Trials and tribulations of highly effective modulator therapies in cystic fibrosis

Lieu, Nathan; Prentice, Bernadette J.; Field, Penelope; Fitzgerald, Dominic A.

doi:10.1016/j.prrv.2023.09.001

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Cited by 5 publications

References 125 publications

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“The expectations of life depend upon diligence; the mechanic that would perfect his work must first sharpen his tools”

Fitzgerald

2023

Paediatric Respiratory Reviews

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“The expectations of life depend upon diligence; the mechanic that would perfect his work must first sharpen his tools”

Fitzgerald

2023

Paediatric Respiratory Reviews

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Unmet challenges in cystic fibrosis treatment with modulators

Corrao,

Kelly-Aubert,

Sermet-Gaudelus

et al. 2024

Expert Review of Respiratory Medicine

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Evaluating the effects of ivacaftor exposure on Staphylococcus aureus small colony variant development and antibiotic tolerance

Bollar,

Shaffer,

Keith

et al. 2024

JAC-Antimicrobial Resistance

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Background Ivacaftor exhibits anti-staphylococcal properties but does not clear Staphylococcus aureus from the lungs of people with cystic fibrosis (pwCF). We assessed whether exposure to therapeutic concentrations of ivacaftor could allow S. aureus to form small colony variants (SCVs), a phenotype commonly associated with bacterial persistence. Methods Humanized G551D-CFTR (hG551D) rats were treated with ivacaftor for 7 days. Concentrations in the plasma, epithelial lining fluid and lung tissue lysate were measured using LC-MS/MS. Survival of S. aureus during ivacaftor treatment was assessed in an hG551D rat model of lung infection. S. aureus adaptation to therapeutic concentrations of ivacaftor was investigated in vitro by serial passage in the presence of 10 µM ivacaftor. Bacterial survival in the presence of antimicrobials was evaluated using growth curves and density assays. Results Ivacaftor plasma concentrations of treated hG551D rats reached 3.488 ± 1.118 µM, with more variable concentrations in the epithelial lining fluid and lung tissue lysate. During S. aureus infection, ivacaftor-treated hG551D rats returned similar numbers of bacteria from the lung, compared with vehicle-treated controls. Exposure of S. aureus to ivacaftor in vitro led to the formation of ivacaftor-tolerant SCVs with an unstable phenotype and increased antibiotic tolerance. Conclusions Treatment with ivacaftor did not alter S. aureus burden in the cystic fibrosis rat and led to the formation of tolerant SCVs in vitro, suggesting that development of an SCV phenotype may allow S. aureus to persist in the cystic fibrosis lung during ivacaftor therapy.

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Trials and tribulations of highly effective modulator therapies in cystic fibrosis

Cited by 5 publications

References 125 publications

“The expectations of life depend upon diligence; the mechanic that would perfect his work must first sharpen his tools”

“The expectations of life depend upon diligence; the mechanic that would perfect his work must first sharpen his tools”

Unmet challenges in cystic fibrosis treatment with modulators

Evaluating the effects of ivacaftor exposure on Staphylococcus aureus small colony variant development and antibiotic tolerance

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