Pseudomonas aeruginosa infections were found to be a risk factor for failed eradication therapy in patients with cystic fibrosis who are resistant to neutrophil antibacterial functions, according to the results of a study published in The Journal of Infectious Diseases.
Infections caused by P aeruginosa in patients with cystic fibrosis are often treated with antibiotics, such as tobramycin, that frequently fail to eradicate the infection. A team of investigators therefore analyzed P aeruginosa isolates from a cohort of 39 children with cystic fibrosis and new-onset P aeruginosa infections to determine factors that may be contributing to treatment failure.
All patients were undergoing eradication therapy with tobramycin, with 30 achieving eradication and 9 having persistent infections. A total of 52 isolates from eradicated infections and 19 from persistent infections were analyzed. Several patients were infected with multiple isolates, so neutrophil assay data for all morphotypes in a patient sample were combined and analyzed.
Compared with eradicated infections, the average phagocytic index of persistent infections was 2-fold lower (9.1% vs 19.5%, P =.0003), and measures of bacterial killing were 2.5-fold lower (2.6% vs 6.7%, P =.018). When characterizing flagellum motility, twitching motility, and mucoidy (alginate overproduction), the investigators found that twitching motility (r=0.27, P =.02) and mucoidy (r= –5.60, P =.04) were significantly associated with neutrophil phagocytosis. For every 1-mm increase in twitching, there was an increase in phagocytosis of 0.27%, while the presence of mucoidy was associated with an average reduction in phagocytosis of 5.6%.
After adjustment for covariables, a significant predictor for persistent infection was in vitro neutrophil phagocytosis (odds ratio, 0.76; 95% CI, 0.62-0.94; P =.01). The investigators reported that every percentage increase in phagocytosis is therefore associated with a 24% reduction in the odds of a persistent infection outcome. After adjustment, in vitro neutrophil phagocytosis was also a significant predictor of failed eradication of infection.
The investigators noted that chronic P aeruginosa infections in the lungs of patients with cystic fibrotic are highly diverse, and they possibly overlooked some phenotypic diversity. Persistent infection was defined using positive sputum culture after completing treatment, and new infections were not ruled out with whole genome sequencing. The study results were not validated in primary human neutrophils because this study used the HL-60 cell lines to obtain robust and reproducible measurements in the face of large numbers of isolates. Small sample size, particularly for persistent infections, also limited the study, the investigators stated.
According to the study investigators, the results did point, however, to the decreased neutrophil phagocytosis of P aeruginosa as an independent predictor for failed tobramycin eradication. The study also offered biologic insights into eradication therapy failure in patients with cystic fibrosis and highlighted the possibility for the use of nonantibiotic therapies that target interactions between P aeruginosa and neutrophils or that enhance neutrophil antibacterial function.
Disclosure: Valerie Waters declared an affiliation with AstraZeneca. None of the other study authors declared any affiliations with the pharmaceutical industry.
Kwong K, Benedetti A, Yau Y, Waters V, Nguyen D. Failed eradication therapy of new onset Pseudomonas aeruginosa infections in cystic fibrosis children is associated with bacterial resistance to neutrophil functions. J Infect Dis. Published online February 19, 2021. doi:10.1093/infdis/jiab102