Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis

Abstract

Background: Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early antipseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response.

Methods: This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardized therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial antipseudomonal therapy. Associations between eradication status and outcomes were assessed.

Results: Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17-.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25-.73) compared with nonsustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with nonsustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline.

Conclusions: This is the first study to quantify the long-term durability of microbiological response associated with early antipseudomonal therapy, demonstrating the critical importance of optimizing antipseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage.

Clinical trials registration: NCT00097773.

Keywords: Pseudomonas aeruginosa; Pseudomonas infections; cystic fibrosis; eradication therapy; treatment outcomes.

© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Overview of study design. Children with cystic fibrosis (CF) aged 1–12 years with newly identified Pseudomonas aeruginosa (Pa) infection within 6 months of enrollment were eligible for the trial. Newly identified Pa was defined as the first lifetime documented Pa-positive culture or a Pa-positive culture after a 2-year absence of Pa culture positivity (requiring at least 1 culture per year). For children aged 12–15 months, at least 1 Pa-positive culture since birth was required. Other eligibility criteria have been previously reported [12]. During the first quarter of the study, all children received initial Pa eradication treatment consisting of tobramycin inhalation solution, with half of the children randomly assigned to a concurrent course of oral ciprofloxacin and half to oral placebo. Children were randomized to 1 of 2 maintenance treatment strategies: (1) cycled therapy—treatment provided in quarterly cycles regardless of findings from scheduled quarterly respiratory cultures; or (2) culture-based therapy—treatment only in response to identification of Pa from quarterly cultures. Sustained Pa eradication was based on the Leeds definition of “Pa-free” [13] and required participants to have been Pa culture negative for at least 12 months prior to the completion of the trial (based on cultures obtained quarterly, with the average number of cultures for the cohort in the 12 months of the trial equal to 4.7). The assessment period for defining sustained Pa eradication allowed up to 6 prior months of intensive antipseudomonal therapy to achieve initial Pa eradication and was defined during the maintenance therapy phase of the trial. Long term follow-up was provided via the Early Pseudomonas Infection Control (EPIC) observational study and the CF National Patient Registry.

Figure 2.

Kaplan–Meier plots of time to chronic Pseudomonas aeruginosa (Pa) infection (A) and time to mucoid Pa infection (B) after completion of the clinical trial, by eradication status.