Video Inhaled Antimicrobial Therapy for MAC Lung Disease Completing the Journey from Diagnosis to Cure Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Inhaled Antimicrobial Therapy for MAC Lung Disease Completing the Journey from Diagnosis to Cure Overview Hi, everyone. Uh My name is Ashley Basavaraj. Uh I'm section chief of Pulmonary Critical Care and Sleep Medicine at Bellevue Hospital Center in New York City and Associate director of our Bronch Eis and N T M program at N Y Un Going Health. We're gonna be talking about mycobacterium avium complex uh and going over a case to highlight some of the management strategies um that's involved with this condition. These are my disclosures. So an overview of this talk, we're gonna talk about the clinical a clinical case of mycobacterium avium complex lung disease. Review the epidemiology, risk factors and diagnostic criteria for mac lung disease, risk factors for progression and decision on when to initiate treatment, which is oftentimes a a difficult uh decision for, for clinicians, we're gonna review uh the revised guidelines um involving mac lung disease uh and the various treatment regimens. And we'll discuss strategies to promote adherence uh and discuss uh side effects and how to uh how to manage that or which can occur with the antibiotics for, for mac lung disease. So to begin, we're gonna talk about a case. Uh This is a 67 year old female who presents with a mild chronic cough, her weight is stable. She has no hemoptysis. She has a past medical history of reflux, never smoker, social alcohol use. She works as a teacher, no known drug allergies and her physical exam is notable for some mild wrong guy in her lower lobes. This is our cat scan and what you can see here is uh bronchiectasis in the right middle lobe and lingula. Uh you also have some bronchiole, bronchiectasis in the left lower lobe and some mucoid and impact and and bronchiolitis. So, because of the bronchia tosis, we underwent uh some routine labs to screen for potential ideologies of her bronchia. So uh we screened for autoimmune conditions. Her A N A was mildly elevated, which you can see in chronic lung conditions. Uh Her rheumatoid factor was negative. We were searching for any sort of immune deficiencies in association with the bronchia for quantitative immunoglobulins were negative and the Aspergillus I G E was negative which we often check for uh to screen for allergic bronchopulmonary aspergillosis or A B P A as a cause for bronchia, the alpha one antitrypsin level was normal and we had some speed cultures sent to look for potential chronic infections associated with the bronchia bacterial and fungal cultures were negative. Three A F B speed cultures were sent and two cultures resulted positive for mac. So let's talk about N T M um a little bit. So we know that N T M are environmental organisms. The way I like to explain it is that uh to my patients is um they tend to be in stagnant water sources. So uh shower heads, humidifiers, um indoor swimming pool, hot tubs, you can see it in soil, oftentimes in avid gardeners, lakes, rivers. Um it's thought to be in water pipes and it can affect certain states and the countries as part of potentially municipal water systems. And it's difficult to treat because it forms a sticky substance around it called called biofilm, which makes it difficult for the antibiotics to penetrate through and attack the N T M, which is one of the reasons why this is this is such a difficult organism to eradicate. There's different ways to classify N T M. One of the more common ways are those that uh are slow growing clinically and in the microbiologic lab and those that are rapidly growing. So for example, for slow growing mycobacteria, the most common one that we see in the United States is mac. Some other examples are mycobacterium, Canasa and mycobacterium zope. You also have some rapidly growing mycobacterium with the most common one being mycobacterium, abscessus. These are some of the more common N T M organisms, but the amount of species for N T M is close to 200 that list is, is growing every day. So mac by itself is a complex of organisms. Um The reason for that is it's difficult to separate out in the lab. Um It often consists of about 12 organisms but it gets lumped into this complex called mac. The predominant organisms involved in the mac complex are mycobacterium, avium, mycobacterium, intracellular and mycobacterium chimera. But just know that Mac is a complex of organism that's oftentimes difficult to separate out. And when we talk about N T M uh lung disease, um that's the predominant presentation for N T M. About 77% of N T M disease is pulmonary. With the most common one being mac. Um about 92% of patients uh with Pulmonary N T M are do present with Mac. But there are other sites of infection that N T M can be involved with. There could be skin and soft tissue infections, there could be disseminated N T M. We saw that oftentimes during the HIV epidemic, um there could be lymph node involvement and other sites of infection, but we're gonna be talking predominantly about Pulmonary N T M and Pulmonary Mac. We know that N T M is increasing in incidents. Uh The map on the left is from 2008. The map on the right is from 2015 with the darker blue um highlighting a higher incidence of N T M. And you can see over time that there's been an increase in the incidence of N T M. And what's also interesting is that the darker blue areas here or the higher incidence of N T M tends to be in areas that are surrounded by water. So does that have something to do with the water supply going into these coastal states? Um It's not quite well understood, but it is interesting to see that not only has incidents increased for N T M, but the highest incidents tends to be in states that are surrounded by water. Now, when we talk about risk factors for N T M, we mentioned some environmental exposure. So air slice water from old showerheads, hot tubs, soil exposure, potential residents in um different areas of the United States. There's also host risk factors, you know, most commonly being uh prior or concurrent bronchus. Um you know, bronchiectasis from uh a prior pneumonia or other various ideologies uh such as autoimmune conditions, immunoglobulin deficiencies, uh and genetic uh deficits such as cystic fibrosis. Um you know, primacy or dyskinesia alpha one anti trips and those are all potential ideologies of bronchia. Um chronic aspiration reflux are o other um conditions that commonly can be associated with N T M and bronchia underlying structural lung disease from smokers with emphysema can be a risk factor for N T M. You also have amino deficiencies um and immunosuppressive agents such as T N F alpha antagonists, which can also be risk factors for N T M. And there's also some post susceptible phenotypes which we know that there's, they're associated with the N T M but we don't, we don't quite understand why there is an exact association. For example, we know that slender individuals with morpho body habitus, potentially with scoliosis hetu escada mit prolapse. They do have a higher incidence of, of N T M and, and tend to be associated with it. But the exact reasoning for that is, is not quite well understood. Now, common symptoms of N T M. Um you know, these are nonspecific symptoms. Um but we oftentimes can see uh fatigue as uh a symptom uh for pulmonary N T M, uh A cough which could be productive or dry shortness of breath. Uh patients can present with night sweats. Um Hoops also can be from the underlying uh N T M infection itself. It could be from the underlying bronchiectasis eroding into a nearby blood vessel causing hoopes. And it also could be from devices that we may be giving as part of their N T M management. So, for example, airway clearance devices, if patients are using it too vigorously, that can lead to irritation of the airways uh and possibly hemoptysis. And we oftentimes ask patients to hold their airway clearance devices. If they are uh experiencing hemoptysis and weight loss, could be a uh a marker of progression of N T M. We know that with uh N T M Pulmonary Disease, if it's not well controlled, it can lead to increased metabolism. And if patients are having unintentional weight loss, that could be a sign that their N T M lung disease is progressing. Now, uh The guidelines were uh originally uh published in 2007. They were revised in 2020. Um This slide highlights the diagnostic criteria as part of the guidelines which did not change uh in comparison to the original guidelines and to diagnose pulmonary N T M. Um patients need to meet three criteria. They need to meet clinical radiographic and microbiologic criteria to make a diagnosis of N T M. Regarding clinical criteria, they need to have suggestive pulmonary symptoms, radiologic criteria. They need to have findings on imaging, suggestive of bronchiectasis um or other findings um consistent with, you know, a chronic infectious process such as um bronchitis, potentially cavitary uh opacities on imaging and patients need to meet microbiologic criteria. And what is the, some of the microbiologic criteria? Um Patients should have positive speed cultures from at least two separate samples that are positive for the same anti M organism or they need to have positive cultures from at least one bronchial wash or la or they need to have a transbronchial or a lung biopsy suggestive of histologic features of N T M. So, potential granulomas inflammation and a positive culture along with that. So if patients do meet clinical radiographic and microbiologic criteria and exclusion of other diagnosis such as tuberculosis, they then meet a diagnosis of N T M. Now let's move on to some treatment considerations for Mac now to talk about this, it's important to uh understand which patients should we be considering treatment and which patients do we have some time and maybe can manage with nonpharmacologic strategies before jumping to antibiotics. The study on the left here looked at 488 patients with Mac Pulmonary Disease. And what they found was that in patients with Mac Pulmonary disease, a majority did progress without any antibiotics. About 62% of patients progressed. However, about a quarter of patients remain stable and out of those patients that remain stable, about half of them spontaneously converted their cultures to negative without any antibiotic treatment. Similarly, the study on the right looked at 551 patients with Mac Pulmonary disease. A majority were treated, about 60% of patients were treated, 40% were not treated with antibiotics. And again, half of those patients that were not treated with antibiotics converted their cultures to negative. So we wanna understand that although a majority of patients do progress with Mac, there is this subset of patients that remain stable and potentially convert their cultures to negative without antibiotics. So, in that particular population, we may not need to, to jump to antibiotics off the bat. And it's important to try to identify which of those patients are likely to progress where we need to consider antibiotics and which are more likely to remain stable where we have some time to consider whether patients need antibiotics or not. So this, these are some risk factors that highlight which patients are more likely to progress with their N T M lung disease. And maybe we should be considering antibiotics um a little bit sooner. Now, patients who are more likely to progress or those who are male who are older in age, they have presence of core morbidities. So for example, immune deficiencies, autoimmune conditions if they have low body mass index, if they have elevated inflammatory markers, anemia hypo alia, they may be more likely to progress if they have a higher extent of disease. So for example, if they have an increased infectious burden associated with cavities, uh on imaging, they may be more likely to progress and we should be considering antibiotics a little bit sooner and the type of species. So for example, rapidly growing mycobacteria uh are more likely to progress if they're seme or positive, they have a higher extent of disease and they're more likely to progress. So these are patients where we may want to have a low threshold to begin antibiotics. So the decision to to treat with antibiotics often involves consideration of those risk factors for progression. So in patients with more virulent N T M, if they have multiple risk factors for progression, if they have a high extent of disease. So for example, you're positive or cavitary disease. If they have many symptoms or poor quality of life, we may want to consider antibiotics a little bit sooner in these patients because they are likely to progress. However, in patients who are, who have less virulent N T M, they don't have any risk factors for progression. No cavities on imaging, they're smear negative if they have few symptoms and uh a good quality of life, we may not need to jump to antibiotics right at the start and we have some time to monitor and see if they do progress and try to manage their comorbidities and treat with nonpharmacologic strategies before initiation of antibiotics. Now, what are some of these non pharmacologic pharmacologic strategies that we can consider in patients? We know that airway clearance is a main state in management of patients with bronch EIS and N T M. Some examples of airway clearance could be positive ator pressure device, hough coughing, postural drainage, active cycle breathing techniques, muco active agents such as hypertonic saline that are nebuli high frequency chest wall oscillation. Those are all examples of of airway clearance therapies that we can offer to our patients. We oftentimes also refer them to chest physiotherapists to reinforce how to use these airway clearance techniques at home. We want to focus on nutrition and weight gain exercise um for general health and also as an airway clearance strategy and treatment of their comorbidities to try to reduce the progression of their N T M. So for example, treatment of their reflux aspiration, potentially sinus issues. Um those all can, can help, um you know, if they are controlled uh prevent uh progression of their N T M potentially. Now, in patients, despite, you know, management of nonpharmacologic strategies, or if they have multiple risk factors for progression, they may warrant antibiotics. And there's different regimens that we can consider based on the severity of their disease. So for patients that have mild to moderate disease, without the presence of cavities, we can label them as nodular bronchia tadic disease. And if they are macrolide susceptible, the guidelines suggest that we can consider a mali a ol and AIC and often revamp. Um we can consider this three times a week and the outcomes with this regimen is just as good as daily antibiotics with less side effects. And we do continue treatment for at least one year from the point of when they convert their cultures to negative or 18 months total. However, in patients that have a higher burden of infection, if they have cavitary disease or if they have severe nodular bronchia cat disease, we tend to give these antibiotics every day again with the Mali Dan and Erythromycin and the dose is adjusted uh based on um you know, a daily regimen. Also, we do consider an aminoglycoside as part of this regimen. For example, if patients do have uh cavitary disease, we could consider adding on an ID aminoglycoside to the three oral antibiotics. We oftentimes continue that for 2 to 3 months. See if they tolerate it and then convert it to inhaled aminoglycoside after that. Now, it's also important to understand which of these patients are susceptible to mali and Amic casein. So, and this is an important point because we oftentimes send the speed cultures to um to a lab that runs susceptibilities. But there's only two classes of antibiotics that have shown to be uh to correlate with what's being reported in vitro and what's being um happening in the patient in vivo. And those two classes of antibiotics are the macrolides and the and Amy case and the immuno glycosides. And not only do we see if these two classes of antibiotics are resistant or susceptible, but we also look at the M I CS to see if a patient is in fact sensitive to these antibiotics. So for example, a A mali is, is thought to be susceptible with an M IC of less than or equal to eight and resistant. Uh if their M IC is greater than or equal to 32 for I V MA case. And it's uh they're sensitive if the M IC is less than or equal to 16 and resistant. If the M IC is greater than equal to 64 for inhale ezo mama case. And the M IC is sensitive, it's considered sensitive if it's less than or equal to 64 or greater or equal to uh greater than or equal to 100 28 where they're considered resistant. So we look at these two classes of antibiotics to see if a patient is sensitive resistant. And we also look at the M IC cup points to see if they are in fact sensitive. Now, patients may run into side effects with antibiotics. They may need consideration of 2nd and 3rd line agents and these are some antibiotics to consider as 2nd and 3rd line agents. So for example, Clozamine, um it is under research protocol, it does require an I I N D. Um but it is an option for patients who uh are not responding to um guideline based treatment or running into side effects from some of the antibiotics. Um You know, we do have to monitor Q T C prolongation with EKG S if they are um receiving Clozamine. But Dakin also may be an option. Oxalin such as linas and tool may be options and inhaled mica may be an option as well. Inhaled parental formulations of Amic casein. And more recently, the lipo a formulation of inhaled Amic casein which has been approved as add-on therapy to guideline based therapy if a patient does remain culture positive. And this was a study looking at um am case and liposomal inhalational suspension. This is the convert study which was a phase three randomized controlled a study looking at Alice or um am a case and liposomal inhalational suspension added on to guideline based therapy. And what did the study show in patients who were receiving guideline based therapy if they were not, um uh if they were not improving, if they were having their cultures positive. After six months of therapy, they were randomized to either continuing their guideline based therapy or to continue their guideline based therapy. And having Alice added on, on top of that, they continued on the treatment phase and then they were monitored off treatment phase to see what happened to these patients. With the primary end point being culture conversion and what the study showed in that in in patients in the Alice plus guideline based therapy arm, more patients converted their cultures to negative by month four. With treatment, about 29% of patients in that in that treatment arm convert their cultures to negative compared to patients in the guideline based treatment arm alone in which 9% of those patients convert their cultures to negative. So because of this, the FDA approved inhaled lipoma and mccain as add-on therapy to guideline based therapy in patients that were culture positive by six months. Now there are adverse effects to monitor for in all of these antibiotics. So for example, with the mali, you should look at Q T prolongation G I side effects, hearing loss, hepatotoxic. So we often time monitor monthly labs with the, you know, complete blood count, liver function tests metabolic panels with a we want to, you know, make sure a patient doesn't have neuritis. We often times get a baseline eye exam and then repeat that every three months while they're on a with the rhythm mycins. You wanna monitor for cytopenias, giant intolerance hypersensitivity or pato toity with Amic cain, we monitor for renal issues, auto toity. So again, we get a baseline hearing test when a patient is being started on amino aminoglycoside and then monitor that every three months. And with inhale amca patients may experience dysphonia. Um if that occurs, we oftentimes ask patients to hold the inhaled Amic casein. If it resolves, we then restart it, we also can pretreat albuterol to help minimize the dysphonia. Patients may experience cough and shortness of breath. And what the convert studies suggested was that most of these side effects do resolve after the first month of therapy as a patient gets used to it. Now, with inhaled um liposome ma case, there's been more recent data that suggests that not only is um it beneficial to add on to guideline based therapy, but it also uh the culture negativity may be sustainable and durable in patients that receive Alice. So in patients that were on a plus guideline based therapy, a recent data suggested that about 63% of patients um who were in the Alice plus guideline based uh guideline based therapy arm remained culture negative while receiving treatment compared to about 30% of patients in the guideline based therapy arm alone. And once patients completed treatment, about 55% of patients in the guideline based therapy arm plus Alice remain culture negative at three months off of therapy. And 46% of patients in the Alice plus guideline based therapy arm remain culture negative after one year of stopping therapy. So some uh decent data suggesting that um patients may remain negative um in terms of their culture conversion while receiving Alice plus guideline based therapy arm uh treatment and also um may remain negative off of completion of treatment. Now, adverse effects with, with these antibiotics, they can be common. Um and it's important to, to really uh manage them appropriately. So, um you know, drug reactions can lead to interruptions of treatment. It can lead to morbidity, it can lead to non adherence and disco discontinuation of therapy which can affect clinical outcomes. So, the first step is really to educate the patients about possible side effects. We want to make sure that, that they understand what to look out for. And if side effects do occur, they contact their provider, they stop all therapy temporarily until side effects resolve and then you know, resume it based on um whatever side effect did occur, potentially without the culprit antibiotic. Uh we want monitor for potential adverse effects early and if side effects do occur, there's different strategies. So for example, we can hold antibiotics, we then can restart it once side effects resolve, we can stagger antibiotics um separated by a few days apart to see which corporate antibiotic potentially could be causing the side effect. And once you identify which antibiotic it is, you could potentially replace it with a second or third line agent. Um We also oftentimes administer antibiotics at night to minimize nausea, um that could be another strategy to help with some of the G I effects that can occur um with this regimen. Now, outcomes, um you know, are oftentimes dependent on whether a patient is mali susceptible or resistant. So, in patients who are mali susceptible, patients have pretty good outcomes. Specifically, if they do not have the presence of cavities, about an 80% chance of culture conversion and about a 50 to 80% chance if they do even have a cavity as long as they're magically susceptible. However, if a patient is mac lead resistant, the chance of cul culture conversion goes way down without any surgery or or aminoglycoside, the chance of culture conversion is about 5%. If we do offer some aminoglycoside or surgery, we can increase the chance of culture conversion to 15%. And if we administer a prolonged aminoglycoside plus surgery, the chance of coal conversion there in male resistance can increase to about 80%. So it is important to, to understand whether a patient is macolyte susceptible or resistant because that does affect treatment outcomes in these patients. Now, surgery could be an option in a select group of patients as a management strategy. It can be used in patients who are not improving or not tolerating therapy if they have complications, such as significant hemoptysis recurrent infection, particularly if it's localized and to help improve symptoms and quality of life is is a goal of surgery. Now, the guidelines suggests that in in selected patients with N T M Pulmonary disease surgical resection can be considered as a adjunctive therapy to medical therapy after expert consultation. And the rationale for this is, you know, observational studies that have been looked at, for example, 15 observational studies here reported um in approximately 700 patients who underwent surgical resection, the outcomes were not bad. And patients who underwent surgical reception, they were more likely to convert their cultures to negative. They had pretty decent complication rates without any operative mortality or post op mortality. But there's a selection bias to be aware of. We want to make sure that patients um who have localized infection are are potentially offered surgery and we wanna make sure this is done by an expert surgeon at a, at an experience center. But in those patients um who do have localized infection and they're not responding to therapy. Surgery may be a a reasonable option. So in summary, mac lung disease is increasing in incidence, the decision to treat with antibiotics should take into account the risk factors for progression. The severity of their disease, nonpharmacologic strategies can be utilized in patients. Um and treatment of co morbidities that are affecting um bronchia and mac armor. If patients are started on antibiotics, there's various treatment regimens and they do depend on the severity and the burden infection and the type of infection we want to monitor for side effects and mitigate any strategies. Um If side effects do occur to try to promote adherence and surgery can be considered in a select group of patients with reasonable outcomes. Thank you for listening. Published June 12, 2023 Created by
