Journal article
Combining Ivacaftor and Intensive Antibiotics Achieves Limited Clearance of Cystic Fibrosis Infections
mBio, Vol.12(6), pp.e0314821-e0314821
12/21/2021
DOI: 10.1128/mbio.03148-21
PMCID: PMC8669489
PMID: 34903059
Abstract
Drugs called CFTR modulators improve the physiologic defect underlying cystic fibrosis (CF) and alleviate many disease manifestations. However, studies to date indicate that chronic lung infections that are responsible for most disease-related mortality generally persist. Here, we investigated whether combining the CFTR modulator ivacaftor with an intensive 3.5-month antibiotic course could clear chronic Pseudomonas aeruginosa or Staphylococcus aureus lung infections in subjects with
, who are highly ivacaftor-responsive. Ivacaftor alone improved CFTR activity, and lung function and inflammation within 48 h, and reduced P. aeruginosa and S. aureus pathogen density by ∼10-fold within a week. Antibiotics produced an additional ∼10-fold reduction in pathogen density, but this reduction was transient in subjects who remained infected. Only 1/5 P. aeruginosa-infected and 1/7 S. aureus-infected subjects became persistently culture-negative after the combined treatment. Subjects appearing to clear infection did not have particularly favorable baseline lung function or inflammation, pathogen density or antibiotic susceptibility, or bronchiectasis scores on CT scans, but they did have remarkably low sweat chloride values before and after ivacaftor. All persistently P. aeruginosa-positive subjects remained infected by their pretreatment strain, whereas subjects persistently S. aureus-positive frequently lost and gained strains. This work suggests chronic CF infections may resist eradication despite marked and rapid modulator-induced improvements in lung infection and inflammation parameters and aggressive antibiotic treatment.
Recent work shows that people with CF and chronic lung infections generally remain persistently infected after treatment with drugs that target the CF physiological defect (called CFTR modulators). However, changes produced by modulators could increase antibiotic efficacy. We tested the approach of combining modulators and intensive antibiotics in rapid succession and found that while few subjects cleared their infections, combined treatment appeared most effective in subjects with the highest CFTR activity. These findings highlight challenges that remain to improve the health of people with CF.
Details
- Title: Subtitle
- Combining Ivacaftor and Intensive Antibiotics Achieves Limited Clearance of Cystic Fibrosis Infections
- Creators
- Samantha L Durfey - University of WashingtonSudhakar Pipavath - University of WashingtonAnna Li - University of WashingtonAnh T Vo - University of WashingtonAnina Ratjen - University of WashingtonSuzanne Carter - St. Vincent's University HospitalSarah J Morgan - University of WashingtonMatthew C Radey - University of WashingtonBrenda Grogan - St. Vincent's University HospitalStephen J Salipante - University of WashingtonMichael J Welsh - University of IowaDavid A Stoltz - Roy J. and Lucille A. Carver College of MedicineChristopher H Goss - University of WashingtonEdward F McKone - St. Vincent's University HospitalPradeep K Singh - University of Washington
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.12(6), pp.e0314821-e0314821
- DOI
- 10.1128/mbio.03148-21
- PMID
- 34903059
- PMCID
- PMC8669489
- NLM abbreviation
- mBio
- ISSN
- 2161-2129
- eISSN
- 2150-7511
- Grant note
- R01 HL148274 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 12/21/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Internal Medicine
- Record Identifier
- 9984259507802771
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