Articles, Blog

PACCARB 13th Public Mtg, Day 1 Pt 4: PANEL 2: Emerging Resistant Fungi – Aspergillus fumigatus

August 20, 2019

>>Martin Blaser: So, welcome back from lunch
everyone. I’d like to now begin the panel session two:
Emerging Resistant Fungi with a focus on Aspergillus. Dr. Aileen Marty will moderate. Dr. Marty.>>Aileen Marty: Yes, good afternoon everyone
I’m so glad to have you all here to talk about this other very important resistant fungus. Aspergillus, as Dr. Blazer said, it has a
tremendous impact on both human and agricultural health, and similar to the previous session
that we had on Candida, our federal government will discuss the issue first followed by the
agricultural implications. And then we have a fantastic presentation
by an international experience from the Netherlands and the lessons learned there. And as a reminder, we do have a timer here
that’ll indicate what your time is and when your time is up. So, now, I welcome Dr. Tom Chiller once again
to the panel.>>Tom Chiller: Well, thanks. I appreciate being able to present twice to
you guys today. It’s definitely a thrill and we’re going to
switch topics now. We’re going to talk about mold. So, we were talking about yeast this morning,
talking about mold now. And hopefully, I can set the stage for both
Sally and Jacque to continue to talk about this emerging — sorry, next slide. I’m used to pushing a button for the slide. So, in the case of candida auris, we talked
about the environment and the fact that it’s an unknown. It’s not an unknown with aspergillus. Right? This is majority an environmental infection
in humans. You get it from inhaling. I like to give lectures on aspergillosis,
and I like to tell you to take a deep breath, ok you just inhaled a hundred spores, but
you’re all still around, you’re all still doing fine. But we’re inhaling this organism all the time. And we’re dealing with it for the most part,
so again it takes a certain host, a pathogen interaction for it to really take hold. Next slide. So, here’s just a little brief clinical tidbit
about aspergillus fumigatus specifically. And we’re talk about aspergillus fumigatus
specifically because it is the most common species of aspergillus that causes aspergillosis
and clinical infection. There are many other species, but this is
really the most common. It’s quite deadly, and I’ll talk a little
bit about mortality in the next slide. Again, it’s a major problem and in our immuno-compromised
patients, transplant recipients, chemotherapy recipients, those who are getting steroids,
et cetera. We have zero U.S. surveillance for this organism. In fact, we don’t have surveillance really
for mini fungi at all. We have a little bit of surveillance for candida,
and we have a little bit of surveillance for valley fever and that’s it. So, we don’t have a good handle on what’s
happening with aspergillus or any other mold for that matter. It’s not notifiable or reportable. Next Slide. The major drug used to treat aspergillus fumigatus
is voriconazole. So, one of these trials all we’ve been talking
about this a lot. Voriconazole and itraconazole can also be
used, but 99 percent of patients treated with aspergillus get voriconazole. Next slide. It was really a game changer actually to get
voriconazole, which really emerged in the 90s and you can see that in what we call the
I’m calling the pre-azole era, but it’s really the pre-voriconazole era because they were
other azoles out like uniconazole and fluconazole at this time, but in the pre-azole era the
mortality of aspergillosis could range anywhere from 50, 60, 80 percent. When voriconazole came about, it was a dramatic
reduction in mortality. Pushing it down into the 30s. And now, in this new era which were calling
azole resistance era, which we’re going to talk about specifically in Europe and its
effects, we see that mortality going back up and that’s despite using non-azole drugs
to treat these patients. Next slide. Here’s a good example of some data that was
just published, actually, I think this year in CID, where you can see that there’s a difference,
a quite dramatic difference between patients that have a susceptible aspergillus fumigatus
and patients that have a resistant aspergillus fumigatus and their 90 day survival. And, again, this despite being given an appropriate
non-azole medicine up front. So, there’s also something within this particular
organism when it acquires resistance that seems to make it more virulent. Next slide. So, I just want to talk about — I’m simplifying
that and hopefully, you know Jacques or Sally and others can talk more specifically about
the mechanisms. We’ve heard a lot about some very detailed
mechanisms early when it came to azole resistance in Canada. But if we break it down to sort of a healthcare-associated
cause of resistance and an environmental cause of resistance, you can see two sort of basic
things emerge. At the top, I’m saying you have a patient
that has susceptible aspergillus, they inhaled it from the environment, but then they go
in for treatment because they have a chronic lung nodule with aspergillus in it, and they
get azoles over time. And we know those patients develop azole resistant
aspergillus being treated chronically with these days, also talking years, and we’ve
described many mechanisms of resistance there. So, they develop this resistance, again in
their lungs while being treated and the resistance mechanisms are multiple, 10, 12 different
mechanisms. The other side of that is the acquisition
of a resistant organism from the environment. So, it starts off as susceptible then these
pesticides, these triazole pesticides that we’ve already talked about, are used. And here we develop a very specific resistance. It’s a tandem repeat, or we would call this
TR, there are two different ones that we see, and it is very specific to this particular
pesticide related use and then patients acquire that resistance from the environment and come
into the hospital with that resistance. Next slide. And so, to illustrate real clear differences
in these two patient populations. I think this slide is really illustrated. You can see a pesticide resistance on one
side of the slide for genotypes and patient resistant genotypes on the other. So, pesticide-resistant, this can be any type
of patient who developed aspergillosis, whereas patient resistant genotypes develop only in
those patients with a lung cavity or who were being treated chronically. The other things that’s interesting about
the azole resistant pesticide genotypes is that two-thirds of them to have zero exposure
to azoles. So, they are acquiring this de novo whereas
all the patients that develop these other mechanisms of resistance have exposure to
azoles. Again, mechanistically, it’s exclusively these
TR mechanisms. Whereas there are multiple non TR mechanism. Multiple 10, 12, 15 different mechanisms in
the patients. The isolates of this pesticide related are
highly genetically related. Whereas their isolates are completely genetically
diverse, what you can imagine because you’re treating patients and they’re developing different
resistant mechanisms. There appears to be no apparent survival disadvantage
or fitness cost to acquiring this pesticide related resistance. Whereas, there is definitely a survival disadvantage
for these other because we know they will revert back if you take them off the azoles. And in Europe, this has really risen to be
the dominant resisted phenotype, this TR resistance, whereas the other types of patient induced
resistance have actually declined in proportion in Europe, and I’m sure Jacques will mention
that. Next slide. So, here, I sort of list to me some of the
evidence that I’ve already stated about why this environmental fungicides Rao has really
led to clinical azole resistance. As I mentioned, most that have this TR resistant
isolates with no history of previous azole therapy, fungicides are structurally similar
as we’ve already talked about. The TR environmental isolates are more closely
related to the TR clinical isolates than they are to other environmental isolates that you
find out there. TR mutations confer resistance to at least
five of these azole fungicides that we’ve been talking about. They confer similar levels of resistance to
Medical azoles that we’ve been talking about. Interestingly, the authorization of five of
the most similar azole fungicides, which occurred 1990, 1997, directly preceded the first TR
isolate that was isolated in 1998. And, again, the global azole usage has increased
really since the 90s. Next slide. And this is just a slide showing you where
people have reported isolation of either a clinical or an environmental TR resistant
isolate. And, you know, this is aspergillus, and so
there’s really no surveillance for this organism. So, you see big swaths that are white and
I’m not clear whether that means they just simply haven’t gone out and looked for it
or it’s not there. Next slide. I also wanted just to show; this is publicly
available data. You can go on the USGS website and find this,
but, to me, this was fascinating and we started looking at siorus, we were actually looking
at this, azole use in our country and it’s fascinating to me how it’s just skyrocketed
in the last 10 years. And I mean this again publicly available data
and you can also look at this actually by state. And it’s interesting, as Dr. Cox was talking
this morning, in his part of the United States, actually, it hasn’t gone up as dramatically
as it has in the Midwest and in the South. So, azole use is much more dominant in other
parts — and you can look at this by state. There are there are these graphs available
online. Next slide. We — obviously, hearing about this azole
resistance in Europe. And, again, I’m not going into the details
of that because I’m hoping Jacques will cover that, but hearing about it, we decided that
we should look and see whether this was a problem in the U.S. or not because, honestly,
when we get an aspergillus patient, we don’t send that isolate for number one speciation
a lot of times, and we definitely never send it for antifungal susceptibility testing. So, if we have patients that are potentially
failing therapy because they’re so sick, we may not know it. And so, we asked clinical labs from around
the United States to just send us their A fumigatuses, you know, without any PIIs and
just a convenience sample so to speak. We found 20 resistant isolates in that collection
of about 1,000, five of which, actually had the TR mutations. Next slide. And published this recently in the MMWR. You can see these seven TR isolates, four
so about the same amount two thirds had no previous azole exposure. Three of them had pretty bad disease and none
of them were epidemiologically linked. Next slide. So, what are we thinking now, at least from
a public health standpoint in the U.S.? We would really like to do surveillance. And so, we need to figure out how to do surveillance
in a field where no surveillance is being done. We’d like to work with others to think about
azole fungicides usage patterns and, again, we’ve been looking online and accessing free
data through USGS and others. It’s interesting, but I think we need to work
with those who are experts in that area because that’s certainly not our expertise. You know, we need to continue to expand our
abilities to do antifungal susceptibility testing. I think the ARLN labs that you’ve all heard
of are potential for some regional capacity, but we need to be thinking about that for
mold not just yeast like we’ve been talking about. And finally, I think from a clinical standpoint. If we need to be aware that these kind of
resistances are going to occur now and in our patients and they’re not responding to
treatment, we really need to be thinking about resistance as a as a possible cost. Next slide. And I think I’ll end there and just remind
everybody that antifungals are antimicrobials too. And I’ll yield back the rest of my time. Thanks.>>Aileen Marty: Thank you. That was excellent Dr. Chiller. And now, we move on to the environment and
azole resistance in aspergillus and Dr. Sally Miller who is a professor of Plant Pathology
and the state extension specialist for vegetable pathology at the Ohio State University.>>Sally Miller: Thank you. I’m very pleased to have the opportunity to
speak to you today about a really amazing and incredible fungus. The more I learned about it and in the preparation
for this presentation, the more I was impressed. I’m the third plant pathologist at your speaking
— or your hearing from today. And we all as plant pathologists, most of
us, live in the mycological world because fungi are the biggest group of plant pathogens. And most plant fungal pathogens do not cause
a problem in people, even immunosuppressed people. Next slide, please. A little bit about the Ohio State University. It’s a Midwestern Public land-grant University,
one of the largest with over 50,000 students. I work on their research, Ag research and
development center in Wooster, Ohio. And I’ve had the privilege of working with
quite a number of health focused people in both my college and the College of vet Med. Next slide, please. Okay, so let’s talk about aspergillus species. They cause this disease. As you already heard from Dr. Chiller, fumigates
is the most important one depending on what you read, but I was particularly interested
also in the flavus and niger and some of the others because, as you’ll see in a moment,
flavus is also a plant pathogen. Now, I will give you a little primer on fungal
taxonomy, whether you want it or not. So, aspergillus is a very big group of fungi
and it’s separated into sections based on morphology historically, but now, it’s genetic
variation that splits different organisms into groups. Now, this remaining aspergillus has been done
on the basis of the animorph, which is the asexual stage. And also, aspergillus is one of the many fungi
that also have a sexual stage that’s called the teleomorph, and this is where it gets
confusing because the different aspergillus species have different genera associated with
their sexual stage. So, this gets quite confusing to all of us. And currently, there is a one fungus one name
initiative, but people are not really buying into it wholesale. So, we’ll continue to hear about aspergillus
and not neos artoria [phonetic sp] or petromyces. Next slide, please. Okay, so we’ll start with a biology of aspergillus. So, aspergillus, the fungi and the genus are
extremely important in the environment as decomposers of vegetation and that’s critical
to carbon and nitrogen cycling. Some of them are weak but very important plant
pathogens, not fumigatus is to my knowledge, but aspergillus flavus is widespread and a
lot of commodities and is particularly important, not just for pre and post-harvest disease
but also because it produces toxins, particularly aflatoxin that causes liver toxicity, liver
cancer, stunting in children, et cetera. And then we have aspergillus niger that also
grows, degrades, and occasionally can be found even on vegetables like the onion. You can probably recognize on the right. Next slide, please. Okay, so one of the amazing features about
aspergillus and why it’s such a problem is that it produces copious amounts of conidia,
which are the vegetative spores and they are resistant to all kinds of environmental stressors. So, they’re resistant to heat and to cold,
to osmotic stress, to high and low PH extremes, drying out and rehydration, low oxygen, ionizing
radiation, UV light — which is also important for reasons I’ll mention a little bit later
— and also starvation. So, fumigatus, for example, has an optimum
growth at 37 degrees C and PH 3.7 to 7.6, most fungi grow better in slightly to moderately
low PH environments, but the growth range pH for temperature and pH as you can see are
quite a lot broader. Now, in the sexual stage this is a heterothallic
fungus, which means it requires two mating types. And so, you can get a genetic recombination,
which is a question we had this morning about these fungi, but these cleistothecia are sort
of the home where the ascospores or the sexual spores are produced, and they are particularly
resistant even more than candida to these environmental stressors. Next slide, please. So where is aspergillus? And how does it behave in the environment? The aspergillus species are ubiquitous; they’re
everywhere. And if you look at decomposing vegetation
of all sorts, then you will find aspergillus is a primary predominant fungi, and they’ve
been found in all kinds of habitats: plants, soil, compost, water, aerosol, animal systems,
indoor environments, and as I mentioned, they’re very important in decomposition. Oh, my time didn’t — okay, in decomposition,
but they also cause problem and product or a structural bio deterioration and food spoilage. How can they do this? How can they bridge between rotting plant
material, or even in some cases live plant material, and survival and causing disease
in humans and animals? It’s because they have an extremely flexible
nutrient utilization pathway. Most fungi don’t consume something and then
digest it. They digest first while secreting enzymes
and then consume the products. So, in this case of aspergillus, it’s mostly
glycosyl hydrolases that break down the plant cell polysaccharides and proteins. Next slide, please. So, I was asked also mention the epidemiology
of aspergillosis and most of the work that I couldn’t find of course is on the human
side, and we would talk about it the community-acquired versus hospital acquired and the community
acquired, this course has become much quite important over the last few years. So, you have airborne and water routes, and
these candida are extremely small, two to three microns, that’s how they can get so
far into a person lungs. But it’s also how they travel on the air currents
for many miles and the fact that they’re so resistant to environmental stressors, including
UV light is that they can go from source to wherever they land in perfectly good condition. They also can settle and then come up again
because they become airborne again. The water route, high candida loads have been
found in surface-water but now groundwater, and they are detected in water in hospitals
and biofilms in the water handling system. And, again, it’s been shown they can be transported
in aerosol due to their small size. There are apparently differences in strains
in their adaptability in these environments. Next slide, please. Okay, so, I have the same slide as Dr. Chiller,
and this is showing the increase in use of triazoles as fungicides in United States. And that started to increase in 2006. In 2007, on corn alone, 11 to 14 of that 76
million acres of corn were sprayed with a fungicide. At that time, their commodity prices were
quite high, and so we also at that time had most of the large crop protection companies
like Syngenta or BS, or Beyer came out with his idea of marketing fungicides for what
they called plant health. And that was encouraging farmers to spray
their soybeans or corn with one of these fungicides to increase their yields, whether or not disease
was present. And this plant health use was registered by
the EPA in 2009, and so that had a big impact on the use of these fungicides. Another thing that had a big impact was the
emergence of U-cerium head scab in wheat, and the triazole fungicides are not only the
most effective, but probably the only really effective fungicides. And this is critical to control this disease
because it’s another mycotoxin producer that’s quite toxic to humans and animals. Okay, next slide, please. So, here, is an indication of triazole use,
and you can see it’s pretty much centered in the Midwest although you have quite a lot
going up into the Southeast, probably mostly on peanuts and various fruits and vegetables
and also in the California and the Pacific Northwest on these kind of crops. Now, how they are used, I can’t really speak
to these other regions but in the Midwest, how these are used is on corn. There’s one application tasseling [phonetic
sp] and it’s usually on triazole alone or paired with another fungicide like, with a
different mode of action like a [unintelligible]. In wheat, it requires one to two applications,
for a head scab it depends on whether one or two or used, depends on the disease pressure,
which is related to weather. Third on soybeans. It’s one application, vegetables and fruits,
as you heard, a similar to the Northeast. There are multiple applications. Some are triazoles alone, but many are combination
project products. In the Midwest, the acreage of fruits and
vegetables are dwarfed by the acreage of corn and soybeans and wheat. Next slide, please. So, are there may be some potential contributing
environmental factors that may affect aspergillus? There’s no data on this that I know of but
going over it I thought these are two issues that could have some roll over the last 15
years because of the changes that have occurred. So, one of them is conservation agriculture
in, which is basically a reduced tillage. So, because of reduced tillage the crop residue
remains on the soil surface. And in the Midwest, corn soybean rotations
or common. Often, wheat is thrown into that rotation,
but these crops are applied, that triazoles are applied to, are often in rotation. Now, these surface residues — oh wow, that’s
all? Okay. Surface residues are known to increase fungal
diseases. And so, the question is are there greater
exposure to fungicides by aspergillus that may be on the surface residues? Also, climate change may have a roll. Next slide, please. Now, I want to take a moment and just talked
about the possible mitigating factors. There are certain factors that may reduce
exposure of aspergillus in the soil or on the surface, two of these triazoles. One is that the corn and soybean crop canopies
are closed when triazoles are applied, so they do not penetrate to the and the soil
surface. Now, that is not the case in vegetable crops. Next slide, please. Another economic factors that the plant health
applications are not used as much when corn and soybean prices are low. So, research has shown that his kind of applying
one of these fungicides for corn, in the absence of disease, the recovery of cost doesn’t happen. So, I think hopefully we’ll see less of that,
and then we have chemical factors such as combination products. In fact, can you reduce the development of
resistance by, and we heard about that in New York with the partner fungicides. Next slide. Lastly, what can we do to reduce on this risk
of environmental azole resistance in aspergillus? Primarily, utilizes integrated pest management,
high varieties with high disease-resistant, cultural practices that Dr. Cox mentioned
earlier, and only applying fungicides when they’re warranted by using economic thresholds. And that’s zero. So, I’ll close there, thank you.>>Aileen Marty: Thank you very much Dr. Miller. And now we move on to Dr. Jacques Meis, on
emergence of azole resistant aspergillus fumigatus and at One Health. He is the deputy director of the Center of
Expertise of Mycology and a consultant at the Department of Medical Microbiology and
Infectious Diseases at Kansas Wilhelmina Hospital, both in the Netherlands.>>Jacques Meis: Thank you. Dr. Marty, members of the committee, it’s
really a pleasure to sit in front of the presidential advisory committee. And what I will do in the next 15 minutes,
I will actually summarize an editorial, which I wrote last year about this topic, this specific
topic, and I will go a little bit deeper into the slide switch Tom Chiller just mentioned. I’m from — next slide, please. I’m from Nijmegen, you can actually see in
the spot. It’s actually — Netherlands is a very small
country, and we are, of course, always the second. But in this case, we have one center of expertise,
and from there we serve the whole of the Netherlands. We do all the consultations for all the difficult
fungal infections, in cases of diagnosis, and they’re treatment. Next slide, please. Next, slide, please. So, how did it all start? It’s about 20 years ago that we discovered
that it was an increase in azole and clinical azole resistant aspergillus [unintelligible]. And as you can see in the slide, in 1999 there
were barely resistance and then from 1999 onwards until now, 2018, it was a steady increase
in clinical azole resistant aspergillus [unintelligible]. These are cultured collections, which are
kept and tested in batch. As you also can see, and Dr. Chiller mentioned
it, it’s actually only one, the majority consists of one type of resistance, and that’s the
TR34L98H mutations. And, now, or last year, 2018, it was above
10 percent in this center. Next slide, please. So, this resistance mechanism consists of
a tandem repeat in the promoter of this SIP51 A gene as you can see here, and this repeats,
which was shown in uses the reading of first SIP51 A. We now, have also a TR96, TR 120,
so this promoter can duplicate itself and becomes even more effective in resistance. Next slide, please. So, Dr. Chiller spoke of the lack surveying
in the United States. In the Netherlands, as you know, is a very
small country, so we can do that and since 2013 we are doing surveillance for azole resistance
and it’s actually included in the in the next map and that’s the surveillance system for
antimicrobial agents and also for antimicrobial resistance among bacteria in humans and in
animals. It’s a book every year. This just came out two months ago — about
one month ago, and you can download it from site, which is down there. It’s a book of 213 pages and 4 pages are devoted
to fungal infections, not to candid but only to aspergillus. And only clinical aspergillus isolates are
included, not environmental isolates. And I really liked the suggestion of Dr. Chiller
that it’s also important to look at the environment because that’s where it starts. Next slide, please. This isn’t a table from this report and the
surveillance was done in five University Medical Centers, and they tested all the clinical
aspergillus fumigatus isolate for resistant and sent them all to our reference center. As you can see, there was a steady increase
from 2013 almost to 2018. In 2013, there was about 7.5 percent resistance
among all these five University Medical Centers. And in 2018, it increased to almost 15 percent. I put there a red line, that’s the University
Hospital in Leiden. And Leiden is in the western part of the Netherlands,
very close — next slide, please — very close to the tulip fields that you are, the center
is really surrounded by agricultural areas and most of them are tulip fields. And most plant pathologists know that if you
want to grow to tulips, you need a lot of fungicides to keep them nice and healthy. Because fusarium, for example, are taking
those beautiful tulips, therefore a lot of fungicides needs to be spread. By doing this, you also attack with the fungicides
the aspergillus, who is just an innocent bystander sitting there waiting to clean up the mess. And it’s been sprayed by fungicides and starts
to get stress reactions. And these stress reactions means that the
fungus becomes a resistant. Next slide, please. So, we think that azole resistant aspergillus
fumigatus is just a side effect of an environmental fungicide use in the environment. As you can see, the plants need protection,
but also hotels, the hotel which we stay in, is also full of fungicides in the material,
the walls. That’s necessary, otherwise the fungus will
destroy the homes. So, the suggestion that is a kind of relation. I was talking about the TF34. It’s another very important resistant mechanism,
it’s called TF46. Can I have the next slide please? TF46 is exclusively associated with foreign
azole resistance. And about 10 years ago, you suddenly saw several
patients with this new, at that moment, new resistance mechanism, and you can see in all
the centers patients were involved. Next slide, please. So, to look where it would have come from,
we went to the houses of the patients involved, which were colonized or infected, and we sampled
the hospitals with air samplers. Next slide, please. And guess what, everywhere we found this resistance
mechanism, in the kitchens, in the living rooms, in the backyards, where the patients
lived, but also in the hospitals, in the walls, and in the hallways. More than 15 years ago, I walked into my hospital
with an air sampler, and when I came back, I had this TR34 growing in the place. So, this means that azole resistant aspergillus
fumigatus spores are everywhere, and especially in places where there is a lot of induction
of this resistant. In my hospitals, actually, at the east of
seeing it — at the east of the country, their resistance is much lower because there is
less agriculture than in the western part of the Netherlands, so, there is a relation
between agriculture and the prevalence of azole resistance. Next slide, please. Well, this is the — I mean, the plant pathologist
spoke a lot about the fungicides, the demethylation inhibitors, and this, actually the demethylation
inhibitors, which have been registered in the Netherlands since the 1970s. And you can that there are five high tech,
high generation [phonetic sp] azoles registered from — and used from the beginning of the
90s, propiconazole, tebuconazole, bromuconazole, all in the first half of the 90s. Next slide, please. And it was also not a surprise to us that
the first isolate in our country in the patient was found at the end of the 90s. These five azole fungicides have a very similar
structure as medical azoles, and they have a very high potential to select the TR34 and
the TR46, mutants out in the in the environment. Next slide, please. So, this is actually simplified [unintelligible]
is continuous pressure of these demethylation inhibitors from the environment and aspergillus
fumigatus has to adapt to survive. So, it started with the TR34, then we have
just the TR53, TR46, and nowadays you find many, many mutations in the environment and
also in patients. I just mentioned the TR30, 92, TR138, so aspergillus
is all the time adapting to this continuous pressure of these fungicides. Next slide, please. This is — what actually the situation is,
you have the environmental route; Tom Chiller just discussed it. Spores are everywhere and if you have resistant
spores, you can get an infection without having been treated with azoles before. Most patients are azole na�ve. The other route is in the patient you have
chronic pulmonary aspergillosis, you give long term treatment, and then you kept the
typical patient root of resistance development. Next slide, please. So, what are the clinical implications of
azole resistance, as Tom just discussed it? If you have an infection in an azole resistant
aspergillus, you have 30 to 40 percent chance of — a higher chance of dying than if you
have an infection with a susceptible azole. But the most important part is, how is azole
resistance selected in the environment? Where is the selection going on, in the fields? What are the places? Next slide, please? And it’s applied in the fields are the plans,
but the remnants, the biomaterial, the organic waste, is collected and put in, so called,
compost heaps. And you remember these fungicides, which are
sprayed, they can be present in the environment for up to a year. And [unintelligible] presence in this compost
heap we ask if aspergillus fumigatus is doing its job by cleaning up the organic material
there. Probably, the resistance is developing. Next slide, please. So, this is a paper that was just published
last week, in Emerging and Infectious Diseases, where a group of Dutch researchers did this
study, which was actually supported by Dutch Ministry of Agriculture. They looked at the hotspots where there’s
typical resistance was going on. And they looked at the compost heap form areas
where there was a lot of spraying and the compost heap where there was almost no azole
use. This is what they found. Next slide, please. If they had a compost heap where there were
remnants of azoles of fungicides, then there was a very, very high chance that most of
the aspergillus isolates culture from these heaps were azole resistant. If there were no fungicide remnants in the
heaps, the chance was very low. So, this is a way of suggesting that there
are hotspots which can contaminate the environment. And if you’re able to eliminate these hotspots,
then maybe the burden of azole resistant aspergillus could be lower. Next slide, please. This is a slide showing the worldwide azole
resistance and the market share of friendly sides and here the U.S. has 9 percent but
this is, I think, from the 90s and in the U.S. the fungicide sales and use is only a
recent phenomenon, maybe 15 to 16 years later than in the Netherlands. As you can see, Europe has a high burden of
resistance. Almost every European country has problems
with azole resistance and there is also high market share of fungicides. The same is true in Asia — Asian countries
and in Latin America. So, this is also suggestive evidence that
there is something, there is a relation with the environment and the emergence of azole
aspergillus infectious. Next slide, please. So, the European Center for Disease Prevention
and Control, the CDC of Europe, had already a meeting, something like this, many years
ago — six years ago. And there, it was identified that azole resistance
aspergillus and the possible environmental origin of this was probably going to become
a public health threat in the future, and they recommended that increased variance and
resistance detection in hospitals was the number one priority. Unfortunately, it only stayed with paper. Nothing happened in these years and the environment
— next slide, please. The environment is still very, very neglected. We have now stewardship in hospitals in the
last five, six years for antifungal drug use, but the antifungal drug use in the environment
is still really underrepresented. And
environmental resistance is really part of the one held, which is also concerning us. Thank you very much.>>Aileen Marty: Thank you so much Dr. Meis. Now, I’d like to open it up to questions from
our members, from the council members. And if you could please put your tents up,
so that I know who has questions. In the meantime, I’ll go ahead and take advantage
and ask a few questions myself. Dr. Chiller, among the many wonderful things
that you mentioned, you mentioned that patient resistance seems to happen when the patient
has a cavity. So, that’s indicative that there’s a certain
environment, a microenvironment, that promotes the resistance, and I’d like you to speak
about that. And before you do Dr. Miller, again, thank
you all for your fantastic presentations. You spoke about the use of these agents for
plant health, and you indicated the fact that has had a very negative impact. Right? And you stated that plant health application
is not consistent with IPM and I of course agree. So, my question to you is do we need policy
that would ban the use of fungicides, specifically for this purpose? And meanwhile, back to Meis, I have a question
for you. You noted that there are specific fungicides,
and you listed a number of them, that pose the highest risks for creating resistance. And would you advise that those particular
ones be withdrawn in favor of fungicides with lower risk? So, we’ll start again with Dr. Chiller.>>Tom Chiller: Yea, thanks. So, basically, what we see is that patients
that have something we called chronic pulmonary aspergillosis, which is often cavitary, where
they essentially have either a fungus ball or they have fungus that’s growing in their
lung that requires often years if not lifelong therapy with an anti-fungal to sort of keep
that in check. Those are the patients that will develop,
essentially in situ resistance in their own body. So, that’s the kind of clinical resistance
that we see develop from use of the antifungal in the patient. And the resistance mechanisms, as Jacques
also described, are very different than these TR, that we’re calling to tandem repeats,
which we really see uniquely coming from the environment. And so, that’s what I was referring to by,
and these are very, this if it’s a very specific group of patients. So, the patient who has a bone marrow transplant
develops invasive aspergillosis in the hospital those patients don’t develop resistance on
therapy, they generally respond or don’t based on sort of their host immune system, and we
don’t see them developing resistance. It’s those patients that have this chronic
form of aspergillosis, which requires years of therapy and there’s a particular Center
in Manchester, England that has a lot of experience with treating is a lot of the data comes out
of that Center in Manchester.>>Aileen Marty: Thank you so much.>>Sally Miller: So, the question was about
should the plant health use be not allowed in agriculture. I think there are a couple factors, one is
that first, I think you would be hard-pressed to find an academic plant pathologist who
was in favor of the plant health application for various reasons, again, not IPM compatible
and also can be economically not sustainable. I think an argument would be against banning,
so the speak is that we don’t know that if corn and soybean fields are a hot spot as
Dr. Meis has mentioned for aspergillus resistance to azole. For some of the reasons I mentioned, we don’t
even know if the triazoles get down into the surface on the soil. So, I I’m going to be very waffely [phonetic
sp] here and not come out either way.>>Jacques Meis: If I remember well your question
was, these five azoles, which I mentioned which were probably involved, why don’t we
ban them and then the problem might be solved? Well, that is a very good question because
there are between two and 300 fungicides out there for a plant pathologist to treat the
plants, and the human medical profession has only one azole — I mean, we have a few azoles,
but they all have the similar structure and these azole fungicides have exactly also the
similar structure, so they can induce the resistance, which is also later seen in the
human. So, the question is why, because I think those
azoles are very, very good. They work very, very good to humans, but also
very, very good in plants, and why shouldn’t you take the best drug for your plant disease
and leave all the other 200 behind. There’s one remark that I would like to make,
and that’s from the previous session, where one of my colleagues from plant pathology
said, “We cannot go back to the older drugs because we haven’t used them for a long time. And now they aren’t effective as they were
20, 30 years ago.” They have a chart of more than 200, so there
should be some choices, and that’s my opinion, but otherwise, everybody wants to have the
best drug. And that’s reasonable I would say.>>Aileen Marty: Thank you, Thank you. Rama [phonetic sp]?>>Male Speaker: Thanks for those excellent
presentation. So, actually one question which probably Dr.
Miller can address, I thought it was interesting this point about climate change and that areas
that were wetter would probably have more need for fungicides as we went forward. Is there any sort of — I mean, presumably
the areas that will also be more dry than in the past, so I’m guessing it doesn’t necessary
go in one direction. But on aggregate, is this something that you
think is going to be a major driver of users of fungicides going forward? And are there any modeling estimates that
that are available that might indicate how much that’s going to increase? And a second point was on — well, I guess
with human infections, when someone has a viral infection then there’s an increasing
risk of secondary bacterial infection for instance. So, there’s sort of a hit on immunity and,
you know, everything sort of piles on. Does that happen for plants? So, when you have a fungal infection does
that also predispose that crop to sort of other microbes, which then means that you’ve
got to pay attention to what else you’ll be doing in anticipation of reduced plant immunity.>>Sally Miller: Okay. So, the first question was about climate change. And, yes, we do feel that the results of climate
change where you have not just increased precipitation, but the intensity of those events are encouraging
a many different types of fungi because most of them almost all but not quite all are promoted
by rainy, humid conditions. So, yes, there would increase use of fungicides
to protect crops, fusarium headlight is a good example. And the fusarium, that diseases is more critical
when you have a wet spring. So, yes, I would expect that maybe you would
use one or two triazoles because those are the only ones that work, instead of none in
the season that’s fairly dry. So, yes, I think that would, that is definitely
a potential issue with climate change. Now,an aspergillus, for example, becomes worse
on as a plant pathogen flavus on corn free sample under hot dry conditions. So, when the plan is stressed it’s more likely
to cause a problem and tag that plant. So, either way dry conditions — but if they’re
more dry you wouldn’t necessarily and generally use more fungicides, but you could have other
issues with reduce crop yields. What’s the other question — what’s about
it — plant immunity. Generally, it’s believed that plants that
are under stress are more susceptible to disease, and so when plants have a fungal infection,
they are sometimes followed up by secondary fungi or bacteria that often that hastened
the demise of that crop. So, yes, that can be an issue also.>>Aileen M. Marty: Thank you, Angie?>>Female Speaker: So, Dr. Meis, I find your
— the comments that you made about why don’t you just quit using azole was interesting,
and I would think that since the data that you showed that the more they’re in the environment,
like, they’re in their pot — in the piles, the fermenting piles. You see resistance. If they’re not, you don’t. And that it’s the same mechanism can lead
to resistance in human azoles. But can you give us a perspective? Because I’m thinking you’ve got to balance
taking azoles out of the picture with what you would do to the economy of the Netherlands
if you didn’t have tulips. And so, are there other ways to — I mean
it seems simple to us. Right? Our whole life doesn’t depend on growing tulips,
but it’s quite complicated. And are there other ways to go about this,
and if you really did take those out of the armamentarium, would that crop be destroyed
or are there other clever ways that you could still do it, it’s just more expensive or more
challenging?>>Jacques Meis: I can tell you that the tulip
growers are fighting these theories, of course, and I also have to say that they’re willing
to do more research. And that’s what you do if you want to delay
a bad decision, but they sponsored the study on what are the hotspots. So, what you can do, you can you can spray
them, but don’t remove — or don’t use the debris. Destroy it, burn it, get rid of the potential
hotspots. That’s, for example, now, a potential way
to look at it. Even if you compost, then do it properly. Composting, the temperature in goes very,
very high inside the compost heap. It can go up to 70, 75 degrees. And there, even the [unintelligible] aspergillus
are dead. So, there will no aspergillus grown after
a proper composting process. That’s also one of the conclusions that they
made. So, there many ways to come together, I mean
I think it’s very difficult to say we should ban then that’s — like we did [unintelligible]
in the chicken industry in the 90’s because of the selection of [unintelligible] and all
kinds of resistant. That was easy because those animals, they
didn’t get — they only got it for growth promotion. And I was surprised to hear that you have
also something like this in plants. Even if the plants are not diseased, you just
give fungicides just for maybe they become even bigger or larger. So, these are things which you should think
about to — these things should be banned of course, but if the plant is diseased, then,
yeah, you have the best drug, then it’s difficult. I think we need some — we didn’t do any research
on this topic. And exactly as here in the U.S., when we apply
for research for this work, we don’t get anything. It’s all going to antibacterial resistant. Although, I said before to somebody, in the
Netherlands, we don’t have antibacterial resistance. Still, they put in so much money. But they still treat our patients with penicillin,
cefazolin, and cefotaxime. We don’t need all these high-tech drugs. We have no amorazeh [phonetic sp], we have
no bacterial infections. And patient don’t die of bacterial — of resistant
bacterial infections in my country, they die of resistant fungal infections. And that’s not grabbed by the people. So, it takes some time to get it into their
heads. And I’m really happy the U.S. is now leading
again. And when it’s here in their heads, the Netherlands
will follow for sure.>>Aileen Marty: Thank you so much Dr. Meis. That’s extremely important comments. Okay, Christine.>>Christine Ginocchio: Thank you. So, I have a more general question for the
panel. So, when we take a look at diagnostics, say,
for fungal resistance, most laboratories, at least in the U.S., don’t do susceptibility
testing for aspergillus. It’s just — it’s just way, way too difficult
to do and to interpret. So — but we do do multiplex PCRs, a lot of
the big labs do whole genome sequencing. We can do all of this. So, how well does a genotypic profile correlate
with phenotypic susceptibility? And if we say only looked for — what is it? The TR mutations, which you could probably
easily detect, you only have a handful of them, what other percentage of mechanisms
would we be missing if we, say, only identified those as far as resistance in this class?>>Jacques Meis: Well, in Europe, we have
commercial tests to look for a non-culture-based diagnosis of invasive aspergillosis. And there, there are four targets, which are
included — which give about — which cover about 80 percent of the resistant. It’s mostly the TR34 and 220 of some [unintelligible]
mutations. But there is, of course, a proportion of 20
percent, where the resistant is not based in the SIP51 A, but it’s somewhere else. It’s multi-drug effects problem and so on. So, you will miss about 20 percent of injections
which are resistant, but where you don’t find in mutations. To say one word about this culture, I — every
American always asks — says the same and asks me. And I really don’t understand, because what
you can do is just have a plate, put in some fungicides in it, and just, if you go in aspergillus,
put it on and see if it grows or not. If it grows, then it’s resistant, if it doesn’t
grow, it’s not resistant. [laughter]>>Christine Ginocchio: Well, and the U.S.
is not that quite easy with regulatory — [laughter]>>Jacques Meis: This, actually –>>Christine Ginocchio: — but we wish we
could.>>Jacques Meis: To be clear, this is a test
which is not recommended by SMed [phonetic sp], it’s in the latest guidelines of aspergillosis. This was just put in the requirements to do. If you culture aspergillus from a patient
which is suspect of having an infection, do this. If you cannot do MICs — we do MICs — but
if you cannot do it, do this. Everybody can do it. And maybe here, the FDA comes in and — [laughter] — that you cannot do it. Like, for candida auris, until one year ago,
I heard that in the U.S., you were not able to use the MALDI to identify candida of — and
say it’s ours. Because it was only FDA approved on year ago,
this MALDI. We were doing it already for the last 10 years. And to be honest, I don’t understand this
–>>Christine Ginocchio: [affirmative] We have
a little bit of different regulatory requirements, but I mean, I agree. But in most everyday laboratories, even diluting
drugs and putting them in plates and growing things is not always that simple.>>Jacques Meis: Combine them, if you can
do molecular test, you buy the place –>>Christine Ginocchio: PCR is easy. That’s a little bit harder.>>Jacques Meis: Sorry?>>Christine Ginocchio: I said for us, PCR’s
a lot easier than to do, sometimes, things along that line. But — so, you’d say about 80 percent, we
could get genotypically –>>Jacques Meis: Yes.>>Christine Ginocchio: — with the resistance. Okay.>>Jacques Meis: At least in Europe. I’m not sure what the epidemiology is here. Probably, you have also a lot of –>>Tom Chiller: We don’t — we don’t know
a lot of the epidemiology, obviously, because we don’t have — we don’t have surveillance
to look at the — honestly. And his — one of his colleagues in Nijmegen
has developed this really nice plate assay, that — where it’s four compartments. And he’s starting to commercialize that. And that’s what we’re using in the United
States, in our lab, to at least do some convenient sampling, do convenience surveillance. And so, I think that may be able to be made
available because it’s just, as he said, it’s a simple — I mean, what we’re worried about
right now is voriconazole resistance, really, in our aspergillus, right, because that’s
our first-line therapy and it works really well. So, I think that we’re sort of contemplating
how we might make that more widely available, at least in, maybe, regional labs. And maybe then it can trickle down to other
labs, et cetera. But so, it’s an active discussion, it’s a
great question. I wish we did have better sort of genotypic,
phenotypic comparisons that we could easily do, but there are more and more of these TR
mutations popping up, as Jacques said. And so, I think we question what is our milieu? And then so how would we look for it? And I think, honestly, just throwing it — you
know, putting in a structured voriconazole culture environment might be the best way
to go for clinically screening, so you can help your clinician to the right thing.>>Christine Ginocchio: At least to do an
initial screen.>>Tom Chiller: Yes.>>Christine Ginocchio: I think people would
be more than happy to do it if we had a convenient tool that was, say, FDA-cleared or whatever,
exactly for that, yes. Female Speaker
Thank you all for those extremely informative comments. We’re running very short on time, but we do
have three more questions very quickly. Marty?>>Martin Blaser: Yeah, I just want to mention
that we’ve been talking about the field of one health for a long time, humans and animals. But maybe we need to include tulips and plants
as well. I’m only half facetious in this regard. So, what did — what did the tulip — what
did the tulip growers do before azoles were invented? How did they control fungal pests beforehand?>>Jacques Meis: I think they had lot of fungicides,
but before that time, they had — the tulip were rotten. I mean, maybe 50 percent of the crop were
saved, and the other were gone.>>Martin Blaser: It was that high?>>Jacques Meis: [affirmative]>>Martin Blaser: I mean — [talking simultaneously] — just today, we’re talking about two medically
important fungi, sedoris and aspergillus. There’s no indication that this will be the
end of resistant fungi.>>Female Speaker: Okay, thank you. Okay, Aileen?>>Aileen Marty: Sure. Dr. Chiller, you made a comment, and I want
to make sure I understood it correctly. And if so, I’d like you to expand a little
bit. Did you not say that there are antifungal
agents in the walls and in the hotels and in our homes? And if so, would you please expand?>>Tom Chiller: That was actually Dr. Meis
who said that.>>Aileen Marty: Well, there you go.>>Tom Chiller: So, I’ll let Dr. Meis explain
that.>>Jacques Meis: It’s called material protection,
and it’s commonly used — fungicides are commonly used in wood and all kinds of — and paint. It’s used everywhere.>>Aileen Marty: Any further comments about
what the implications are of that, if–>>Jacques Meis: Well, if the wood, for example,
be a water leakage, and there’s a high concentration of fungicides in there, and aspergillus would
come in there, it could be — become, potentially, a hot spot. Just fantasizing, but that might be the case.>>Female Speaker: Okay, we have time for
just one more question. David.>>David White: Great, thanks. And I’ll try to make it very quick. I’m wondering if there’s an opportunity to
bring in principles of risk analysis into how antifungals are used in agriculture, much
like how we did with FDA, with veterinary drugs, Guidance 152, that looked at the importance
of these agents to human medical therapy. So, there’s so many anti-fungals out there,
you could take a look and say, well, you know, azoles, obviously in FDA, they’re critically
important, highly important, and important, compared to medical drugs. Is there an opportunity to do something like
this for all these antifungals and try to rank them in terms of cross-resistance to
a human medical drug?>>Jacques Meis: I completely agree that there
should be more input from the plant pathologists as well. And I think they do, already, a lot. I just saw, about last week, a paper from
the U.S., where they developed a test to — that the farmers can, if they suspect the form
of infection and they can send it quickly for a molecular test. And they have, the next day, they have the
species and which antifungal they should spray to prevent more spreading. I think that’s the way to do it, targeted
therapy, not spreading everything, but targeted. Just do a diagnosis and then do it. Not — and that’s, I think, what this — what
some plant pathologists are doing right now. But I agree, you should take more opinion
from plant pathologists who are actually doing this work.>>Tom Chiller: And I would just, to comment
on the Guidance 152 idea, I mean, it would a lot easier because we basically have three
classes. And so I think that that’s something that
we’ve been talking about, thinking through a little bit more with this, and certainly
with the azole class at least, and thinking through how — you know, I always — you know,
I always think that, as you know, David, it’s a balance, and these are wonderful drugs as
pesticides. And we have to figure out how do we use them
judiciously, or not at all in certain — with certain ones, or in certain situations in
others? And I think the real challenge will be if
the — let’s say if in the Netherlands, they pull all these drugs from tulips. And they already have resistance levels of
20, 25 percent. And I’m just wondering if those will even
drop or not, in your clinical situation. I mean, if they were to drop, you know, as
we saw in some of the bacteria, you even — even pulling drugs from certain markets didn’t
change the resistance much because once it was established, it was there. I do not know if that’s going to be the case
in aspergillus –>>Jacques Meis: Unfortunately, the fitness
cost of these TR34 mechanism is zero. So, they are exactly as the [unintelligible],
they will not go away. That’s the very unfortunate thing. But, I mean, fitness costs for efflux pump
inhibitors that’s one. If you pull away the drug, then they will
refer to [unintelligible], but not with the TR, tandem repeat, imitations. That’s — they will stay there forever.>>Female Speaker: Produced by the U.S. Department
of Health and Human Services at taxpayer expense.

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