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Updated: Jul 16, 2025
Antibiotic Efficacy Testing in an Ex vivo Model of Pseudomonas aeruginosa and Staphylococcus aureus Biofilms in the Cystic Fibrosis Lung
Published on: January 22, 2021
Parallel evolution of linezolid-resistant Staphylococcus aureus in patients with cystic fibrosis
Nicholas J Pitcher1, Andries Feder2, Nicholas Bolden3
1Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine , Iowa City, Iowa, USA.
Importance:
Patients with cystic fibrosis have persistent lung infections with Staphylococcus aureus that require extensive antibiotic treatments. Linezolid, an antibiotic given by oral or intravenous route, is prescribed repeatedly for patients whose lung disease has progressed. After treatment with linezolid, S. aureus strains can evolve antibiotic resistance through multiple genetic mechanisms. In addition to a common mutation in the 23S ribosomal RNA known to confer linezolid resistance, S. aureus strains can evolve novel resistance based on a combination of mutations affecting the bacterial ribosome. This combination of mutations was observed in a strain that exhibited hypermutation owing to the loss of the DNA repair genes mutS and mutL. In this cohort of patients with cystic fibrosis, linezolid resistance was transient, possibly due to the growth disadvantage of resistant strains. However, ongoing chronic exposure to linezolid may create optimal conditions for the future emergence of resistance to this critical antibiotic.
Insights
Linezolid resistance in Staphylococcus aureus is rare but can emerge in cystic fibrosis patients with repeated antibiotic exposure. Multiple genetic mechanisms, including ribosomal mutations and hypermutation, contribute to this resistance.
Area of Science:
- Microbiology
- Genetics
- Infectious Diseases
Background:
- Cystic fibrosis (CF) patients often experience persistent Staphylococcus aureus infections requiring extensive antibiotic treatment.
- Linezolid is a critical antibiotic used for serious infections, including those caused by MRSA.
- Repeated linezolid exposure in CF patients raises concerns about the potential emergence of antibiotic resistance.
Purpose of the Study:
- To determine the incidence of linezolid-resistant MRSA in a cohort of CF patients.
- To identify the molecular mechanisms underlying linezolid resistance in S. aureus from CF patients.
- To investigate the genetic basis of resistance in S. aureus isolates from patients treated with linezolid.
Main Methods:
- Retrospective identification of CF patients treated with linezolid between 2008-2018.
- Microbiological analysis of S. aureus isolates for linezolid susceptibility using broth microdilution.
- Whole genome sequencing for phylogenetic analysis and identification of resistance-conferring mutations or genes.
Main Results:
- Four out of 111 CF patients treated with linezolid developed linezolid-resistant S. aureus.
- Linezolid resistance was associated with specific genetic backgrounds (ST5 or ST105).
- Identified G2576T mutation in 23S rRNA in three patients; one patient had a hypermutating strain with multiple ribosomal mutations due to mutS/mutL loss.
Conclusions:
- Linezolid-resistant S. aureus can emerge in CF patients through diverse genetic pathways.
- Mechanisms include common ribosomal RNA mutations and novel combinations of mutations in hypermutating strains.
- While resistance appeared transient, chronic linezolid exposure may foster future resistance development.
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