Antibiotic Regimen Changes during Cystic Fibrosis Pediatric Pulmonary Exacerbation Treatment.

Rationale/Objectives: Antibiotic selection for in-hospital treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) is typically guided by previous respiratory culture results or past PEx antibiotic treatment. In the absence of clinical improvement during PEx treatment, antibiotics are frequently changed in search of a regimen that better alleviates symptoms and restores lung function. The clinical benefits of changing antibiotics during PEx treatment are largely uncharacterized. Methods: This was a retrospective cohort study using the Cystic Fibrosis Foundation Patient Registry Pediatric Health Information System. PEx were included if they occurred in children with CF from 6 to 21 years old who had been treated with intravenous antibiotics between January 1, 2006, and December 31, 2018. PEx with lengths of stay <5 or >21 days or for which treatment was delivered in an intensive care unit were excluded. An antibiotic change was defined as the addition or subtraction of any intravenous antibiotic between Hospital Day 6 and the day before hospital discharge. Inverse probability of treatment weighting was used to adjust for disease severity and indication bias, which might influence a decision to change antibiotics. Results: In all, 4,099 children with CF contributed 18,745 PEx for analysis, of which 8,169 PEx (43.6%) included a change in intravenous antibiotics on or after Hospital Day 6. The mean change in pre- to post-treatment percent predicted forced expiratory volume in 1 second (ppFEV1) was 11.3 (standard error, 0.21) among events in which an intravenous antibiotic change occurred versus 12.2 (0.18) among PEx without an intravenous antibiotic change (P = 0.001). Similarly, the odds of return to ⩾90% of baseline ppFEV1 were less for PEx with antibiotic changes than for those without changes (odds ratio [OR], 0.89 [95% confidence interval (CI), 0.80-0.98]). The odds of returning to ⩾100% of baseline ppFEV1 did not differ between PEx with versus without antibiotic changes (OR, 0.94 [95% CI, 0.86-1.03]). In addition, PEx treated with intravenous antibiotic changes were associated with higher odds of future PEx (OR, 1.17 [95% CI, 1.12-1.22]). Conclusions: In this retrospective study, changing intravenous antibiotics during PEx treatment in children with CF was common and not associated with improved clinical outcomes.

Approach to eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis.

The primary cause of morbidity and mortality in children with cystic fibrosis (CF) is the progression of obstructive lung disease secondary to chronic endobronchial infection, mainly caused by Pseudomonas aeruginosa (Pa). Initial Pa isolates are typically non-mucoid, usually susceptible to most anti-pseudomonal antibiotics, and potentially amenable to eradication. Preliminary studies of early intervention suggest a "window of opportunity" with anti-pseudomonal antibiotics to eradicate Pa from upper and lower airways. Several large trials in young children with CF are currently ongoing with the goals of (1) investigating if early intervention at the time of initial Pa acquisition is effective and safe and (2) identifying the least invasive and safest treatment regimen to achieve both microbiologic and clinical benefits.

Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis.

Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease.

Prevalence of cystic fibrosis pathogens in the oropharynx of healthy children and implications for cystic fibrosis care.

OBJECTIVE: To describe the prevalence of the CF pathogens Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae in OP cultures from healthy children. METHODS: Oropharyngeal (OP) swabs were collected from 100 healthy children ≤18 years of age undergoing a clinically indicated procedure. RESULTS: P. aeruginosa was isolated from the OP swab of one participant, S. aureus from 48 participants (including 4 methicillin-resistant) and H. influenzae from 47 participants. Cultures from 75 participants grew one or more of these organisms (55 grew one, 19 grew 2 and one grew 3 organisms). CONCLUSION: P. aeruginosa is rarely recovered from the oropharynx of healthy children ≤18 years of age, while recovery of S. aureus and H. influenzae is common. It is important to understand what the "normal" prevalence of CF pathogens is in the oropharynx in order to aid interpretation of OP cultures in CF patients.

No detectable improvements in cystic fibrosis transmembrane conductance regulator by nasal aminoglycosides in patients with cystic fibrosis with stop mutations.

Cystic fibrosis (CF) is an autosomal recessive disorder caused by many types of genetic defects, including premature stop codons. Gentamicin can suppress stop mutations in CF transmembrane conductance regulator (CFTR) in vitro and in vivo, leading to improvements in CFTR-dependent ion transport and protein localization to the apical surface of respiratory epithelial cells. The primary objective of this study was to test whether nasally administered gentamicin or tobramycin could suppress premature stop mutations in CFTR, resulting in full-length, functional protein. A secondary objective was to obtain data to aid in the design of multicenter trials using the nasal potential difference as a study endpoint. A multicenter study was conducted in two cohorts of patients with CF, those heterozygous for stop mutations in the CFTR gene and those without nonsense mutations, to investigate the effects of both gentamicin and tobramycin administered over a 28-d period on sequential nasal potential difference and airway cell immunofluorescence endpoints. Eleven patients with CF with stop mutations were enrolled in a randomized, double-blinded, crossover fashion to receive each drug, while 18 subjects with CF without stop mutations were randomized 1:1 in a parallel fashion to receive one drug. After demonstration of drug delivery, neither aminoglycoside produced detectable changes in nasal ion transport or CFTR localization in brushed cells from either study group. These results with first-generation suppressive agents suggest the need for improved drug delivery methods and/or more potent suppressors of nonsense mutations to confer CFTR correction in subjects with CF heterozygous for nonsense mutations. The study provides valuable information on parameters of the nasal potential difference measurements for use in future multicenter clinical trials.

Disease-specific reference equations for lung function in patients with cystic fibrosis.

RATIONALE: Forced expiratory volume in one second (FEV1), an important measure of pulmonary disease severity in patients with cystic fibrosis (CF), is frequently expressed as a percentage of a predicted value derived from a healthy reference population. There are limitations to comparing the lung function of a patient with CF to that of healthy control subjects, and potential advantages to comparing it to that of other patients with CF. OBJECTIVE: To estimate CF-specific percentiles of FEV1 as functions of height, age, and sex. METHODS: We used 287,108 FEV1 observations among more than 21,000 patients with CF in the CF Foundation National Patient Registry between 1994 and 2001. The percentiles were estimated using quantile regression methods. RESULTS: FEV1 percentile "growth grids" are presented, allowing comparison of an individual's FEV1 to that of patients with CF of the same sex, age, and height. Their potential uses in clinical practice and research are illustrated. CONCLUSIONS: CF-specific reference equations allow individual patients' FEV1 to be placed in the context of the distribution of lung function of their peers with CF, and should improve generalizability of CF clinical trials by setting entry criteria that are equitable across sex and age ranges. They may serve as a useful adjunct to conventional reference equations.