The Effect of CFTR Modulators on Airway Infection in Cystic Fibrosis

Abstract

The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed. Several studies have demonstrated the vast improvement CFTR modulators have on normalization of sweat chloride, CFTR function, clinical endpoints, and frequency of pulmonary exacerbation. However, their impact on other aspects of the disease, such as pathogenic burden and airway infection, remain under explored. Frequent airway infections as a result of increased susceptibility and impaired innate immune response are a serious problem within CF, often leading to accelerated decline in lung function and disease progression. Current evidence suggests that CFTR modulators are unable to eradicate pathogenic organisms in those with already established lung disease. However, this may not be the case for those with relatively low levels of disease progression and conserved microbial diversity, such as young patients. Furthermore, it remains unknown whether the restorative effects exerted by CFTR modulators extend to immune cells, such as phagocytes, which have the potential to modulate the response of people with CF (pwCF) to infection. Throughout this review, we look at the potential impact of CFTR modulators on airway infection in CF and their ability to shape impaired pulmonary defences to pathogens.

Role of inhaled antibiotics in the era of highly effective CFTR modulators

“…Some studies reported that the CFTR modulators may reduce bacterial load, microbial burden and restore innate immune responses and bacterial diversity similar to people without CF, thereby yielding an airway microbiome which reduces the incidence of acute airway infection and the rate of lung decline [38,39]. Another study contradicts this by reporting that treatment with ivacaftor does not reduce the odds of culture positivity with common CF-related microorganisms such as S. aureus [39]. CFTR modulators have not demonstrated change in antibiotic susceptibility of microorganisms and have no impact on the control of viral infection in the CF airway epithelial cells [40][41][42].…”

“…However, the literature reveals contrasting reports on this topic. Some studies reported that the CFTR modulators may reduce bacterial load, microbial burden and restore innate immune responses and bacterial diversity similar to people without CF, thereby yielding an airway microbiome which reduces the incidence of acute airway infection and the rate of lung decline [ 38 , 39 ]. Another study contradicts this by reporting that treatment with ivacaftor does not reduce the odds of culture positivity with common CF-related microorganisms such as S. aureus [ 39 ].…”

Modulators of CFTR protein function in the treatment of cystic fibrosis - a literature review

“…Weight gain (BMI increase) [27,33]. Current scientific evidence suggests that modulators of CFTR protein function are unable to eliminate airway colonization by pathogens in patients with advanced lung disease [37,38]. This seems to be an important observation considering that patients often have symptoms of infection and chronic inflammation of the airways, and most people with cystic fibrosis die of advanced lung disease [38].…”

“…Current scientific evidence suggests that modulators of CFTR protein function are unable to eliminate airway colonization by pathogens in patients with advanced lung disease [37,38]. This seems to be an important observation considering that patients often have symptoms of infection and chronic inflammation of the airways, and most people with cystic fibrosis die of advanced lung disease [38]. For this reason, the prevention of infections and the use of antimicrobial agents should be a necessary complement to the therapy using modulators of CFTR protein function.…”

Synergistic Activity of Repurposed Peptide Drug Glatiramer Acetate with Tobramycin against Cystic Fibrosis Pseudomonas aeruginosa

“…In part, this may relate to heterogeneity of deposition within partially obstructed airways, giving rise to subtherapeutic drug concentrations. Few new treatments are being developed for chronic P. aeruginosa , and the growing adult population means this unmet need will persist into the era of novel modulator drugs targeting the underlying cellular defect in CF ( 9 – 12 ).…”