Activity Transcript

Matteo Bassetti, MD, PhD: Hello, I am Matteo Bassetti, professor of infectious diseases at the University of Geneva in Geneva, Italy. Welcome to this program titled "Invasive Fungal Infections -- A Growing Threat: Meeting the Challenge with 21st Century Solutions."

Joining me today are Dr Oliver Cornely, who's a hematologist, infectious disease specialist and professor of translational research at the University Hospital Cologne in Cologne, Germany. And Dr Peter Donnelly, retired from the Department of Hematology in Radboudumc in Nijmegen, the Netherlands. So welcome all of you.

In this program we will discuss the burden of invasive fungal infections, the current landscape of antifungal therapeutics and also the novel therapeutic approaches for the treatment and prophylaxis of severe fungal infections.

So let me start with a brief overview on the epidemiology and burden of invasive fungal infections. So we know that fungal infections represent a global problem. There are more than 300 million people worldwide that are affected by a serious fungal infection, and many of these have coexisting conditions. So we have several risk factors and we have different fungal diseases from the aspergillosis to invasive candidiasis, to histoplasmosis and cryptococcosis, and they interact with a lot of underlying conditions.

So invasive fungal infections are increasing in prevalence worldwide due to increased number of patients at risk for such infections. We know that we have almost 3 very important pathology, first is invasive candidiasis. That is the most common invasive fungal infections in many countries. That is mostly due to increasing complicated medical issues including catheters, immunosuppressive agent, broad spectrum antibiotic and abdominal surgery. Then we have invasive aspergillosis that is the most invasive of infections and the second most common invasive fungal infection after invasive candidiasis. And in general these factors are represented by advances in the treatment of pathological malignancy that have increased the number of patients with prolonged neutropenia and graft versus host disease. But then we have also mucormycosis that is the second most common invasive mold infections and this incident increased significantly in the last 20 years.

So invasive fungal infections in patients with hematological malignancy present a very heterogeneous incidence. In US, it is in general higher than in Europe for Candida. For Aspergillus, we have some bimodal distribution in stem cell transplantation, and we have data from Italy that show an incidence of about 2.6%, and the same is for zygomycoses that is increasing or for Scedosporium.

But what is important to know is the burden of the life-threatening fungal infections worldwide that is absolutely important in term of case fatality rate. And also in term of estimated death. We can see that we have more than 600,000 death per year for cryptococcal meningitis, more than 100,000 for invasive aspergillosis and even for chronic pulmonary aspergillosis.

So we have a lot of risk groups for invasive fungal infections, the commonly identified groups represent by acute leukemia, allo-transplant recipient, neutropenia and GvHD and lung transplant. But now we have some emerging groups like patients on immunomodulating drugs, patient with chronic pulmonary disease, patient with chronic lymphoproliferative disease and intensive care unit patients. And in the past 10 years we have 2 more groups of patients, patients with influenza and patients with COVID-19, particularly for some of diseases.

So after this brief introduction, I'd like to go to Peter and to ask him what can you tell us about the rise of antifungal resistance?

J. Peter Donnelly, BSc, PhD, FRCPath: Thank you very much Matteo. I'm actually going focus on Aspergillus because that's very interesting. If you see the slide in the early 1990s, we didn't expect to see any azole resistance at all. But in Nijmegen we've been keeping these strains since 1994 and when they were looked at, we noticed from the year 2000 onwards there was an increasing number of strains that were actually resistant to itraconazole.

And a group went out to different parts of the Netherlands where the hospitals were, the academic hospitals and they discovered where you look for a fungi with these mutations, particularly TR34 and L98H, you found them. So was this a Dutch problem? Well, no it wasn't because wherever people looked, they began to find azole-resistant Aspergillus fumigatus.

Many people thought this was due to chronic long-term treatment with antifungals and that is true in some cases, but in fact the majority of cases seem to have come through what's become known as the environmental route. In other words, food stuffs, agriculture, where fungicides were actually used to keep fruits fresh for example, when they were being transported. They're used widely across agriculture and horticulture.

So one of the things we want to do is to say, "well how does this actually affect our patient population?" So what we did was we took the retrospective cohort study to include all the patients we gave chemotherapy for AML and myelodysplastic syndrome and all allogeneic stem cell transplants from 2006 to 2012 inclusive and we had of total of 432 patients, just under half were AML patients and the others were stem cell transplant recipients. We diagnosed "probable" or "proven" invasive aspergillosis in 8.3%, which is exactly the same as what Pagano et al. published some years ago.

But the interesting thing was we looked at, well what were the strains that we isolated from their respiratory samples? Patients who had no evidence of aspergillosis, we found 13 cases with Aspergillus fumigatus of which 3 were already azole resistant. For "possible" we didn't have samples. So in 34 cases we had no samples, so we couldn't say much about them. And for "probable" we had 32 cases of which 10 we isolated Aspergillosis fumigatus, 1 of those 10 was azole resistant. And for "proven", we had 4 cases of which 1 involved azole resistant and that was actually tested by PCR.

So although the overall prevalence of voriconazole resistance was low among these patients and voriconazole was the drug we were giving at that time, the low detection rate was probably based on our poor sample rate and we would strongly urge people to use PCR to detect resistance, at least among Aspergillus fumigatus.

Dr Bassetti: So Peter, after discussing about antifungal resistance so could you please tell us how is diagnosis made in general?

Dr Donnelly: The EORTC and MSGERC groups have had 3 iterations of what they call the consensus definitions and 1 of them is "proven" disease. And that's the same no matter how far back you go in the literature, that requires obtaining tissue or a sterile fluid from a body site that's affected from the fungal infection and to either demonstrate the fungus by culture or by histology. And nowadays you can also have molecular techniques for detecting that. But however, we very seldom get these samples in life.

So we came up with this idea of having 3 pillars. 1 of them was host factors, you've heard some of them from Matteo, allogeneic stem cell transplant for example is 1 and neutropenia is another. And clinical features and that requires imaging and that requires modern imaging. And with modern imaging you can find out where the lesions are, and you can judge whether they're consistent with invasive fungal disease or no. And very importantly, mycology.

So when you have these 3 elements together, you can actually create the "probable", the "proven" and the "possible" categories of disease. And these have been used successfully for drug trials, some of which will be mentioned later on in this presentation, for epidemiological purposes and for diagnostic tests. They were not intended to guide clinical practice, however they obviously do.

And one of the things is host factors. You've got the patient, Matteo mentioned some of these, you have clinical signs which are consistent with an invasive fungal disease and if you only have them, you have what we call a "possible" diagnosis of invasive fungal disease. But if you have mycology, you then could convert that to "probable". And most of the cases we see where we have evidence of invasive fungal disease are between "possible" and "probable", but not "proven".

And what can we do with mycologically speaking? Well, you have direct mycology which is culture and microscopy of an appropriate specimen. And you have indirect mycology which includes nowadays detecting antigens in blood and for example, for cryptococcosis, it's a very successful antigen test you can use in cerebral spinal fluid. Beta-D-glucan in serum, and also importantly nucleic acid amplification tests which we now have for Aspergillus, mucorales and Pneumocystis.

Dr Bassetti: So Peter, what strategies can we use in our practice to manage this type of infections? So I mean obviously invasive fungal diseases.

Dr Donnelly: Well what we did was, and this is based on mainly Nijmegen and a few other people, this is our version of it, we adopt a screening approach whereby a patient who is at risk, as soon as they enter the hospital, we start screening their blood for the presence of galactomannan and beta-D-glucan and PCR. We do that twice a week, others do it 3 times a week. We screen and if any of the tests are positive, we move on to the next panel but if they remain negative, we only allow treatment when the clinical triggers are present so such as refractory fever, which is defined as at least 4 days of continuous fever despite antibiotics. If they don't have any of those, we don't give them any antifungals at all.

And then we have a diagnostic-driven strategy, and this is important because this is what more or less everyone's doing, albeit at different stages. If you have a screen positive, you move into this panel where you actually attempt to make a diagnosis clinically by using imaging and obtaining appropriate specimens, particularly bronchoalveolar lavage. And I don't know whether Oliver will be going into this, but it is the most important specimen if you can get it. And if any of those tests are positive, then you would consider treating the patient with the appropriate antifungal. But we do have a ghetto and that is when you cannot obtain a specimen or you cannot actually manage to get the test done, a weekend is a classical example, we allow refractory or refractory fever antifungal therapy but only to buy time until the diagnosis is confirmed or excluded.

There is 1 caveat, if you were to use mold-active prophylaxis, it is almost impossible to screen. And so your choice actually is screening and giving an antifungal like we did of fluconazole which is only active against a number of the Candida species or you opt for mold-active prophylaxis, which Oliver will be going into presently.

Dr Bassetti: So Oliver, who are the patient at risk for invasive fungal infections? And if we cannot screen for invasive fungal infections, what can we do for prophylaxis?

Oliver A. Cornely, MD, FECMM, FACP, FIDSA, FAAM: Well thank you for that question. There is an entire universe of all kinds of patients where we see invasive fungal diseases infections happen and some of them are well defined, and it's patients where we already expect an invasive fungal infections and others are not. So for example, let me start with some neglected patient groups at risk. Acute lymphoblastic leukemia during the induction phase, so during the first chemotherapy, they have a very high risk and because of drug-drug interactions we can actually not prophylax them. So that is a group well known and they have a high risk, but you can't prophylax so you would go for screening as Peter just outlined in his presentation.

Another group is aplastic anemia or specifically the very severe aplastic anemia. They have a very long neutropenic phase, weeks and weeks of neutropenia below 500 neutrophils per microliter and that's the key risk factor. And then there are others like CLL patients, chronic lymphatic leukemia, specifically if they received multiple courses of treatment already. And palliative AML acute myeloid leukemia patients are another group.

To understand the wording of induction and remission, etc., let me briefly go with you through that sketch, The leukemia treatment path is what I titled it. If there is a new diagnosed leukemia that's practically the same as an uncontrolled leukemia so in a relapse situation you would be actually in the same setting. What you try to do with your chemotherapy, you want to induce remission and that is why we call it induction chemotherapy. Once remission is achieved, remission is achieved, then actually you give a consolidation treatment. So to consolidate that remission. If remission is not achieved, you go back and circle back and give another induction chemotherapy. So these terms need to be clear, then it's much easier to understand the current literature on prophylaxis and different approaches.

And of course one aspect is can we identify a group at high enough risk so that it's worth exposing them to prophylaxis? And in the past, now it's 15 years ago, we did the posaconazole study which compared posaconazole and prophylaxis in AML patients vs fluconazole or itraconazole, whatever the standard in the hospital was in the participating site. And when we, after a successful study with posaconazole being a life saving measure, when we then went into subgroup analyses and tried to tease out is it those with more mucositis? Is it the advanced age patients? Is it those who are underweight, etc? We couldn't tell apart cause all the groups had benefit from posaconazole prophylaxis.

And that is actually reflected in the current guidelines, and I brought 3 guidelines today with me and you in all of the see an A1 recommendation for posaconazole prophylaxis in patients where you opt for prophylaxis because of high risk and opt not for or opt against a screening approach. So it's a strategic question whether you go for prophylaxis or not. I'm a big fan of prophylaxis and maybe some of you know that. So in the German guideline it's an A1 for those with a long duration deep neutropenia. So that's more than 1 week of less than 500 neutrophils.

And then there are 2 European guidelines. The estimate guideline on prophylaxis of invasive fungal disease says the same for that population, it's top line of the tables usually because they are usually sorted by the A1 recommendations first and then the less strong recommendations following. And the ECIL guideline, which is a guide specifically focusing on prophylaxis of invasive fungal disease in leukemic patients, has practically the same result again A1 for posaconazole prophylaxis.

Apart from the strategic decision do I screen? So have all the tests available with the record turnaround time. Or do I prophylaxis? Apart from that, if you go for prophylaxis then all the new anti-leukemic drugs that are currently being licensed, there's at least 1 new drug per month, then if you use these, and most hematologists do because they are lifesaving with regards to their efficacy against AML. So what you find is that the vast majority will meet your azole prophylactic drugs in the liver it's P450 and then you have drug-drug interactions and we just very recently in June or July 2022, there was a publication addressing these interactions and giving practical advice on how can I prophylax or should I rather go for screening depending on which drugs are in that patient, so that's my take on prophylaxis for you.

Dr Bassetti: So Peter, would you like to comment on the need of a multidisciplinary approach in the identification and management of patient that is for invasive fungal infections, please Peter?

Dr Donnelly: Yeah, I think it's been obvious throughout this presentation so far that many different disciplines are involved. I've tried to display them here. Most important one of course is the physician attending the patient they see a problem. The next one is if you have a radiologist or a specialist in imaging, you're going to rely on them to do their job. And oftentimes you need a pulmonary specialist to actually take the sample of a bronchoalveolar lavage and aided in a bed by a nurse who actually helps with a bronchoscopy, and they send the specimen to the microbiologist who then examines the bronchoalveolar lavage fluid quite comprehensively and thoroughly, both for culture microscopy and also PCR, galactomannan and any other tests that are on the go at that moment.

And then you have the ID physician, the infectious disease physician who can advise on management. Oftentimes you have guidelines but oftentimes also you need specific advice for that particular patient and their particular problem. And you have a pharmacist or pharmacologist who advises on antifungal courses, you just heard there are often bad interactions or dangerous interactions and so the pharmacist can assist with that. And then last, but by no means least you have the nurse who actually administers the antifungals. And the point being is they all help but they all need to communicate effectively with each other.

Dr Bassetti: So thank you Peter. Oliver, can you tell us what are the current practice guidelines for the management of invasive fungal infection?

Dr Cornely: Yeah, the treatment guidelines apart from prophylaxis, there's of course a lot of scenarios where they actually really need to treat a patient and we do have the One World One Guideline program where many scientific societies are working together and you can see that we do have guidelines on Candida aspergillus and mucormycosis, that is certainly the most important because the most prevalent infections and diseases. But there are others of course, the corona-associated was already mentioned during the changing epidemiology part of today's. And then we do have guidelines on really rare molds and rare yeasts and endemic mycoses.

So let's see what's in there for the most important and most prevalent fungi. We do have unchanged for the targeted treatment of candidemia, echinocandin as the number 1 drug. So A1 recommended all 3 of them you see on the slide. And in a rapid turn to aspergillosis. So what is the top recommendation there? We do have A1 recommendation again for more than 1 drug, it's for isavuconazole and voriconazole for the first-line treatment of aspergillosis and that is primarily pulmonary aspergillosis but we often derive from what we knew and learned in pulmonary because it's so frequent, we derive what we do in more delicate and difficult cases where other organs are being involved.

Dr Bassetti: So if we look at the current landscape of antifungal therapeutics, we have actually a lot of drugs available. So if we look in the past 50 years, so during the 50s there was only amphotericin B. And after that, during the 70s and the 80s we had the azoles and then the lipid formulation of amphotericin B and then we start with a echinocandin, start with caspofungin and then with micafungin, anidulafungin and isavuconazole, and now we have also on study many of new antifungals.

But actually we have different classes of systemic antifungals and obviously they have different cellular targets. So they work on the cell wall and the cell membrane and obviously they have a completely different ways and mechanism of action.

But what is important I think is to look at the in vitro activity of the different antifungals. So almost all the antifungals from the echinocandins, to the azoles to the polyenes work very well against Candida. Obviously echinocandins and amphotericin B are probably better against Candida than fluconazole that actually presents some of the resistance problems. Regarding Cryptococcus, echinocandins are not active, all the other are active. Again in Aspergillus we prefer to use the azoles or amphotericin B than using obviously fluconazole that doesn't have any activity or echinocandins, then regarding Mucor and Fusarium we know that there are some difficulties for the antifungal so we have amphotericin B that is very active and also some of the newer azoles.

But one of the most interesting and important point to be discussed is the one regarding the toxicity of the systemic antifungal agents. So we know that almost all the antifungals present some toxicity but there are classes that has more problems like for voriconazole we know very well all the side effects of voriconazole, the CNS, the photopsia and the hepatic side effects but also the cutaneous so be careful when using antifungals because we have some of the antifungals that present more toxicity than others. We remember very well all the toxicity problem for conventional amphotericin B, the renal side effects or the problem with fever and shaking.

So after discussing about the drugs, I would like to go back again to Oliver and ask him what data is available on the novel approaches to the treatment of invasive fungal infections please Oliver?

Dr Cornely: Yeah, it's interesting times because there are new developments and we will see new antifungal, none of the new ones are currently licensed for these invasive infections. But let's have a look. For example, at rezafungin, as you immediately realize from the word is an echinocandin so what is different is that rezafungin was chemically modified to have a very long half-life. It's a half-life of more than 120 hours and actually that allows to just give it once a week, which is interesting for our patients, interesting for those who need a echinocandin for a long term. And rezafungin as you would expect from an echinocandin has activity against Candida, against Aspergillus and against Pneumocystis that is from animal models but it's currently being tested, evaluated in clinical trials.

Phase 2 has actually been already published and phase 3, not yet, but in a presentation during ECCMID earlier in 2022 the patients were pooled from phase 2 and 3 because the studies were practically identical design. So what you can see here in this sketch is that rezafungin was compared with caspofungin in these 2 studies. So the groups were well balanced at baseline and what we can see when we turn to the efficacy results, specifically the cure rates at day 14, which was the primary endpoint of the study, what you can see is that the overall cure, the global cure are actually at least as good in the rezafungin as compared to the caspofungin treated patients. This would state non-inferiority for the analyses of this point in both studies.

And there is more good news on the horizon and that is, for example the oral drug, ibrexafungerp. This is a novel triterpenoid glucan synthase inhibitor, so it has a very similar mode of action as the echinocandins, but it's not what it’s occasionally being named the oral echinocandin. That's not true because this drug was broader by spectrum of activity than the candins we are currently working with. And it's broader in 2 ways. One is that there are more species beyond Candida, Aspergillus and Pneumocystis where that drug exhibits activity against. And the other aspect of being broader is that strains of Candida and Aspergillus where there were echinocandin resistance being established, they still sometimes can be treated with ibrexafungerp, which is of course good news since resistance is spreading and we are confronted more and more. So we will have another drug that will help us treat our patients in the future.

Dr Bassetti: Peter, I have just a couple of practical questions. So the first is all the labs all over the world are able to determine the antifungal resistance or is something that is difficult to do?

Dr Donnelly: Well I can't speak for all the world but I think I can speak for Europe, it tends to be academic centers that are able to do this, provided they've invested in mycology. And so for example in the Netherlands, all 8 academic hospitals are able deliver the service. There is a discussion about whether you should have a reference center. In the UK, I understand the UK has 2 reference centers that do this but it’s not available in every hospital. And I suspect that's true throughout Europe.

Dr Bassetti: Obviously there are difference between one lab to another for anti-fungi susceptibility tests but what do you know regarding the availability of PCR or other diagnostics? I mean in all the hospital because we know that the invasive fungal infections are everywhere, not only in the reference centers.

Dr Donnelly: Well yes, we have been running an ISHAM working group called the Fungal PCR Initiative. So we have an idea of how labs are actually doing their PCRs and what we know is that none of the labs have a commercial PCR platform. They're using commercial elements of PCR and they're all doing their own version. And what we've managed to do is to create guidelines to help people arrive at a similar answer.

Dr Bassetti: Okay. A question for Oliver. So if we do universal prophylaxis for all the patients in the hematological world that should be treated with the antifungal prophylaxis, what is your strategy if you suspect a fungal infection? So you move from 1 class to another or you remain in the same class?

Dr Cornely: Well prophylaxis would usually be done with an azole, let's say posaconazole and now my patient develops either a fever, a persistent fever over 72 to 96 hours, or develops respiratory symptoms because sometimes they're only that symptom but no fever. Either 1 would trigger a CT scan and so that I know what's going on in the lung and if I see an infiltrate in the lung then we need to go for bronchoalveolar lavage and send the fluid off to the microbiology lab and of course it's a precious material so you would send it to virology as well and maybe to pathology so that you really make the best use of that material.

Whatever comes back will tell you what to do because if this really is Aspergillus breakthrough during posaconazole prophylaxis, what you often find is that the galactomannan index from serum sample that you would take during that workup as well remain negative, but in BAL fluid you find galactomannan so that is a quite frequent thing in those who do have breakthrough during prophylaxis.

Dr Bassetti: So if I ask you Oliver to give us your opinion about the new options for treating fungal infection, what is your opinion in term of the new drugs?

Dr Cornely: Well, to stay with prophylaxis, that is relatively easy because as far as I know only 1 of the drugs is currently being evaluated for prophylaxis. That's rezafungin in allogeneic stem cell transplant population, which is of course very appealing to do it there because they have, in addition to Candida, Aspergillus and Pneumocystis risk, as an echinocandin it covers all 3 and with the only weekly dosing it will be an ideal drug and ideal schedule for prophylaxis.

Well other new drugs, I referred to ibrexafungerp, certainly that will be a solution for quite some of the situations that I went through. And there are more new drugs out there, there is whole pipeline of drugs, and so we will see quite some progress there.

Dr Bassetti: Thank you very much Oliver and I would like to thank you and Peter for this great discussion and also I would like to thank you all of you for participating in this activity. I hope you enjoy discussing with this very interesting topic. So please continue on to answer the questions that follow and please complete the evaluation form.

This transcript has not been copyedited.