Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities

Nichols, David P.; Durmowicz, Anthony G.; Field, A G; Flume, Patrick A.; VanDevanter, Donald R.; Mayer-Hamblett, Nicole

doi:10.1513/annalsats.201812-863ot

Cited by 35 publications

(35 citation statements)

References 34 publications

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“…Endpoints such as forced expiratory volume in 1 second which were used for regulatory approvals of drugs such as inhaled tobramycin in the past cease to have relevance in populations that have largely preserved lung function, while there is evidence that these endpoints are less responsive in adult compared to a paediatric CF population. 7 Pulmonary exacerbations remain a key driver of morbidity and mortality in cystic fibrosis but widespread recognition of this has led to advances in care to prevent exacerbations that mean the average exacerbation rate in CF populations is at a historically low level and projected to fall further as CFTR modulators also reduce exacerbations. 8 There is hope, as improved physiological measures such as LCI and imaging modalities (CT/MRI) allow us to characterise bronchiectasis as never before, but these remain surrogates that do not answer the crucial regulatory question of "does the medication change how a patient feels, functions or survives"?…”

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confidence: 99%

“…This issue was the topic of a Food and Drug Administration workshop in 2018. 7 Large parts of the world will remain unable to access CFTR modulator therapies due to cost and other considerations and randomized trials are increasingly looking to such countries to enrol patients for clinical trials. This presents significant ethical concerns, since trial participants may not be able to ultimately access the trial medications, but also raises the question of how such data can be extrapolated to the new reality in countries such as the UK and US.…”

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confidence: 99%

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Cystic fibrosis lung disease and bronchiectasis

Chalmers

2020

The Lancet Respiratory Medicine

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confidence: 99%

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confidence: 99%

Cystic fibrosis lung disease and bronchiectasis

Chalmers

2020

The Lancet Respiratory Medicine

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“…We recognize that this analysis was not focused on incident or first AZM use and that the baseline characteristics of the TOB and AZLI cohorts differed. Patients are increasingly cycling between TOB and AZLI, and such data were necessarily excluded from our analyses, which may limit generalizability ( 35 ). Nonetheless, our results are consistent with a growing body of evidence supporting the hypothesis of a selective drug interaction between AZM and TOB, but this question may not be fully addressed until the ongoing prospective clinical trial testing this theory is completed ( ClinicalTrials.gov identifier NCT02677701).…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis

Nichols

Odem‐Davis

Cogen³

et al. 2020

Am J Respir Crit Care Med

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Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV 1 . Long-term effects are unknown. Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam. Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV 1 % predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted. Measurements and Main Results: Across 3 years, FEV 1 % predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, −1.53 versus −2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30–1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV 1 % predicted per-year decline of −0.16 versus nonusers (95% CI, −0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, −0.11 to 1.10). Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.

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“…All these studies emphasize that the use of continuous therapy with different combinations of inhaled antibiotics has grown over time. Therefore, it is not surprising that the prevalence of CF patients receiving more than one inhaled anti- P. aeruginosa antibiotic class increased from 2009 to 2012, as reported by the United States Cystic Fibrosis Foundation Patient Registry (CFFPR) [ 97 , 98 ]. Comparing these sequential treatments with inhaled aztreonam and tobramycin to tobramycin monotherapies, Estrella Rojo-Molinero and co-authors found that alternating antibiotics produced an increase in antibiofilm activity against the laboratory and clinical strains of P. aeruginosa [ 99 ].…”

Section: Inhaled Antibiotic Therapy For P Aeruginosa mentioning

confidence: 99%

“…Inhaled antibiotics play a crucial role in preventing acute exacerbations. Large numbers of CF patients receiving tobramycin and aztreonam by means of continuous alternating therapy continue to experience the exacerbations associated with lung function decline, highlighting the need for developing new and more effective therapies based on inhaled antibiotics [ 98 ]. Associating inhaled antibiotics with standard intravenous therapy has also been studied in patients with CF (6–21 years) who were hospitalized due to pulmonary exacerbations [ 103 ].…”

Section: Inhaled Antibiotic Therapy For Preventing Pulmonary Exacementioning

confidence: 99%

Cystic Fibrosis: Recent Insights into Inhaled Antibiotic Treatment and Future Perspectives

et al. 2021

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Although new inhaled antibiotics have profoundly improved respiratory diseases in cystic fibrosis (CF) patients, lung infections are still the leading cause of death. Inhaled antibiotics, i.e., colistin, tobramycin, aztreonam lysine and levofloxacin, are used as maintenance treatment for CF patients after the development of chronic Pseudomonas aeruginosa (P. aeruginosa) infection. Their use offers advantages over systemic therapy since a relatively high concentration of the drug is delivered directly to the lung, thus, enhancing the pharmacokinetic/pharmacodynamic parameters and decreasing toxicity. Notably, alternating treatment with inhaled antibiotics represents an important strategy for improving patient outcomes. The prevalence of CF patients receiving continuous inhaled antibiotic regimens with different combinations of the anti-P. aeruginosa antibiotic class has been increasing over time. Moreover, these antimicrobial agents are also used for preventing acute pulmonary exacerbations in CF. In this review, the efficacy and safety of the currently available inhaled antibiotics for lung infection treatment in CF patients are discussed, with a particular focus on strategies for eradicating P. aeruginosa and other pathogens. Moreover, the effects of long-term inhaled antibiotic therapy for chronic P. aeruginosa infection and for the prevention of pulmonary exacerbations is reviewed. Finally, how the mucus environment and microbial community richness can influence the efficacy of aerosolized antimicrobial agents is discussed.

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Developing Inhaled Antibiotics in Cystic Fibrosis: Current Challenges and Opportunities

Cited by 35 publications

References 34 publications

Cystic fibrosis lung disease and bronchiectasis

Cystic fibrosis lung disease and bronchiectasis

Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis

Cystic Fibrosis: Recent Insights into Inhaled Antibiotic Treatment and Future Perspectives

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