Mannitol Does Not Enhance Tobramycin Killing of Pseudomonas aeruginosa in a Cystic Fibrosis Model System of Biofilm Formation

Cystic Fibrosis (CF) is a human genetic disease that results in the accumulation of thick, sticky mucus in the airways, which results in chronic, life-long bacterial biofilm infections that are difficult to clear with antibiotics. Pseudomonas aeruginosa lung infection is correlated with worsening lung disease and P. aeruginosa transitions to an antibiotic tolerant state during chronic infections. Tobramycin is an aminoglycoside currently used to combat lung infections in individuals with CF. While tobramycin is effective at eradicating P. aeruginosa in the airways of young patients, it is unable to completely clear the chronic P. aeruginosa infections in older patients. A recent report showed that co-addition of tobramycin and mannitol enhanced killing of P. aeruginosa grown in vitro as a biofilm on an abiotic surface. Here we employed a model system of bacterial biofilms formed on the surface of CF-derived airway cells to determine if mannitol would enhance the antibacterial activity of tobramycin against P. aeruginosa grown on a more clinically relevant surface. Using this model system, which allows the growth of robust biofilms with high-level antibiotic tolerance analogous to in vivo biofilms, we were unable to find evidence for enhanced antibacterial activity of tobramycin with the addition of mannitol, supporting the observation that this type of co-treatment failed to reduce the P. aeruginosa bacterial load in a clinical setting

Diagnostic Performance of a Machine Learning Algorithm (Asthma/Chronic Obstructive Pulmonary Disease [COPD] Differentiation Classification) Tool Versus Primary Care Physicians and Pulmonologists in Asthma, COPD, and Asthma/COPD Overlap

Funding The study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States. Acknowledgement The studies were funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States. Under the direction of authors, Rabi Panigrahy, Preethi B and Ian Wright (professional medical writers; Novartis) assisted in the preparation of this article in accordance with the third edition of Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3)Peer reviewedPublisher PD

Artificial intelligence/machine learning in respiratory medicine and potential role in asthma and COPD diagnosis

Acknowledgments We thank Ian Wright, PhD, of Novartis Ireland Ltd, for providing medical writing support in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).63Peer reviewedPublisher PD

Patient-reported barriers to accepting a technological adherence package in the MAGNIFY trial.

Peer reviewedPostprin

Maximizing Adherence and Gaining New Information For Your Chronic Obstructive Pulmonary Disease (MAGNIFY COPD):Study Protocol for the Pragmatic, Cluster Randomized Trial Evaluating the Impact of Dual Bronchodilator with Add-On Sensor and Electronic Monitoring on Clinical Outcomes

Background: Poor treatment adherence in COPD patients is associated with poor clinical outcomes and increased healthcare burden. Personalized approaches for adherence management, supported with technology-based interventions, may offer benefits to patients and providers but are currently unproven in terms of clinical outcomes as opposed to adherence outcomes. Methods: Maximizing Adherence and Gaining New Information For Your COPD (MAGNIFY COPD study), a pragmatic cluster randomized trial, aims to evaluate the impact of an adherence technology package (interventional package), comprising an adherence review, ongoing provision of a dual bronchodilator but with an add-on inhaler sensor device and a connected mobile application. This will compare time to treatment failure and other clinical outcomes in patients identified at high risk of exacerbations with historic poor treatment adherence as measured by prescription collection to mono/dual therapy over one year (1312 patients) versus usual care. Treatment failure is defined as the first occurrence of one of the following: (1) moderate/severe COPD exacerbation, (2) prescription of triple therapy (inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]), (3) prescription of additional chronic therapy for COPD, or (4) respiratory-related death. Adherence, moderate/severe exacerbations, respiratory-related healthcare resource utilization and costs, and intervention package acceptance rate will also be assessed. Eligible primary care practices (N=176) participating in the Optimum Patient Care Quality Improvement Program will be randomized (1:1) to either adherence support cluster arm (suitable patients already receiving or initiated Ultibro® Breezhaler® [indacaterol/glycopyrronium] will be offered interventional package) or the control cluster arm (suitable patients continue to receive usual clinical care). Patients will be identified and outcomes collected from anonymized electronic medical records within the Optimum Patient Care Research Database. On study completion, electronic medical record data will be re-extracted to analyze outcomes in both study groups. Registration Number: ISRCTN10567920. Conclusion: MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring

Medication Adherence and Asthma Control with Once-Daily Indacaterol/Glycopyrronium/Mometasone Furoate Breezhaler Digital Companion: 90-Day Analysis from Germany

Abstract Introduction Suboptimal adherence to inhaled asthma therapy is associated with poor clinical outcomes. Digital companion paired inhaler devices record medication use and provide reminders, thereby improving treatment adherence and asthma outcomes. This analysis assessed the impact of indacaterol/glycopyrronium/mometasone furoate (IND/GLY/MF) Breezhaler® digital companion on medication adherence and symptom control in adults with asthma from Germany. Methods This retrospective analysis included adults (≥ 18 years) with asthma and prescribed Breezhaler digital companion. Assessments included: mean medication adherence (number of puffs taken/prescribed × 100) and change in Asthma Control Test (ACT) scores [well controlled (≥ 20), not well controlled (15–20) and poorly controlled (≤ 15)] at 1 month after the first ACT (second ACT). The percent of patients with ≥ 80% medication adherence (days 16–30 and 76–90) and the change in ACT (baseline and ≥ 30 days) were analysed. Results Of the 163 patients with 90 days data, ≥ 80% medication adherence was achieved in 82.8% and 72.4% of patients at months 1 and 3, respectively. Change in asthma control was examined in ~ 60% (n = 97) of patients who completed ≥ 2 ACTs through the application. At baseline, 33.0% of patients were well controlled and 53.6% were well controlled at second ACT. Furthermore, 43.3% patients reported very poor control at baseline which decreased to 22.7% at second ACT. Conclusion The use of IND/GLY/MF (Breezhaler) with a digital companion (sensor + application) may be associated with improved symptom control and high level of controller medication adherence in patients with asthma

Strains used in this study.

<p>^a Minimum inhibitory concentration of tobramycin for <i>P</i>. <i>aeruginosa</i> strains as measured by Biomerieux E-test strips according to manufacture’s instructions.</p><p>Strains used in this study.</p

Mannitol does not sensitize non-mucoid, laboratory strain <i>P</i>. <i>aeruginosa</i> PA14 to tobramycin.

<p>A. Mannitol is minimally cytotoxic to CFBE cells. Normalized cytotoxicity as measured by fraction of LDH release. Cytotoxicity was measured after 24 hours of treatment with 0, 40 or 60 mM mannitol as indicated. Cells lysed with Triton X-100 served as a control to determine total lysis. Columns indicate mean of at least three biological replicates, error bars indicate standard deviation (S.D.). **, P<0.01, comparison of indicated sample to total lysis control by ordinary one-way ANOVA with Tukey’s post test for multiple comparisons. B. Viability of <i>P</i>. <i>aeruginosa</i> PA14 grown as a biofilm on CFBE cells after treatment with 0 μg/mL tobramycin (open bars), 8 μg/mL tobramycin (hatched bars), 0 mM mannitol (white bars), 60 mM mannitol (gray bars) or co-treatment with 8 μg/mL tobramycin and 60 mM mannitol, as indicated. Columns indicate mean of at least three biological replicates, error bars indicate S.D. ***, P<0.001 by ordinary one-way ANOVA with Tukey’s post test for multiple comparisons. There is no significant difference between <i>P</i>. <i>aeruginosa</i> PA14 treated with tobramycin +/- mannitol.</p

Mannitol does not sensitize <i>P</i>. <i>aeruginosa</i> clinical isolates grown as biofilms on CF airway cells to tobramycin.

<p>A. Viability of <i>P</i>. <i>aeruginosa</i> clinical isolates grown as biofilms on CFBE cells and treated with 0 μg/mL tobramycin (open bars), 8 μg/mL tobramycin (hatched bars), 0 mM mannitol (white bars), 60 mM mannitol (gray bars) or co-treatment with 8 μg/mL tobramycin and 60 mM mannitol, as indicated. Columns indicate mean of at least three biological replicates, error bars indicate S.D. **, P<0.01 by ordinary one-way ANOVA with Tukey’s post test for multiple comparisons. B. The viability of strains <i>P</i>. <i>aeruginosa</i> PAO1 (left) and FRD1 (right) as biofilms on CFBE cells and treated with 0 μg/mL tobramycin (open bars), 8 μg/mL tobramycin (hatched bars), 0 mM mannitol (white bars), 60 mM mannitol (gray bars) or co-treatment with 8 μg/mL tobramycin and 60 mM mannitol, as indicated. **, P<0.01 or ***, P<0.001 by ordinary one-way ANOVA with Tukey’s post test for multiple comparisons. ns, not significant compared to tobramycin treatment in the absence of mannitol. C. The viability of strain <i>P</i>. <i>aeruginosa</i> PAO1 as a biofilm on plastic and treated with 0 μg/mL tobramycin (open bars), 80 μg/mL tobramycin (hatched bars), 0 mM mannitol (white bars), 60 mM mannitol (gray bars) or co-treatment with 80 μg/mL tobramycin and 60 mM mannitol, as indicated. *, P<0.05 compared to treatment with 80 μg/mL tobramycin with no mannitol. **, P<0.01 or ***, P<0.001 by ordinary one-way ANOVA with Tukey’s post test for multiple comparisons.</p