Pseudomonas aeruginosainfection in cystic fibrosis: pathophysiological mechanisms and therapeutic approaches

Abstract

Pseudomonas aeruginosa is a remarkably versatile environmental bacterium with an extraordinary capacity to infect the cystic fibrosis (CF) lung. Infection with P. aeruginosa occurs early, and although eradication can be achieved following early detection, chronic infection occurs in over 60% of adults with CF. Chronic infection is associated with accelerated disease progression and increased mortality. Extensive research has revealed complex mechanisms by which P. aeruginosa adapts to and persists within the CF airway. Yet knowledge gaps remain, and prevention and treatment strategies are limited by the lack of sensitive detection methods and by a narrow armoury of antibiotics. Further developments in this field are urgently needed in order to improve morbidity and mortality in people with CF. Here, we summarize current knowledge of pathophysiological mechanisms underlying P. aeruginosa infection in CF. Established treatments are discussed, and an overview is offered of novel detection methods and therapeutic strategies in development.

Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa

“…These infections are difficult to treat due to the intrinsic and acquired antibiotic resistance of P. aeruginosa (18) that is further compounded by its ability to form antibiotic tolerant biofilms (19). P. aeruginosa is the predominant cause of morbidity and mortality in individuals with cystic fibrosis (CF), since it forms biofilms, thereby establishing chronic lung infections that are impossible to eradicate with antibiotic treatment (20). The necessity of new therapeutic options for the treatment of P. aeruginosa infections was highlighted in a recent World Health Organization report in which this pathogen is top ranked among pathogens for which new antibiotics are urgently needed (Priority 1: Critical [http://www.who.int/en/news -room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are -urgently-needed]).…”

Anti-Infectives Restore ORKAMBI® Rescue of F508del-CFTR Function in Human Bronchial Epithelial Cells Infected with Clinical Strains of P. aeruginosa

“…Chronic infection and inflammation are the primary causes of declining lung function in CF patients [6][7][8][9]. Our studies provide the first in vitro evidence that anti-infectives-in addition to eliminating growth of lab and clinical strains of P. aeruginosa-help to restore infection-mediated losses in CFTR function (Figure 7).…”

“…A deficient CFTR function causes the failure of chloride secretion and sodium hyperabsorption at the apical airway surface, leading to the dehydration of the airway surface, impaired mucociliary clearance, and the accumulation of viscous mucus at the epithelial surface [4,5]. As a result, CF patients are prone to contracting bacterial lung infections with the opportunistic pathogen P. aeruginosa [6]. Prolonged P. aeruginosa infections have been linked to chronic inflammation in the CF lung [7,8], worsening the damage to lung tissue, and leading to eventual respiratory failure [9].…”

Comparative evaluation of methods testing in vitro sensitivity to azithromycin in multi-drug resistant Pseudomonas aeruginosa isolated from cystic fibrosis patients

“…Current therapeutic strategies aim at eradicating initial or first infection with P. aeruginosa. When eradication fails, chronic infection can develop and then therapy tries to suppress P. aeruginosa load (2,3).…”