Introduction
Cystic fibrosis (CF) is a life-limiting autosomal recessive condition caused by variants in the gene encoding the CF transmembrane conductance regulator (CFTR) protein.1 More than 160 000 people are estimated to be living with CF worldwide.2 The major cause of mortality in people with CF (pwCF) is progressive lung disease characterised by bacterial, fungal and viral infections, the accumulation of viscous mucus, airway inflammation, structural damage and recurrent pulmonary exacerbations.3–5 Dysfunctional mucociliary clearance in the CF airway allows pathogens to colonise the respiratory tract, where they can cause chronic airway infections and persistent inflammation, resulting in structural damage (eg, bronchiectasis and airway destruction) and deteriorating respiratory function.6 7
Pseudomonas aeruginosa, a gram-negative bacterium, is one of the most prevalent and important pathogens in adult CF lungs,6 with the prevalence of infection rising steeply in the teenage years (figure 1).8 9 The prevalence of P. aeruginosa infection increases with age,10 affecting 5%–20% of children with CF aged ≤2 years11 and approximately 40%–50% of adults with CF aged approximately 30–45 years (figure 1).8 9 Acquisition occurs from environmental sources or via transmission from other pwCF4 6 12; most first infections are caused by unique, non-clonal strains, whereas shared strains are disproportionally observed in older pwCF.10 P. aeruginosa evades the immune system via several adaptive behaviours, including downregulation of flagella expression and production of exopolysaccharides, which facilitate biofilm formation.4 Chronic infection with P. aeruginosa is associated with increased pulmonary exacerbations, accelerated decline in lung function and premature death in pwCF; therefore, antibiotics should be initiated in response to the first P. aeruginosa-positive respiratory culture, with the aim of eradication, as chronic infections require long-term antibiotic therapy.13–17 Inhaled antibiotics achieve higher airway concentrations and have limited toxicity compared with systemic regimens; therefore, selected antipseudomonal antibiotics have been developed as inhaled formulations.18
CFTR modulators (CFTRm) are novel drugs that bind to the CFTR protein during or after protein processing.19 The most commonly used CFTRm are a combination of three modulator drugs (elexacaftor, tezacaftor and ivacaftor (ETI), originally indicated for pwCF with ≥1 copy of the F508del variant but now approved in some regions for pwCF without a F508del variant20 21) and ivacaftor alone (indicated for pwCF with selected gating mutations22 23). These agents have demonstrated remarkable efficacy in reducing sweat chloride concentrations, respiratory symptoms (eg, cough and sputum production) and pulmonary exacerbations while enhancing the quality of life and increasing forced expiratory volume and body mass index in pwCF with appropriate CFTR variants.24–29 By the end of 2021, 88% and 62% of eligible patients in the US-based Cystic Fibrosis Foundation and European Cystic Fibrosis Society registries, respectively, were prescribed CFTRm, with the majority receiving ETI.8 9 It is important to note, however, that ETI is not readily available in some European countries and many non-European countries,2 30 and that pwCF without an F508del variant are currently not eligible for this treatment in many regions.31
In addition to beneficial effects on lung function, there is evidence that CFTRm may reduce bacterial infections32 33 and potentially act in conjunction with some antibiotics to decrease infections via changes in airway surface liquid and pH, improvements in microbiome diversity, modified inflammatory and immune responses and activation of innate molecules.34 However, our understanding of the interactions between CFTRm and antibiotics is limited, and investigations into the effects of CFTRm on CF pathogens have been inconclusive. Despite observations from CF registries that the prevalence of P. aeruginosa infections has markedly decreased since the introduction of CFTRm,8 9 recent evidence showed that chronic P. aeruginosa infections often persist in pwCF treated with CFTRm, suggesting that these patients may benefit from inhaled antibiotics to maintain long-term control of infections.33–35 It is also important to note that the COVID-19 pandemic may have impacted the availability of P. aeruginosa prevalence data, with a widespread lack of access to telehealth specimen collections for pathogen surveillance.36
This article provides an overview of the changing perceptions of how to diagnose and manage P. aeruginosa infections in pwCF during the CFTRm era, including considerations of the CF treatment burden and the future role of inhaled antibiotics.