Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. CONCLUSIONS: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Increased Fat Absorption From Enteral Formula Through an In-line Digestive Cartridge in Patients With Cystic Fibrosis.

OBJECTIVES: Supplemental enteral nutrition (EN) is used by approximately 12% of people with cystic fibrosis (CF). The objective of this study was to evaluate the safety, tolerability, and fat absorption of a new in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula provided to patients with CF. METHODS: Patients with CF receiving EN participated in a multicenter, randomized, double-blind, crossover trial with an open-label safety evaluation period. Plasma omega-3 fatty acid (FA) concentrations were measured and used as markers of fat absorption. Gastrointestinal symptoms were recorded to evaluate safety and tolerability. Information regarding the effect of EN on appetite and breakfast consumption was also collected. RESULTS: Before study entry, participants had received EN for a mean of 6.6 years at a mean volume of approximately 800 mL, yet had a mean body mass index of only 17.5 kg/m and omega-3 FA plasma concentrations were only 60% of levels found in normal healthy subjects. Compared with placebo, cartridge use resulted in a statistically significant 2.8-fold increase in plasma omega-3 FA concentrations. There were no adverse experiences associated with cartridge use, and a decrease in the frequency and severity of most symptoms of malabsorption was observed with cartridge use. Participants reported increased preservation of appetite and breakfast consumption with cartridge use compared with their pre-study regimen. CONCLUSIONS: Use of this in-line digestive cartridge was safe and well tolerated, and resulted in significantly increased levels of plasma omega-3 FA used with enteral formula, suggesting an overall increased fat absorption.

Can a patient designate his doctor as his proxy decision maker?

Most lawyers and bioethicists recommend that patients enact a durable power of attorney for health care designating somebody as their proxy decision maker should they become unable to make decisions. Most people choose family members as their agent. But what if a patient wants his or her doctor to be his or her proxy decision maker? Can the doctor be both physician and surrogate decision maker? Or should those roles necessarily be kept separate? We present a case in which those issues arose, and sought comments from Sabrina Derrington, a pediatric palliative care physician; Arthur Derse, an emergency department physician and lawyer; and Phil Black, a pulmonologist.

Pharmacokinetics of single-dose doripenem in adults with cystic fibrosis.

The pharmacokinetics of doripenem and doripenem-M-1 (inactive metabolite) were evaluated in an open-label, 2-period, single-sequence study in which single 1-g and 2-g doses of doripenem were administered intravenously over 4 hours to adult patients with cystic fibrosis (CF). The systemic exposure to doripenem and doripenem-M-1, as measured by observed apparent maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC), increased approximately proportionally to the increase in dose. Other pharmacokinetic parameters of doripenem and doripenem-M-1, including clearance, volume of distribution, and elimination half-life, were similar for the 1-g and 2-g doses. The results from this study were also compared with those from a previous study in adult healthy volunteers (HVs) without CF, from a previously conducted pharmacokinetic study, who received single doses of 500 mg and 1 g doripenem administered over 4 hours. The pharmacokinetics of doripenem in adult patients with CF are similar to those from adult HVs, noting some differences in the disposition when comparing body mass index-adjusted pharmacokinetic parameters.

Fetal hydrops and familial pulmonary lymphatic hypoplasia.

Two siblings were born with pleural effusions and hydrops. The first infant was a 26-week-old gestation male and died at 8 hours of life with radiographically small lungs and pulmonary insufficiency. No lung tissue was obtainable. This pregnancy was followed by two normal term infants, a male and female. The fourth pregnancy resulted in a female born at 35 weeks' gestation with pleural effusion and hydrops who died at 32 months of age. This infant was discharged from hospital at 32 days of age with small pleural effusions, but needed supplemental oxygen and daily diuretics to control edema. There were 14 additional admissions until death-all for respiratory distress or infections. An open lung biopsy at 2 months, showed dilated pleural lymphatics, with hypoplasia of the acinar and terminal bronchiolar lymphatics. At postmortem examination there was a markedly thickened pleura, and slit-like hypoplastic lymphatics of the acinar and terminal bronchioles and interlobular septal regions. This is the second family reported with these distinctive pulmonary intra-acinar and peri-acinar hypoplastic lymphatics. This disease is compatible with an autosomal recessive mode of inheritance.