Initial Pseudomonas aeruginosa treatment failure is associated with exacerbations in cystic fibrosis

Abstract

Rationale: The risk of pulmonary exacerbation following Pseudomonas aeruginosa (Pa) acquisition in children with cystic fibrosis (CF) is unknown.

Objectives: To determine if failure of antibiotic therapy to eradicate Pa and frequency of Pa recurrence are associated with increased exacerbation risk.

Methods: The cohort included 282 children with CF who participated in the EPIC trial ages 1-12 with newly acquired Pa, defined as either a first lifetime Pa positive respiratory culture or positive after two years of negative cultures (past isolation of Pa but >2 years prior to the trial). All received antibiotics to promote initial eradication followed by 15 months of intermittent maintenance antibiotics. Quarterly cultures were used to define initial eradication success and subsequent number of Pa recurrences. A standardized symptom-based definition of exacerbation was utilized. Cox proportional hazards models were used to estimate exacerbation risk.

Results: Failure to initially eradicate Pa was associated with exacerbation risk (hazard ratio [HR]: 2.49, 95% confidence interval [CI] 1.26, 4.93). In 245/282 with successful initial eradication during the trial, past isolation of Pa >2 years before the trial was the most significant predictor of exacerbation (HR 1.62, 95% CI 1.12, 2.35). In 37/282 who failed initial eradication, persistent Pa during the maintenance phase (1 or more Pa recurrences after failure to initially eradicate) added even greater exacerbation risk (HR 4.13, 95% CI 1.28, 13.32).

Conclusions: Children with CF who fail to eradicate after initial antibiotic treatment are at higher risk of subsequent exacerbation, suggesting clinical benefit to successful early eradication of Pa infection.

Figure 1

Kaplan Meier plot of time to first pulmonary exacerbation treated with either IV antibiotics (a and c) or antibiotics by any route of administration (b and d), comparing those with newly acquired Pa who entered the trial with no history of Pa colonization versus those who entered with past isolation of Pa (>2 years prior to enrollment) (a and b), and those who achieved successful initial eradication at week 10 to those who failed to achieve successful initial eradication (c and d).

Figure 2

Distribution of the number of Pa positive cultures from week 10 through the end of the 15-month maintenance phase for subgroups defined by initial eradication success at week 10.