SummaryWhat is known and objective: Pseudomonas aeruginosa is the leading cause of lung infection in patients with cystic fibrosis (CF) and is associated with significant morbidity and mortality. Antibiotics are regarded as the foundational pharmacological treatment for the suppressive management of chronic P. aeruginosa infections and to eradicate the first infection by P. aeruginosa. Inhalation remains a preferred route for drug administration, providing direct access to the site of infection while minimizing systemic side effects. Effective suppressive management of P. aeruginosa infections, however, requires an understanding of the location of the bacteria in the lungs and consideration of the factors that could limit access of the inhaled antibiotic to the infected area. This review provides a systematic assessment of the scientific literature to gain insight into the location of P. aeruginosa in the lungs of patients with CF and its clinical implications. The characteristics of antibiotic inhalation systems are also discussed in this context.
Methods:We reviewed evidence-based literature from both human and animal studies in which P. aeruginosa lung location was reported. Relevant publications were identified through a screening strategy and summarized by reported P. aeruginosa location.Results and discussion: Most areas of the conductive and respiratory zones of the lungs are susceptible to P. aeruginosa colonization. Deposition of an inhaled antibiotic is dependent on the device and formulation characteristics, as well as the ability of the patient to generate sufficient inhaled volume. As patients with CF often experience a decline in lung function, the challenge is to ensure that the inhaled antibiotic can be delivered throughout the bronchial tree.
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.
Background:This study assessed the ease of use of tobramycin inhalation powder (TIP)
administered via T-326 inhaler versus
tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both
administered via nebulizers, for the treatment of chronic
pulmonary Pseudomonas aeruginosa infection in patients with
cystic fibrosis (CF).Methods:A real-world, open-label, crossover, interventional phase IV study was
conducted in CF patients aged ⩾6 years with forced expiratory volume in 1
second (FEV1) ⩾25% to ⩽90% predicted. Patients were assigned to
one of the three treatment arms in Cycle 1; all patients received TIP in
Cycle 2. Each cycle consisted of 28 days on and 28 days off the
treatment.Results:A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were
allocated to three treatment arms [TIS/TIP (n = 14);
COLI/TIP (n = 28); TIP/TIP (n = 18)] in
Cycle 1. The mean total administration time, which included device setup and
cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP,
and TIP/TIP arms were 37.0 versus 5.0 min, 16.4
versus 3.8 min, and 4.2 versus 3.4
min, respectively. The difference in mean total administration time was
significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP
(p = 0.0112) and COLI/TIP (p = 0.0016)
arms. Overall, 12 patients were found to have contaminated devices across
the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326
inhaler was observed in either cycle. Treatment satisfaction, assessed by
the Treatment Satisfaction Questionnaire for Medication and ACCEPT®
questionnaire, was better overall for TIP compared with TIS and COLI. There
were no unexpected adverse events and most were mild or moderate in
intensity.Conclusion:The T-326 inhaler used to deliver TIP was easy to use, required shorter total
administration time, and was much less frequently contaminated than the
nebulizers. The safety findings observed for TIP were generally consistent
with its established safety profile.
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 β 2agonist/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 reextracted to analyze outcomes in both study groups. Registration Number: ISRCTN10567920. Conclusion: MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring.
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