Ciprofloxacin resistance in Pseudomonas aeruginosa from people with bronchiectasis

Abstract

Bronchiectasis is a chronic respiratory condition characterised by irreversible bronchial damage and dilation, with Pseudomonas aeruginosa infections linked to increased hospitalisations and poor outcomes. Ciprofloxacin, a key antibiotic for P. aeruginosa eradication and managing pulmonary exacerbations, has also been studied as a long-term treatment via liposomal inhalation in chronic infections (ORBIT-3/ORBIT-4). This thesis investigates ciprofloxacin resistance in clinical P. aeruginosa isolates from bronchiectasis patients enrolled in the iBEST-1 trial. Phenotypic, DNA- and RNA-based analyses, combined with experimental evolution studies under planktonic and biofilm growth conditions, had been carried out. Resistance correlated with fluoroquinolone prescriptions and was driven by mutations in quinolone resistance-determining regions (QRDR) of gyrA and parC, along with mexEF-OprN efflux pump overexpression. These mutations also coincided with impaired motility (swimming and swarming), reduced pyocyanin production, and slower growth, characteristic of chronic respiratory adaptations. Furthermore, biofilms of P. aeruginosa and Staphylococcus aureus exhibited enhanced ciprofloxacin resistance compared to single-species biofilms, with P. aeruginosa dominating the biofilm structure. These findings highlight the ease of resistance development in P. aeruginosa during ciprofloxacin exposure and the phenotypic changes that promote persistence in the lung environment. Co-cultured biofilms also suggest a mechanism of passive resistance contributing to treatment failure. This research underscores the clinical challenges posed by ciprofloxacin resistance in managing P. aeruginosa infections in bronchiectasis patients.

Thesis embargoed until 31 December 2027.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Laura Sherrard (Supervisor) & Michael Tunney (Supervisor)