Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease

Olivier, Kenneth N.; Griffith, David E.; Eagle, Gina; McGinnis, John P.; Micioni, Liza; Liu, Keith; Daley, Charles L.; Winthrop, Kevin; Ruoss, Stephen J.; Addrizzo-Harris, Doreen; Flume, Patrick A.; Dorgan, Daniel; Salathé, Matthias; Brown‐Elliott, Barbara A.; Gupta, Renu; Wallace, Richard J.

doi:10.1164/rccm.201604-0700oc

Cited by 219 publications

(175 citation statements)

References 31 publications

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“…However, this study demonstrated a significant decrease in the positivity of semiquantitative sputum cultures for AFB over the course of treatment with CFZ in both the initial treatment and salvage treatment groups, suggesting that CFZ-containing regimens can help to decrease the mycobacterial burden. Semiquantitative AFB culture positivity is likely to reflect disease burden and was used to assess microbiological responses to the treatment of NTM lung disease in some recently reported studies (38)(39)(40). Given that M. abscessus lung disease is regarded as a chronic, incurable infection and that there are limited antibiotic options, improvement in the health-related quality of life is a reasonable treatment goal, especially in refractory cases (32).…”

Section: Discussionmentioning

confidence: 99%

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Yang

Jhun

Moon

et al. 2017

Antimicrob Agents Chemother

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Patients with lung disease caused by Mycobacterium abscessus subsp. abscessus (here M. abscessus) typically have poor treatment outcomes. Although clofazimine (CFZ) has been increasingly used in the treatment of M. abscessus lung disease in clinical practice, there are no reported data on its effectiveness for this disease. This study sought to evaluate the clinical efficacy of a CFZ-containing regimen for the treatment of M. abscessus lung disease. We performed a retrospective review of the medical records of 42 patients with M. abscessus lung disease who were treated with CFZ-containing regimens between November 2013 and January 2015. CFZ was administered in combination with other antibiotics as an initial antibiotic regimen in 15 (36%) patients (initial treatment group), and it was added to an existing antibiotic regimen for refractory M. abscessus lung disease in 27 (64%) patients (salvage treatment group). Overall, there was an 81% treatment response rate based on symptoms and a 31% response rate based on radiographic findings. Conversion to culture-negative sputum samples was achieved in 10 (24%) patients after CFZ-containing antibiotic treatment, and during treatment, there were significant decreases in the positivity of semiquantitative sputum cultures for acid-fast bacilli in both the initial (P ϭ 0.018) and salvage (P ϭ 0.001) treatment groups. Our study suggests that CFZ-containing regimens may improve treatment outcomes in patients with M. abscessus lung disease and that a prospective evaluation of CFZ in M. abscessus lung disease is warranted.

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Section: Discussionmentioning

confidence: 99%

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Yang

Jhun

Moon

et al. 2017

Antimicrob Agents Chemother

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“…Since then, the field of nanomedicine has only scored hits with two oncology drugs. However, pulmonary nanomedicine may soon witness a new dawn because promising nanotechnologies, such as inhaled liposomal amikacin for bronchiectasis, are supported by strong data in late-stage clinical trials (9).…”

Section: Opinions and Ideasmentioning

confidence: 99%

Nanomedicine for the Treatment of Acute Respiratory Distress Syndrome. The 2016 ATS Bear Cage Award–winning Proposal

Brenner

2017

Annals ATS

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After dozens of clinical trials, there are still no Food and Drug Administration-approved drugs that improve mortality in acute respiratory distress syndrome (ARDS). These poor results may be caused in part by three unique pharmacological challenges presented by ARDS: (1) Patients with ARDS are fragile because of concomitant multiple organ dysfunction, so they do not tolerate off-target side effects of drugs; (2) inhaled drug delivery is impeded by the column of proteinaceous fluid covering the injured alveoli; and (3) ARDS is heterogeneous in its underlying pathophysiology, so targeting one pathway is unlikely to improve most patients. To address these three pharmacological problems, I present the development of pulmonary endothelium-targeted liposomes (PELs). PELs are approximately 100-nm drug carriers coated with antibodies that bind to the pulmonary capillary endothelium. In model organisms, intravenously injected PELs strongly concentrate drugs in alveoli, even in animal models displaying severe, spatially heterogeneous pathology similar to severe ARDS. By concentrating drugs in inflamed alveoli, PELs solve pharmacological challenge (1) above. By being obligate intravenous medications, they solve challenge (2). Finally, because PELs can be loaded with at least three drugs, they can solve challenge (3) with combination drug therapy. My colleagues and I are currently testing PELs loaded with numerous candidate drugs in mouse models of ARDS, and we are testing drug distribution in live pigs and ex vivo human lungs. We aim to use such preclinical validation to move PELs into a partnership with industry, and then to patients.

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“…Inhaled liposomal amikacin is currently being evaluated in phase II trials for the treatment of nontuberculous mycobacterial infections [45]. The results of an interim analysis were promising, which prompted the data safety monitoring board to recommend continuing the randomized, double-blind, placebo-controlled trial [45].…”

Section: Amikacinmentioning

confidence: 99%

Clinical Pharmacokinetics of Inhaled Antimicrobials

2015

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Administration of inhaled antimicrobials affords the ability to achieve targeted drug delivery into the respiratory tract, rapid entry into the systemic circulation, high bioavailability and minimal metabolism. These unique pharmacokinetic characteristics make inhaled antimicrobial delivery attractive for the treatment of many pulmonary diseases. This review examines recent pharmacokinetic trials with inhaled antibacterials, antivirals and antifungals, with an emphasis on the clinical implications of these studies. The majority of these studies revealed evidence of high antimicrobial concentrations in the airway with limited systemic exposure, thereby reducing the risk of toxicity. Sputum pharmacokinetics varied widely, which makes it challenging to interpret the result of sputum pharmacokinetic studies. Many no vel inhaled antimicrobial therapies are currently under investigation that will require detailed pharmacokinetic studies, including combination inhaled antimicrobial therapies, inhaled nanoparticle formulations of several antibacterials, inhaled non-antimicrobial adjuvants, inhaled antiviral recombinant protein therapies and semi-synthetic inhaled antifungal agents. Additionally, the development of new inhaled delivery devices, particularly for mechanically ventilated patients, will result in a pressing need for additional pharmacokinetic studies to identify optimal dosing regimens.

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Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease

Cited by 219 publications

References 31 publications

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Nanomedicine for the Treatment of Acute Respiratory Distress Syndrome. The 2016 ATS Bear Cage Award–winning Proposal

Clinical Pharmacokinetics of Inhaled Antimicrobials

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