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Think Fungus, Part 2: Aspergillus, Ringworm · Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner

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I'm Holly Wayment and this is Pediatrics Now, cases, updates,
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and discussions for the busy pediatric practitioner.
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Click on the link in this podcast for free credit that may include CME,
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MOC, or ethics credit, depending on our topic or podcast.
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Today, I'm joined by Nathan Widerhold, PharmD, Professor of Pathology and Laboratory
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Medicine and Director of the Fungus Testing Laboratory at UTHealth San Antonio.
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Dr. Widerhold is also a pharmacist and an internationally recognized expert
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in medical mycology, whose research focuses on antifungal resistance,
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emerging fungal pathogens,
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and the development and evaluation of new antifungal therapies.
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Dr. Widerhold, welcome to Pediatrics Now. Thank you for having me.
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Let's talk about aspergillus and when to think fungus.
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What does the practicing pediatrician need to know about aspergillus and antifungal resistance?
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So aspergillus, these are ubiquitous fungi, meaning they are found everywhere in the environment.
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You know, with it being nice, hot, and humid, you and I have probably breathed
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in some aspergillus spores into our lungs. But we're relatively healthy individuals.
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Our innate immune response can take care of that. We don't have to worry about that.
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Aspergillus really becomes a problem in patients who have profound immunosuppression.
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And so these are patients who have no white blood cell counts.
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High-dose corticosteroids receiving some very cytotoxic chemotherapy.
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So these are very rare infections when you think about the general population.
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They don't cause problems. Where we really start to worry about them,
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again, are very highly immunocompromised individuals.
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And we see them primarily developing in the lungs. Because as I said,
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you and I have probably inhaled some spores into our lungs, And so that's the
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portal of entry for this type of fungus.
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In the United States, we don't have a huge problem with antifungal resistance in Aspergillus.
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The species we typically worry about the most is called Aspergillus fumigatus.
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There is well over 200 different Aspergillus species, but the one that we primarily
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see in humans is called Aspergillus fumigatus.
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Again, in the United States, our resistance to a class of antifungals called
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the azoals is very low, maybe 5% or less.
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In different parts of Europe, though, it's much more of a problem.
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In some institutions, it's reached as high as 20% resistance to that particular class of drugs.
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And so, but it's something we're starting to kind of become more concerned about over time.
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Because while we have a lot of different drugs for, well, not a lot of different
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drugs, our drugs are limited for Candida R.S., they're even more limited for
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molds, infections such as those caused by Aspergillus species.
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What is Aspergillus? So aspergillus is what we like to refer to as a mold.
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And so in general terms, we like to classify fungi based on some very general characteristics.
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You have your yeast and you have your molds. Your yeast, like candida auris,
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if you have it growing on a petri dish, it kind of looks like bacteria.
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It's not, but it kind of looks like that.
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Your filamentous fungi are your molds. Think about that, what might be growing
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on your bread in your kitchen when it gets a little old, kind of like fuzzy and stuff like that.
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That is a filamentous fungi. That's a mold. Aspergillus falls into that big category of a mold.
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Wow. And as we know, mold is scary. So can you give us some more examples of
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where you would find this aspergillus?
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Sure. So it's ubiquitous in the environment.
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And so aspergillus you can find on a lot of different decaying organic material.
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And so one of the places that we've recognized that it kind of is a hotspot
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for aspergillus is in compost piles, you know.
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And so, for example, after a crop has been harvested and they're kind of taking
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the remnants and they're putting them into compost piles and that plant material
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is starting to degrade, that's where aspergillus likes to be.
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That's kind of its role is to help break down decaying organic material.
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Let's make this very practical. Is there a clinical scenario where a child isn't
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improving and you would want the pediatrician to stop and say,
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could this be fungal? What are the clues?
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So, yeah. So, one of the things that oftentimes happens is clinicians think
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bacterial infections first.
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Bacterial infections are oftentimes easier to diagnose, and we have a lot more
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antibiotics available to use.
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Unfortunately, when patients don't respond, then they start to think different
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things. Could this be viral? Could this be antibacterial resistance?
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Or could this be some type of fungal infection. And oftentimes,
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patients then go untreated with an antifungal, if it is a fungal infection,
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until the disease really becomes established.
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What are you the most optimistic about? What am I the most optimistic about? That's a good question.
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Let's talk about something optimistic. Sure. So one of the things that you mentioned
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at the beginning that our lab is involved with is in the evaluation of
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novel agents, either in the preclinical arena or,
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in clinical studies that are moving forward to hopefully being approved by the
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FDA and other regulatory bodies for use in humans.
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Right now, we have two promising agents.
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One that has completed a phase three
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study, and the results have been very promising, is called Allorafem.
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And that has great activity against aspergillus and other types of molds.
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Unfortunately, it has no activity against yeast like Candida auris.
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But still, it's going to be an improvement to our antifungal armamentarium,
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if you will, because it has activity against a lot of more rare molds that we
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have very few, if any, treatment options.
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Then there's another study that is currently in phase three clinical trials
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that has very broad spectrum activity. It's called Fosmanogepix.
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It covers Candida auris. It covers the azole-resistant aspergillus.
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It has a very broad and potent spectrum of activity.
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There's only a few things it doesn't cover, but we're really looking forward
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to both of those agents, hopefully within the next one to,
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hopefully not three years down the road, but sooner than that,
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becoming approved and available for use in these very difficult-to-treat patients.
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There's even some other agents as well that are in development.
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One is a drug that falls into the class called the polyenes.
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And so one of the oldest drugs that we've had to treat fungal infections is called amphotericin B.
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Now, clinicians like to refer to it as either amphoterrable or awfultericin
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because of all the adverse effects and toxicities that it causes.
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This is a new drug, is kind of a modification of amphotericin B.
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It's in a class called the polyenes, but the developers have made some chemical
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changes such that it avoids the big toxicity that we've seen with amphotericin
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B, at least we are thinking it does, in the limited number of patients.
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And that's the nephrotoxicity or the damage to the kidneys that is done by amphotericin B.
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It seems, again, and at least in the limited data that's available,
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that this new drug doesn't have that nephrotoxicity.
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And so that would be great because it's a very broad spectrum and potent agent.
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So that we make sure and cover this, I know we've touched on this,
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but if a pediatrician does suspect a fungal infection, what should happen next?
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What testing matters and when should
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infectious disease specialists or a specialized lab become involved?
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So trying to get an early diagnosis is probably the most important thing.
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If you don't know what you're treating, then it's hard to know if you're treating with the right drug.
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And so getting the lab involved, letting them know you might be suspecting a
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fungal infection because certain types of specimens for fungal infections have
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to be handled a little differently than specimens that you're just worried about a bacterial infection.
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Ordering the right types of tests and making sure the lab knows to run those
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certain diagnostic tests is important.
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And then if patients are failing therapy, even before antifungals are started,
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it's a good idea to consider getting an ID consult, especially in some of these
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patients with multiple risk factors for fungal infections.
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They're difficult to diagnose and they're difficult also to get on the right drug.
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You direct the Fungus Testing Lab here at UT Health San Antonio.
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What actually happens when a difficult fungal isolate reaches your laboratory?
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What are you able to learn that clinicians may not be able to determine from
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routine testing? Sure. So we're a reference laboratory.
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And so we have a unique group of individuals who are highly experienced in working
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with different types of fungi.
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So we are able to do species identification. It's actually kind of a dying art form, if you will.
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We have some very capable people in our laboratory that are able to do this based on the fungus's
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morphologic and phenotypic characteristics, as well as some more advanced molecular
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techniques in order to identify exactly what fungus it might be.
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There are diagnostic assays that are able to kind of,
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identify and diagnose the more common types of fungal pathogens,
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but a lot of these things can't be diagnosed in your routine clinical diagnostic laboratory.
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In addition, we have a lot of experience with what we call antifungal susceptibility testing.
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This is when we are taking the organism and testing different types of drugs
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against it to see if resistance may be there or if it is fully susceptible to different agents.
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And then last but not least, we do what is called therapeutic drug monitoring.
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And so patients who are on antifungals, oftentimes the clinician will get a
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blood sample and then send us either the serum or plasma to measure the concentration
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of the antifungal within the bloodstream.
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And that information that we provide back to them helps them to determine,
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hey, I need to increase the dose currently at a subtherapeutic level.
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Or, hey, this level is very high and that might be causing some of the toxicities
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that I'm seeing in my patients.
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And so it really helps to tailor a drug regimen for an individual patient.
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So it's truly individualized medicine at that point. Wow.
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And how would pediatricians or clinics in general, doctors in general in the
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area, what is the best way to contact your lab?
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So they can call us if they have questions about a specific fungus or a drug.
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We're on the phone constantly with clinicians. Look up UT Health San Antonio.
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Yeah, UT Health San Antonio. Fungal lab.
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Fungus testing lab. Fungus testing lab. It's the only one that will come up.
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It's one of the top ones, yes. So that or they can contact their clinical micro lab.
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A lot of the clinical micro lab directors are in contact with us on a fairly
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regular basis, asking about some testing that we perform or what does this result mean.
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And so we're able to talk to anyone and everyone who gives us a call,
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whether it be the clinician treating the patient or the folks in the lab who
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have questions about the specimens that they're handling.
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Do you want to say anything, Nathan, about the process that we hear about spraying
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the crops, antifungal, how that is also creating more problems?
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Sure. And so to kind of give background, antifungal resistance,
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we've kind of learned, can develop in two major ways.
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There is clinical exposure, just like with a lot of antibiotics.
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Antifungal resistance can develop in a patient who's receiving either the wrong
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drug or the wrong dose of a drug.
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Definitely can occur with Candida auris, can definitely occur with Aspergillus.
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One of the things we've learned over the last two decades is that we also have
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to worry about environmental exposure to antifungals.
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So there are a lot of fungal, different fungi, that are not only capable of
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causing disease in humans and animals, but are also major plant pathogens.
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Aspergillus is not a plant pathogen, But we use antifungals on crops to try
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to fight some of the fungal plant pathogens.
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And this goes back to the aspergillus liking to be in the compost heaps, the compost piles.
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So one of the major classes of fungicides that used are azoles or azole-like compounds.
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And they have a lot of similarities to the azoles that we use in humans.
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They're not the same drugs, but structurally and chemically, they're very similar.
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And so after those fungicides have been sprayed on crops and those crops have
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been harvested, the remnants are then put in compost piles. and that's where
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the aspergillus can be exposed to those fungicides or remnants of the fungicides.
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That aspergillus can then develop resistance in the environment because of that
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exposure, and it releases the spores of what we call canidia.
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And then patients who are at risk can inhale those spores and develop azole-resistant aspergillus.
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In fact, that is probably one of the major mechanisms of antifungal resistance
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in aspergillus right now is our environmental use of fungicides.
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This is a difficult problem, though, to address because we have to use fungicides
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in agricultural settings.
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It would be very detrimental to our food supply to stop using them.
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And so we're kind of in this kind of precarious situation now of what's the right balance?
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And so I know, for example, the FDA and the EPA are really having better communication
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now about fungicides that are in development for agriculture use, as well as antifungals
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that are either used now clinically or that are in development for clinical use in the future.
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Is there anything that our listeners can do in their own diet or homes or anything?
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There's not anything we can do. No, not really. No.
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But is there anything else you want to say about why fungal infections can be
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so difficult to diagnose? And I'm wondering just as one reason because it wasn't
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initially considered, could that be?
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It's a variety of factors, but one of the things that's at the top of the list
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is that they weren't initially in the differential diagnosis.
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The other thing is that because fungi have a lot of similarities with our cells,
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fungal cells and human cells have a lot of similarities,
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not only does it make it difficult in the development of new drugs,
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but also in the development of diagnostic assays.
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We have some good assays out there, but they're not perfect.
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They have their limitations, and they're best used in the right patient population.
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But in order for them to be used in that patient population,
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the clinicians have to have a fungal infection in their differential diagnosis.
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And if a patient asks the pediatrician, what's an assay?
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What do you say? An assay, think of it as a lab test.
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That's the best way to describe it. It's just a fancy way to say a lab test.
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So better testing, more ways to test. Yes, we need better diagnostic tools for sure.
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And once you've identified the fungus, how do you determine whether an antifungal
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medication is actually going to work against it?
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So there are different things that affect response to therapy.
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One of the things that we do is the antifungal susceptibility testing that I
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mentioned earlier. It's an in vitro assay.
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The techniques that we use have been used for decades. And it's just basically
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seeing if the different drugs kill the organism in a test tube.
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That's one thing. But that's not the end-all and be-all.
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There are many other factors that can influence whether or not a patient has
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a successful outcome when treated with an antifungal.
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Their comorbidities, just how sick they are. Drug-drug interactions that might,
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influence or inhibit the use of the proper drug because the patient just can't receive that drug.
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Where is the infection? If the infection is within the central nervous system,
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that makes it much more difficult to treat patients because
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a lot of times the drug exposures in those what we call anatomically privileged
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sites are lower than what they need to be in order to be effective treatments.
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And then, of course, early diagnosis and the start of appropriate therapy.
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So there's a lot of different things that can influence a patient's outcome.
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The results of the in vitro susceptibility testing can help guide therapy,
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but it should never be used as the sole basis in making treatment decisions.
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Also, one of the fascinating things
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scientists are learning is just how adaptable these organisms can be.
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What's happening genetically that allows a fungus to essentially outmaneuver a drug once it's worked?
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There are a lot of different ways that fungi can become resistant to antifungals.
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And the list keeps growing and growing, to be quite honest.
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So, yeah, especially in some of these pathogens like Candida auris.
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Candida R seems to be very effective or adaptive in overcoming different antifungal drugs.
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There's a lot of different mechanisms. It can be point mutations that affect
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the enzyme that the drugs target.
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They're what we call efflux pumps. And so drugs have to get inside the fungal cell.
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They have these pumps that then pump them out of the cell, so they're not where
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they need to be to have activity.
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You can have just, it produces so much of the target that the drug is overwhelmed.
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There are genetic rearrangements. And in many of these fungi,
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it's not just one thing that's causing resistance. It's a multitude of factors
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that can lead to high-level antifungal resistance.
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So fungi are extremely adaptive at developing resistance to drugs.
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It just sounds just so tough to outsmart.
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It is. It's very tough to outsmart, but it's also very tough then to develop
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rapid diagnostic assays for resistance.
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You know, there are some assays that have been developed that will look at what we call gene mutations.
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But if the organism isn't using a gene mutation, it is using like an efflux
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pump or some other type of mechanism, those lab tests, those assays aren't going to detect it.
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And so it's very difficult from a diagnostic standpoint to have a very rapid
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and readily available diagnostic assay for detecting resistance to antifungals.
19:52
We often talk about antibiotic stewardship. Should we also be talking about
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antifungal stewardship and what does responsible antifungal use look like?
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Absolutely. And there is something now that is on a bunch of people's radars
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is antifungal stewardship,
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using the right drug in the right situation, making sure that we're not using,
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our big guns, if you will, at the very beginning when another drug that has
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a less spectrum of activity and
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might be better tolerated by the patient will do just as good of a job.
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And so, yes, antifungal stewardship is now just as important as antibiotic stewardship,
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using the right drug in the right patient.
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Are there things happening outside the doctor's office or hospital?
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We talked a little bit about agriculture or the environment,
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even changes in climate that may be contributing to the emergence of this or
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spread of the resistant fungi.
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I think the biggest thing that's contributing to fungal infections in general,
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not just resistant fungal infections, is the number of patients with multiple
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risk factors for disease.
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You know, the number of patients that are immunocompromised is not getting lower.
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We have more and more patients who are immunocompromised. We have more and more
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drugs, immunotherapies, that we don't have a good understanding of what places
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the patient at risk. We know they are at risk, but we don't necessarily what they're at risk for.
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The number of those drugs, those biologic, those immune modulators keeps growing
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and growing, whereas the number of antifungal drugs and diagnostic tools that
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we have is growing, but at a snail's pace compared to other things.
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The risk factors are just increasing so much faster than our diagnostic and
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treatment options are. Good.
21:42
Nathan, if you could change one thing about how clinicians approach fungal disease, what would it be?
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Kind of like what we talked about first. Think fungi. Have it in your differential diagnosis.
21:53
Trying to recognize these infections faster is probably going to be one of the
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most important things that's going to improve patient outcomes.
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Because if you wait too long and the disease becomes established,
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we know outcomes, including mortality rates, are not very good.
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And when that pediatrician walks into the next exam room, what's the one thing
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you hope they know how to explain to parents about fungal infections without
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unnecessarily frightening them?
22:21
I think it's important for them to be reassuring.
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Not all in fungal infections are going to be the end of the world.
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We do have treatment strategies. We do have diagnostic assays that can assist
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as long as the clinician is keeping fungal infections in their differential diagnosis.
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I think we are making great strides in educating not only the general public,
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but also clinicians about fungal infections and their risks.
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So I think making sure that the clinicians are going to be honest,
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but also reassuring to the patients that this is something that they can address.
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And I'll put the number for your lab in the text for the podcast.
23:05
We haven't talked about ringworm. Do you want to say anything? Sure.
23:09
What do we need? What's important for the pediatrician and for parents to know there?
23:13
So one of the, there's several different emerging fungal infections that we've
23:18
started to recognize in the last decade. Candida auris, of course,
23:21
is the one at the top of the list and it gets all the headlines.
23:25
There's another type of fungal infection, a dermatophyte specifically,
23:29
that, you know, when we think ringworm, we think, okay, like maybe a quarter-sized
23:34
lesion, very easy to treat. We have topical agents that can be easily applied.
23:40
About a decade ago, we started to recognize in parts of the world,
23:44
specifically South Asia, that there were some pretty bad ringworm infections,
23:50
tinea infections, I guess to use the official term,
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not just causing small lesions, but causing these massive lesions on multiple
24:00
parts of the patient's bodies.
24:03
It's now been described that this is caused by a specific emerging dermatophyte
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called tricofinin indontiniae.
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It's a hypervirulent strain that is also highly resistant to a commonly used
24:20
antifungal we use to treat dermatophyte infections called terbenafine.
24:25
But we've also seen some of these strains develop resistance to other drugs like the azoles as well.
24:32
Started, like I said, in South Asia, but now it's been recognized to have spread
24:37
throughout the world. We've definitely seen a lot of cases here in North America,
24:41
including in Canada, as well as here in the United States, as well as in Texas.
24:47
Again, when you see a small ringworm, your typical ringworm lesion,
24:52
you're not thinking of that species.
24:54
These are very virulent infections, again, that have very large lesions,
25:00
and the patients can often complain about it being very, very uncomfortable.
25:06
And the patients also aren't going to be responding to the typical drugs that
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we use that you can get oftentimes over-the-counter in pharmacies.
25:15
So a review quickly, just what do you typically use that you can get over the counter?
25:20
And then what do you do if it turns out to be maybe what you're talking about?
25:24
So one of the drugs that you can often get either by prescription or oftentimes
25:28
in lower concentrations in over-the-counter products is called terpenafine.
25:32
You might think of it as lamisil,
25:35
And that's oftentimes what people use to treat their ringworm infections.
25:40
In instances where we see resistance to terbinafine, then the patients have
25:45
to put on other drugs. One of the ones that's commonly used is called itraconazole.
25:50
It's an azole that has to be given orally.
25:53
It's not an easy drug to take, but the patient does have to be on it for a prolonged period of time.
25:59
And unfortunately, we know that there have been a few reports of these types
26:03
of infections, even not responding to itraconazole.
26:08
Anything else you want to say about that that we didn't cover that's important
26:12
for the pediatrician to know? No, I mean, again, this is one of those things.
26:15
So dermatophyte infections are one of the things that actually can be spread
26:19
from human to human by contact between individuals.
26:22
So again, going back to something we've hammered on before, wash your hands.
26:27
Good hand hygiene is very important.
26:29
What about walking with bare feet? I've always heard that with ringworm,
26:33
you could get it from walking on the subway?
26:36
Yeah, we're not typically worried about this type of ringworm infection being
26:39
spread by walking barefoot, though.
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And how likely would it be this type of ringworm infection? How likely would it be?
26:49
It's still relatively rare. Yeah, I wouldn't say it's a zebra,
26:53
but it's becoming more common, but still very rare compared to the typical ringworm
26:59
infections that we see. Okay.
27:01
And anything you want to mention to pediatricians in case they do see that,
27:05
anything you didn't go over, what to do?
27:07
What to do then is probably think of getting a dermatologist involved.
27:13
They're becoming much more aware of it. The American Academy of Dermatology
27:16
actually has a webpage devoted to these types of ringworm infections.
27:21
So there's a lot of good information there.
27:24
Could it go away on its own or it has to be treated? It's very difficult to
27:27
have go away on its own, especially this type of one, one that's caused by that
27:31
hypervirulent strain. Does it keep growing? No.
27:36
The lesions can initially spread, but after a while they stop,
27:40
but they're persistent. They don't keep growing, but they don't go away without treatment.
27:46
And if someone in someone's household has that, wash hands. Wash hands,
27:51
wash clothes, wash, try to disinfect surfaces.
27:55
Stuff like that becomes important, yes.
27:58
This has been so insightful. Thank you so much for helping us all to think fungus.
28:05
Dr. Nathan Widerhold, PharmD, professor of pathology and laboratory medicine
28:10
and director of the Fungus Testing Laboratory at UT Health San Antonio,
28:15
thank you so much for being here on Pediatrics Now. It was my pleasure. Thank you.
28:21
Okay, great job. Thank you.