposure-promoting resistance, but certainly decreases costs. So a lot of us have stewardship programs in place or certainly in the works to develop.

The components of the antifungal stewardship program really had been laid out very nicely in JID in 2020. This was a consensus paper written by multiple members of the Mycoses Study Group that really outlined essential aspects of a stewardship program. That's things that really should be a part of your key program right now.

Achievable, those are things we think really can be done, but do need some time and really resources to be allocated to achieve those goals. And then aspirational, and that's things a lot of our programs really would like to see happen over the next 5 to 10 years. Essential aspects of a stewardship program, that's really to identify the patients at highest risk, those patients that really must be on antifungal prophylaxis, really to identify patients that would benefit from empiric therapy in the ICU. Certainly education programs that target those that prescribe the most antifungals, so that's our hematology, oncology colleagues, the infectious disease colleagues, and certainly our ICU nurse practitioners and PAs, really to make sure they have a good grasp of the antifungals and patients at high risk. Certainly, be able to screen patients for drug-drug interactions, really to identify those early rather than allow toxicity to occur. And then really to have handshakes -- we've discussed these patients daily with our ICU colleagues to make sure that we're all on the same page in the treatment and prophylaxis of these patients.

We are very aggressive about an IV to oral transition program. Once they've improved, able to tolerate oral medications, we like to transition them from IV to oral medications in preparation for downgrade from the ICU and hopefully home just over a short amount of time. Then really, a lot of conversations with our microbiology lab. We want to identify resistance patterns early rather than just check on those things once a year. Those are really key elements of an antifungal stewardship program.

The achievable goals require a lot of conversations with your microbiology lab. This is going to be to make sure you have early diagnostics available. Some programs use beta-glucan for this. Certainly, Aspergillus galactomannan is a big part of that program to identify those patients at high risk who have infection early. Again, I mentioned antifungal susceptibility. It's really key to know your local susceptibility profile. The antifungal susceptibility reports really need to be relayed to the end user. So the people prescribing antifungals need to physically see those and we make sure that happens yearly.

So therapeutic drug monitoring, again we talked about the variability of a lot of these different antifungals, so we want to make sure our patients are at target goals. We don't want too much for toxicity and we certainly don't want too little that's going to promote resistance or just lack efficacy.

Then certainly in the US, I think we really struggle with this last component and that's really to dig into autopsies, patients who failed and did not do well really to determine what was the underlying cause. I think our European colleagues do a much better job of this with having autopsies for their deceased patients.

Aspirational, so those are things that require a national presence. We want to see what the country's antimicrobial susceptibility profile is from a big picture standpoint, what diseases are on the move. We'd really like to move to a genetic-based screen. If we knew a patient's genetics, we may know how they metabolize drugs and be able to put them within the therapeutic window at a much earlier timepoint. And really, our use of radiology, that has really improved over the last few years. But certainly new radiologic modalities and knowing your institutional specific CT parameters is really key for certainly, the diagnosis of invasive aspergillosis.

These are outlined really nicely in this JID paper. I'd encourage you to take a look at that as you formulate and bring your antifungal stewardship program online.

We talked a little about the problems with existing antifungals, but there's a number of new agents that are in various stages of clinical trials and clinical development that are going to be on the market over the next several years. We're really excited about a number of these compounds. They have a variety of new mechanisms, which you can see here on this slide. They have more favorable pharmacokinetics than some of the agents we currently use on a day-to-day basis.

We're really excited about the potential for reduction in toxicity because again, some of these patients are on these for weeks or months.

We'll go through these and what should be coming on the market or is already on the market. The first one is already out. It's SUBA-itraconazole. This is a new itraconazole formulation that's more readily absorbed. It really does not have the acid effects or the food effects that we saw with conventional itraconazole. SUBA-itraconazole is used quite frequently for blastomyces, histoplasma, and Aspergillus in the non-neutropenic setting.

The echinocandins, there's a novel echinocandin which is called rezafungin. Rezafungin is a once a week echinocandin. It has a much more favorable pharmacokinetic profile. It has a front-loaded effect, so it does have the advantage of probably clearing blood cultures more rapidly than say, caspofungin.

The terpenoid antifungal class is a new class. That agent is ibrexafungerp. It's not technically a echinocandin, but it works on the same target site and it does overlap a little bit with the echinocandin-binding site. Most mutants of Candida that are resistant to echinocandins will have susceptibility to ibrexafungerp, but not all. So you do have to check if you have resistant Candida species to ensure they're susceptible to ibrexafungerp.

The orotomides are also a new antifungal class. Olorofim is the agent in that group. I think that's a drug that really has a lot of promise. It's an oral antifungal. It's fungicidal for Aspergillus. It does not work for Candida, but does work for Scedosporium, Lomentospora, and the endemic mycoses.

The HDAC inhibitors have been around for about a decade. Those are in phase 2 trials right now. Those are fungal histone deacetylase inhibitors. We'll see how that comes out after the phase 2 studies are complete.

A new amphotericin B formulation, so this is amphotericin B cochleate, and that should have lower toxicities. It's an oral formulation of amphotericin which does have certainly some advantages. It works for Candida. It may be an advantage too for Cryptococcus in resource-limited settings, such as in Africa for treatment of cryptococcal meningitis. We'll see how the early studies for that bear out as well.

Then the tetrazole class, which are azole-like, so VT-1129, VT-1161, VT-1598. One of these is oteseconazole. I think that one has a lot of promise, certainly for the endemic mycoses. Those studies, I think, are planned over the next several years as well.

Fosmanogepix has a very unique mechanism of action. It inhibits fungal Gwt1 GPI-anchored protein and does not appear to inhibit the human homolog, or I'm sorry, ortholog of that. It works for Candida species with the exception of Candida krusei. Works for Aspergillus and hyaline molds, most mucormycosis. That's an oral agent that really we're very excited about the possibility of, really fills a niche from some problematic organisms we don't have other good options for.

Then opelconazole, which is an inhaled first-in-class novel triazole currently in phase 2 as an inhaled agent. It's probably going to be used for prophylaxis against Aspergillus such as in lung transplant patients. It could be used in treatment of Aspergillus in non-neutropenic patients. We'll see what happens with their phase 2 trials over the next few years as well.

Then the last agent that's in current development is an arylamidine, which is T-2307. It's thought to inhibit fungal mitochondrial synthesis. It works for Candida, Aspergillus, and some hyaline molds. That currently has just completed phase 1 studies, but phase 2 studies are certainly planned. Structurally, very similar to pentamidine, so we'll see the efficacy and toxicity of that.

These are the agents that are in development. There are a number of papers that review these agents really nicely. A lot of these are obviously ongoing. Investigation will be a big component of ECCMID, certainly ID Week over the next few years as you see these agents roll out and come on the market.

So in conclusion, invasive fungal infections continue to increase. We see these on a daily basis within our intensive care unit and our hospital wards. Treatment of these fungal infections is hampered by the toxicity, drug-drug interactions, the emergence of resistance, and that's always going to occur. We need to continually develop this pipeline for new antifungal agents. New agents and classes again are really important in this antifungal treatment armamentarium. We're excited about what's coming over the next few years. Certainly, a lot of agents are coming out on the market and we'll see what ultimately determines their place and their niche during treatment.

Thank you so much for your attention. I really appreciate your time and this opportunity to talk about new antifungal agents.

This is a verbatim transcript and has not been copyedited.