Pseudomonas aeruginosa antimicrobial susceptibility test (AST) results and pulmonary exacerbation treatment responses in cystic fibrosis.

Background Antimicrobial susceptibility testing (AST) of bacterial isolates is a time- and resource-intensive procedure recommended by cystic fibrosis (CF) treatment guidelines for antimicrobial selection for pulmonary exacerbation (PEx) treatment. Methods We studied relationships between Pseudomonas aeruginosa (Pa) isolate AST results, antipseudomonal PEx treatments, and treatment responses as change in weight and percent predicted forced expiratory volume in 1 s (ppFEV1) as well as future antimicrobial treatment hazard for PEx occurring at a CF care center from 1999 through 2018. Treatments were categorized by "Pa coverage" as complete (all Pa isolates susceptible by AST to at least one administered agent), none (no isolates susceptible), incomplete (some, but not all isolates susceptible), and indeterminant (administered antipseudomonals not evaluated by AST). Weight and ppFEV1 responses were compared across Pa coverage categories using unadjusted and adjusted general estimating equations; hazard of future treatment was assessed by Cox and logistic regression. Results Among 3820 antimicrobial PEx treatment events in 413 patients with Pa, 62.6% (2390) had complete Pa coverage; 8.9% (340), 2.4% (99), and 26.2% (1000), had no, incomplete, and indeterminant Pa coverage, respectively. Mean baseline to follow-up weight change was +0.74 kg [95% CI 0.63, 0.86]; ppFEV1 change was +1.60 [1.29, 1.90]. Pa coverage category was not associated with significant differences in weight or ppFEV1 change or with future antimicrobial treatment hazard. Conclusions We did not observe superior responses for AST-defined complete Pa coverage treatments versus lesser coverage treatments, suggesting that AST may be of little utility in choosing antimicrobials for CF PEx treatment.

Association of High-Dose Ibuprofen Use, Lung Function Decline, and Long-Term Survival in Children with Cystic Fibrosis.

RATIONALE: Cystic fibrosis deaths result primarily from lung function loss, so chronic respiratory therapies, intended to preserve lung function, are cornerstones of cystic fibrosis care. Although treatment-associated reduction in rate of lung function loss should ultimately improve cystic fibrosis survival, no such relationship has been described for any chronic cystic fibrosis therapy. In part, this is because the ages of most rapid lung function decline-early adolescence-precede the median age of cystic fibrosis deaths by more than a decade. OBJECTIVES: To study associations of high-dose ibuprofen treatment with the rate of forced expiratory volume in 1 second decline and mortality among children followed in the Epidemiologic Study of Cystic Fibrosis and subsequently in the U.S. Cystic Fibrosis Foundation Patient Registry. METHODS: We performed a matched cohort study using data from Epidemiologic Study of Cystic Fibrosis. Exposure was defined as high-dose ibuprofen use reported at ≥80% of encounters over 2 years. Unexposed children were matched to exposed children 5:1 using propensity scores on the basis of demographic, clinical, and treatment covariates. The rate of decline of percent predicted forced expiratory volume in 1 second during the 2-year follow-up period was estimated by mixed-effects modeling with random slopes and intercepts. Survival over 16 follow-up years in the U.S. Cystic Fibrosis Foundation Patient Registry was compared between treatment groups by using proportional hazards modeling controlling for matching and covariates. RESULTS: We included 775 high-dose ibuprofen users and 3,665 nonusers who were well matched on demographic, clinical, and treatment variables. High-dose ibuprofen users declined on average 1.10 percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 0.51, 1.69) during the 2-year treatment period, whereas nonusers declined at a rate of 1.76% percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 1.48, 2.04) during the corresponding 2-year period, a 37.5% slower decline among users compared with nonusers (95% confidence interval; 0.4%, 71.3%; P = 0.046). The users had better subsequent survival (P < 0.001): the unadjusted and adjusted hazard ratios for mortality (high-dose ibuprofen/non-high-dose ibuprofen) (95% confidence interval) were 0.75 (0.64, 0.87) and 0.82 (0.69, 0.96). CONCLUSIONS: In a propensity-score matched cohort study of children with cystic fibrosis, we observed an association between high-dose ibuprofen use and both slower lung function decline and improved long-term survival. These results are consistent with the hypothesis that treatment-associated reduction of lung function decline in children with cystic fibrosis leads to improved survival.

One-year safety and efficacy of tobramycin powder for inhalation in patients with cystic fibrosis.

UNLABELLED: This is an integrated analysis of data from patients with cystic fibrosis (CF) aged 6-21 years who were treated with up to seven cycles of tobramycin powder for inhalation (TIP(TM) ) over a period of at least 1 year. Safety and key efficacy endpoints were analyzed. RESULTS: The improvement in lung function and decrease in sputum P. aeruginosa (Pa) density from baseline were sustained over the 1-year treatment period. The number of adverse events (AEs) was low and did not increase with additional cycles of TIP treatment. Some increase in tobramycin minimum inhibitory concentration (MIC) was observed, but there was no significant increase in emergence of resistant strains based on the parenteral breakpoint for tobramycin. CONCLUSION: Efficacy of TIP was maintained for up to seven cycles. Long-term treatment with TIP was generally safe and well tolerated with no increase in AEs.

Behavioral and nutritional treatment for preschool-aged children with cystic fibrosis: a randomized clinical trial.

IMPORTANCE: Evidence-based treatments that achieve optimal energy intake and improve growth in preschool-aged children with cystic fibrosis (CF) are a critical need. OBJECTIVE: To test whether behavioral and nutritional treatment (intervention) was superior to an education and attention control treatment in increasing energy intake, weight z (WAZ) score, and height z (HAZ) score. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial included 78 children aged 2 to 6 years (mean age, 3.8 years) with CF and pancreatic insufficiency (intervention, n = 36 and control, n = 42). The study was conducted at 7 CF centers between January 2006 and November 2012; all 78 participants who met intent-to-treat criteria completed through follow-up. INTERVENTIONS: Behavioral intervention combined individualized nutritional counseling targeting increased energy intake and training in behavioral child management skills. The control arm provided education and served as a behavioral placebo controlling for attention and contact frequency. Both treatments were delivered in person or telehealth (via telephone). Sessions occurred weekly for 8 weeks then monthly for 4 months (6 months). Participants then returned to standard care for 1 year, with 12-month follow-up thereafter. MAIN OUTCOMES AND MEASURES: Changes in energy intake and WAZ score were examined from pretreatment to posttreatment (6 months) and change in HAZ score was assessed pretreatment to follow-up (18 months). Covariates included sex, Pseudomonas aeruginosa status at baseline, and treatment modality (in person vs telehealth). RESULTS: At baseline, mean (SD) energy intake was 1462 (329) kcals/d, WAZ score was -0.44 (0.81), and HAZ score was -0.55 (0.84). From pretreatment to posttreatment, the intervention increased daily energy intake by 485 calories vs 58 calories for the control group (adjusted difference, 431 calories; 95% CI, 282 to 581; P < .001) and increased the WAZ score by 0.12 units vs 0.06 for the control (adjusted difference, 0.09; 95% CI, -0.06 to 0.24; P = .25). From pretreatment to follow-up, the intervention increased the HAZ score by 0.09 units vs -0.02 for the control (adjusted difference, 0.14 units; 95% CI, 0.001 to 0.27; P = .049). Measured treatment integrity and credibility were high for both groups. CONCLUSIONS AND RELEVANCE: Behavioral and nutritional intervention improved energy intake and HAZ score outcomes but not WAZ score outcomes. Our results provide evidence that behavioral and nutritional treatment may be efficacious as a nutritional intervention for preschoolers aged 2 to 6 years with CF and pancreatic insufficiency. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00241969.

Use of ibuprofen to assess inflammatory biomarkers in induced sputum: Implications for clinical trials in cystic fibrosis.

BACKGROUND: High-dose ibuprofen (HDI) is a clinically beneficial anti-inflammatory regimen that may be a useful reagent to study induced sputum inflammatory marker changes over short study periods appropriate for early-phase CF clinical trials. METHODS: We conducted a 28-day, open-label, randomized, controlled trial among 72 clinically stable CF subjects (FEV1≥40% predicted) randomized to HDI or routine care that assessed IL-6, IL-8, TNF-α, IL-1-ß, free neutrophil elastase, and white cell counts with differentials change from baseline in induced sputum. RESULTS: IL-6 was the only biomarker with significant within-group change: 0.13 log10 pg/mL mean reduction among ibuprofen-treated subjects (p=0.04); and no change in the control group. IL-6 change between groups was statistically significant (p=0.024). No other inflammatory biomarker differences were observed between groups after 28 days. CONCLUSION: Although we studied only one agent, HDI, these results suggest that one month may be inadequate to assess anti-inflammatory candidates using markers from induced sputum.

Trends in the use of routine therapies in cystic fibrosis: 1995-2005.

Many therapies are used to treat manifestations of cystic fibrosis (CF). Trends in routine therapy use in Epidemiologic Study of Cystic Fibrosis patients were studied from 1995 to 2005. Patients (15,087) were assessed in 1995; 12,778 in 2005. Observed differences in therapy use of ≥2% were statistically significant at P < 0.001. Comparing the 1995 and 2005 populations, mean age was 13.9 versus 15.5 years; weight-for-age percentile was 30.3 versus 36.9; and mean forced expiratory volume in 1 sec (FEV(1)) was 73.7% (n = 7065) versus 78.7% (n = 7867) predicted. Use of several therapies increased, including airway clearance (69.9-89.6%), inhaled bronchodilators (72.0-84.0%), dornase alfa (44.8-67.2%), inhaled corticosteroids (16.0-49.3%), inhaled antibiotics (6.5-43.1%), oral nutritional supplements (18.3-24.5%), and insulin/oral hypoglycemic agents (4.9-10.2%). Use of mast cell stabilizers (from 22.0% to 5.3%) and oral bronchodilators (from 10.4% to 1.5%) decreased. Less dramatic changes occurred for pancreatic enzymes (92.6-91.0%), oral nonquinolone antibiotics (44.7-39.8%), oral corticosteroids (7.8-5.2%), mucolytics (4.4-2.5%), NSAIDs/high-dose ibuprofen (3.6-3.3%), enteral nutrition (5.2% vs. 8.2%), and oxygen (4.7-4.5%). Therapies not tracked in 1995 were evident in 2005, including oral macrolide antibiotics (33.8%), leukotriene inhibitors/antagonists (10.8%), and inhaled hypertonic saline (2.6%). Routine therapies were generally used more often by older patients and those with lower FEV(1). Notable increases in use of therapies, particularly of inhaled therapies, suggest that overall patient treatment burden must have risen correspondingly.

Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis.

RATIONALE: High-dose ibuprofen in a 4-year controlled trial slowed FEV(1) decline in young subjects with cystic fibrosis, but the effectiveness of ibuprofen has not been assessed in a large group of patients treated clinically with this therapy. OBJECTIVES: To assess the effect of ibuprofen therapy on FEV(1) decline in children and adolescents with cystic fibrosis, using observational data from the Cystic Fibrosis Foundation Patient Registry. METHODS: The rate of decline in FEV(1) percent predicted over 2-7 years among patients age 6-17 years with FEV(1) > 60% predicted, and who were treated with ibuprofen (1,365), was compared with patients of similar age and disease severity who were not treated with this therapy (8,960). Multilevel repeated-measures mixed-regression models were used to estimate rates of decline, adjusting for characteristics and therapies that influenced FEV(1) decline. Adverse effects were compared among those treated versus not treated with ibuprofen. MEASUREMENTS AND MAIN RESULTS: FEV(1) declined less rapidly among patients treated with ibuprofen (difference, 0.60% predicted per year; 95% confidence interval, 0.31 to 0.89; P < 0.0001); a 29% reduction in slope based on an average decline of 2.08% predicted per year for patients not treated. Those treated with ibuprofen were more likely to have an episode of gastrointestinal bleeding requiring hospitalization, but the occurrence was rare in both groups (annual incidence, 0.37 vs. 0.14%; relative risk, 2.72; P < 0.001). CONCLUSIONS: Slower rates of FEV(1) decline are seen in children and adolescents with cystic fibrosis who are treated with ibuprofen. The apparent benefits of ibuprofen therapy outweigh the small risk of gastrointestinal bleeding.

Pharmacological approaches for the discovery and development of new anti-inflammatory agents for the treatment of cystic fibrosis.

Some of the most important pathobiology in cystic fibrosis occurs not as a direct result of impaired chloride transport, but the downstream consequences of defective CFTR function, particularly the lung infection and inflammation that ultimately takes the lives of most patients. Interrupting the vicious cycle of infection and inflammation is effective in slowing the course of the disease, and antibiotics have long been the staple of pulmonary therapy. However, limiting the inflammatory response in the CF lung is also effective. High dose ibuprofen clearly retards progression of lung disease, but also entrains adverse events that mar its therapeutic utility, so alternative anti-inflammatory agents are necessary. Because of the remarkable therapeutic success of ibuprofen, consideration should be given to finding less toxic alternatives. However, it is also appropriate to consider the mechanisms by which the inflammatory response occurs in the CF lung, and identify sites to interrupt it. Sites at which therapeutic intervention is possible are the neutralization of cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, or IL-8 with specific antibodies or receptor antagonists, inhibition of the intracellular signaling cascades that result in cytokine production (for example, at the level of p38 MAP kinase), application of cytokines such as Il-10 that are themselves anti-inflammatory, or modulating the arachidonic acid cascade with inhibitors directed at leukotriene B(4). In addition, interventions designed to limit the consequences of the inflammatory response, such as protease inhibitors and reagents to limit the ill effects of DNA accumulation in airways, are in use. To limit adverse effect and concentrate the therapeutic effect, there may be value in targeting delivery of the therapeutic reagents to the inflamed site, either by specifically directing systemic delivery or by exploitation of the aerosol route. Treating the inflammatory response is important, for the data from the ibuprofen study show that the effects of anti-inflammatory therapy are additive or even synergistic with intensive conventional therapy and alter the rate of decline of pulmonary function, and therefore benefits for survival of patients with CF are to be expected.