Failed Eradication Therapy of New-Onset Pseudomonas aeruginosa Infections in Children With Cystic Fibrosis Is Associated With Bacterial Resistance to Neutrophil Functions

Abstract

Background: Antibiotics, such as inhaled tobramycin, are used to eradicate new-onset Pseudomonas aeruginosa (PA) infections in patients with cystic fibrosis (CF) but frequently fail due to reasons poorly understood. We hypothesized that PA isolates' resistance to neutrophil antibacterial functions was associated with failed eradication in patients harboring those strains.

Methods: We analyzed all PA isolates from a cohort of 39 CF children with new-onset PA infections undergoing tobramycin eradication therapy, where 30 patients had eradicated and 9 patients had persistent infection. We characterized several bacterial phenotypes and measured the isolates' susceptibility to neutrophil antibacterial functions using in vitro assays of phagocytosis and intracellular bacterial killing.

Results: PA isolates from persistent infections were more resistant to neutrophil functions, with lower phagocytosis and intracellular bacterial killing compared to those from eradicated infections. In multivariable analyses, in vitro neutrophil responses were positively associated with twitching motility, and negatively with mucoidy. In vitro neutrophil phagocytosis was a predictor of persistent infection following tobramycin even after adjustment for clinical risk factors.

Conclusions: PA isolates from new-onset CF infection show strain-specific susceptibility to neutrophil antibacterial functions, and infection with PA isolates resistant to neutrophil phagocytosis is an independent risk factor for failed tobramycin eradication.

Keywords: Pseudomonas aeruginosa; antibiotic eradication therapy; cystic fibrosis; neutrophil phagocytosis.

Figure 1.

Pseudomona s aeruginosa isolates from patients with persistent infections exhibit lower neutrophil antibacterial functions compared to those from patients with eradicated infection. Neutrophil phagocytosis (A) and intracellular bacterial killing (B) of the persistent (n = 9 patients) group and the eradicated (n = 30 patients) group. The data were analyzed per patient by averaging the neutrophil results of all P. aeruginosa isolates from each patient. Results are shown as median and interquartile range. Statistical comparisons were performed using Mann–Whitney test (*P < .05, ***P < .001).

Figure 2.

Neutrophil phagocytosis is significantly associated with intracellular bacterial killing. Association was calculated by Spearman correlation coefficient.