All right, I'm going to talk about Carotary Amavium Complex Lung Disease, and I want to use a case to kind of talk you through guideline-based management of that disease entity. That's me. I'm currently working at the University of Tübingen, which is in Germany, so I came up all the way from Europe, a little bit jet-lagged, but here I am. These are the objectives of this talk. We're going to look at how to apply guideline-based management to a real-life case, and we'll have a look at drug susceptibility testing and its intricacy in interpreting pertaining to lung disease. We're going to look at drug-drug interactions in this particular case, and we'll have a look at the rationale for safe surgical resection. So this, I think this comes up, again, there are a couple of polling questions. You can use that barcode to enter the system. I'm going to make reference to this treatment table. This is from a summary of the most current clinical practice guidelines to treat NTM lung disease, and again, I'm going to make reference to that table during the talk. So this was a 62-year-old woman I took care of when I was at Mount Sinai in New York. She had a history of right-sided breast cancer that was treated with radiation therapy 15 years prior to this presentation. Two years prior, she had presented with major hemoptysis and found to have what was described as a right middle lobe syndrome. You guys all have probably a visual image of that. It's an electrotic middle lobe with fibrotic changes, and there was a hemorrhage coming from and she underwent resection of that middle lobe at the time. The pathology of the specimen revealed necrotizing granuloma. I'm not sure if cultures were taken. There were at least no positive culture data available. Now she presented again with right lower chest pain, cough, mild hemoptysis, and low-grade temperature, and that was her chest x-ray. You can imagine the right middle lobe should be gone, so you have here all these abnormalities in the right upper lobe. Sputum was taken, was collected, it was smear positive, and the culture grew up on several occasions. So we send this off to drug susceptibility testing, but here comes my first question. How would you consider treating that disease entity if it turns out to be susceptible MAC disease? So we have a couple of potential answers here. Treat as fibrinodular disease with a three-weeks regimen, triple regimen, azithromycin, rifampin, etambutol was usually used. Treat as carotid disease with daily three-drug treatment. Treat as extensive disease with daily treatment and add IV amication, or treat as extensive disease with daily triple therapy and add inhaled liposomal amication. All right, so we have a variety of answers here. Treat as carotid disease with daily rifampin, etambutol, and rifampin, I think, was a majority. It looks like this is extensive disease. I'm going to show you some CAT scan images also that there's evidence of cavitation. So we elected to treat as extensive disease, which would imply to add intravenous amication to the regimen. But before we start it, we got some drug susceptibility testing back. And I want to go over this in a little bit more detail because I think there's a lot of room for confusion. Because this is a readout we got back, amicacin, you've got the MICs here, oops, what happened? All right, that's a button, of eight, what was labeled as resistance. The same etambutol resistant, rifampin sensitive, and then there was clarithromycin on it without a disclaimer. So I'm asking you, again, how would you, based on that result, how would you modify your treatment choice? A, would you change azetone to clarithromycin because that was a drug that was tested? Stop etambutol and add marxifloxacin, stop amicacin and add clofazamine, or continue the current regimen? Okay. We've got a couple of votes. Let's see what you guys said. Continue the current regimen. And we've got a couple of votes to modify the regimen, stop amication at clofazimine. So let's go over that drug susceptibility testing again. So the problem is, with most of these readouts, especially when they come from commercial labs, that the breakpoints they use to qualify it as resistant or susceptible or intermediate are based on tuberculosis, on the breakpoints of tuberculosis. And we know that these breakpoints are not correct when we use them for NTMs. In fact, there are only two drugs where clinical breakpoints are associated with clinical outcomes. And these are amicacin and the macrolides. And here from the table, from the summary I've got here, you can see that the actual breakpoints for M. avium disease are different, right? So for claritomycin, it's less than 8 micrograms per ml. And our specimen here had an MIC of 1. So that means susceptible. Also take note that the lab uses claritomycin because they're set up to use claritomycin. It correlates one-to-one with azitomycin. So the fact that you don't find azitomycin on this panel doesn't mean that you couldn't use it. Amicacin here was qualified as resistant, but has an MIC of 8 micrograms per ml. That is considered to be susceptible. So you can keep using that drug. And I think the most important part is when it comes to etambutol. There are no breakpoints for etambutol that correlate with treatment failure or success. The role of the etambutol is actually thought to be protective for the macrolide. So one of the potential mistakes people could do is, oh, it says resistant to etambutol. I take it out, and I'm going to use a quinolone. And we know that with that combination, the risk of getting acquired macrolide resistant is significantly higher. So you want to keep the etambutol in. You're going to ignore the MICs. You're going to keep it in to protect the macrolide. So with this, this is the regimen we chose. We chose daily azitomycin, etambutol, and rifampin. And we added amicacin three times weekly for the first eight weeks. So as we followed the patient along, the smear that was initially AFB positive turned negative. And from subsequent cultures, which we sent to the lab, we noticed an increasing time to positivity, which means that the bacillary load was continuously declining. That's a sign that the treatment is working. And after eight months, the cultures had returned negative. That's a little late. But since we saw this steady decline in previous cultures, we were optimistic that we would be able to achieve culture conversion. So we did. Now, two months later, however, that means 10 months into treatment, the patient was again admitted with hemoptysis and chest pain. And these are the CAT scan images during the new admission. What you can see, some of the cavities indeed got bigger. But when you look at this cavity, the walls also got smaller. But there is more to it. I think I highlighted it here. There's a little air fluid level in this cavity. And you see this ball there, which turned out to be a fungus ball. The patient underwent bronchoscopy. We did not isolate any AFBs or any mycobacteria. But there are spirulina secretions. There were no significant other bacteria. We were worried about staph or pseudomonas or something like that. So she was treated with a bronchocosm of Augmentin for bacterial superinfection. And we found the Aspergillus fumigatus. And we decided to treat that in that situation, because this is probably the one that's giving the problem. So she was started on voriconazole. With that, however, we had to modify the treatment regimen. Reason is that voriconazole and rifampin have a negative drug interaction. The rifampin ramps up the metabolism of the voriconazole. You're not able to get therapeutic drug levels. So we decided to change the rifampin to clofasamine. And there's evidence for that that's also spelled out in the clinical practice guidelines. Here it says only regimens using rifampin, rifamicin, and etambutol or clofasamine and etambutol have been shown to prevent the emergence of macrolide resistance during treatment. So we're OK to doing that and still protecting the macrolide. What would we have done if there was an emergence of M. avium? We would have probably treated her as refractory disease. And that's where the inhaled M. acacia in the liposome inhalation suspension comes into play. It's been approved for refractory disease. So it means culture positivity beyond six months or recurrent culture reconversion. That was not the case in our patient, so we didn't go that route. So this is what the patient was treated on. And after several months and clinical stability, we decided to do a completion hemoanectomy. Remember, the right middle lobe was already removed. So we decided she had good enough lung function to do that. We did a completion hemoanectomy. The pathology revealed necrotizing granuloma, but there was no growth of mycobacteria. And all the cultures remained negative. So that's my take-home points. It was a case of pre-existing focal lung destruction. That's the risk factor for NTM superinfection. When you have that clinical presentation, your differential remains broad. You think about mycobacteria. You also have to think about aspergillus and bacterial superinfection. That's what happened subsequently down the line. We talked about the drug susceptibility testing with the intricacies and the most important thing to protect the macrolide. We talked about drug-drug interaction, how that may modify your treatment approach. And we talked about the time of safe resection. That I'm going to end. And I want to actually thank the team at Sinai and also at the National Jewish Hospital, which we conferred a lot about this case, our time. Also, it's Andrew Kaufman and Chuck Daly, who's actually here. Thanks again. Hi, everybody. Happy Sunday. And welcome to Hawaii. All right. I'm Taryn Imai. I'm a thoracic surgeon here locally at the Queens University, with the Queens University Medical Group at the Queens Medical Center, probably about 10 to 15 minutes down the street. I've been here for about a year. This is home to me. Actually, Hawaii is home to me. Prior to this, I was at Cedars-Sinai in Los Angeles since 2016. So I'm going to just kind of, I'm a little outnumbered here for the first time. Probably the only surgeon in the room. So I'm going to go through this slide deck here. So I have no disclosures. So although targeted antimicrobial therapy remains the mainstay of therapy, failure of medical therapy, of course, is not uncommon in MTM disease. And the reasons for treatment failure are many, which many of you all know, drug resistance, patient intolerance, lack of access, and presence of parenchymal lung damage, and more specifically, severe bronchiectasis and cavitary lung disease. Now adjunctive surgical resection is really only used as part of a multimodality treatment approach, only in conjunction with antimicrobial therapy. And really, the purpose of surgical resection is actually used to improve treatment success rates of your antimicrobial therapy, especially in those patients that have focal parenchymal damage, again, bronchiectasis and cavitary disease, which in those situations, the antimicrobials are actually poorly penetrated. And therefore, these areas of parenchymal disease actually serve as a reservoir for organisms to sort of trigger recurrent infection. So when we talk about indications for surgery in MTM, there are basically three major ones. The first one is failure of medical therapy. The second one is symptom control, including life-threatening symptoms. And the last is to limit disease progression. So when we talk about the first indication, failure of medical therapy, this can happen and present in patients that have recurrent infections, have antibiotic resistance, presenting with recurrent treatment failures, antibiotic intolerance in patients, an overall poor response to antibiotic treatment, which is lack of sputum clearance or ongoing features of active disease or progressive disease with progression of lung destruction on imaging. Clarithromycin susceptibility is an important factor when considering surgical resection, mainly because resistant strains have reduced sputum conversion rates compared to clarithromycin-susceptible strains. And the goal of surgery for this indication is really to induce a treatment success. For the second indication for surgery is symptom control. And surgery is used to either reduce or eliminate troubling or life-threatening symptoms. So chronic persistent cough can definitely decrease the quality of life of a patient. And then when we talk about life-threatening symptoms, hemoptysis, which is the most common symptom leading to surgical resection. And the goal of surgery as far as symptom control is to actually alleviate the symptoms and not actually to eradicate disease. And many times when surgery is performed for symptom control, residual disease may still remain. And the third indication, limiting disease progression. Basically, we want to just slow down disease progression or debulk some of the parenchymal damage. And what we mean by debulking is when a patient presents with unilateral disease that may be severe, whereas the contralateral lung may be spared. We want to address the severe disease in that lung so that it doesn't progress and affect the good lung, so to speak. Surgery is not likely to produce eradication of disease at all. And really the goal, again, is to slow down disease extension and to really spare the good areas of the remaining lung. So who can have surgery? So patients that undergo surgery will often meet the American Thoracic Society criteria for pulmonary NTM infection, have focal parenchymal disease that's amenable to resection with the remaining lung still somewhat structurally free of any sort of tissue damage, and have adequate pulmonary reserve. These patients undergo quite an extensive preoperative evaluation, cardiac stress testing and perfusion scanning, as well as exercise testing to really test their, you know, robustness of their cardiac status is important. Of course, any kind of lung resection, pulmonary function testing is a must. These patients will get high resolution CT scans, not only to sort of evaluate the true extent of the disease, but also to help us determine whether minimally invasive approaches can be used as far as for resection. Repeat imaging after antibiotic courses, mainly to see what the treatment sort of outcomes are. Bronchoscopy is used to either rule out or rule in concomitant endobronchial pathology. In the case of symptoms and hemoptysis, to localize hemoptysis or localize areas of bleeding, and then also to obtain cultures. And lastly, nutritional assessment. As you know, most of these patients are very malnourished, and in order for them to optimize and achieve the best perioperative outcomes, we really have to optimize their nutrition as best as possible in the preoperative state. So, when is surgery performed? So, usually surgery is performed after antibiotics and antimicrobial therapy has been initiated about 8 to 12 weeks preoperatively, and usually this is with a three or four drug combination. Now, the goal of preoperative therapy is sort of to achieve that nadir in the mycobacterium counts before going to surgical resection, and that's used to sort of help minimize the perioperative complications. Now, too much antimicrobial therapy or too long of a time interval is also not great, and as found in this study, that patients that were on the longest treatment course of antibiotics prior to surgery actually took longer to achieve sputum clearance postoperatively. And so, that suggested that there is an increase in the acquisition of drug resistance in surgery if surgery is delayed too long. Now, going over the surgical approaches with the sort of the more common patterns of disease with MTM, Lady Windermere Syndrome, kind of an antiquated name, but however, describes a patient with right middle lobe and lingular bronchiectasis occurring exclusively in women. And in this approach, a staged thoracoscopic resection spread out by six weeks apart after an antibiotic pretreatment. And so, many people will say, well, how come you just can't do both sides at the same time? And I would say whether for this as well as for any kind of lung cancer or any kind of resection, we usually like to space out our operations by about four to six weeks just to give the patient some time to recover and to optimize our chances to get single lung ventilation in the operating room. Focal bronchiectasis or cavitary lung disease, also very common, requiring resection. However, if the patient is actually presenting with bilateral disease, the surgical approach is actually to do the less severe side first. And the reason for that is because if the less severe side is taken care of first, then when you're going back in after so many weeks and trying to take care of the more severe side or the more diseased side, the ability for that patient to tolerate one lung ventilation during surgery is definitely more increased. And then complete lung destruction, which often requires a pneumonectomy. So, as far as how surgery is performed and what the surgical technique is, so anatomic lung resection is preferred in order to minimize post-operative complications and to ensure a complete resection of the involved area is performed. And mainly that's sort of like, I guess, in comparison to wedge resections. Oftentimes these lungs are actually not the usual nice, spongy lungs. And a lot of times our staplers won't actually deploy or fire appropriately because of the thickness of the lung. We have many different sizes of thickness as far as staplers go, but whenever we're dealing with infection, oftentimes the staplers either won't deploy, which means you're doing the old fashioned cut and sewing technique, or they will deploy, but you'll get staple line dehiscence. And so that often will lead to a prolonged air leak, as well as a space post-operatively, which is never great in an infected field. As far as the approach, lateral thoracotomy or open surgery versus minimally invasive, either with fats or now even robotics. And so some of the differences between an anatomical lung resection done for cancer versus mycobacterial disease includes in an infection, there's a significant more amount of sort of adhesions. The bronchial circulation is actually hypertrophied. So I think you have to be pretty ready for a lot of bleeding. Type and crossing, having blood in hand, aggressive with the blood transfusions is always necessary. The higher lymph nodes are numerous and often enlarged. And lymph nodes can actually be very densely adherent to adjacent structures. And meaning the adjacent structures that are important are usually blood vessels. So lymph nodes actually follow blood vessels and the airway. And so you have to be ready for a high incidence of pulmonary artery injury, which is probably one of the more devastating intraoperative complications. And really sometimes to actually get across and sort of transect the blood vessels, you kind of have to actually pull away those lymph nodes in order to get a clear safe window. And then lastly, the fissures may also be fused. So as far as determining how, whether a patient is appropriate for open surgery versus a minimally invasive approach, this study by Yen et al looked at image characteristics as predictors for patients that may have feasible disease for a minimally invasive approach. And in this study, they evaluated 50 of their patients and half of them underwent VATS and half of them underwent thoracotomy. And they looked at five different characteristics and graded them on this grade of severity with zero being the least severe and two being the most severe. And in the VATS group, there was a significantly lower gratings in pleural thickening, peribronchial lymph node calcification, tuberculoma cavities, and aspergilloma. The mean operative time, blood loss, and complication rates were actually similar. And like most other things, especially in cancer, mean hospital length this day was actually shorter in the VATS group, 10 days versus almost 15 days. Now some other surgical considerations that need to be sort of accounted for when you're doing surgery for NTM disease is bronchial stump buttressing. And this is really to prevent bronchial stump blowout. We're not really too concerned with this in the oncology world unless the patient has preoperative radiation. But in infection, absolutely. So usually the most robust flap would be the latissimus dorsi muscle, which is usually harvested either by a thoracic surgeon or in these days a plastic surgeon. And it drops between the intercostal space and onto the hilum. Another one that's used more very commonly are the intercostal pedicled muscle flaps, and that's usually easy to perform. The residual lung can often be poorly compliant, and it actually fails to fill that space. And you really don't want these empty spaces in infected areas because they're just an itis for infection. And in order to fill that space, one can either use autologous tissue, oftentimes by bringing omentum from the belly into the chest and sort of stuffing the empty space with omentum, or performing a limited thoracoplasty. And really in that picture of the x-ray below. So the thoracoplasty is really an operative approach that essentially sort of resects the thoracic cage with multiple rib resections. And sort of the principle is to sort of take away that skeleton, that bony skeleton of the chest wall, and have the soft tissue chest wall sort of collapse down and adhere to the visceral pleura. As you can see, it's quite deforming. And lastly, if a patient is undergoing pneumonectomy, they may require extra pleural dissection if the intrapleural space is completely frozen. Now when we talk about surgery, this seems like all very extensive. And I guess one needs to ask, well, is surgery really worth it for this patient population versus just medical treatment alone? And in this first study, which is probably one of the first studies that were published that sort of compared antibiotics versus surgery plus antibiotics, and this was back in 1970, they found that sputum conversion rates after operative management was 91% compared to only 27% with medical treatment alone. Now mind you, this was actually conducted in the pre-clarithomycin era. In a more current study in 2011, they also looked at the same comparison in 107 patients and actually found that the surgical resection group actually had a higher rate of culture conversion and remained culture negative at one year compared to the medical group alone. And when we continue to look at surgical outcomes, more specifically sputum conversion rates, the sputum clearance rates reported across multiple studies have ranged anywhere between 81 to 100% with better conversion rates of antibiotics were continued post-operatively. As far as relapse rates, which were about 0 to 20% with ongoing antibiotic therapy, really one of the risk factors for recurrence is the presence of a persistent cavitary lesion after surgery. And therefore, anatomic resection may be performed safely and can be efficacious in the treatment of these infections. Now how long should the antibiotics stay on after surgery? So the current ATS IDSA guidelines advocate for treatment for 12 months after culture conversion, not after surgery, but actually after culture conversion. And some centers will actually recommend treatment for two years if a pneumonectomy is performed. And that's mainly because stump breakdown of that pneumonectomy of the main, either the right or left main stem bronchus, is actually a complication that can be fatal. And speaking of complications that are very fatal, bronchopleural fistula. So when you look at these three studies that have been published, all of them have pretty much used muscle flap coverage for their bronchial stumps. And the bronchopleural fistula rate is not insignificant. It's 25% to 60%, which is still kind of high. There's a high rate of bronchopleural fistula after pneumonectomy, more so on the right side. The right side does have a four to five fold increase of BPF versus like performing a left-sided pneumonectomy. And the reasons mainly are because the anatomy of the right and left main stem are very different. The right side bronchus actually does not have much tissue coverage in the mediastinum versus the left-sided stump will actually retract under the aorta and actually have a bit of natural buttressing and flap coverage there. Additionally, the right bronchial stump is usually more vertical. And so secretions are more likely to sort of fester in that stump and break it down. And then also as far as blood supply, the left bronchial stump actually will have a great blood supply with large vessels versus the right side. We often will devascularize that bronchial stump as we're doing in the lymph node dissection. So those are sort of the reasons why the right side is definitely much more susceptible to BPF formation than the left. Now, overall risk factors for BPF development include those patients that have poorly controlled infection, significant cavitary disease, those patients that are undergoing completion pneumonectomy, and those patients that have a positive sputum at time of surgery. And therefore, the overall sort of take-home message is there needs to be aggressive buttressing of that bronchial stump during surgery. Now, with overall post-operative complications, the overall complication rate averages about 28%. And it does vary across studies ranging anywhere between 0% to 63%. Most complications do occur, of course, after the pneumonectomy is performed. And some predictors of poor prognosis include patients that are undergoing pneumonectomy, patients with a low BMI because these patients are likely malnourished, old age, and residual cavitary disease. So in conclusion, surgery for NTM is used as part of a multimodality treatment approach and can actually improve treatment success rates. The indications for surgery include failure of medical therapy, control of life-threatening symptoms, and limiting disease progression. Minimally invasive surgical approaches can be performed safely in the appropriate patient. And surgery for NTM requires nuances that differ from surgery from cancer. Thank you very much. Hello. Good afternoon, everyone. Thank you for inviting me to speak. So I'm certainly outnumbered here. I'm not sure if there's anybody else who's infectious disease trained. So I am. So nice to be here and to see you all. So I'm going to talk about work in New York. I'm going to talk about antibiotics that are used for the treatment of common NTM infections with a focus on adverse events and toxicity monitoring and just overall talk about the challenges that are associated with NTM antibiotic therapy. So as we think about treating our patients with NTM pulmonary infection, as has already been said during the previous two talks, it's important to think of treatment as multimodal. This is a unique infection in that antibiotics are one part of a larger scheme of things. And this can be understood in context of the pathophysiology of bronchiectasis and of NTM pulmonary disease. As we all know, it's a constellation of various factors, mucociliary clearance, structural damage, and infection, which are perpetuating a cycle of inflammation and causing the pulmonary disease that occurs. So as we think about treatment, of course, thoughtful consideration to antibiotics for your patients, but contributing causes like GI dysmotility, gastroesophageal reflux disease, or any high-risk environmental exposures need to be addressed. And then, of course, we need to make sure that we address the bronchiectasis itself, the irreversible structural air damage that needs mucociliary clearance measures. So just in general, why is it so hard to treat this infection? The challenges associated with NTM antibiotic therapy. Most of these are very well known to us, of course. There's need for prolonged combination therapy. Sebastian has touched upon the nature of these bacteria. So because of intrinsic microbial resistance, treatment options are limited to begin with. We only have a few antibiotics to work with. And then, of course, there's risk of acquired drug resistance and necessitating combination therapy in which the macrolides play the main role. Certainly, the lack of clinically validated susceptibility breakpoints for most drugs, and we've touched upon this as well, that we don't really know the correlation, how in vitro susceptibilities correlate with clinical response. There are multiple drug-related toxicities due to specific agents, due to a high pill burden, drug-drug interactions. And lastly, the epidemiology of this disease, of NTM pulmonary disease, as we all know, most commonly affects the elderly, frail, malnourished humans who have several comorbid conditions to begin with, and they're hence at very high risk of drug intolerance and drug-drug interactions. So antibiotic therapy needs to be an individualized decision. It needs to be thoughtfully considered for each individual patient, taking into account clinical factors, microbial factors, the patient's commitment to a very long disease course, because the last thing you want is non-adherence with therapy and to create resistance. And then also, the psychological impact of the disease process itself is huge. And then, of putting somebody on harsh treatment for such a long time, all of those things need to be taken into consideration as you're deciding whether antibiotics are right for your patient or not. And if antibiotics are offered, it's important to discuss the risk of toxicities, any areas of where there's lack of clarity, and the expected benefits. And you need to have a toxicity monitoring plan in place. All right, so listed here are the agents that we're all familiar with, that we use for treatment of slow-growing mycobacteria and rapid-growing mycobacteria. For the rapid-growing mycobacteria, like Mycobacterium abscessus, it's a combination of intravenous drugs and oral drugs that we use. OK. So you just started your patient on triple therapy for MAC pulmonary disease. I'm sure all of us have had this call that in a few days the patient calls you and really complains of essentially feeling worse than they did before the antibiotics were started. Feeling really very specific, but feeling lack of energy, fatigued, a general ill feeling, poor appetite, certainly they can manifest with a rash, et cetera. We deal with this a lot. And one of the things that has been talked about, it is in practice in various places and was also published by pharmacists at Mayo Clinic, is that you take a staggered start. That's one way to introduce medications for your patient and to make it easier that you introduce one medication at a time over four to five days or so with monitoring for intolerance in between. It can help you identify which drug is causing the problem, the drug that is predominantly responsible for the intolerance that the patient is receiving. And as was described in this paper here, another example of a staggered, like a gradual treatment start is also gradual titration of drug dosages. So I'm going to start with the antibiotics that are used for treatment of NTM. So the rifamicin, we have rifampin and rifabutin, the sister drug. Rifampin is an important drug, of course, but really a beast when it comes to adverse events. There's a wide range of adverse events that can occur, everything from hepatitis, which is more common in patients who have existing liver disease, are on other hepatotoxic medications, heavier use of alcohol, et cetera. It can cause a blood dyscrasia, like so leukopenia, thrombocytopenia, neutropenia, hemolytic anemia. A flu-like syndrome can occur within the first few weeks after starting rifampin. It can cause renal failure because of interstitial nephritis. It accelerates the breakdown of endogenous cortisol, and so it can precipitate adrenal insufficiency. Pneumonitis can occur, and this would be a patient with fever, cough, interstitial infiltrates. And certainly, like any other drug, you can get a drug rash, which can be just a general exanthem, but something more significant, like a cutaneous vasculitis and histone-positive lupus has also been reported. Orange-colored secretion, certainly important to tell people if they're wearing contact lenses, et cetera, or light-colored clothes, because all your fluids will be colored orange, which can be distressing. So the sister drug rifabutin, a very similar adverse effect profile. It can cause a hepatitis, drug-induced lupus can occur, pancytopenia, very common in women. Pneumonia can occur, and then it can also cause a uveitis. So talking about the rifamicin still, drug interactions are really common. So rifampin, it's important to remember, is a potent inducer of CYP3A4, and it can cause therapeutic failure of many, many substrate drugs. Rifabutin is similar, but generally considered a less potent inducer of CYP3A4, so the drug interactions are not that significant. So it often becomes our choice when we're dealing with a very difficult drug interaction, but are stuck with the rifamicin. So the list is long. This is certainly not a complete list of drug interactions that can occur with rifampin, but everything from oral contraceptives, hormone replacement therapy, levothyroxine, glucocorticoids, azole antifungals, blood thinners, anticoagulants, calcium channel blockers, beta blockers, et cetera, can be affected. Our patients are, of course, often really sick with multiple comorbid conditions. So here are some of the common drug interactions that you may run into with rifamicin. Rifampin and prednisone, for example. So this could be a patient with COPD, and you're wanting to treat an exacerbation. It's important to recognize this interaction. Rifampin is inducing the CYP3A4, reducing the serum concentration of prednisone. So watch out for steroid effectiveness, and consider doubling, increasing the dose of the prednisone if you're treating a COPD exacerbation or something else. Rifampin and voriconazole, and this was the case that Sebastian presented. This is a class D interaction, so really not recommended to use in combination, because you will not be able to get therapeutic levels of voriconazole due to the induction by rifampin. And it cannot be overcome. There is data which actually showed that it cannot be overcome by an increase in the dose of voriconazole. Rifabutin and clarithromycin is another one. This is a more complex two-way interaction where the concentration of clarithromycin can be reduced, and the concentration of rifabutin can be driven up significantly. And you can end up with rifabutin toxicity with uveitis, pancytopenia, et cetera. Also a class D interaction, so avoid the combination whenever possible. And if you're really stuck with it, then use a lower dose of rifabutin, although when it's an interaction that that's strong, we really do try to just avoid it completely. So the use of Paxlovid, like since COVID-19, the interaction between rifampin and Paxlovid driven because of the ritonavir component, again, like strong CYP3A4 induction increases the metabolism of Paxlovid. It's important to remember that for certain drugs like Paxlovid and other drugs that contain something like a protease inhibitor, there's actually a washout period. The inducing effect lasts for a while. So you really can't stop and start the other drug right away. So it becomes limiting with medicines that are timely. The macrolides that we have, azithromycin and clarithromycin, they're used interchangeably. As Sebastian mentioned, we usually get a result on our drug susceptibility profile for clarithromycin, but we use azithromycin more commonly. Just some differences between the two drugs, like azithromycin, of course, has a longer half-life, less frequent dosing. Clarithromycin requires twice a day dosing at least because of a shorter half-life. GI side effects do occur with both drugs, but in general, clarithromycin is more poorly tolerated with a lot of dyskousia, dyspepsia, et cetera. Generally azithromycin is better tolerated. Azithromycin does not have any effects on P450, CYP3A4, whereas clarithromycin is an inhibitor and you can see drug interactions with warfarin, etraconazole, rifabutin, as we just discussed. Hearing loss and QTC prolongation are other two characteristics which are common to the two drugs. So when it comes to making a choice between the two drugs, this was addressed in the most recent guidelines and the recommendations of the panel were that azithromycin is preferred over clarithromycin because of better tolerance, less drug interactions, lower pill burden, single daily dosing, and equal efficacy. So unless there are other reasons, availability, et cetera, azithromycin is the preferred macrolide. Moving on to ethambutol, another part of the combination regimen. More slow-growing mycobacteria. I think we all are familiar with optic neuritis. That is the most prominent side effect of ethambutol. It manifests as a change in visual acuity or red-green color blindness, more commonly seen in patients with MAC versus tuberculosis according to some data, which basically is because of prolonged duration of therapy for MAC than for tuberculosis. This is a dose-related side effect, so seen more commonly with higher doses of ethambutol. Important to remember that ethambutol accumulates in renal failure and you can see more toxicity, so important to dose adjust and exercise caution there. Similar to optic neuritis, you can have other nervous system side effects with peripheral neuropathy, AGI distress, and certainly you can see hypersensitivity, although not as common. It is important and part of standard care to have a regular assessment of visual acuity and color vision, a self-assessment at home. Patients should be doing that. And certainly upon your clinic follow-up, you should be asking about any visual symptoms that are new. And then, of course, they need to be under ophthalmology care for serial ocular examinations. Optic neuritis due to ethambutol can be devastating. It is, however, reversible in most cases. So if you do see signs of that, please stop the ethambutol and start steroids and send the patient to the ophthalmologist. Moving on, inhaled liposomal amikacin indicated for the treatment of refractory MAC pulmonary disease. And this is the only drug that has been FDA approved for treatment of MAC, so 590 milligrams once daily inhalation. It comes with its own special nebulization system. When it comes to toxicities, the most common thing you will see is dysphonia, bronchospasm, cough, worsening symptoms of bronchiectasis, hemoptysis. Rarely, you can see an actual pneumonitis, a hypersensitivity pneumonitis. But most of these side effects have to just do with the airway, throat irritation, et cetera. More prominent early on. For most patients, as time goes on, these symptoms do tend to get better. There's ototoxicity. This is an aminoglycoside, of course, so hearing loss, tinnitus, et cetera. And then there are nervous system side effects with fatigue, headache. You can certainly see some diarrhea as well. Parenteral amikacin, so intravenous, so strong consideration in cases of cavitary MAC disease. Generally dosed at 15 mg per kick, three times a week. And this, of course, is very ototoxic and nephrotoxic, so there needs to be stringent toxicity monitoring for otovestibular and nephrotoxic side effects. Hypersensitivity, of course, can occur, but it's rare. And then the other side effect, similar to what we already talked about with liposomal amikacin, neurotoxicity. So you can see respiratory depression, circumoral paresthesias, which you can manage by slowing down the infusion rate, like muscle twitching, et cetera. And this, of course, is an IV medication, so you're looking at OPAT with home nursing and line care, et cetera. Audiology monitoring. A lot of questions about what the correct frequency of audiology monitoring is. So the general approach that we all tend to follow is that for someone on intravenous amikacin, monthly audiology monitoring is put in place. What the correct frequency is for inhaled amikacin, for macrolides, we don't really know. All of these drugs are ototoxic. It's important to do a baseline exam, especially if you're considering IV amikacin, and recognize that high-risk patient who is more likely to develop otovestibular toxicity so that you can monitor them appropriately. And consider formal audiology testing on any form of amikacin at least once a month. All right, coming on to the rapidly growing mycobacteria, like M. abscesses most commonly. So as I had mentioned, it's a combination of oral and intravenous drugs that are used. And usually you're looking at three to four agents at least based on susceptibility testing. So as the backbone, like are the good old betalactams, imipenem certainly is an important one alongside cefoxitin, which becomes an alternative betalactam backbone, although sometimes they have been used in combination for difficult cases of M. abscesses. They're renally cleared, important to remember that. You can see a drug rash. You can see myelosuppression, drug-induced hepatitis, C. diff, of course, interstitial nephritis. And I encourage you to look at the guidelines, which do make recommendations on monitoring for some of these drugs. There's a nice table in the NTM guidelines from 2020. So the monitoring on betalactams is clinical. And then, of course, your CBC, kidney function, LFTs should be monitored. The other drug that is important is tegacycline. Often the NTM are susceptible to this. This is, however, a very tough drug to get your patient through because there's severe nausea and vomiting. And oftentimes you have to prescribe an antiemetic to help get the patient through the course and also reduce the dose. Even with an antiemetic, sometimes it's just not possible. It's cleared through the hepatobiliary system. So monitoring of liver functions is important. Amikacin we already touched upon, so I won't go into that. Part of the monitoring, of course, is looking at drug levels, peak and trough levels alongside the audiology exam and your renal function. Clofazamine, so a novel mechanism of action, a very old drug, though, developed in the 1950s to use tuberculosis, used to treat leprosy, et cetera. Preventative against NTM does have a special status in the United States, so you can't get it from pharmacies. You have to get it from the FDA or get it through an expanded access program by the pharmaceutical company. Fairly well tolerated, the universal property is of skin darkening. Skin takes a bronze, tan-brown appearance, so important to counsel patients on that. It is a reversible effect, so happens slowly and goes away slowly, but your skin does return to its normal color. Otherwise, there can be extensive dryness of skin, photosensitivity, too important to talk to patients about that, and then QTC prolongation is the other property. Another drug that we use, linazolid, and the sister drug, tadizolid, hepatic clearance, protein synthesis, inhibition, good bioavailability, the side effects are listed here. The most prominent is myelosuppression, more so with linazolid than with tadizolid. Lactic neuropathy, there's mitochondrial toxicity with these drugs, so you can see lactic acidosis, and then reversible MAO inhibition, so you need to counsel patients on certain foods in addition to drugs. Fluoroquinolones, not first line, just listed here, DNA gyrase inhibitors, cleared by kidneys, and it's important to tell patients to space out any type of dairy products, divalent cations, calcium, et cetera, by at least an hour to allow absorption. I think we're all familiar with the side effects. So in conclusion, treatment of NTM disease is challenging, but while it can feel so, certainly should not be worse than the disease. I think there are many ways we can make it easy for the patient as well as ourselves. Give thoughtful consideration to risk versus benefits of antibiotic therapy for individual patients. Treatment is long, so take into account both physical, psychological impact of prolonged therapy. Treat the bronchiectasis, the airway clearance measures are critical. Address underlying causes, high risk exposures, get to know your antibiotics, work with your ID, OPAT colleagues, they can make your job easier. Lots of unknowns still, but we're all in it together. So thank you for your attention. Thank you. So I was asked by Sebastian to discuss ongoing challenges with the treatment of M-obsessives. Thank you so much. I thought you were my friend. The last count, these are my disclosures, the last count, there were 350 challenges. And I will cover all of them in the next three minutes. So you know the guidelines, you've heard people referring to the guidelines, and this is really our document in which we try to build a treatment regimen. But I can tell you, as the chair of these guidelines, it's not enough for you to cure your patients with M-obsessives. You need more than what's in the guidelines. The guidelines can only look at what evidence was available at the time that they're written. But things are happening all the time, publications are occurring, experiences in our clinics. So I'm really going to focus on four challenges. I may not get to the third time-wise. One is, it's a crazy taxonomy in nomenclature, trying to understand what to call these things and the names keep changing. I'm going to try to put a little clarity to that. One of the challenges, just the high levels of in vitro resistance and really understanding the importance of macrolide resistance. Probably the biggest challenge is actually treating a patient with M-obsessives. And then, because the guidelines aren't enough, you have to look beyond the guidelines and look for novel agents that might be available to you to add to the treatment regimen. I was going to use a patient, this is one of my patients, a 79-year-old woman who presented with kind of typical NTM pulmonary symptoms. She had been previously treated for MAC. Why she had bronchiectasis? Well, she had had pertussis as a child. She also had tuberculosis, severe tuberculosis that required surgical resection and the underlying bronchiectasis. And then, the treatment. So she was treated previously for Mycobacterium younginensis. Anyone ever heard of younginensis? So it's one of the 12 or so species of MAC. She got a typical regimen. She had cavitary disease at the time, so she got a parenteral amication. I mentioned the surgical resection for TB, and these are her medications. She was using hypertonic saline and a flutter valve for her airway clearance. Her physical exam, she was borderline hypoxemic, 90%. This is at altitude in Denver. Chronically ill, was mostly in a wheelchair. She had crackles in her lung feel. You can see the CT here, particularly right-sided disease, some cavitary disease. She had a slightly elevated CRP. She had some anemia and borderline low albumin. These are known in the setting of MAC to be risk factors for progression. We obtained sputum specimens, and these grew Mycobacterium obsessus, subspecies obsessus. We used a Lyme probe assay, which showed there was no RRS mutation. So she should be immunoglycoside susceptible, but unfortunately she had a positive RRL mutation. That means she has macrolide resistance. She has mutational resistance. Why is that? Maybe because she was treated for MAC previously and probably had some obsessus at the time, may have been subclinical, and she also had inducible macrolide resistance. So why do I say she has subspecies obsessus? Oh, sorry, and we always confirm resistance patterns phenotypically. All right, so why do I say she has obsessus? Well, this is one of the challenges today, because the name keeps changing. This was discovered in this person's knee and subcutaneous buttocks in 1953, but obsessus wasn't named until 1992. In 2006, it was recommended that it's not one species, but it's three, obsessus, mycelians, and biletii, but there was a naming violation claimed, and so mycelians' name was removed. It was just someone broke a rule, but what happened is then mycelians was collapsed with biletii into a new subspecies, and then in 2011, we just had two subspecies, but the problem is there's very little biletii, and almost all of those that the labs were telling us were biletii were actually mycelians, and that's important based on their macrolide resistance. In 2013, with my good friend and late Wenjing Ko, we did another genomic study, and we recommended they be split back out into subspecies and to reinitiate the name mycelians. This was confirmed in 2016, and then in 2018, Gupta suggested that we change the name to mycobacterioides obsessus. This has been officially accepted, but it turns out taxonomically, once named, always named, unless someone formally retracts it, that has not happened. So you can say mycobacterium, or you can say mycobacterioides. I'm an old guy. I'm saying mycobacterium. So from the right over is now considered appropriate nomenclature. Now, where you live determines what you see, so these are studies from across the world looking at the frequency of the subspecies. If we focus on mycelians, which I'd call the good obsessus, you can see that as we get into Asia, the rates start increasing to account for almost 50% of the infections. This, again, is the good one because of its macrolide susceptibility, and you may be saying, well, why do we really need to know this? Because most laboratories don't tell you the subspecies. I would argue that we do. We're still learning about these different species. We know that both M. obsessus and mycelians have been documented in multiple studies now to be likely transmitted from CF patient to CF patient, but both have been. In terms of disease progression, there does not seem to be a difference between mycelians and obsessus, but there are risk factors for progression for both of them, which are basically the same as we see for MAC. Where they're different, mycelians is usually susceptible to the macrolides, and what that means to you as a provider is you're much more likely to cure your patient who has mycelians because that organism will be responsive to the macrolides. Now, so let's talk about this resistance. This is a study we published last year. We looked at thousands of strains in our reference laboratory and used CLSI guidelines to do susceptibility testing, and this is why it's so hard to treat these people. Everything in red is very resistant, and if you look across all the drugs that we use or have to use in this setting, most of them have in vitro resistance. As we get to amikacin, tends to be one of our more active compounds, and in the macrolides, if you only look at day three to five and don't look for mutational resistance, you'll see that most of the time it's susceptible, particularly in the setting of mycelians. So understanding macrolide resistance is important because whether you have it or not determines the outcome, and it's because there are two types of resistance, mutational resistance. This is what our patient had, probably because of previous therapy. So this is high-level resistance. There's also inducible, and that's much more common and a bit more complex. This is due to an ERM gene, ERM41 in particular here. In M-obsessive strains, about 80% of the time, they have a functional ERM gene. What that means is in the presence of a macrolide, that the isolate becomes resistant, and it starts to happen quickly. But in myceliates, it's almost none of the genes, none of the isolates have a functional ERM gene. They have an ERM gene, but it has a deletion in it, so it's non-functional. Boletii is like obsessives, and it basically always has a functional ERM gene. This is a study, again, we did with Dr. Koh years ago, just demonstrating very early on what happens with obsessives in the setting of macrolide incubation. 19 strains of obsessives. They all started out in the susceptible range at day 3, which is a typical time to measure. But you can see by day 7, they had all become resistant. MICs had increased. And by day 14, they continued to increase. High-level resistance, and that's why we recommend you measure MICs at day 3 to 5, and day 14, to identify inducible resistance. But this is myceliates, and with myceliates, despite incubating with clarithromycin out to 14 days, there was no change in MIC. So it remains susceptible, and that is a critical issue related to treatment. And this is how we think about this, in terms of developing your treatment, and whether you should or should not use a macrolide. If at day 3 to 5 and day 14, the culture shows that the isolate's susceptible, this is an ERM gene that's not working. That means it's probably myceliates, could be one of the C28M obsesses. So this is macrolide susceptible, and please use a macrolide. If it's susceptible at day 3 to 5, but resistant at day 14, that has a functional ERM gene. The macrolide is not going to work. It's not going to have activity. You may use it for its immunomodulatory capability, but you can't count it in the regimen. And if there's resistance, both in day 3 to 5 and 14, this is high-level mutational resistance. Basically, it means the same thing as inducible resistance. Don't count on it, but if you use it, it's for immunomodulatory purposes. So treatment. These are basically the treatment guidelines published in CID and the European Respiratory Journal. If you have M obsesses, this is the most important thing your lab can tell you. Is it macrolide susceptible or not? If it is, it's probably myceliates. We recommend a macrolide, one or more other drugs, and amikacin. You give it for two plus months, depending on severity of disease, resources, tolerance, and then we usually transition to inhaled amikacin. Now, the problem in this setting is, what are those other drugs? This is what's listed in the guidelines. This is it. And if you try to build a regimen with just this, it's going to be very difficult, either because of underlying resistance or intolerance or not even available. It's worse if you do have macrolide resistance, because now you've lost the macrolide and you're going to have to find another drug to add to that regimen. And that list doesn't get longer. So it becomes, again, difficult. It's a challenge to treat a patient. The difference in outcomes is quite significant. With myceliates, it's somewhere in the 60% to 80% range, and less than 40% with biletii and abscesses. We're trying for 12 months of culture negativity, but you can imagine if you can't build an effective regimen, that's a difficult goal to achieve. So these are early studies which just demonstrate the importance in terms of the impact of macrolide resistance has on outcome. These were early studies that looked at the subspecies and looked at things like sputum conversion. And you can see very quickly here that myceliates had 80% to 90% culture conversion, but we see 25% to 40% with abscesses. So a huge difference. But really, that's just culture conversion. If you look at treatment success, meaning people who converted, stayed converted, and did not have a recurrence, the treatment success is lower. This was a study we did with Dr. Kwok in South Korea. It's an individual patient meta-analysis, about 300 patients. You can see treatment success, 45% for when it was abscesses and not further speciated, 33% when it was subspecies abscesses, and almost 60% when it was myceliates. And factors that were associated with good outcome was the use of imipenem, the use of azithromycin, and parenteral amikacin. So back to the case of what I did is I started her on amikacin, imipenem, clofazamine, and then we were trying to get some other drugs. I changed on two months later to inhaled liposomal inhalation suspension, which was off-label use, but I was able to get it. She was on clofazamine, and we were still trying to get omatocycline or clonazotuzelid. Ultimately, we could not get those because of insurance issues. And then over the next few months, she continued just really to disappear before my eyes, losing weight, you know, in a wheelchair. Albumin dropped to 3.1. She was anemic. She was a mess. And cultures were still positive. So I restarted the IV because I felt at that time she was going to die. So I needed help. And so what could I do? Well, I mean, right now we can go use dual beta-lactams. We know that obsessus has a beta-lactamase, and that we can use dual beta-lactams where we see synergy in the laboratory. Or you can add a beta-lactamase to a beta-lactam, and we can also see synergy. I could try to get omatocycline. It has very good activity against obsessus, as does tuzelid. But I couldn't get them. And then we were talking to her about using phage therapy, which has been shown in a recent report that 11 of 20 patients, mostly who had obsessus, one of the subspecies, that they had a response to phage. But what I was able to get was beta-lactams. So you can see her CTs on the right. In December of 2019, I started her on dual beta-lactams. The cavity was starting to get smaller, but she was still culture positive, still anemic, still high CRP. And over the next six months, a miracle occurred to me. She completely closed her cavity. For the first time in years, she became culture negative. She gained 5 kilograms. She normalized her CRP for the first time. Her albumin normalized. Her anemia resolved. I don't know. It seems like a miracle to me. I still follow this lady. She has been culture negative for three years and completely different, no longer, and has not been in a wheelchair for years. So for me, this is an early wow moment that there are things that I can reach out and sometimes get that can have an impact on my patient. It does require persistence. The good news is there are better things coming. These are things that are in phase one, phase two, phase three. Don't have time to talk about them. But just be hopeful. These are very active compounds, more active than anything we have right now. And hopefully, they make it through the drug development pipeline, and we'll have better regimens, better outcomes for our patients. So I didn't do that in four minutes. But anyway, thank you for listening.

mycobacterial lung disease

Carotaryum Independenti Complex

NTM

guideline-based management

drug susceptibility testing

drug-drug interactions

safe surgical resection

case study

necrotizing granuloma

positive culture data