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• CF airways are prone to opportunistic infections that can drive local inflammation. • Prevalence changes were studied from 2001-2019 for 7 CF bacterial opportunists. • Overall opportunist prevalence generally fell as population health improved. • Year-to-year prevalence change rates differed across organisms and birth cohorts. • More people changed infection status yearly than was suggested by prevalence change. Opportunistic bacterial infection is a hallmark of cystic fibrosis (CF) lung disease and early mortality. Poorly characterized prevalence changes have accompanied two decades of health improvements, with CFTR modulators likely to further affect infection epidemiology. Bacterial prevalence change trends across birth cohorts were assessed with linear regression using 2001–2019 US CF Foundation Patient Registry data. Informative missingness was assessed, as was age-to-age infection status. Bacterial prevalence constantly changed from 2001 to 2019, with changes differing across birth cohorts. Informative censoring affected prevalence change for some organisms. Age-to-age infection status changes were greater than net changes in bacterial prevalence and varied by age. CF infection epidemiology changed over two decades and will continue to do so. Understanding how modulators affect infection epidemiology will require creative designs for longitudinal prevalence change studies emphasizing prevalence changes independent of effects on lung biology. [ABSTRACT FROM AUTHOR]

Progress in the development of new therapies for cystic fibrosis (CF) has benefited from therapeutically responsive biomarkers to streamline drug development. Paradoxically, these response biomarkers have been proven to be essential even in the presence of data demonstrating a lack of correlation with clinical outcomes across individuals with CF. This finding is unsurprising, particularly in the setting of a rare disease given complex disease processes and an often-limited pool of clinically effective therapies by which to link biomarkers and clinical responsiveness. While many response biomarkers will be unable to progress from their status as markers of biological efficacy to either established correlates of clinical efficacy or surrogate endpoints, they remain critical to the overall success of therapeutic development. Therapeutic drug development in cystic fibrosis (CF) benefits from streamlined drug development programs relying on reliable early-phase response biomarkers. While the rare disease setting remains a compelling setting for the use of surrogate endpoints to reduce the burden and/or time of late-phase development efforts, the CF experience demonstrates that proven response biomarkers exhibit a complicated association with clinical response, prohibiting further progression towards their evaluation as surrogates. Quantifying the levels of uncertainty associated with the use of less established response biomarkers and understanding where they reside on the continuum of qualification with respect to their association with clinical outcomes provides an optimal framework for their application throughout therapeutic drug development. [ABSTRACT FROM AUTHOR]

Non-cystic fibrosis bronchiectasis (NCFBE) with Pseudomonas aeruginosa has been associated with increased pulmonary exacerbation (PEx) and mortality risk. European Respiratory Society guidelines conditionally recommend inhaled antimicrobials for persons with NCFBE, P aeruginosa and three or more PEx/year. We report microbiological results of two randomized, 48-week placebo-controlled trials of ARD-3150 (inhaled liposomal ciprofloxacin) in individuals with NCFBE with P aeruginosa and PEx history [Lancet Respir Med 2019;7:213–26]. Respiratory secretions from 582 participants receiving up to six 28-day on/off treatment cycles were analysed for sputum P. aeruginosa , Streptococcus pneumoniae , Haemophilus influenzae , Moraxella catarrhalis , Staphylococcus aureus and Escherichia coli densities, P. aeruginosa susceptibilities to ciprofloxacin and nine other antimicrobials, and prevalence of other bacterial opportunists. Associations between PEx risk and sputum density, antimicrobial susceptibility and opportunist prevalence changes were studied. Sputum P. aeruginosa density reductions from baseline after ARD-3150 treatments ranged from 1.77 (95% CI 2.13–1.40) versus 0.54 (95% CI 0.89–0.19) log 10 CFU/g for placebo (second period) to 2.07 (95% CI 2.45–1.69) versus 0.70 (95% CI 1.11–0.29) log 10 CFU/g for placebo (fourth period) with only modest correlation between density reduction magnitude and PEx benefit. ARD-3150 (but not placebo) treatment was associated with increased P. aeruginosa ciprofloxacin MIC but not emergence of other bacterial opportunists across the study; ciprofloxacin MIC 50 increased from 0.5 to 1 mg/L, MIC 90 increased from 4 to 16 mg/L. Other antimicrobial MIC were mostly unaffected. Microbiological changes over 48 weeks of ARD-3150 treatment appear modest. Ciprofloxacin susceptibility (but not other antimicrobial susceptibility) decreases were observed that did not appear to preclude PEx risk reduction benefit. [ABSTRACT FROM AUTHOR]

• The impact of home vs hospital care is an important clinical question in the treatment of pulmonary exacerbations (PEx). • We assessed treatment responses for adults with CF treated for PEx with intravenous antibiotics at home, in the hospital, or both. • Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital. Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location. In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV 1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only. Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home. [ABSTRACT FROM AUTHOR]

Abstract: Background: Rate of lung function decline (RLFD) (as FEV1 percent predicted/yr) is a robust measure of CF therapeutic efficacy rarely used as a study endpoint, in part due to uncertainty of sample size requirements. Methods: Sample size requirements for 1:1 randomizations to detect RLFD treatment effects from 20% to 80% were assessed in Epidemiologic Study of CF (ESCF) patients. Effects of measuring FEV1 1–4 times per year in studies of 1- to 4-year durations were assessed in 399 patients age ≥6years with FEV1 ≥70%. Impacts of inclusion/exclusion based on risk factors in 2369 ESCF patients were assessed over 1.5years using semi-annual FEV1 measures. Results: Increasing study duration and exclusion of lower risk patients (e.g., no P. aeruginosa infection) both substantially reduced requirements. Conclusions: CF RLFD studies of 1.5years in duration appear feasible provided that investigators account for the beneficial effects of subject inclusion/exclusion based on risk factors in power estimates. [ABSTRACT FROM AUTHOR]