Bacteriophage Therapy in Cystic Fibrosis: Emerging Strategies for Managing Chronic Pseudomonas aeruginosa Infections.

Abstract

Pseudomonas aeruginosa is the leading cause of chronic respiratory infection in people with cystic fibrosis (pwCF) and remains a major driver of morbidity and premature mortality. The unique environment of the CF lung promotes persistent colonisation, biofilm formation, and the emergence of multidrug-resistant (MDR) phenotypes, severely limiting the effectiveness of conventional antibiotic therapies. Despite aggressive and prolonged antibiotic regimens, eradication of chronic P. aeruginosa infection is rarely achieved, and repeated exposure accelerates resistance development. Consequently, there is an urgent need for alternative or adjunctive therapeutic strategies. Bacteriophage (phage) therapy has re-emerged as a promising approach for treating MDR P. aeruginosa infections due to its strain specificity, self-amplifying activity, and capacity to disrupt biofilms. Importantly, phage-driven selection pressure can impose fitness costs on bacteria, including reduced virulence and increased susceptibility to antibiotics, providing a potential route to antimicrobial resensitisation. However, translating phage therapy into routine clinical practice faces challenges, particularly in the context of CF lung disease, where heterogeneous bacterial populations, thick mucus, biofilms, and host immune responses complicate treatment efficacy. This scoping review synthesises current understanding of P. aeruginosa pathogenesis in CF, focusing on antibiotic resistance mechanisms, virulence factors that function as phage receptors, and the evolutionary trade-offs exploited by phage therapy, including the role of phage-encoded depolymerases that degrade protective biofilms and bacterial defence mechanisms that drive phage resistance. We critically evaluate clinical evidence supporting phage use in pwCF, highlighting key limitations in existing studies, and priorities for future research required to establish phage therapy as a viable, regulated treatment option.