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.

Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices.

BACKGROUND: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community. METHODS: We engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing. RESULTS: Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results. CONCLUSIONS: Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions.

Reconciling Antimicrobial Susceptibility Testing and Clinical Response in Antimicrobial Treatment of Chronic Cystic Fibrosis Lung Infections.

Median cystic fibrosis (CF) survival has increased dramatically over time due to several factors, including greater availability and use of antimicrobial therapies. During the progression of CF lung disease, however, the emergence of multidrug antimicrobial resistance can limit treatment effectiveness, threatening patient longevity. Current planktonic-based antimicrobial susceptibility testing lacks the ability to predict clinical response to antimicrobial treatment of chronic CF lung infections. There are numerous reasons for these limitations including bacterial phenotypic and genotypic diversity, polymicrobial interactions, and impaired antibiotic efficacy within the CF lung environment. The parallels to other chronic diseases such as non-CF bronchiectasis are discussed as well as research priorities for moving forward.

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.

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.