Assessing effects of inhaled antibiotics in adults with non-cystic fibrosis bronchiectasis––experiences from recent clinical trials

ABSTRACT

Introduction: Non-cystic fibrosis bronchiectasis (NCFB) results from a permanent and progressive destruction of the airways leading to poor lung function. NCFB is characterized by recurrent lung infection, sputum production, and cough, often requiring long-term antibiotic therapy and hospitalization. At present, there are no approved therapies available. Clinical trials of inhaled antibiotics have shown promise against sputum bacterial load, but mixed results on clinical outcomes.

Areas covered: The objective of this review is to provide an overview of NCFB and critically evaluate the evidence supporting the outcome measures used in recent clinical trials of inhaled antibiotics. These include quantitative changes in bacterial load, sputum purulence and yield, inflammatory markers, and lung function, as well as clinical changes in exacerbations, exacerbation frequency, hospitalizations, and health-related quality of life.

Expert commentary: Recently completed large trials of inhaled antibiotics in NCFB did not consistently meet pre-specified end points, suggesting that we have not yet found the best enrollment criteria or outcome measures to evaluate efficacy, although reduced exacerbation frequency may be clinically most meaningful. Future trials may focus on specific patient populations at high risk with new information obtained through analyses of large international patient registries.

Abbreviations: 6-MWT: Six-Minute Walk Test; AIR-BX: Aztreonam for Inhalation Solution in Patients with Non-Cystic Fibrosis Bronchiectasis trial; BSI: Bronchiectasis Severity Index; CAT: COPD Assessment Test; CF: Cystic Fibrosis; CFTR: Cystic Fibrosis Transmembrane Conductance Regulator; CFU: Colony-Forming Units; COPD: Chronic Obstructive Pulmonary Disease; CRP: C-Reactive Protein; DPI: Dry Powder for Inhalation; EMA: European Medicines Agency; ERS: European Respiratory Society; FACED: FEV1, Age, Chronic colonization by P. aeruginosa, Extension of bronchiectasis and Dyspnea; FDA: US Food and Drug Administration; FEV₁: Forced Expiration in 1 s; FVC: Forced Vital Capacity; HFCC: High-Frequency Chest Compression; HRCT: High-Resolution Computed Tomography; HRQoL: Health-Related Quality of Life; LCQ: Leicester Cough Questionnaire; MID: Minimal Important Difference; NCFB: Non-Cystic Fibrosis Bronchiectasis; NTM: Nontuberculous Mycobacteria; ORBIT: Once-daily Respiratory Bronchiectasis Inhalation Treatment trial; PRO: Patient-Reported Outcomes; QoL-B: Quality of Life-Bronchiectasis; SGRQ: St. George’s Respiratory Questionnaire; SWT: Shuttle Walk Test; TORCH: Towards a Revolution in COPD Health trial; UPLIFT: Understanding Potential Long-term Impacts on Function with Tiotropium trial

KEYWORDS:

• Clinical outcomes
• inhaled antibiotics
• non-cystic fibrosis bronchiectasis
• pulmonary exacerbation
• health-related quality of life

Acknowledgments

The authors thank Dr David Macari, PhD and Dr Alex Loeb, PhD, CMPP of Evidence Scientific Solutions, Philadelphia, PA for providing writing and editorial assistance which was funded by Grifols, Research Triangle Park, North Carolina.

Declaration of interest

A Schmid is a consultant for Insmed and has received research funding from Insmed, The Flight Attendant Medical Research Institute and the National Institute of Health. M Salathe is a consultant for Arrowhead Pharmaceuticals, Inc., Entrinsic Health Solutions, Inc., and previously Insmed. They have also received research funding from Gilead, Insmed, Aradigm, Vertex, Savara, Parion, Novartis, Concert, Boehringer Ingelheim, Abbvie, Pharmaxis, CSL Behring, Bayer, Anthera, PTC Therapeutics, Kalobios, JHP Pharmaceuticals, Pearl Therapeutics, Hologic, MPex, Sound Pharmaceuticals, Forest Pharmaceuticals, the Cystic Fibrosis Foundation, the Flight Attendant Medical Research Institute, the James and Esther King Florida Biomedical Research Program, the COPD Foundation and the National Institute of Health. A Quittner has received research funding from the National Institute of Health and the Cystic Fibrosis Foundation, and has received consulting income in the past three years from Abbvie Pharmaceuticals, ProQR and Vertex Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they consult for several companies developing inhaled antibiotics for airway diseases including non-cystic fibrosis bronchiectasis. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has received medical writing assistance that was funded by Grifols, Research Triangle Park, North Carolina.