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

Abstract

Recurrent and chronic bacterial infections are common in people with cystic fibrosis (CF) and contribute to lung function decline. Antibiotics are the mainstay in the treatment of exacerbations and chronic bacterial infection in CF. Inhaled antibiotics are effective in treating chronic respiratory bacterial infections and eradicatingPseudomonas aeruginosafrom the respiratory tract, with limited systemic adverse effects. In the past decade, highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have become a new therapy that partially corrects/opens chloride transport in patients with selected CFTR mutations, restoring mucus hydration and improving mucociliary clearance. The recent triple CFTR modulator combination is approved for ∼80–90% of the CF population and significantly reduces pulmonary exacerbations and improves respiratory symptoms and lung function. CFTR modulators have shifted the focus from symptomatic treatment to personalised/precision medicine by targeting genotype-specific CFTR defects. While these are highly effective, they do not fully normalise lung physiology, stop inflammation or resolve chronic lung damage, such as bronchiectasis. The impact of these new drugs on lung health is likely to change the future management of chronic pulmonary infections in people with CF. This article reviews the role of inhaled antibiotics in the era of CFTR modulators.

Considerations for the use of inhaled antibiotics forPseudomonas aeruginosain people with cystic fibrosis receiving CFTR modulator therapy

“…With the advent of CFTRm, pwCF are feeling healthier, with many experiencing a significant reduction in sputum volume,34 which may lead them to believe they are free from airway pathogen infection 37. Indeed, some pwCF decide to stop taking inhaled antibiotics when they feel better (eg, upon reduction of their previously abundant sputum), despite continuing to have positive cultures for P. aeruginosa 38…”

“…Some aspects of CF care may need redefining following the introduction of CFTRm. For example, pulmonary exacerbations still occur in pwCF receiving CFTRm, but the symptom profile may be different versus the pre-CFTRm era 34. Concern also exists around the detection of P. aeruginosa in pwCF receiving CFTRm due to the significant reduction in sputum, which has limited the frequency and quality of sample collections.…”

“…Such investigations may include the use of induced sputum to monitor infection, with multiple negative cultures indicating clearance. More data are needed before clear guidelines can be developed 34. Despite the lack of evidence on this topic, anecdotal observations suggest that many pwCF receiving CFTRm are keen to reduce their treatment burden by discontinuing antibiotics once they are asymptomatic 34.…”

“…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.…”

“…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…”