StAR: Protect the Macrolide! NTM Pulmonary Disease

Hi everyone, welcome to Febrile, a culture podcast about all things infectious disease. We use console questions to dive into ID, clinical reasoning, diagnostics, and antimicrobial management. I'm Sarah Dong, your host at Ahmed Pete's ID Doc. Today, we are getting back to one of our star episodes. These are based on the Clinical Infectious Disease Journal, CID, state-of-the-art reviews. Today, our topic is going to be non-debraculous mycobacterial pulmonary disease, or NTM. So, I'll introduce our guest stars. First up is Dr. Min Vu Nguyen. Min Vu, or simply Vu, is a recent, former, mycobacterial research fellow at National Jewish Health. He is now a new assistant professor of medicine in the Division of Infectious Diseases at UC Davis Health in Sacramento, California. There, he and his pulmonary colleagues have started building a multidisciplinary NTM care center. Hi, this is Vu from UC Davis. Pleasure to be here. Next we have Dr. Charles Daley. Chuck is a professor of medicine at National Jewish Health, University of Colorado, and the Icon School of Medicine at Mount Sinai. He is the Chief of the Division of Mycobacterial and Rostatory Infections at National Jewish Health and Chief Research Officer at the New Brunke Ectasis and NTM Association. Hey, this Chuck, I'm very excited to be here and glad that you're joining us today. And closing out our group of guest stars today is Dr. Reethi Kare. Reethi is an associate professor and infectious disease laboratory director at National Jewish Health. Thanks so much for having us. I'm excited to be here. My name is Reethi. So before we jump in, as everyone's favorite cultured podcast, we like to ask our guests to share a little piece of culture, basically just something that you enjoy or brings you happiness. So what have you guys had in mind for today? I love anything chocolate on chocolate that's been my favorite thing to do, like anything that's disgustingly chocolate, molten lava chocolate cake. Excellent, excellent. For me, I don't know if this considered culture, but I just adopted two cats while on consults. So it's been hectic, but they're nice. Are they small cats or like adult cats? They are adolescent cats. So I got them when they were nine months and they act exactly like adolescents. And in fact, they've been banging the door for the last hour, but maybe now they're calming down because I hear other voices. Well, we'll see if they make an appearance. They will try. What about you, Chuck? Yeah, you know, one of the things I really enjoy is Forrest Gump. We have a lot in common and I always watch the movie if I run across it. Excellent. That's kind of surprising. No one said Forrest Gump before, I love it. Well, thank you guys so much for being here and also for creating this article that we're going to talk about today. We're talking about your state of the art review, non tuberculosis, mycobacterial pulmonary disease, patients, principles and prospects. NTM, which I'm going to say for short, is a huge topic and we know that NTM pulmonary disease is an increasing problem and something that I feel like we all encounter at least a little bit of in the ID clinic. And I thought maybe we would just start by a quick kind of background on these organisms and maybe a little bit about how humans can be infected. Okay. Yeah, of course. Well, actually, we can begin by asking you a question, Sarah. How do you think the name mycobacteria got its name? Oh, I have no idea. I didn't prepare. Well, I didn't know this until this morning either, but Chuck, maybe you can tell us. Yeah. So when mycobacteria were first discovered and their growth on the culture media looked like a mold, so it was thought they may be a fungus, so the word "mycobacteria" was used. I mean, certainly if they were discovered today, they would have a different name. Love it. Yeah. So, yeah, so mycobacteria, the most famous one is obviously tuberculosis and you guys probably heard of the new book that just came out, everything's tuberculosis, but if he's going to write a second book, everything else would be non-tuberculosis mycobacteria. And it includes over 190 species of soil and water-inhabiting mycobacteria, excluding obviously m-tuberculosis and m-lepre. And again, they live in the soil, they're all around us, plumbing, dust, natural and municipal water. And most patients who get it, they get it from either inhalation of these mycobacterial laden soil, water and dust aerosols, or they ingest fluid or dirt or whatever into their GI tract and then aspirate them into the lungs by a two-step route. Now, since we are all kind of inhaling or ingesting mycobacteria, not all of us actually get disease, right? So who gets disease and it's only a very susceptible host, patients particularly with local or pulmonary anatomical structural abnormalities and local immune dysfunction, particularly chiefly bronchiectasis. And then we can talk about, there's two big categories of NTM and, Redi, do you want to jump in? Oh, sure. Yeah. It's sort of helpful to think of these non-tuberculous mycobacteria as being divided into two major groups. Those that grow on solid media from subculture within seven days, those are the rapid growers. And then those that grow after seven days, those are the slow growers. And that's important because they have different diagnosis, different treatment and they look different in the laboratory. And, Redi, do you know anything special? What makes mycobacteria special in terms of their cell wall or capsule compared to, let's say, your typical gram positive or gram negative bacteria? Yeah, mycobacteria are special because they have this unique cell wall. Their outer cell wall is kind of embedded with these mycolic acids that make them very resistant to things going into the cell and things coming out, which means that all of a sudden they become impermeable to things like plasmins, so they can't mutate that way. They become impermeable to antibiotics and so that has a lot of implications on how we manage them. Well, awesome. Chuck, do you have anything to add to that? Well, the only thing I would say is that even though we have so many species, fortunately most of them don't harm us. This will come back when we talk about the laboratory and why it's so important to know which species has been isolated from your patient. Sarah, do you have any other questions? Is that a good intro? Yeah, I'm going to bring you into clinic with me today and talk about someone who's shown up. So, we're in clinic. We have a seven-year-old woman who's been referred for possible NTM infection. So to give you a little background, she had been seen in the emergency room actually for some urinary symptoms, got a CT for abdomen pelvis to rule out kidney stones, hydronephrosis, and they noticed that in some of those cuts towards the base of the lungs that there's some scattered tree and bud nodularity. And so she has a follow-up CT chest that shows some subacute versus chronic changes that are consistent with bronchiectasis, more of those tree and bud nodularities, and then a couple scattered pulmonary nodules, all pretty small under a centimeter. And so when you're talking to her, she kind of reflects back and says, "I guess I always did have bronchitis. Every time I had a cold, it progressed to this chest cold. It happens probably three to four times a year. And in between, she has some rare intermittent cough, usually nonproductive, and has a little bit of chest pressure. Things her weight has been mostly stable. She kind of feels like she hasn't been paying attention to it. She herself is a lifetime nonspoker, but notes that both of her parents smoked heavily in the home until she became 18 and moved out. And she spends most of her time in Florida, travels frequently around various places, but she's just in general a pretty active person. She kayaks, she hikes, she runs, and she's just noticed that her activity recently has gone down and she blamed it mostly on just getting older. She does have a hot tub as well as an outdoor saltwater pool at her home in Florida. And so we're not even going to get to micro results right away. I'm going to pause here and just ask what you're thinking about. For this patient so far, does this story fit with NTM pulmonary disease? What other information are you going to be trying to gather to help put this all together? Yeah, I'll speak to this first. I think I saw this same patient multiple times last week, she must be moving around. So you know, this is pretty classic for us, right? This postmenopausal woman who comes in with a cough, maybe some declining exercise tolerance. And it's not unusual these days to have these incidental diagnoses made where they often get a CT of the abdomen and they see the base of the lungs and they see the bronchiectasis and/or the tree and bud. And that's really good, right? Because this is usually an early diagnosis, earlier than if we waited for them to come in because of their cough, which could have possibly been years from that time. So you know, cough and fatigue, the most common. She doesn't mention fatigue, but cough and fatigue, about 80% of patients with pulmonary NTM present with that. Some shortness of breath. It's usually a productive cough. It's like this case. If you catch them early, it's often a dry cough. And that doesn't trigger people, you know, that it's when it becomes productive and they're failing antibiotics, then sometimes they'll order the CT. So she was lucky that this was found earlier. Radiologic findings, we always talk about kind of two different types, which is the, what is called the classic. And by classic, it means it was what was described many years ago, which is fibrocavitary, upper load, cavitary with volume loss, looks like TB. They often enter the health care system in a TB clinic and then they don't grow TB. They grow Mac and then they, they come back out to us. And the other, which now I would say is kind of the classic, the more common is the nodular bronchiectatic disease, which it sounds like she has with bronchiectasis and some tree and bud nodularity. All of these things should make the clinician suspect pulmonary NTM. And that should lead to getting a culture, a respiratory culture to try to confirm that. And unlike TB, I mean, as you know, we don't make a diagnosis just because someone grew an NTM, because who said earlier, these things are found everywhere. We all are, we're showering in them, drinking them, swimming in them, we're, we're surrounded by them. So we, we came up with these diagnostic criteria back in 2007. But let me just tell you now, in 2025, no one has validated these criteria. So they should be used as a guideline, you know, and, and that is that we look for symptoms consistent with NTM, radiographic findings, and then we confirm that with the, the laboratory, which is a critical component of this diagnostic algorithm. So we take a peek at her records. We find that she has one expectorated sputum culture from about six months ago that had mycobacterium chimera. And she had a second sputum culture that was drawn a couple months later that has M. abscesses. And so we make a plan now to gather more information, get multiple sputum. And so, you know, why does testing take so long? You know, why can't we develop a rapid test to detect NTM like we have for TB? Well, yeah, testing does take a long time, right? Culture is six to eight weeks. And that's just really because we are waiting for mycobacteria to grow to detectable levels. And they only double once every 24 hours. And then, of course, once we get a positive, there's more time needed to identify it. And then once we identify it, it takes at least two to four weeks to grow up enough biomass and actually do susceptibility testings. So molecular testing is definitely a question I get quite often about doing that directly from a specimen so we can try to speed up results for an NTM diagnosis. I mean, we do this for TB and it works, but it's a little bit more nuanced for NTM because unlike TB, NTM are not always considered pathogens. Just detecting an NTM from a sputum could be a contaminant, it could be a dead bug. It could be DNA from a previous exposure. And so a positive result doesn't necessarily mean anything. And then the flip side is true as well. A negative result doesn't necessarily mean anything either. A PCR could be falsely negative because our assay is too broad, it's not sensitive enough. Or it's too narrow, we've just focused on a few NTM and missed the other NTM that's actually in our sample. So molecular testing has the ability to speed up testing. It can do more than ID, it can look for drug resistance markers. So it has a lot of opportunity. We just need the right test designed optimally that will actually give us enough information to change our management. We're not quite there yet. Maybe I can ask a question, Ribi, how often do you see a mixed infection like this? Mixed infections are actually fairly frequent in our samples. About two to 12% will have at least two mica bacteria, but I don't know what that looks like from a patient number of patients. How often do you see co-infections? I would say more common. We published a number of years ago, our experience with obsesses and 55% of our patients with pulmonary obsesses had concurrent or previously had MAC. So it's pretty common to see mixed infections. And one reason why people hearing this might see the discrepancy is that from a lab point of view, Ridi is comparing in a single sample, two to 12 or two to X, Y, Z percent is growing two different NTM in the same sample, whereas Chuck is talking about from a whole patient who has coughed multiple samples. So multiple samples, you're more likely to have a mix of different NTM over several samples. So that's why you might see the discrepancy and the percentage. And your paper has this really nice focus on patient-centered care and how we can walk through these discussions with our patients, which is really hard. Before we talk anything about antibiotics, I thought we could pit stop there and have you share some of that about how you approach these cases, how you talk about the goals of treatment and set expectations with them. And I think part of that, of course, is counseling on sort of risks and management of comorbidities. But for such a huge nebulous topic, especially in the early stages when you don't have micro, I think many of us very much welcome resources like this that help set the stage. But I'd love to hear your insight. Yeah, of course. Well, I can start out. I know that, like you said, it is nebulous. But you alluded to something really important that you said a lot of times we're still waiting on micro, right? And I think the non-nebulous part is in the beginning is that let's get the diagnosis correct first. Let's make sure they truly, truly have NTM pulmonary disease rather than just colonization or something else going on, but maybe they accidentally grew an NTM from one sputum culture. So you know, kind of reiterating what Chuck said in the 2020 guidelines, and that started from the 2007, the general guidelines, you need to meet three criteria in order to be diagnosed with NTM pulmonary disease. That is, one, the microbiologic criteria on where you have to have repeated growth of the same species or subspecies radiologic criteria. So imaging particularly chest CT consistent with NTM pulmonary disease could be caviteric, could be nodular bronchiatatic. And then finally, symptoms compatible with NTM pulmonary disease while excluding other diagnosis. Now, this is a big caveat because you probably know yourself, some patients will deny symptoms or they do have symptoms, but they just don't recognize it. So that itself is a little nebulous, but during the first meeting, especially if they only have one or maybe just two sputums and you don't have a convincing picture, getting to the right diagnosis first is the first important step of patient center care. Yeah, I mean, you know, one of the first PICO questions that we addressed in the 2020 guidelines was, should you start treatment? So you know, you weigh what VU said, the whole picture, symptoms, microbiology and radiology to try to make a decision if you're going to treat. If you decide to treat, it is a very important at the very beginning to go through the goals of treatment. And this is where the discussion between the patient and the physician or provider is critical because we're not going to make that decision. The patient ultimately will make that decision. And we need to make sure that we're providing them with realistic expectations. And unlike TB, it's the discussion is always the same because we expect to cure our patients with drug-susceptible TB and most even our drug resistant. Here that is not always the case. So that discussion takes on kind of a different flavor depending if they have mycobacterium chinsaceae, where we can treat and cure 95% of the time, mac where it's more like 70-80%. And then the discussion with mycobacterium obsesses is that, you know, cure really is difficult to achieve, and Voo knows that when people come here, I tell them we don't use the cure word with obsesses. We use the control word first. And if we get to cure, that's fantastic. But that's not realistic discussion. And a lot of patients who come to us are failing treatment, they're not culture-converting, and they're frustrated because they were told they would be cured. And it was not a realistic expectation. So when we do get NTM, that grows in culture, you mentioned we need to identify it, of course. And your paper talks a bit about how those kind of imprecise or challenging components of identification. So why, as like for ID learners on here that are listening, why does it matter for them to know that identification beyond just the complex level for these mycobacteria? One of the biggest reasons for a full and accurate identification is because of differences in treatment patterns. We know that slow growers and rabid growers have different treatment patterns, but even within these groups, even within closely related organisms like the obsesses subspecies, they can carry resistance genes at different rates. So for example, the erm gene, erm genes cause inducible resistance to macrolides and some obsesses subspecies have them, some don't. Same thing with the fortuitum complex, some of those species carry an erm gene and some don't. Knowing which mycobacteria you are actually dealing with will help you pick the right drug, especially the important drugs like the macrolides. There's a few other reasons too. I think, Voo, do you want to speak to those? Yeah, of course. You know, Riddie said that the best treatment patterns will change based on the species and subspecies, but another thing too is kind of going back to diagnosis. It helps us determine whether a species or subspecies is likely causing disease or not. So again, part of the diagnostic criterion for microbiology is repeated growth of the same species and subspecies, and it convinces us that it's more likely to be disease causing. When different species and subspecies grow sporadically, which we often see too, and none of them has grown repeatedly, it suggests that these cultures are more likely, I'm not saying absolutely, but just more likely to be colonization. In the case of identification of mac, the most lab will call it simply Mavian complex or I've seen Mavian-introcellular group, various renditions of that. But basically, remember, a complex, and Chuck will always tell you this, a complex is a collection of different species and subspecies, and knowing that just a complex doesn't help us decipher whether this is the same species or subspecies growing and therefore likely causing disease or versus just colonization. It also helps providers try to sort out if somebody is responding to treatment or if they are just getting re-exposed to another very similar bug that we haven't differentiated out, and we can also, by knowing exactly what we have, we can start identifying organisms that could potentially be causing outbreaks, and that's what actually happened a few times. We know that intracellular subspecies chimera can be associated with outbreaks in heart surgeries with these heater-cooler units. We have recently found an outbreak of M-obsessesus subspecies miscelliants in stem cells. So that's another reason why we want to do that. And so reaching out to your laboratory and requesting that full identification as well as any potential drug markers that may be associated with the bugs may be really important for you to know. But something I'd like to point out is that it's not always possible for your lab to be able to do it. There are actually dozens of tests available for NTM testing, but only one or two of them are available in the US. So access is a real problem. Even our laboratory, we get our tests from Europe, and they get stuck in customs every single time. Validating these tests is difficult, especially when you don't see a lot of these organisms. So a lot of providers may have to rely on reference labs to get the results that they need. Yeah. I might add to this mycobacterium avium complex. I like to say it's probably more complex than you recognize. So we used to have the MAI, right? That's when we knew there were two species, avium and intracellular. Now there are 10 species, and two of them, avium, it has four subspecies, and intracellular has three subspecies, chimera, which used to be a species, and yangonets, which used to be a species, they're now subspecies. And therefore, many labs will just stop at the intracellular, and you won't know. So for example, I mean, this was a real life example during the heater/cooler unit outbreak years ago. Unfortunately, believe it or not, it's still happening, but at its height, I know of a hospital that they ran their clinical micro logs and they grew no chimera. They were so excited. They had no chimera cases until they figured out their lab didn't identify chimera. They just stopped at intracellular. So ultimately, they did have cases. So first outbreak investigation. But the other is of those 10 species, I bet you most providers don't know all of those names because they don't get it reported to them. So they don't even know they exist. But let me give you an example. You have a patient, some tree and bud nodularity. If they grew avium three times, particularly if they were symptomatic, you'd consider treating them. But what if they grew vulnerous? Well, that's MAC. That's one of those MAC species. I probably wouldn't treat that. I'd probably just go right to airway clearance and see if I could clear that without. Because this clearly not as pathogenic. The other ones that are within MAC, they're just not as pathogenic as avium and intracellular. So most providers in the U.S. don't know what actually is growing in their patients, respiratory specimen. Many people who listen probably know that there are these available guidelines and consensus articles for when we do want to treat our patients with NTM pulmonary disease. And certainly your paper is focused on kind of giving a more as a broad approach and framework for people to start thinking about this when they're selecting antibiotics. And I'm going to highlight figure five from your paper that hopefully folks have pulled up and can look at. What things should we know? After you implement step one, and you decide to start antibiotics, then in step two, you must start with the macrolide if the target NTM in a specific isolate from the patient is macrolide susceptible. Your whole regimen will build around this macrolide. This is because the macrolide and the main glycoside are the two most poing classes of antibiotics against NTM that are susceptible to them, with the amino glycoside reserve for severe or treatment limited disease because of toxicity, something that we will touch on later. In mac pulmonary disease, spleen conversion rate goes from 70 to 95% when the MAC is macrolide susceptible down to 5 to 36% when it's not. We see the same pattern in M-obsesses from 72 to 88% in macrolide susceptible down to 25 to 35% in macrolide resistance. This leads us to step three. If you have an SGM or a slowly growing macropacteria like MAC, you need to add ethambutol to protect the macrolide to prevent the isolate from developing acquired macrolide resistance, irrespective of the ethambutol MIC. This is why NGH does not report ethambutol MICs anymore in their MIC panels for SGM because many providers were incorrectly dropping ethambutol when they saw an elevated ethambutol MIC. I think this is a nice lead-in into step four, which will heavily involve the whole discussion about interpreting MICs in NTM disease in general. How do we use our susceptibility results? We send our sample to National Jewish, we get it back. How do we understand those? Are they reliable? I'll start with the testing, and then you guys can take it from there. As much as I love lab testing, the thing to know about NTM's susceptibility testing is that it just doesn't correlate with clinical response as well as we'd like. We know that ASC results are fairly reliable for some drugs like amacasin and macrolides, and we're famping for Kansas CI. But the others? Maybe not so much, but why? Why is it like that? And I think there's a few technical reasons. The big one is the way we do testing. We use broth microdilution, which is very routinely used in bacterial testing. We borrowed the method from routine bacteria, and it works very well for routine bacteria. But the premise of the technique is to test one bug against another drug independently. So one bug, one drug independently. But that's not how NTM treatment works. We need to treat NTM with three, four more drugs, and sometimes those drugs work synergistically, sometimes antagonistically, but we're not testing them that way because we just don't have the methods yet to do it. Another possibility is that we're not accounting for heterogeneity of NTM infection. We know that mycobacterium tuberculosis is heterogeneous. That's why we test it with a completely different method. We use the proportion method. But for NTM, again, we use broth microdilution. We pick one colony and we test it against all these drugs, and this ignores the probability that all the bugs from the patient are not going to be the same. And then there's the share length of time it takes. We have to incubate these mycobacteria with the various drugs for days, sometimes up to two weeks just to get enough growth to read, and by then the drugs themselves might be breaking down. Yeah. Yep. Pretty much. And, I mean, to add on to the complexity of it, so that's just a testing part. But let's say hypothetically, for whatever antibiotics and bug that you have, the test is fairly accurate. Why do some combinations don't have "in vitro" and "in vivo" correlation? And most of the time, it's actually because of a lack of data. There's so many bugs, there's so many antibiotics, there's just no enough to do studies to say, confirming that this myc at this break point will lead to this good outcome. There are a few bugs and antibiotics combination that has been looked at with some decent data that show there is no correlation. That's like rifampin and ethambutol in MAC, or INH in M. consasi. But that's only a few where there's actually some decent maybe trials/observational clinical data stating that, okay, we looked at it and there actually is no correlation, at least at this break point. But to further add complexity, maybe one other reason is because clinical outcomes also depends on the host, not just purely killing the bug. You can kill the bugs all you want, but if you have an airway that is malformed from bronchiectasis, they're just going to be stuck there and you're not going to get somewhat equivalent to maybe source control inside the lungs. Let's look at it in a different analogy. Let's look at, let's say, MSSA, you know, staff or is. So we know MIC matters in staff or is, that's why there's MSSA and MRSA. But the MSSA, no matter how much naphthalene or cephalozole you give them, if they have an undrained abscess, the patient's not going to get better. And as ID doctors, for us, that's a no brainer. So are you going to say naphthalene and MSSA and cephalozole and MICs don't matter in MSSA? No, because we know it's a source control issue. Almost the same, not perfectly analogous. Maybe it's the same thing in NTM pulmonary disease with these bronchiectatic airways that the NTM just gets stuck or even if you get them out with airway cleaners, the patients might inhale them back. So therefore they don't get, quote, unquote, the clinical outcomes you would expect purely from a bug-killing MIC point of view. The only thing I would add is that there are two drugs for which we do believe the MIC determinations and that's the mafrolides and amikacin. So I do want the listeners to believe those MICs and that those cut points that determine susceptibility from resistance, and those are based on trials, data that show that there is worse outcomes when we're above those MIC breakpoints. But then that's it. The rest are laboratory-derived cut points. That doesn't mean they're not useful. It just means they're not as definitive of a cut point. And so, you know, when I have to build a regimen for mycobacterium obsessus, you know, I'm going to look down that list and there are some I believe more, like imipenem was mentioned by RETI, it's an unstable compound. By the time we read the Rappergur or three to five days, I don't know what the concentration is. So I don't pay attention to that one. But other drugs that are more stable that I do tend to pay a little bit more attention. But even if they cross that magic resistant cut point, that doesn't mean I'm not going to use them as I build that regimen. Because we know we see people respond to treatment even when drugs are in the regimen that don't look that active. But it's all we have. Exactly. Exactly. I think a lot, as ID doctors, we love that, right? We love antibiotics. We love MICs. What's the lowest MIC and what's the best antibiotic? But at National Jewish, I learned the importance of treating the underlying disease, whether it's bronchiectasis, COPD, acid reflux, et cetera, optimizing nutrition. And finally, if they have bronchiectasis, airway clearance therapy, airway clearance therapy, airway clearance therapy. So that's why in figure five, at the very top, the number one is do those three things, then think antibiotics after. And that's going to be a big lesson for a lot of purely ID folks out there who are not familiar with airway clearance. They just deal with the antibiotics part, but I want them to understand the importance of airway clearance. Yeah. And I feel like that's a big part of it, is finding a good pulmonologist to partner with if you're not, if you need help thinking about those and managing the, especially the airway clearance. Yeah. I have run to a number of ID docs in the past few years that they start the airway clearance because the pulmonary docs are not doing it. And I applaud them because they're watching videos and trying to learn more about airway clearance. Because at the end of the day, the patient in front of us is who we're trying to help and we sometimes have to do things that we may not have been trained in. But if we don't have that available around us, then let's do it. Correct. So, I made this patient up and kind of gave a background saying that they've had a culture that's had MAC in it. There's been one with imapsesis and I'm going to leave this broad and just say we repeated cultures and there could be a variety of things that happen. Maybe we have a couple cultures that subsequently have MAC that maybe we confirm imapsesis. Maybe it's a mixture and rather than just picking one and focusing on that, I thought maybe you could kind of compare and contrast the types of possibilities and the context of that treatment framework that you gave, like how you make decisions more than us focusing on kind of one specific example. So I mean, this is a tough question, right? So let's say they're growing multiple organisms over a series of sputas. So they're growing, let's say imapsesis, imapsesis, same species, subspecies, or MAC, MAC, and then they're intermingled. So we have to find the one that grows the most and that's likely the one that's driving. That's the primary one. So let's say it is imapsesis, mycelians growing four different times and you get two other cultures that's also MAC and maybe unsubspecies, something something. So you know you're going to want true imapsesis, I mean, when they meet the diagnostic criteria. Did you ignore the MAC? That's the question, right? And that's a tough one and we see this is where a lot of nuance come into play. And it comes down to the macrolide, the macrolide, and protecting the macrolide. So if we are treating the imapsesis with a macrolide therapy, which we likely are because it's mycelians and we want to use a macrolide when we can. And I'm assuming that the MAC is also macrolide resistant. If you're just treating the imapsesis without any other MAC drug, you're basically subjecting that MAC to evolutionary pressure with just purely monotherapy with zithromycin. So even in this case, even if we don't think the MAC is driving the disease and it's only secondary/colonization, we don't want it to become macrolide resistant. So in this case, we might throw on ethambitol, in addition to the imapsesis regimen, broadening it to cover both organisms, understanding that we're trying to treat only the imapsesis, but we're also preventing macrolide resistant development in the MAC. How did I do, Chuck? Well, you learned well to protect the macrolide. That's the mantra. And these are often very complex decisions and sometimes we can't define a dominant one to go after. And we have to treat both, but you can do that. We have to do it. That's usually going to take about five drugs to do that, so it's not easy. And I would just say this is when I would consider calling a friend, trying to get some encouragement with the best way to approach this. Because unfortunately, we do see people preferred here who develop macrolide resistance because one of the two was treated and one drug was exposed to basically monotherapy and they're now macrolide resistant. And whether that's obsesses or macrolide resistant MAC, you've taken someone who's likely to be cured now to someone who's likely not to be cured. I think one other sort of branch that I thought we could just touch on is how you adjust your approach if patients have severe or treatment-limited disease and maybe actually just starting by saying how you explain what is considered severe or treatment-limited disease. Okay. I'll talk about this. So, severe is a little more easy. Usually for the sake of this paper only, severe was referring to cavitaria disease, so any form of cavitaria disease, or even if they have nodrobronchatecatech, a very profound like multiple lobes, a lot of involvement of nodrobronchatech and the patient is really sick and a BMI of 15 or something, I would consider that severe even without cavity. Treatment-limited is a term we designed just for this paper and it's not well-established as standard terminology in the NTM world because we're basically combining, for the sake of word count limitation and meeting it, we just basically, we use a treatment refractory, meaning NTM disease that got treated with guideline-based therapy and by six months still haven't culture converted. That's based on MAC, but we are extrapolating it to other NTM, but basically that's the MAC term for treatment refractory MAC. But we're also adding in NTM where their primary best drug is resistant to. For example, macrolide resistant MAC will be, I will squeeze it into treatment-limited disease because you can't use a macrolide. For the sake of the paper, I squeeze those two in simply because I think the next step would be something that a lot of ID doctors or most doctors are afraid of, and that is adding on IV mCasin. Chuck, do you have anything else to add? Yeah, I mean, I think now the other option is ALICE mCasin liposome ventilation suspension, which in the 2020 guidelines, it was frankly one of the few novel recommendations and it was one of only four strong recommendations in the whole guideline. And it's because we had phase two and phase three randomized data showing that in people with treatment refractory MAC that if you added ALICE two guideline-based therapy, culture conversion was 30% by four months versus only about 9% and people who didn't get it. So that did make it into the guidelines, of course it was FDA approved also. So I still think though that if it's cavatary disease that you're looking at and you haven't already given them IV mCasin, I would probably give IV mCasin in that setting and then transition them after a couple of months. Now, this is not in the guidelines, this is that art of medicine, but it's something to I think consider, but I do think it gives us, ALICE gives us another tool to use. You guys want to talk about surgery at all? Yeah. I mean I figured since these episodes we obviously can't cover such a huge topic in one, so that's why I thought we'd focus on the framework and maybe spend the rest of the time thinking about how we monitor these patients, what are other therapies and that actually was going to be one of my questions of when and how you identify patients to refer for surgical resection and how you think about that. So for surgery, you know, we do it a lot at NGH because we have a surgeon who is a well-known expert in it, but usually they should be referred for evaluation lung surgery if they have very uncontrolled severe symptoms, most commonly is homoptysis that doesn't improve on any treatment, particularly if they have focal disease, doesn't really have to be perfectly focal and unifocal, it could be widespread, but mainly the disease, the biggest disease site is in a single segment or lobe of a lung, and if we think they're unlikely to achieve response by antibiotic therapy alone. So in this case, a lot of times we refer to patients with macrolide resistant MAC that maybe have a severely bronchiactatic right middle lobe to get that right middle lobe removed and that's our most common surgical referral at National Jewish. Yeah, we do a lot of surgery, it's done at the University of Colorado by Dr. John Mitchell who's basically done all our surgeries for over 20 years, he's probably done about a thousand patients by this time and he has almost all of it robotically. So he's pretty amazing, it's still a very small minority of the number of patients we see that actually go to surgery, and to those point, they often have resistant organisms, may have already been failing therapy, have focal disease, probably cabinetry diseases is the most common reason people go to surgery, but they do well afterwards, he's published with robotic approach, a 7% complication rate which is very low, zero mortality in 20 years at the time of surgery and culture conversion rates of 80 plus percent, in fact, if you look at 15 studies, we did a systematic review part of the guidelines, the culture conversion rate was 80 to 100%. So at least on the microbiologics, how you are now getting control, we always say it may not lead to cure, but it will help us get control. And you're experiencing a lot of these patients, I thought maybe I would just ask if you have any big take-homes or pearls for us to consider for those who are on therapy, either monitoring their response or monitoring for adverse effects of the antimicrobials. Yeah, I would say you kind of need to have pretty frequent follow-up, but more importantly, the thing that we see lacking the most among a lot of referring providers is that they don't get surveillance cultures frequently enough. And ideally, we want, once they start therapy, we do want repeat spew to every one to two months as possible. And this is helpful because it determines total length of treatment and to help monitor disease treatment progress. You know, we have to balance the treatment response that we're evaluating with the adverse events. And unfortunately, we know those are common. And it's just part of the management of these patients. So the things that we're looking at are usually a complete blood count, comprehensive metabolic panel. That kind of goes without saying, but I think the thing to remember is that if amputol can produce optic neuritis, and although it's not common, it can be catastrophic. So we really want those patients receiving a tambutol to have visual acuity monitoring, red-green color discrimination. No one has ever studied the optimal frequency in which that should be done. And we really kind of get into details and the guidelines on this. But I think that it's a very important thing to do. What we tell patients is, read the same font every day, you know, because don't wait until your next ophthalmology appointment. But just every day, same font. If you feel like you're seeing some visual decrement, then you stop the drug, we empower the patient to feel you stop the drug and you inform us, and then we'll go from there. So I think that's important. And the other is amukasin, ototoxicity is unfortunately a common adverse event. So we want to monitor audiograms for that. We usually do baseline. If they're getting IV, we typically do monthly audiograms. But one thing we're seeing is people with alice are not getting audiograms, but it's still possible, much less common than with IV, but it is possible. So same thing, we do baseline audiogram and so on, beginning alice. And then we check much less frequency anywhere between three and six months, probably three months and so on, who we see already has a little hearing loss, maybe six, and someone who doesn't, but I think both should be monitored. And to start closing us out, I'm going to change gears and just ask you guys, what is on the horizon? What are you excited to learn more about, understand better, maybe studies that are in process? What should we all get excited to learn about in the coming years about NTM? Well, I'll probably take this one. There are a number of clinical trials that are occurring and a number of drugs in the pipeline that have not quite made it to the clinical trial arena, but I hopefully will. Some of the things that I think we're very excited, exciting is and things that we're interested in here at National Jewish. Some of the new drugs, for example, alice is enrolled into a trial for treatment, Naive MAC, not waiting until they get refractory and two trials and the first has been resulted and it was a very positive trial in pretty much every way, but primary and secondary. And so it's in now a larger trial, that was a six month trial. This is, we're waiting for the results of a 52. We trial and that ends in October. So we're going to know hopefully later this year the results of that. Omatocycline completed a phase two trial, also very positive trial. This was in, this was a monotherapy trial and people with mycobacterium obsesses and again, primary and secondary, very positive. And we look forward to see that drug and we're using it now, but we would like to see evidence to help us. Inhaloclophazamine is a trial that is beginning now and is already enrolling. And so that's a very interesting approach of giving very intermittent inhalational treatments because of the long half life. Mycobacteria phage, this is, you know, also not just with mycobacteria, but with bacteria in general is a very interesting area of investigation. There are trials for pseudomonas, but there are no NTM trials now, but there are cohorts that are being studied. So that's pretty cool. I will end, I think with something called ORC. ORC is a compound that in a murine model was basically a hundred percent protected against ototoxicity from an immunoglycoside. That trial is beginning now, several sites under the leadership, Kevin Winthrop at Oregon, but we're very excited to see, you know, can we take an active drug like the immunoglycosides and make them safe or safer than they are now? But anyway, I think a lot of things that are very exciting are happening. We could, we'd have to do a whole nother podcast to talk about that. That's great. I'm very excited to hear all those and I guess I'll just open it up, you know, for any closing thoughts you guys have, anything else that we didn't cover so far? I guess I'll just reinforce the, the unofficial title of this talk, which is protect the macrolide, protect the macrolide, protect the macrolide. But in addition, do air clearance therapy if they have bronchiectasis, and for slowly growing mycobacteria, particularly MAC, do not drop ethambutol because ethambutol, guess what, protects the macrolide. So please do not drop ethambutol from your MAC regimen unless the patient is going blind. And also don't treat them only with a macrolide and a rifomycin because the rifomycin does not protect the macrolide. Correct. And I guess the other thing we should do, we should thank the authors. We're not the only authors and, and there was a cat theme here. So Vu, he adopted two cats, but to get this thing written, he had to herd the cats and he did an incredible job of that. Yeah. Well, thank you. Yeah. The authors were amazing. Like all, I think 12 of them. I remember getting the bits and pieces of everyone and I know, um, CID said 5,000 words and then I put it all together and it was 9,000 words. And I was like, wow, this is going to be, this is going to be fun. It's like telling your cats to like stop eating, but they keep eating kind of equivalent. You know, it's like, okay, how do you stop them? But yeah, they were, I mean, the authors were amazing, obviously, Reedy and Chuck. But the others, particularly, I want to give a shout out to the very, one of the very middle author who doesn't get enough credit. His name is Vinicius. He wears multiple hats. He's like a microbiologist and data analyst and researcher all at the same time, but he's the one who actually kind of designed these figures, like particularly the, that fancy figure one with that Michael bacterium. Yeah. I drew that. I drafted a really ugly version of that on pen and paper and he made it like not ugly, which is great. Oh. And that has it right there. Wow. I love a good graphic. This is the place to give a shout out for that. Yeah. Awesome. Well, I am just again, very, very grateful that you guys took the time to do this. Yeah. It was a pleasure. Thanks for having us. Thanks. Thanks, sir. Great. We appreciate you. Thanks again to our guests for joining February today. Make sure to check out their state of the art review and CID entitled non tuberculosis mycobacterial pulmonary disease patients, principles and prospects. Check out the website, February podcast.com, where you will find the console notes, which are written supplements to the episodes of links to references, our library of ID infographics and a link to the merch store. February was produced with support from the infectious diseases society of America. Please reach out if you have any suggestions for future shows or want to be more involved with several. Thanks for listening. Stay safe. And I'll see you next time. Bye. Bye.