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Amikacin Liposome Inhalation Suspension as a Treatment Option for Refractory Nontuberculous Mycobacterial Lung Disease Caused by Mycobacterium avium Complex

      To the Editor:
      We read with much interest the review by Shulha et al.
      • Shulha J.A.
      • Escalante P.
      • Wilson J.W.
      Pharmacotherapy approaches in nontuberculous mycobacteria infections.
      The article is a comprehensive and well-written overview of pharmacological treatment approaches of nontuberculous mycobacterial (NTM) diseases. Table 2 (titled “NTM Medication Dosing, Adverse Effects, and Recommended Monitoring”), however, did not include an approved treatment option for NTM lung disease caused by Mycobacterium avium complex (MAC), namely, amikacin liposome inhalation suspension (ALIS; Arikayce). Amikacin liposome inhalation suspension is the first Food and Drug Administration (FDA)–approved medication with a specific indication for refractory MAC lung disease (MAC-LD). It was granted accelerated approval by the FDA in September 2018 and is “indicated in adults who have limited or no alternative treatment options, for the treatment of Mycobacterium avium complex (MAC) lung disease as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of six consecutive months of a multidrug background regimen therapy.”
      (p1)
      The accelerated FDA approval was based mainly on the results of the phase 3 CONVERT study (clinicaltrials.gov Identifier: NCT02344004),
      • Griffith D.E.
      • Eagle G.
      • Thomson R.
      • et al.
      CONVERT Study Group
      Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.
      which reported a more than 3-fold increase in culture conversion rates by month 6 when ALIS was added to a background multidrug regimen compared with those treated with their continued background regimen alone (n=65/224, [29.0%] vs n=10/112 [8.9%]; P<.001).
      • Griffith D.E.
      • Eagle G.
      • Thomson R.
      • et al.
      CONVERT Study Group
      Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.
      It should be noted that a rigorous definition of culture conversion was used in CONVERT in that patients had to have 3 consecutive monthly negative sputum cultures by month 6 to meet the primary end point. Importantly, data from CONVERT presented at American Thoracic Society annual meeting in May 2019 demonstrated that among patients with treatment-refractory disease who received ALIS in addition to a background regimen and met the primary end point of culture conversion by month 6, 80% (n=52) were confirmed culture negative at the end of treatment and 63% (n=41) remained culture negative 3 months after discontinuing all MAC treatments.
      • Griffith D.E.
      • Thomson R.
      • Addrizzo-Harris D.J.
      • et al.
      Sustainability and durability of culture conversion in patients receiving amikacin liposome inhalation suspension (ALIS) for treatment-refractory Mycobacterium avium complex lung disease (MAC-LD) in the CONVERT study.
      Because relapse and reinfection are common in MAC-LD, the durability of sputum conversion reported in CONVERT is particularly encouraging. The most common adverse reactions reported in CONVERT at the month-6 safety analysis were primarily respiratory (ALIS plus background regimen, 87.4%; background regimen alone, 50.0%), predominantly mild to moderate in intensity, and included dysphonia, cough, dyspnea, hemoptysis, and oropharyngeal pain.
      • Griffith D.E.
      • Eagle G.
      • Thomson R.
      • et al.
      CONVERT Study Group
      Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.
      As noted in a 2012 review by Griffith and Aksamit,
      • Griffith D.E.
      • Aksamit T.R.
      Therapy of refractory nontuberculous mycobacterial lung disease.
      “the choices for effective treatment of these patients [with refractory NTM lung disease] are depressingly sparse.”(p218) Physicians who manage patients with refractory MAC-LD should have access to information on all potential treatment approaches, as this disease remains quite difficult to treat and is associated with poor outcomes and high mortality.
      • Griffith D.E.
      • Aksamit T.R.
      Therapy of refractory nontuberculous mycobacterial lung disease.
      Amikacin liposome inhalation suspension is currently the only FDA-approved pharmaceutical product with a specific indication in patients with MAC-LD and is an important therapeutic option for some patients with treatment-refractory disease. The CONVERT study, together with the phase 2 study mentioned in Shulha’s review,
      • Shulha J.A.
      • Escalante P.
      • Wilson J.W.
      Pharmacotherapy approaches in nontuberculous mycobacteria infections.
      (p1574) represents the largest body of evidence for antibiotic efficacy and safety in this rare and difficult-to-treat pulmonary disease.

      References

        • Shulha J.A.
        • Escalante P.
        • Wilson J.W.
        Pharmacotherapy approaches in nontuberculous mycobacteria infections.
        Mayo Clin Proc. 2019; 94: 1567-1581
      1. Arikayce [package insert]. Insmed Inc, Bridgewater, NJ2018
        • Griffith D.E.
        • Eagle G.
        • Thomson R.
        • et al.
        • CONVERT Study Group
        Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT): a prospective, open-label, randomized study.
        Am J Respir Crit Care Med. 2018; 198: 1559-1569
        • Griffith D.E.
        • Thomson R.
        • Addrizzo-Harris D.J.
        • et al.
        Sustainability and durability of culture conversion in patients receiving amikacin liposome inhalation suspension (ALIS) for treatment-refractory Mycobacterium avium complex lung disease (MAC-LD) in the CONVERT study.
        Am J Respir Crit Care Med. 2019; 199: A7359
        • Griffith D.E.
        • Aksamit T.R.
        Therapy of refractory nontuberculous mycobacterial lung disease.
        Curr Opin Infect Dis. 2012; 25: 218-227

      Linked Article

      • Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections
        Mayo Clinic ProceedingsVol. 94Issue 8
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          Nontuberculous mycobacteria (NTM) comprise a heterogeneous group of organisms, with only a small subset known to cause disease in humans. Although NTM infection is not a reportable disease, both the increasing clinical recognition and recent advancements in laboratory diagnostic capabilities of NTM infections in immunocompromised and immunocompetent patients are rapidly evolving. We reviewed antimicrobial agents used to treat the most frequently encountered NTM infections and examined optimized drug dosing strategies, toxicity profiles, drug-drug interactions, and the role of therapeutic drug monitoring.
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      • In reply—Amikacin Liposome Inhalation Suspension as a Treatment Option for Refractory Nontuberculous Mycobacterial Lung Disease Caused by Mycobacterium avium Complex
        Mayo Clinic ProceedingsVol. 95Issue 1
        • Preview
          We thank Swenson and Del Parigi1 for their comments on our article.2 The article originally submitted on September 6, 2018. This formulation of amikacin inhalation (Arikayce) received Food and Drug Administration approval on September 28, 2018. Although we agreed that liposomal amikacin is an important therapeutic option for refractory mycobacterium avium complex pulmonary disease, at the time of our original submission we had included timely information on pages 1574 to 1575. Unfortunately, we did not have the Food and Drug Administration–approved dosage of Arikayce at the time of submission nor did the reviewers request us to include this information in Table 2 upon editing.
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