New anti-pseudomonal agents for cystic fibrosis- still needed in the era of small molecule CFTR modulators?

ABSTRACT

Introduction: Cystic fibrosis is characterized by bacterial lung infection, a majority of adults being chronically infected with Pseudomonas aeruginosa. Treatment is a major challenge, with frequent courses of antibiotics contributing to antimicrobial resistance. New approaches are clearly required. Over the last few years, a major shift in our approach to treating CF has occurred with the availability of the first drugs targeting the CFTR protein and leading to improvements in lung function, weight gain and frequency of exacerbations.

Areas covered: There are emerging, but limited, data exploring the effect these drugs have on airway infections, some studies suggesting a beneficial impact. CFTR modulators probably possess very little direct antimicrobial activity, but both synergy with conventional antibiotics and alternative mechanisms of bacterial killing have been proposed. This article reviews the current published evidence.

Expert opinion: The picture is far from clear concerning the impact of CFTR modulators on lung infections. However, currently, such drugs restore CFTR function incompletely, are most commonly introduced when lung damage is already present, are not suitable for all CF patients and not reimbursed in some areas. Therefore, whatever their eventual anti-infective potential, we need to continue our search for effective anti-pseudomonal therapies for the foreseeable future.

KEYWORDS:

• Antibiotics
• CFTR
• ivacaftor
• lumacaftor
• CFTR modulator
• Pseudomonas aeruginosa

Declaration of Interest

JC Davies declares that she has sat on advisory boards for Algipharma AS, Bayer AG, Boehringer Ingelheim, Galapagos NV, ImevaX, Nivalis Therapeutics Inc., ProQR Therapeutics III B.V., Proteostasis Therapeutics INC., PTC Therapeutics International Ltd, Raptor Pharmaceuticals Inc., Vertex Pharmaceuticals, Enterprise, Novartis, Pulmocide, Flatley and Nivalis Therapeutics Inc. She has also held clinical trial leadership roles for clinical trials run by Algipharma AS, Bayer AG, Galapagos NV, and Vertex Pharmaceuticals. Furthermore, she has assisted with clinical trial design for ImevaX GmbH, ProQR Therapeutics III B.V .and Proteostasis Therapeutics INC and has provided educational activities for Teva. Finally, she has received research grants from AmpliPhi and the Cystic Fibrosis Trust (through grant SRC 001). I Martin has, under a research collaboration, received research materials in the form of anti-pseudomonal bacteriophages from Ampliphi as well as from the Cystic Fibrosis Trust. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• chronic infection with P. aeruginosa is a major causative factor in the progressive lung disease which limits life expectancy in patients with cystic fibrosis

• the increased understanding of CFTR genetics and biology has transformed the drug development field over the last 5-10 years

• new CFTR modulating drugs have led to substantial clinical benefit, improving lung function and reducing episodes of exacerbation and the need for hospitalization; long-term rates of lung function decline are also impacted. Numerous molecules are currently at preclinical and clinical trial stages, providing significant hope for the future of the disease

• data are beginning to emerge suggesting that CFTR modulators may impact lower airway infection; in some studies, a direct antimicrobial effect has been proposed although this is largely lacking for the major gram negative, P. aeruginosa. Synergy with conventional antibiotics or alteration of airway surface pH through increased bicarbonate secretion have also been proposed

• emerging evidence points to a CFTR-related defect in circulating immune and inflammatory cells. Understanding the role this plays in lung disease and the ability of CFTR modulators to impact this will be of crucial importance in future drug development.

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Additional information

Funding

This manuscript has not been funded.