Video Practical-, Evidence- and Guideline-Directed Advances in Antimicrobial Treatment for MAC Lung Disease Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Practical-, Evidence- and Guideline-Directed Advances in Antimicrobial Treatment for MAC Lung Disease Overview Hello, my name is Steven Field and I'm gonna talk to you about the practical evidence and guideline, directed advances in antimicrobial treatment for mycobacteria avium complex lung disease. I'm a professor of Respiratory Medicine at the University of Calgary. Calgary is a city of approximately 1.5 million in the province of Alberta in the western part of Canada. And we're just east of the rocky mountains through the uh presentation. I will show you a few of the scenes from our uh local area. So this is a um C M E certified webinar jointly provided by the University of Massachusetts Medical School and C M Education resources with commercial support from an educational grant from internet. So today I'm gonna talk to you about the epidemiology of non mycobacteria, specifically mycobacterium complex. I'll present one of my cases. We'll discuss the 2020 nontuberculous Mycobacterial guidelines. I'll talk about the treatment of the different presentations of mac lung disease. I'll talk a little bit about amica and liposomal inhalation solution, which I will refer to as Alice and specifically, I'll present two studies and I wanted to declare a conflict of interest in that I was involved in both of those studies. So over the last half century, the prevalence of nontuberculous mycobacterial pulmonary disease has been increasing. The annual prevalence prevalence in Canada and the United States is estimated to be between 5.5 and 10 per 100,000. And if one looks at the population of patients who are 65 years or older, the prevalence ranges anywhere from 20 to 47 per 100,000 N T M. Lung disease is more common in females and N T M patients tend to be taller and leaner than average chest wall disorders including scoliosis and pectus excavatum, mit valve prolapse and the presence of C F T R gene mutations also increased the risk of getting N T M lung disease. N T M lung disease can be debilitating with five year mortality rates reported up to 40%. There are approximately 160 non tuberous mycobacterial species that have been identified but only a minority cause lung disease. There is no evidence of human to human transmission. So there's no risk of contagion. As far as we know, non bela mycobacteria tend to reside in biofilms and plumbing and are found in drinking and shower water. They're also found in potting soil and dust but water is the usual source of infection. The uh Troilus mycobacteria are have lipid rich mycotic acid containing odor membranes that results in cells that are the most hydrophobic among bacteria. Their cell surface hydrophobic contributes to their concentration and water droplets arising from bodies of water. Their adherence to plumbing pipe surfaces and broad spectrum resistance to disinfectants and antibiotics, disinfection of water systems systems. With chlorine eliminates other bacteria that compete for organic carbon and facilitates the growth of non tuberculous mycobacteria. Since the prevalence is higher in the elderly, the grading of the population has increased has resulted in an increase in prevalence. Hot water is not heated as high as it was previously to conserve energy. And now this mycobacteria can actually grow in hot water systems and showering is also more popular. So, more patients are exposed to the organism in the aal water in the lab. Better microbiology techniques result in more infections being identified. Pulmonary disease is the most common presentation of non tuberous mycobacterial infections. And these often occur in patients with underlying airway disease. Usually bronchiectasis or C O P D. Mycobacterium avium complex or Mac is the most common cause of non Tuli mycobacterial lung disease worldwide. And the prevalence is increasing. Mac includes 11 species but only three mycobacteria, avium, mycobacteria, intracellular and mycobactin chimera commonly cause lung disease. The other eight species in this group are listed at the bottom of the slide. Typical presentations are nodular bronchiectasis and fibro capita disease. A few patients will develop hypersensitive pneumonitis from exposure to hot tubs contaminated with mac, but I will not discuss that today. The case I'm gonna present is one of mine who uh when I first met her was 54 years old, she had never smoked and had no history of lung disease. She was thin and she initially presented in April 2014 with a chronic productive cough, chest discomfort and weight loss. She had three speed of specimens collected that were smear negative but culture positive for Mac. This was her C T scan at the time and you can see that she had Pran disease in a right middle lobe and also in the anterior segment of the right upper lobe where there was possibly some early cavitation. She was started on treatment with rifAMPin 600 mg, a Zithromycin, 250 mg and AAM 1000 mg daily in that month by October, she was feeling better. Her cough had improved, was rarely productive and her speed culture had converted to negative in April 2015, her treatment was stopped because of side effects. Primarily she was developing flu leg syndrome from the rampant, but she was also experiencing a fair amount of G I upset. She remained well until September 2016 when her cough increased and became more productive. Her speed at that time was one plus smear positive for A and M. Avium was cultured which was sensitive to, to Clarithromycin and AMCA. Initially, she was reluctant to restart therapy because of the problems she'd had previously. But over the next few months, her speed remained culture positive for mac, her cough and speed increased and she began to lose weight since she had had difficulty with rifAMPin. Previously, she was started on Clofazimine 100 mg a day. And the M IC for Clofazimine was less than 1000.5 micrograms per M L along with the Zithromycin 250 mg daily and a tham 100 1600 mg three times a week, all given orally. And this was started in March 2017, she remained on these three oral medications. And in January 2018, despite treatment, she was still experiencing poor appetite, fatigue and she was having difficulty maintaining her weight over 60 kg, she had a repeat C T scan at that time that shows that she had persistent disease in the right lung. Although she didn't have any obvious cavitation and she now had some disease also in the left lung at that time, Forca was inserted and she was started on intravenous Amic application in a dose of 1000 mg three times a week. Her speed remained culture positive. And in August of that year, her G F R declined from 74 to 58 mils per minute because of the decline in renal function. Her Amic application was temporarily suspended and unfortunately, her ral function recovered and she was restarted on intravenous Amic application at a dose of 900 mg three times a week. Over the following uh period, she required several week drug holidays on several occasions because of nausea which persisted despite her being on, on Daron in August 2019, her speed and specimens were still one plus smear and culture positive. So application was made through the Compassion Access Program for her to receive AMCA and liposomal inhalation solution. We finally received approval through health Canada and then from the company in November. And so at that time, she was started analysis in a dose of 500 milli 590 mg a day, which was added to her oral therapy of Colas and Seromycin and Aam. And the intravenous Amic application was stopped through 2020. Her SPM specimens were intimately culture positive but she's remained culture negative. Since December 2020. In July 2021 she developed paraesthesias in both feet. So the Hambo was stopped and the paraesthesias resolved. She continued on treatment with a Zithromycin fas and ally until November 2021. And at that point, the Alice supply was exhausted. And since she's been uh culture negative, her students have been culture negative for nearly a year. At that point, we decided to stop therapy. Since stopping treatment, she's remained well. She's regained her weight and her speed of specimens. Since most recently in January of this year have remained culture negative. So in 2020 updated guidelines for the management of non tuberculous mycobacterial lung disease were published in Clinical Infectious Disease for this effort. They recruited an international group of infectious disease and pulmonary experts. These experts generated 22 picot questions to address diagnosis who should be treated and provided recommendations for the treatment of the non tuberculous mycobacteria that most commonly cause lung disease. They recommended that induced that and made the point that induced feed is nearly as sensitive as bronchial wash or B A L to isolate non tuberculous mycobacteria in patients with cavitary disease, in patients with fiber nodular bronchia tosis, they found that some but not all studies suggested that bronchoscopy is more sensitive than sputum. However, the studies that found Broncos be more sensitive were all relatively small, but the largest study found that freedom to be as sensitive. And so they recommended that bronchos be limited to those unable to produce proper speed of specimens. They recommended that a minimum of three speed specimens be collected. They also recognize that a small proportion of patients are diagnosed by B A L but that is really only the minority. Also a small number are recognized when they have suspicious lesions that are biopsies. But these patients don't require treatment unless they also have speed or B L that are culture positive. And the patients are symptomatic in the lab, spe is decontaminated with 1% anti cystine and 1% sodium hydroxide. Increasing the concentration of sodium hydroxide, decreases the contamination rates but also decreases. The sensitivity. Specimens are stained with oram fluro chrome and cultured in liquid and on solid media at 36 to 42 degrees Celsius to maximize the uh sensitivity for culturing mac smear positivity is reported semi quantitatively from one plus to four plus one plus. Refers to 1 to 10 organisms per low power field and four plus refers to 10 to greater than 10 per high power field. So much more concentrated. If there is a high suspicion in patients whose cultures are negative, it's recommended that the use of supplemental media and molecular techniques may be helpful. Isolate should also be treated for sensitivity to macrolides. And if patients are being considered for treatment with amma cases and isolate should also be tested for susceptibility to them. Resistance to clarithromycin is defined as isolates that have an M IC that's equal or greater than 32 micrograms per M L for parental Amic resistance is considered if the isolate is resistant to isolates that are 64 or great up to 64 or um more micrograms per M L. And with Alice, the cut off is 100 and 28 micrograms per M L. The diagnosis of mac lung disease is based on the following three criteria. The presence of symptoms such as cough, sputum, hemoptysis and radiological findings such as nodular opacities, cavities or bronchiectasis on either chest x-ray or C T and microbiological confirmation with two or more positive cultures of the same mycobacterial species or one positive bronchoscopy culture or lung biopsy with consistent pathological features and one positive bronchoscopy or speed of culture. In most cases, treatment should be reserved for patients in whom all three of these criteria are present. So, symptom being symptomatic, having consistent radiological findings and microbiological confirmation treatment of these patients is challenging. It usually requires a combination of three or more antibiotics for longer than a year. Along with regular lab monitoring, treatment is associated with numerous potential adverse effects. So, the decision to treat requires input from both the physician and patient considerations to treat include the impact of the symptoms on the patient's quality of life. The presence in severity of lung disease, immune system function, the presence of comorbidities, the risks and benefits of treatment. The microbiological burden is also important. Patients who sputum is also smear positive rather than just culture positive are at greater risk. The extent of radiological abnormalities, progression on serial imaging studies and the presence of cavities, all increase the likelihood of disease progression and are features that face to be the favor initiating therapy. It is important that prior to initiating therapy, patients be fully aware of the rationale for treatment, the potential side effects of the medications, the requisite blood work that will be required along with regular speed collections and vision and hearing monitoring that will be required while they are on therapy, whether patients are started on treatment or not, they should be followed because of the risk of progressive disease. In addition, patients that have been treated should be followed subsequently because of the risk of recurrence recommended treatment. The recommended treatment regimen depends on the patient's radiologic pattern and whether patients are failing initial therapy, the appropriate treatment for underlying conditions should be continued in these patients. So for if for example, if patients have bronchia cystic fibrosis, they should continue their regular chest physiotherapy. And patients with C O P D should remain on bronchodilator therapy. Macrolite therapy, either Clarithromycin or Zithromycin is the core antibiotic for treatment of mac lung disease outcomes are better with macrolite containing regimens and macrolite resistance is associated with poor outcomes. A zithromycin is preferred over clarithromycin since patients have fewer G I side effects with it, it's uh it requires fewer pills. It allows once daily dosing and the risk of drug interactions particularly with rabin is greater with Clarithromycin monotherapy with a macro light is not feasible because of the rapid development of macrolite resistance in patients with nodular bronchiectasis. The Zithromycin 500 mg, ayol and a dose of 25 mg per kilogram and rifAMPin 600 mg should be given thrice weekly. The rationale for this is that thrice weekly therapy is better tolerated and outcomes in those patients with nodular bronchia tosis were as good as those who were given daily therapy. In patients with fibro cavitary disease. The results with daily therapy are superior to intermittent therapy and so patients should be treated with a Zithromycin in a dose of 250 to 500 mg daily. A thin and a dose of 15 mg per kilogram daily. And revamping 10 mg per kilo or generally 450 or 600 mg daily, all given or an intravenous Amic case. And uh one in a dose of 15 to 25 mg per kilo and the dose should be adjusted with drug monitoring. It's important the trough levels be under 1.1 microgram per mel to minimize the risk of toxicity. And Amic application is given thrice weekly for the first 2 to 3 months of therapy in patients with refractory disease. The recommendations are the pay that the patients be given a zithromycin and a dose of 250 to 500 mg daily, abuttal 15 mg per kilograms daily and rabin 450 or 600 mg daily. My general practice is that if patients weigh under 50 kg, we give them 450 mg and over 50 mg uh over 50 kg, we give them 600 mg daily and now these are all given orally and they should also be given Amic application in one of three forms either intravenous and a dose of 15 to milligram, 15 to 25 mg per kilo three times a week or inhaled intravenous Amic application solution in a dose of 250 to 500 mg daily or Alice in a dose of 590 mg daily. It is recommended that inhaled intravenous Amic solution or Alice be reserved for patients with refractory disease. That is those patients who fail to have their speed convert to negative. Despite being treated on appropriate treatment. As based by the as suggested by the guidelines for six months or longer, it is recommended that treatment be continued for 12 months after the speed converts to negative. There are no control trials but a retrospective observational cohort study reported convert to negative rates of 22% in those patients who were treated the to for less than 12 months and 86% in those who are treated for 12 months or longer. So many patients with mac lung disease are elderly with multiple comorbidities requiring medications that are not compatible with rifAMPin. Although not endorsed by the guidelines, we have treated some with clofazimine and we published our results in 2016. And basically, we found that the regimens with clofazimine to be were non inferior uh in our patients who mostly have non cavitary disease. And so in those patients, we are often substituting clofazimine for rifAMPin. If rifAMPin is uh cannot be given with the medication the patients are taking or if they're intolerant to it. Others have also reported success with cosine and I've listed some of the authors there, there are no clear definitions for clofazimine resistance and di different authors have reported different M IC values as resistance. And I think that this is one of the reasons that there was reluctance to recommend it in the guidelines. However, the guidelines do recommend that it can, it can be used uh if a thol cannot be used and it, it can, in that case, a thol can be substituted with cosine or Amic rain and a macrolite or moxi floxin and amaro light are not considered to be adequate regimens to prevent macrolide resistance from developing in patients with cavitary disease or those who fail to convert to negative with oral therapy. Amica is recommended has stated. The traditional approach is to give it intravenously but intravenous administration is associated with the challenges of maintaining intravenous access for months and the risks of hearing loss and renal dysfunction. The intravenous formulation has been given by inhalation to target the site of infection and avoid or minimize risks associated with intravenous aminoglycoside. A case in liposomal inhalation solution or Alice was designed to be given by inhalation in the Alice formulation. Amic application is encapsulated in liposomes composed of the natural lipids, dipalma, phosphatidylcholine and cholesterol. And you can see what it looks like in, in the cartoon on the left and there's an electron microscopy of these uh liposomes on the right. Alice is administered by a nebulizer that was specifically designed for its use the mira nebulizer system in patients with non tuberculous lung disease. 43% of the dose was deposited in the lungs during nebuli organization. Approximately 70% of the amca remains encapsulated within liposomes, increasing its access into macrophages and biofilms. In studies in rats, Alice increased Amic casein uptake into the macrophages 5 to 8 fold compared to inhale free Amic casein allowing targeting of the intracellular organisms. Approximately 30% has released this free AMCA to deal with the extracellular organisms with Alice posto SPM concentrations are greater than that observed in serum and systemic exposure is low, reducing the risk of toxicity. So, I'm gonna talk about the phase three study with Alice and an open label extension trial with it. These two studies were presented in three published papers. The convert phase retrial recruited patients refractory to guideline based therapy for six months or longer. And it compared speed convert to negative rates in patients treated with Alice plus guideline based therapy to those patients treated with guideline based therapy alone. The second paper reported those patients who speed them converted to negative and compared the relapse in recurrence rates in those treated with Ali plus guideline based therapy to those treated with guideline based therapy alone. The third paper reported an open study of patients who failed to convert to negative and convert and received Alice plus guideline based therapy for 12 months. So the first study uh was the first author of the first study was David Griffith. And for this study, they recruited patients with Mac who were persistently culture positive despite being on guideline based therapy for six months or longer exclusions for this trial were patients with cystic fibrosis, those with active tuberculosis immune deficiency syndromes or patients whose isolates were resistant to Avoca. The patients recruited for this trial had a mean age of 65. 69% were female. They tended to be thin with a mean B M I of 21 and 63. These 63% of these patients had bronchos, 14% had C O P D and 12% had both patients that were randomized to Alice plus guideline based therapy had had Mack lung disease for a median duration of 4.5 years. And those randomized to receive guideline based therapy alone had had mac lung disease for a uh for a median of 3.3 years. This was a randomized open label non placebo control trial. It was felt that nebuli nebulization of empty liposomes may have made it difficult to distinguish adverse effects with the liposomes from Alice inhalation. So the uh so this was the um the study design adults with treatment refractory mac lung disease were randomly assigned 2 to 1. So twice as many received a plus guideline based therapy than those that received guideline based therapy alone and substitute achieved culture conversion by month four and remained culture negative at month six, continued in the trial to complete 12 months of treatment from the first negative culture that defined conversion. So some patients received up to 16 months of treatment of Alice or I should say of treatment in general. Um The patients not achieving culture conversion by month four or who were not culture negative at month six exit. The trial at month eight and all were eligible to enroll in the extension study. This slide shows the proportion of patients achieving culture conversion displayed by the first month at which speed cultures were mac negative patients receiving Alice plus guideline based therapy are shown in the dark bars and patients treated with guideline based therapy alone are uh shown in the light with the lighter bars. Month four was the latest time at which a patient could achieve the first of three consecutive monthly negative speed cultures and be considered a converter at month six by month. 4 29% of the ali plus guideline based therapy treated patients had converted to negative and remained negative at six months. Whereas only 8.9% of the guideline based therapy alone cohort achieved culture conversion. Among the patients recruited in this trial, 22% had Clarithromycin resistant isolates defined as an M IC of 32 micrograms per M L or greater. Among the pill, the patients who were chloro and resistant, 14% converted to negative who were randomized to receive a plus guideline based therapy. And in the guideline based therapy alone, cohort 5% only um were able to convert to negative secondary objectives in this trial that were assessed hierarchically included the six minute walk test time to culture conversion and quality of life is assessed with the Saint George respire questionnaire. There were no significant difference between the arms in terms of the six minute walk test or Saint George respiratory questionnaire. However, if some, if one compares the subjects in either arm who achieved culture conversion to those that did not, there was a significant improvement in six minute walk test of approximately 25 m. So this slide shows the time course of the onset of the most frequent treatment, emergent adverse effects defined as those that occurred in 10% or greater of the patients in either arm on the left. The show I show the uh the cohort that were treated with Alice plus guideline based therapy and on the right, the guideline based therapy alone. And one can see that dysphonia Disney and cough were more common in the patients who received guideline based therapy. However, if one looks at the prevalence or the occurrence of any treatment, emergent adverse effect, serious treatment, adverse effects or deaths, the results were similar in the two arms. So the conclusions for this study were that after four months, the speed of 29% of the patients who were randomized to receive Alice plus guideline based therapy had converted to negative compared to only 9% of the patients who did not receive Alice respiratory side effects including cough, dystonia, dysphonia and dysnea were more common in patients treated with Alice but did not usually result in patients leaving the study. The prevalence of serious side effects was similar in the two arms. So the second paper showed the results of the patients who successfully converted to negative uh during treatment in the convert study. And a total of 75 patients achieved culture conversion by month six. That included 65 to 224 or 29% of the patients who were randomized to receive Alice plus guideline based therapy compared to 10 of the 112 who were treated with guideline based therapy alone in the follow-up speed was collected at four weeks, 36 and 12 months after the patient said I finished treatment, paso speeds were genotypes to determine whether those patients that uh had recurrence were due either to a relapse of the original isolate that they had or that they were reinfected with a different isolate. This slide shows the results of the subjects who received cul who achieved culture conversion. Each pair of bar graphs compares the results of the Alice plus guideline based therapy cohort to the guideline based therapy, cohort alone. The results at the end of treatment in convert are shown on the left three months off treatment in the middle and 12 months off treatment on the right. The percentage of subjects who met culture conversion criteria by month six, completed 12 months of post conversion treatment and showed sustained and gerbil conversion is shown in red 11 subjects in the Alice plus guideline based therapy, cohort completed less than 12 months of post conversion treatment and had negative culture results at the last visit. And they are shown in the dark blue samples with positive cultural results for MAC were geno typed and shown as reinfection with a different ice living gray or relapse with the same ice li and orange patients. In the other category shown in light blue did not have speed culture results due to missed visits, missed feed data or study discontinuation. So the summary from this paper was that those who converted to negative with Alice plus guideline based therapy were more likely to sustain negative cult results. After completing treatment, culture conversion at six months is predictive of the sustained and gerbil effect and treatment with Alice up to 16 months did not result in any new safety signals. The third paper reported the open extension study for the ins non converters. So in this study, adults with treatment refractory mack lung disease originally rolled in the convert study who did not achieve conversion or had recurrent mac infection by month six, exit converted month eight and were eligible to enroll in this open label safety extension study. Patients originally randomized to receive Alice plus guideline based therapy and convert continued their assigned treatment and patients originally as re assigned to receive guideline based therapy alone had Alice added to their ongoing guideline based therapy at the baseline of this study. The baseline of this study coincided with the end of treatment visit in in uh convert. So this slide displays the patient disposition diagram. 100 and 63 subjects enrolled in the study of these 90 had not received Alice in convert and uh 73 had the reasons for withdrawing from this study. Are shown on the right and 100 and seven or 66 or two thirds of the patients completed uh completed this trial. The proportion of patients who did not receive Alice in the convert study who achieved culture conversion is displayed by the first month at which speed cultures were negative for MAC as bar graphs. In the upper panel of this slide and Kaplan Meyer analysis in the lower panel, the convert to negative rate at month four was 26.7% which was similar to the 29% seen in the convert trial at month 10. The convert to negative rate was 33.3%. Month 10 was the latest time a subject could achieve the first of three consecutive narrative speed cultures and be considered a converter by month 12. A subject with missing monthly culture data was considered positive for Mac unless they were unable to produce freedom. Even after induction, this slide shows the proportion of subjects who had, who had received Dallas in convert, but uh who were able to who were unable to have negative cultures in convert but achieve culture conversion in this study, you can see that the uh scale is very different. And at month four, only nine per 9.6% of these subjects had converted to negative and 13.7% at month 10. So the conclusions here where the culture conversion rates were similar to the convert study at four months, 27 versus 29% safety and tolerability of Alice plus guideline based therapy were consistent with convert respiratory adverse effects. Cough Disney and dysphonia were common early on but rarely resulted in discontinuation, nephrotoxicity and hearing adverse events which are obvious potential concerns with intravenous application were infrequent over the 12 month treatment phase. There were no safety, no new safety signals detected in patients who were treated up to 20 months with Alice that included the aided convert and 12th in the in the open label study. So this is what I do. My practice is to see patients one month after initiating therapy to ensure that medications are being tolerated and being taken properly at three month intervals. While on treatment. While on oral therapy with the Zithromycin Thabit and rifAMPin monthly blood work including A CBC and liver function tests are done along with monthly visual acuity and color vision testing. And these are done because of the potential risk to vision. With uh th patients submit speed of specimens monthly to determine when they convert to negative to start the 12 month countdown to completing therapy. Patients also undergo an electric cardiogram for Q T C interval measurement and an autograph. Prior to initiating the initiation of therapy, the E C G is repeated after one month. If patients in, at their initial E C G had a Q T C that was 450 milliseconds or greater and every six months while on therapy, since macro lights can increase the Q T C interval, audio grams are repeated every six months while on therapy, since it is isthmic may cause hearing loss. So can chloro for that matter, renal function and hearing are monitored in patients being treated with amica creating measurements should be done monthly and our practice is to monitor predose Amic communication levels which should be less than 1.1 micrograms per M L every two weeks. Patients who could not be treated with rabin in those patients, Clozamine is a potential option. Although not endorsed by the guidelines. The most common side effect with clofazimine is skin hyper pigmentation, but it can also cause Q T C interval prolongation and patients require more regular E C G monitoring if they're also on clofazimine. So there've been surgical case series that have been published uh but there are no control trials for surgery in patients with non break this mycobacterial disease. A systematic review and meta analysis of surgical case series reported a convert to negative rate of 93% recurrence rate of 10% and serious complications of 17% have due to prolonged air leak, postoperatively and mortality rates of less 1%. This systematic review uh was published chest on uh in chest online in October this year and still isn't actually uh published in a journal. These optimistic results are from centers that are highly experienced in this type of surgery and patients are highly selected. The surgery is difficult because infected areas increase the risk of deficits and blood vessels to affected areas are often urged. So risk of bleeding is obvious the need for reasonable lung function be generally healthy otherwise and to have relatively localized disease for surgery, to be consideration means that only a relative minority of the patient of patients with N T M lung disease can be considered for a surgical approach. So to summarize the prevalence of Mack lung disease is increasing and is difficult to treat. Treatment requires three or more antibiotics for an extended period of time and treatment success is not guaranteed. In addition, those who are successfully treated remain at risk for recurrence and so follow up is required even after they complete therapy. Convert was the first controlled trial of any therapeutic agent against treatment. Refractory Mack lung disease. Alice offers an option for the management of patients who fail to respond to oral therapy. It avoids most of the challenges of long-term intravenous therapy, increases the likelihood of successful treatment and reduce, reduces the risk of early recurrence. So at this point I'm going to stop and I'd like to thank you for your attention and for those of you that know, the Canadian Rockies. This is a picture of more lake. Thank you very much. Published April 25, 2023 Created by
