Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Clostridium difficile Infection and Proton Pump Inhibitor Use in Hospitalized Pediatric Cystic Fibrosis Patients.

Children with cystic fibrosis (CF) often take proton pump inhibitors (PPIs), which helps improve efficacy of fat absorption with pancreatic enzyme replacement therapy. However, PPI use is known to be associated with Clostridium difficile-(C. diff-) associated diarrhea (CDAD). We retrospectively evaluated the incidence of C. diff infection from all pediatric hospital admissions over a 5-year period at a single tertiary children's hospital. We found significantly more C. diff-positive stool tests in hospitalized patients with CF compared to patients with no diagnosis of CF. However, use of a PPI was not associated with an increased risk of CDAD in hospitalized CF patients. In summary, C. diff infection is more common in hospitalized pediatric CF patients although PPI use may not be a risk factor for CDAD development in this patient population.

Population pharmacokinetic and pharmacodynamic modeling of high-dose intermittent ticarcillin-clavulanate administration in pediatric cystic fibrosis patients.

BACKGROUND: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)-approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen. OBJECTIVES: The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF). METHODS: This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses. RESULTS: A total of 127 patients (age, 0-19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 µg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 µg/mL. CONCLUSIONS: The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs <16 µg/mL. Bacteriostatic and bactericidal effects were not frequently achieved among P. aeruginosa isolates with MICs >32 µg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.

Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis.

OBJECTIVE: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection. DESIGN: Randomized controlled trial. SETTING: Multicenter trial in the United States. PARTICIPANTS: Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection. INTERVENTIONS: Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures. MAIN OUTCOME MEASURES: The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures. RESULTS: The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups. CONCLUSIONS: No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00097773.

A survey of the utilization of anti-pseudomonal beta-lactam therapy in cystic fibrosis patients.

The purpose of this study was to characterize the utilization of anti-pseudomonal beta-lactam antibiotics in the treatment of acute pulmonary exacerbations (APE) among Cystic Fibrosis Foundation (CFF)-accredited care centers. An anonymous national cross-sectional survey of CFF-accredited care centers was performed using an electronic survey tool (SurveyMonkey.com®). One hundred and twenty-one of 261 centers completed the survey (46%) representing 56% (14,856/26,740) of patients in the CFF Patient Registry. One hundred and nineteen of 121 (98%) respondents reported using beta-lactams for the treatment of APE. Intermittent dosing regimens constituted 155/167 (93%) reported regimens, while extended infusions were 12/167 (7%). Ceftazidime was the most commonly utilized beta-lactam comprising 74/167 (44%) of all infusions (intermittent and extended) of which 70/74 (95%) were intermittent infusions. The majority of intermittent ceftazidime regimens (56/70; 80%) were at doses lower than CFF and European guidelines recommended doses. In conclusion, a great majority of respondents use intermittent anti-pseudomonal beta-lactam antibiotics, with over half of respondents utilizing lower than guidelines recommended doses. While this is of concern, it is not known if optimization of dosing strategies according to guidelines recommendations will result in clinical benefit.

Pulmonary nodules in a newborn with ATP-binding cassette transporter A3 (ABCA3) mutations.

Mutations in the gene for adenosine triphosphate-binding cassette transporter A3 (ABCA3) have been reported in infants and children with fatal surfactant deficiency and interstitial lung disease. Previously reported radiographic lung findings include ground-glass opacification, streaky infiltrates, and interstitial septal thickening. We report here the unusual case of a newborn who rapidly developed large rounded masses in the lung soon after birth that then resolved spontaneously by 3 months of age. She was found to be a compound heterozygote for both a known and a novel mutation in the ABCA3 gene. This report underscores the diverse clinical presentation of this condition.

High dose intermittent ticarcillin-clavulanate administration in pediatric cystic fibrosis patients.

BACKGROUND: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400mg/kg/day divided every 6h, (maximum 24 g/day). This dosing strategy is higher than the Cystic Fibrosis Foundation (CFF) recommendations and the Food and Drug Administration (FDA) approved package labeling. The purpose is to determine the safety of this dosing regimen. METHODS: A retrospective study of pediatric cystic fibrosis (CF) patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Baseline and follow-up laboratory parameters were recorded. Statistical analysis was performed. RESULTS: 127 patients met inclusion criteria. The mean (+ or - SD) ticarcillin dose was 3.5 g (+ or - 2.16) every 6 h; while the mean (+ or - SD) total ticarcillin dose was 13.5 g (+ or - 6.5) per day. No significant differences occurred in liver function tests, white blood count, and platelet count from baseline. Serum creatinine showed a statistically significant decrease from baseline. CONCLUSIONS: Higher than FDA approved doses of ticarcillin-clavulanate may be safely used in the treatment of exacerbations in pediatric cystic fibrosis patients.

Duration of treatment effect after tobramycin solution for inhalation in young children with cystic fibrosis.

RATIONALE: Among young children with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality. Early intervention strategies include tobramycin solution for inhalation (TSI), which can eradicate lower airway Pa from cultures obtained at the end of 28 days of treatment in young children. METHODS: We conducted an open label, sequential cohort study of TSI in young children with CF to investigate duration of antimicrobial treatment effect. The primary outcome was lower airway Pa eradication per bronchoalveolar lavage (BAL) fluid culture. Sequential treatment cohorts varied by duration of treatment (28 or 56 days) and timing of follow-up BAL (at Days 56, 84, or 112). Subjects (N = 36) were treated with TSI, 300 mg twice daily, for 28 days or 56 days per cohort assignment. RESULTS: Among 31 evaluable subjects, culture based, lower airway Pa eradication was observed in the majority of subjects for up to 1-3 months following TSI treatment: 75% in Cohort 28/56 (days of treatment/day of follow-up BAL), 63% in Cohort 28/84, 82% in Cohort 56/112, and 75% in Cohort 28/112. Non-mucoid Pa at baseline and/or exotoxin A seronegativity were associated with higher rates of eradication. There was a less pronounced effect of TSI treatment on Pa eradication from oropharyngeal cultures in all cohorts. TSI treatment was associated with reduced neutrophilic airway inflammation and was not related to any serious adverse events. CONCLUSION: TSI monotherapy is safe and can eradicate lower airway Pa for up to 3 months after treatment in young children with CF.