Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection

Abstract

Rationale: Chronic infection with Pseudomonas aeruginosa is associated with an increased exacerbation frequency, a more rapid decline in lung function, and increased mortality in patients with bronchiectasis.

Objectives: To perform a randomized placebo-controlled study assessing the efficacy and safety of inhaled colistin in patients with bronchiectasis and chronic P. aeruginosa infection.

Methods: Patients with bronchiectasis and chronic P. aeruginosa infection were enrolled within 21 days of completing a course of antipseudomonal antibiotics for an exacerbation. Participants were randomized to receive colistin (1 million IU; n = 73) or placebo (0.45% saline; n = 71) via the I-neb twice a day, for up to 6 months.

Measurements and main results: The primary endpoint was time to exacerbation. Secondary endpoints included time to exacerbation based on adherence recorded by the I-neb, P. aeruginosa bacterial density, quality of life, and safety parameters. All analyses were on the intention-to-treat population. Median time (25% quartile) to exacerbation was 165 (42) versus 111 (52) days in the colistin and placebo groups, respectively (P = 0.11). In adherent patients (adherence quartiles 2-4), the median time to exacerbation was 168 (65) versus 103 (37) days in the colistin and placebo groups, respectively (P = 0.038). P. aeruginosa density was reduced after 4 (P = 0.001) and 12 weeks (P = 0.008) and the St. George's Respiratory Questionnaire total score was improved after 26 weeks (P = 0.006) in the colistin versus placebo patients, respectively. There were no safety concerns.

Conclusions: Although the primary endpoint was not reached, this study shows that inhaled colistin is a safe and effective treatment in adherent patients with bronchiectasis and chronic P. aeruginosa infection. Clinical trial registered with http://www.isrctn.org/ (ISRCTN49790596).

Figure 1.

Flow diagram of patients enrolled in a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of up to 6 months of therapy with inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. *Treatment difference in incidence of treatment-emergent adverse events leading to discontinuation (P = 0.56). ^†Patient (placebo) was withdrawn from the study after one dose of investigation medicinal product because she did not meet the entry criteria (>15% fall in FEV₁ within 30 min of the first dose). AE = adverse event; ITT = intention-to-treat.

Figure 2.

Kaplan-Meier plot of estimate of time to first exacerbation within (A) the whole intention-to-treat population, and (B) adherence quartiles 2–4 of the intention-to-treat population.

Figure 3.

Change from baseline in log₁₀ CFUs Pseudomonas aeruginosa within the whole intention-to-treat population. The treatment difference in change from baseline in P. aeruginosa CFUs was analyzed using the Wilcoxon rank sum test. Error bars denote SEM.

Figure 4.

Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score within the whole intention-to-treat population. An analysis of covariance with treatment and center included in the model was used to examine treatment differences between groups for SGRQ total score. Error bars denote SEM.