Benefits of early treatment initiation in non-tuberculous mycobacterial pulmonary disease (NTM-PD)

Treatment of non-tuberculous mycobacterial pulmonary disease (NTM-PD) with antimicrobial agents offers the possibility of cure.¹ In patients who meet the clinical, radiographical and microbiological diagnostic criteria for NTM-PD, the 2020 ATS/ERS/ESCMID/IDSA clinical practice guideline for NTM-PD recommend initiation of treatment rather than watchful waiting.¹ Initiation is especially important in the context of positive acid-fast bacilli sputum smears and/or cavitary lung disease¹as there may be an increased rate of progression and poor treatment outcomes if treatment is delayed.¹

Evidence of disease progression in untreated MAC-PD

Several studies have shown that most patients diagnosed with Mycobacterium avium complex pulmonary disease (MAC-PD) have progressive disease resulting in the need for antibiotic treatment.^2,3 In a recent study of 488 newly diagnosed patients at the Asan Medical Center in South Korea, 305 (62.5%) patients showed progressive MAC-PD resulting in treatment initiation within 3 years of diagnosis.² Similarly, in another study of 40 untreated patients with the nodular bronchiectatic form of MAC-PD (most with minimal symptoms), who underwent serial chest computed tomography (CT) scans for a minimum of 4 years, 39 (97.5%) experienced disease progression with a significant increase in overall CT score.³ It is noted in the 2020 NTM-PD guidelines that some subgroups (minimal nodular/bronchiectatic disease) may be safely, but regularly, followed without antimicrobial therapy; however, those with cavity disease should always receive prompt antibiotic treatment.¹

Factors influencing the decision to initiate treatment

The decision to treat may be influenced by both host factors and infecting bacterial species. Certain factors like cavitary disease and low body mass index have been associated with progressive disease and may necessitate earlier consideration of antibiotic treatment.² In very frail patients with very mild nodular bronchiectatic disease, the balance between efficacy and tolerability may favour watchful waiting.¹

The clinical relevance of NTM varies significantly between species (Figure 1) and may also differ geographically.^1,4 For example, species such as M. gordonae have low pathogenicity and rarely cause disease in humans, whereas M. kansasii is highly pathogenic.^1,4  

Figure 1. Clinical relevance (the percentage of patients with isolates of these species that meet the ATS/IDSA diagnostic criteria) of non-tuberculous mycobacterial species. M., Mycobacterium. Adapted from Zweijpfenning (2018).⁵

The most common NTM pathogens include MAC, M. kansasii and M. xenopi among the slowly growing NTM and M. abscessus among the rapidly growing NTM.¹

Meeting the guideline-recommended diagnostic criteria for NTM-PD

Diagnostic criteria within the guideline is based on:

• Clinical symptoms e.g. worsening of symptoms of underlying lung conditions, or onset of new, persistent symptoms in patients at risk of NTM-PD e.g. haemoptysis, weight loss, fatigue
• Radiological findings on X-ray or hight-resolution CT scan such as nodular or cavitary opacities
• Microbiological findings from a) at least two expectorated sputum or b) positive culture from at least one bronchial wash or lavage or c) positive culture for NTM and biopsy from transbronchial or lung biopsy plus one or more culture positive sputa or bronchial washing.

Patients suspected of having NTM-PD who do not meet the diagnostic criteria should be actively managed and followed with serial CT scans until the diagnosis is firmly established or excluded and should start or continue recommended techniques such as airway clearance.⁶

The decision to initiate antibiotic treatment

NTM-PD is associated with diminished health-related quality of life that correlates with severity of lung impairment;⁷ antimicrobial treatment may be associated with improvement.⁸

NTM-PD treatment decisions are often difficult and require experience in managing the disease. This can mean that it may be necessary for a peer consultation or referral to a pulmonologist or infectious disease specialist with experience in NTM-PD.^1,9 The virulence and potential for progressive disease must be evaluated once the NTM species is identified in order to determine treatment. In the 2020 ATS/ERS/ESCMID/IDSA clinical practice guideline for NTM-PD for example, it is recommended that for species of low pathogenicity such as M. gordonae, treatment is only indicated if repeated positive cultures over several months are observed, along with strong clinical and radiological evidence of disease whereas in many patients only one positive M. kansasii sputum culture may be required in order to initiate treatment.¹ Similarly, clinically significant MAC-PD is unlikely in patients who have a single positive sputum culture during the initial evaluation but can be as high as 98% in those with ≥2 positive cultures.¹ Two or more MAC-positive cultures indicate active MAC infection requiring a treatment decision, whereas for patients identified with M. kansasii, treatment should be initiated as soon as a single positive culture is obtained.¹

Regardless of the infecting organism, the decision to initiate antibiotic treatment should be individualised considering the patient’s symptoms, the pathogenicity of the organism, radiological findings, microbiological results and importantly, the patient’s wish and ability to receive treatment as well as the goals of therapy.¹ Any treatment decision should include a discussion with the patient that outlines the potential side-effects of antimicrobial therapy, the uncertainties surrounding the benefits of antimicrobial therapy and the potential for recurrence including reinfection (particularly in the setting of nodular/bronchiectatic disease).¹ Guidelines recommend regular sputum cultures and routine monitoring to assess disease progression.¹

Following treatment initiation, sputum specimens should be obtained for culture every 1 to 2 months to document when sputum cultures become negative and to survey for the appearance of other organisms. ¹

Clinical and radiographical assessments should be performed alongside the microbiological assessments to determine if the patient is responding to therapy.¹

Retrospective studies have shown that most patients with MAC-PD who convert on treatment do so within 6 months of starting treatment.^11–13

If you decide not to initiate antibiotic treatment, an active monitoring plan is recommended by the guidelines.¹ Study data suggest that untreated NTM-PD could progress.^2,3

References:

1. Daley Cl, et al. Clin Infect Dis 2020;71:e1–e36.
2. Hwang JA, et al. Eur Respir J 2017;49:1600537.
3. Park TY, et al. PLoS One 2017;12:e0185774.
4. van Ingen J, et al. Thorax 2009;64:502–6.
5. Zweijpfenning SMH, et al. Semin Respir Crit Care Med 2018;39:336–42.
6. Lipman M, et al. BMJ Open Respir Res 2020 ;7 :e000591
7. Mehta M, Marras TK. Respir Med 2011;105:1718–25.
8. Czaja CA, et al. Ann Am Thorac Soc 2016;13:40–8.
9. Ryu YJ, et al. Tuberc Respir Dis 2016;79:74–84.
10. Lee MR, et al. Clin Microbiol Infect 2015;21:250.e1–250.e7.
11. Furuuchi K, et al. Chest 2020;157:1442–5.
12. Koh WJ, et al. Eur Respir J 2017;50:1602503.
13. Moon SM, et al. Eur Respir J 2019;53;1801636.

Medical writing and editorial support was provided by Highfield, Oxford, UK. This support was sponsored by Insmed.

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An overview of the rationale and approach to diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD)

Mycobacterium avium complex pulmonary disease (MAC-PD) is difficult to diagnose with symptoms similar to underlying lung conditions.¹ Correct, early diagnosis and treatment are paramount to prevent disease progression.^1–4 The 2020 international guidelines recommend clinical, radiographical and microbiological diagnostic criteria for non-tuberculous mycobacterial pulmonary disease (NTM-PD) to facilitate timely and appropriate treatment.⁵

NTM-PD: an overlooked disease caused by ubiquitous mycobacteria

Non-tuberculous mycobacteria pulmonary disease (NTM-PD) is a chronic and potentially debilitating disease.^6–10 Mycobacteria are ubiquitous in the environment^11–13 and comprise almost 200 species and subspecies that can cause opportunistic infections in both pulmonary and extrapulmonary sites.⁵ NTM infections can be difficult to diagnose and treat and are particularly prevalent in those with lung damage or disease, cancer and immunodeficiencies.¹⁴

A series of 12 molecularly related Mycobacterium species have been identified that together comprise the Mycobacterium avium complex (MAC).¹⁵ Within MAC, the two most clinically relevant species are M. avium and M. intracellulare.^16,17 MAC is the most common cause of NTM.¹⁸

Figure 1. Worldwide distribution of respiratory NTM isolates.

(Adapted from Hoefsloot, 2013)¹⁸

Increasing prevalence of NTM-PD

The incidence and prevalence of NTM-PD is increasing in many parts of the world.^1,5,19,20 This may reflect increased awareness of the importance of NTM,¹ the incidence of risk factors such as chronic obstructive pulmonary disease (COPD) and bronchiectasis,^21,22 the use of immunosuppressive treatments,²³ testing for NTM-PD and the effectiveness of diagnostic tools.^1,17,24 NTM should be ruled out in at-risk patients to identify infection early and begin treatment in appropriate patients before there is disease progression.

Early diagnosis of NTM-PD is paramount to prevent disease progression.

NTM-PD is associated with increased mortality and morbidity – increasing the risk of pulmonary exacerbations⁹, lung cancer²⁵ and other lung infections²⁶ (e.g. tuberculosis [TB], aspergillosis) and atrial fibrillation.²⁷ NTM-PD is difficult to diagnose as the symptoms of NTM-PD – cough, fatigue, haemoptysis, weight loss – are similar to underlying lung conditions.¹ Many patients with NTM-PD may experience symptoms for >10 years before diagnosis.²⁸ Correct, early diagnosis and treatment are paramount to prevent disease progression.^1–4 One study has shown that without treatment, 97.5% (n=39/40) of MAC-PD patients will have disease progression within 6 years.¹⁷ Another study showed that for those with M. kansasii progression can be very rapid in untreated patients within 1 year (progression in up to 63% of patients) and a median survival of 71 days.²⁹ Late diagnosis, misdiagnosis or inappropriate management of NTM-PD is likely to increase the risk of deterioration in lung health and health-related quality of life.

NTM-PD – not all species are equal

Not all NTM species will cause disease, and when they do, they may not need to be treated.^1,30 Likewise the geographical distribution of species differs, driving local epidemiology. Knowledge of the local situation and species virulence is essential for daily clinical practice. MAC is most frequently associated with NTM-PD across all continents with M. avium causing about 63% of infections meeting ATS/IDSA criteria for treatment and M. intracellulare about 88%. Species such as M. gordonae are rarely clinically relevant.³⁰

Who is at risk of NTM-PD?

For many at-risk patients NTM-PD symptoms are similar to symptoms of coexisting lung disease.¹ These include chronic cough, fatigue, weight loss and low-grade fever.

Patients most at risk of developing NTM-PD include those with:

• Lung diseases e.g. bronchiectasis, COPD, asthma, prior TB.^31–34
• Diseases/disorders causing structural lung damage e.g. cystic fibrosis, rheumatoid arthritis, genetic mutation.^35–38
• Thoracic skeletal abnormalities – scoliosis, kyphosis, pectus excavatum:^39,40 five times more likely to have NTM.³⁴
• Diseases/disorders reducing cell-mediated immunity e.g. HIV AIDS, cancer, genetic mutation.^37,38,41
• Therapies resulting in immunodeficiency e.g. organ transplant, anti-tumour necrosis factor (TNF) therapy, corticosteroids, immunosuppressants.^{34–36,41–44}
• Marfanoid body habitus/Lady Windermere syndrome^39,40,45 – tall, slender elderly patients with a below normal body mass index (BMI) (<18 Kg/m²) are three times more like to have NTM.³⁴

* Relative risk, odds ratio or relative prevalence

Rates of NTM-PD are high in older individuals and those with underlying bronchiectasis.^46,47 Many patients with bronchiectasis also have COPD (36–51%) or asthma (28–42%).²³

In which patients should I rule out NTM?

NTM-PD should be ruled out in patients with underlying structural lung disease who:

• are being considered for long-term macrolide therapy to reduce exacerbations⁴⁸
• are already receiving long-term macrolide therapy⁴⁸
• present with worsening symptoms despite treatment optimisation⁴⁹
• present with new pulmonary and non-specific systemic symptoms (e.g. chronic cough, fatigue, fever or dyspnoea).⁴⁹

MAC-PD: difficult to treat

MAC-PD can be difficult to treat; MAC organisms evade host defences; they accumulate in biofilms and their uptake in macrophages gives them a place to hide from many antibiotics, which have poor penetration of these cells.^50–54 Once inside macrophages, MAC limits normal macrophage function and reproduces unhindered, ready to trigger macrophage destruction so MAC bacteria can be released to infect the lung and invade other macrophages.^55–57

Diagnostic criteria for MAC-PD

The 2020 international guidelines recommend that MAC-PD is diagnosed with either X-ray or computed tomography (CT) scan and the presence of MAC-positive sputum on multiple occasions. For radiological evidence of MAC-PD, either nodular or cavitary opacities on a chest radiograph, or bronchiectasis with multiple small nodules on a high-resolution CT scan is required. For microbiological confirmation, the 2020 guidelines recommend:^5,19

• >1 positive sputum culture (to avoid spurious results from environmental contamination) with >3 respiratory samples collected over 1 week (to distinguish MAC-PD from occasional presence of MAC in the tracheobronchial tract).
• If sputum specimens are not obtainable, bronchoalveolar lavage fluid/bronchial washing cultures can be used to diagnose nodular/bronchiectatic NTM disease.
• Transbronchial or other lung biopsy with mycobacterial histologic features e.g., granulomatous inflammation or acid-fast bacilli (AFB) and positive culture for NTM or biopsy and one or more culture positive sputum or bronchial washings

Species identification helps determine clinical relevance and treatment selection.^1,30 Where the same species is isolated in ≥2 sputum cultures over an interval of ≥1 week, there is a 98% likelihood of clinically significant MAC.

Following confirmation of a MAC-PD infection and the decision to treat, the next step is to test for antibiotic susceptibility⁵ to facilitate the selection of appropriate antimicrobial therapy.

Decision to treat MAC-PD

The decision to initiate antibiotic therapy for MAC-PD should not be based on diagnostic criteria alone.^5,19 It is influenced by the severity of the disease, risk of disease progression, species/pathogenicity of infecting Mycobacterium, drug susceptibility, presence of comorbidity and the goals of treatment.^1,5,19

Factors favouring treatment include those associated with poor prognosis (e.g. cavitary disease, low BMI, low albumin and elevated inflammatory markers), isolation of a species that is virulent and/or responsive to antimicrobial therapy, underlying immune suppression and major symptoms causing decreased health-related quality of life (e.g. fatigue).^5,19 International NTM management guidelines recommend early treatment, as the benefits may outweigh the risks.⁵ Patients with NTM may already have a high treatment burden from their underlying chronic condition^58–60 which could lead to  a reluctance to add to it by starting treatment for NTM-PD immediately. However, with evidence from a study which suggests that left untreated, MAC-PD will progress,¹⁷ and increase risk of all-cause mortality^27,61 and morbidity^6–9,62 lowering patient quality of life,^26,63 prompt treatment is essential.

Summary

Understanding which patients with underlying lung conditions are at risk of developing MAC-PD is important in order to deliver prompt and effective therapy. Treatment for MAC-PD is most successful at first initiation¹ and a study has shown that refractory disease is associated with use of non-standard treatment regimens as outlined in the guidelines.⁶⁴

Understanding the need to identify at-risk patients, implement effective diagnostic protocols and prompt robust therapy is a medical imperative with the potential to reduce patient mortality and morbidity.

References:

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4. Wagner D, et al. Poster presented at: European Respiratory Society Annual Congress 6–10 September 2014; Munich, Germany. P1067.
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6. Park HY, et al. Chest 2016;150:1222–32.
7. Kobayashi T, et al. J Clin Tuberc Other Mycobact Dis 2018;11:17–21.
8. Lee MR, et al. PLoS One 2013;8:e58214.
9. Huang CT, et al. Int J Tuberc Lung Dis 2012;16:539–45.
10. Marras TK, et al. Emerg Infect Dis 2017;23:468–76.
11. Falkinham JO. J Appl Microbiol 2009;107:356–671.
12. Falkinham JO. Clin Chest Med 2015;36:35–41.
13. Nishiuchi Y, et al. Front Med 2017;4:27.
14. Ratnatunga CN, et al. Front Immunol 2020;11:303.
15. van Ingen J, et al. Int J Syst Evol Microbiol 2018;68:3666–77.
16. Boyle DP, et al. Am J Respir Crit Care Med 2015;191:1310–17.
17. Park TY, et al. PLoS One 2017;12:e0185774.
18. Hoefsloot W, et al. Eur Respir J 2013;42:1604–13.
19. Daley CL, et al. Clin Infect Dis 2020a;71:e1–e36.
20. Diel R, et al. BMC Infect Dis 2018;18:206.
21. Terzikhan N, et al. Eur J Epidemiol 2016;31:785–92.
22. Snell N, et al. Respir Med 2019;158:212–3.
23. Chalmers JD, et al. Pulmonol 2018;24:120–31.
24. Chalmers JD, et al. Chest 2018;165:1272–3.
25. Taira N, et al. Am J Case Rep 2018;19:748–51.
26. Yeung MY, et al. Respirology 2016;21:1015–25.
27. Park CS, et al. Sci Rep 2019;9:15503.
28. Kotilainen H, et al. Eur J Clin Microbiol Infect Dis 2015;34:1909–18.
29. Liu C-J, et al. Respir Med 2019;151:19–26.
30. Zweijpfenning SM, et al. Semin Respir Crit Care Med 2018;39:336–42.
31. Aksamit TR, et al. Chest 2017;151:982–92.
32. Andrejak C, et al. Thorax 2013;68:256–62.
33. Jones MM, et al. PLoS One 2018;13:0197976.
34. Dirac MA, et al. Am J Respir Crit Care Med 2012;186:684–91.
35. Winthrop KL, et al. Ann Rheum Dis 2013;72:37–42.
36. Brode SK, et al. Thorax 2015;70:677–82.
37. Wu UI, et al. Lancet Infect Dis 2015;15:968–80.
38. Szymanski EP, et al. Am J Respir Crit Care Med 2015;192:618–28.
39. Kim RD, et al. Am J Respir Crit Care Med 2008;178:1066–74.
40. Holt MR, et al. Eur Respir J 2019;54:1900252.
41. Henkle E, et al. Clin Chest Med 2015;36:91–9.
42. Ose N, et al. Surg Case Rep 2019;5:11.
43. Friedman DZP, et al. Transpl Infect Dis 2020;22:e13229.
44. Chao WC, et al. BMC Infect Dis 2017;17:796.
45. Ku JH, et al. Diagn Microbiol Infect Dis 2020;96:114916.
46. Prevots DR, et al. Am J Respir Crit Care Med 2010;182:970–6.
47. Prevots DR, et al. Clin Chest Med 2015;36:13–34.
48. Smith D, et al. BMJ Open 2020;7:e000489.
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51. Ganbat D, et al. BMC Pulm Med 2016;16:19.
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Medical writing and editorial support was provided by Highfield, Oxford, UK. This support was sponsored by Insmed.

The efficacy, sustainability and long-term safety of ALIS for patients with treatment-refractory MAC-PD

The CONVERT study [NCT02344004] evaluated the efficacy and safety of amikacin liposomal inhalation suspension (ALIS) in adult patients with treatment-refractory non-tuberculous mycobacterial pulmonary disease (NTM-PD) caused by Mycobacterium avium complex (MAC) in addition to oral guideline-based therapy (GBT) compared with oral GBT alone. ALIS plus oral GBT demonstrated high rates of culture conversion in 6-month data published in 2018 compared with GBT alone (29% vs 9%) and a follow-up study demonstrated culture conversions were often sustained and durable, and there were no new safety signals emerged with long-term use of ALIS.

MAC-PD is a difficult-to-treat pulmonary infection. When initial oral GBT fails, outcomes are poor and options are limited.^1,2 ALIS is a novel amikacin formulation that penetrates alveolar macrophages and biofilms while limiting systemic exposure.^3–5 ALIS is currently recommended by guidelines for patients with MAC-PD who fail to achieve culture conversion after at least 6 months of oral GBT in combination with oral GBT.⁶ ALIS has been previously tested in a Phase II study of treatment-refractory non-tuberculous mycobacterial pulmonary disease (NTM-PD) where the addition of ALIS to standard oral GBT achieved higher rates on negative sputum cultures compared with oral GBT alone.⁷

CONVERT was a prospective, open-label, randomised trial that evaluated the efficacy and safety of daily ALIS in addition to oral GBT in patients with refractory MAC-PD compared with oral GBT alone. A total of 336 patients with amikacin-susceptible MAC-PD and MAC-positive sputum cultures after receiving at least 6 months of oral GBT were randomised at a 2:1 ratio to receive either ALIS plus oral GBT or oral GBT alone. The primary endpoint was the proportion of patients achieving culture conversion, which was achieved if patients had three consecutive monthly MAC-negative sputum cultures by Month 6 of the study. The study was conducted in 127 centres across 18 countries in North America, Asia-Pacific and Europe. Patients were mostly female (69.3%) with a mean age of 64.7 years and many patients had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%) or both (11.9%). The majority of patients (89.9%) were receiving GBT at enrolment, with the remainder off treatment for 3–12 months. Most patients (69.3%) were on a three-drug regimen at baseline, with 54.9% on regimens which included a macrolide, ethambutol and a rifamycin.⁸

Initial results of the trial demonstrated the efficacy of ALIS in addition to oral GBT in achieving culture conversion by Month 6.⁸ Patients treated with ALIS in addition to oral GBT were almost four times as likely to achieved culture conversion by Month 6,⁸ with 29% (n=65/224) of patients on ALIS plus oral GBT achieving culture conversion compared with only 8.9% (n=10/112) on oral GBT alone (P<0.0001).^8,9

In a follow-up study published in 2021, patients who achieved culture conversion by Month 6 continued treatment for an additional 12 months, followed by off-treatment observation in order to assess the sustainability and durability of culture conversion. Following 12 months of post-conversion treatment, 63.1% (n= 41/65) of converters in the ALIS plus oral GBT arm and 30.0% (n=3/10) in the oral GBT alone arm achieved sustained conversion (P=0.0644). In the intention-to-treat population, which includes patients who did not culture convert, 18.3% (n=41/65) of patients in the ALIS plus oral GBT arm achieved sustained culture conversion compared with only 2.7% (n=3/10) in the oral GBT alone arm (P<0.0001). Three months following end of treatment, 55.4% (n=36/65) of ALIS plus oral GBT culture-converted patients also achieved durable culture conversion whereas no patients on oral GBT alone achieved durable culture conversion (P=0.0017). In the intention-to-treat population, 16.1% (n=36/224) of all patients on ALIS plus oral GBT achieved durable culture conversion versus no patients treated with oral GBT alone (P<0.0001).⁹

Re-emergence of a MAC strain with an identical genotype to the strain identified on initiation of treatment may indicate relapse, particularly if this occurs within the first 8 months of treatment. At the end of treatment, only 7.7% (n=5/65) of patients on ALIS plus oral GBT had relapsed compared with 30% (n=3/10) of patients on oral GBT alone. In contrast, recurrence of MAC after 8 months of treatment may indicate reinfection, in which MAC has been reacquired from the environment, and is treated as a new MAC infection. In total, 4.6% (n=3/65) of patients on ALIS plus oral GBT were reinfected with MAC, compared with 10% (n=1/10) of patients on oral GBT alone.⁹

Treatment emergent adverse events (TEAEs) occurred mainly in the first 8 months of treatment and were mainly respiratory. Respiratory TEAEs were reported more frequently in the ALIS plus oral GBT arm and included dysphonia (61.5%), cough (41.5%), dyspnoea (21.5%), and haemoptysis (20.0%). Nephrotoxicity TEAEs were balanced between the two arms (n=2 in both arms) and ototoxicity-related TEAEs in the ALIS plus GBT arm were primarily tinnitus (10.8%) and dizziness (7.7%). Only four patients discontinued treatment because of TEAEs in the ALIS plus oral GBT converter arm. Three patients who achieved culture conversion died, all in the oral GBT alone arm.⁹

The CONVERT study showed that the addition of ALIS to oral GBT significantly increased the likelihood of culture conversion by Month 6 compared with oral GBT alone, providing the first evidence in a randomised trial in addition to the Phase II study of efficacy against treatment-refractory MAC-PD (Figure 1).⁸ In addition, culture conversion in patients treated with ALIS in addition to oral GBT was generally sustained and durable with low risk of relapse (Figure 1).⁹ Long-term exposure to ALIS did not present any new safety concerns, with most TEAEs consistent with administration of an inhaled add-on antibiotic and generally occurring in the first 8 months of treatment.⁹ Overall, these results highlight the clinical utility of ALIS in the management of patients with refractory MAC-PD.

Figure 1. Proportion of patients achieving culture conversion by the first month of conversion.^8,9

Month 4 was the last time point at which the first of three negative sputum cultures could be achieved for a patient to be considered a converter at Month 6.

ALIS, amikacin liposomal inhalation suspension; GBT, guideline-based therapy.

References:

1. Griffith DE, Aksamit TR. Therapy of refractory nontuberculous mycobacterial lung disease. Curr Opin Infect Dis 2012;25:218–27.
2. Jo K-W, Kim S, Lee JY, Lee SD, Kim WS, Kim DS, et al. Treatment outcomes of refractory MAC pulmonary disease treated with drugs with unclear efficacy. J Infect Chemother 2014;20:602–6.
3. Rose SJ, Neville ME, Gupta R, Bermudez LE. Delivery of aerosolized liposomal amikacin as a novel approach for the treatment of nontuberculous mycobacteria in an experimental model of pulmonary infection. PLoS ONE 2014:9:e108703.
4. Malinin V, Neville M, Eagle G, Gupta R, Perkins WR. Pulmonary deposition and elimination of liposomal amikacin for inhalation and effect on macrophage function after administration in rats. Antimicrob Agents Chemother 2016;60:6540–9.
5. Zhang J, Leifer F, Rose S, Chun DY, Thaisz J, Herr T, et al. amikacin liposome inhalation suspension (ALIS) penetrates non-tuberculous mycobacterial biofilms and enhances amikacin uptake into macrophages. Front Microbiol 2018;9:915.
6. Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J 2020;56:2000535.
7. Olivier KN, Griffith DE, Eagle G, McGinnis JP 2nd, Micioni L, Liu K, et al. Randomized trial of liposomal amikacin for inhalation in nontuberculous mycobacterial lung disease. Am J Respir Crit Care Med 2017;195:814–23.
8. Griffith DE, Eagle G, Thomson R, Aksamit TR, Hasegawa N, Morimoto K, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium aviumcomplex (CONVERT). A prospective, open-label, randomized study. Am J Respir Crit Care Med 2018;198:1559–69.
9.  Griffith DE, Thomson R, Flume PA, Aksamit TR, Field SK, Addrizzo-Harris DJ, et al. Amikacin liposome inhalation suspension for refractory Mycobacterium avium complex lung disease: sustainability and durability of culture conversion and safety of long-term exposure. Chest 2021; https://doi.org/10.1016/j.chest.2021.03.070

Medical writing and editorial support was provided by Highfield, Oxford, UK. This support was sponsored by Insmed.