A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.

M Di Paolo,M C Fisher,A Vidal-Diaz,M Ni,D Armstrong-James,A Shah,E Nwankwo,L Hewitt

doi:10.1093/jacamr/dlab026

Abstract

BackgroundIndividuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide.ObjectivesIn this retrospective study we analysed the ‘real-world’ TDM of azole therapy in a large CF cohort, risk factors for subtherapeutic dosing, and the emergence of azole resistance.MethodsAll adults with CF on azole therapy in a large single UK centre were included. Clinical demographics, TDM and microbiology were analysed over a 2 year study period (2015–17) with multivariate logistic regression used to identify risk factors for subtherapeutic dosing.Results91 adults were treated with azole medication during the study period. A high prevalence of chronic subtherapeutic azole dosing was seen with voriconazole (60.8%) and itraconazole capsule (59.6%) use, representing significant risk factors for subtherapeutic levels. Rapid emergence of azole resistance was additionally seen over the follow-up period with a 21.4% probability of CF patients developing a resistant fungal isolate after 2 years. No significant relationship was found however between subtherapeutic azole dosing and azole resistance emergence.ConclusionsOur study demonstrates a high prevalence of subtherapeutic azole levels in CF adults with increased risk using itraconazole capsules and voriconazole therapy. We show rapid emergence of azole resistance highlighting the need for effective antifungal stewardship. Further large longitudinal studies are needed to understand the effects of antifungal resistance on outcome in CF and the implications of subtherapeutic dosing on resistance evolution.

Highlights

Cystic fibrosis (CF) is the most common, life-limiting autosomal recessive genetic disorder in the world.[1]
Dysfunction of the CFTR protein leads to abnormal anion transport and mucociliary clearance, resulting in a multisystem disorder characterized by chronic sinopulmonary infection, and pancreatic insufficiency.[3]
A total of 91 adults with CF were treated with azole medication in the study period and were included in analysis (48 male; 43 female)

Summary

Introduction

Cystic fibrosis (CF) is the most common, life-limiting autosomal recessive genetic disorder in the world.[1] It is most prevalent in the Caucasian populations of Europe and North America wherein it affects 1 in 2400 live births.[2] CF is caused by deleterious mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. Dysfunction of the CFTR protein leads to abnormal anion transport and mucociliary clearance, resulting in a multisystem disorder characterized by chronic sinopulmonary infection, and pancreatic insufficiency.[3] Ineffective clearance of inhaled pathogens from the airways leads to a cycle of infection and progressive inflammation, culminating in bronchiectasis and respiratory failure.[4] Over 90% of mortality in CF relates to pulmonary infection,[5] highlighting the clinical need for efficacious therapy. Individuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide

Objectives

Results

Conclusion