Parallel Evolution of Linezolid Resistant Staphylococcus aureus in Patients with Cystic Fibrosis

Nicholas J. Pitcher; Andries Feder; Nicholas Bolden; Christian F. Zirbes; Anthony J. Pamatmat; Linda Boyken; Jared J. Hill; Andrew L. Thurman; Valérie C. Reeb; Harry S. Porterfield; Ahmed M. Moustafa; Paul J. Planet; Anthony J. Fischer

doi:10.1101/2023.05.02.539145

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Parallel Evolution of Linezolid Resistant Staphylococcus aureus in Patients with Cystic Fibrosis

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Parallel Evolution of Linezolid Resistant Staphylococcus aureus in Patients with Cystic Fibrosis

Nicholas J. Pitcher, Andries Feder, Nicholas Bolden, Christian F. Zirbes, Anthony J. Pamatmat, Linda Boyken, Jared J. Hill, Andrew L. Thurman, Valérie C. Reeb, Harry S. Porterfield, …

bioRxiv

Cold Spring Harbor Laboratory

05/02/2023

DOI: 10.1101/2023.05.02.539145

PMCID: PMC10187253

PMID: 37205485

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https://doi.org/10.1101/2023.05.02.539145View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Background Linezolid is an antibiotic used to treat serious Staphylococcus aureus infections. Resistance to linezolid is considered rare but could emerge with repeated dosing. We recently reported widespread prescription of linezolid for a cohort of patients with cystic fibrosis (CF). Objectives The goals of this study were to determine the incidence of linezolid resistance in CF and identify molecular mechanisms for linezolid resistance. Methods We identified patients with S. aureus resistant to linezolid (MIC > 4) at the University of Iowa CF Center between 2008 and 2018. We obtained isolates from these patients and retested susceptibility to linezolid using broth microdilution. We used whole genome sequencing to perform phylogenetic analysis of linezolid resistant isolates and examine sequences for mutations or accessory genes that confer linezolid resistance. Main Results Between 2008 and 2018, 111 patients received linezolid and 4 of these patients cultured linezolid resistant S. aureus. We sequenced 11 resistant and 21 susceptible isolates from these 4 subjects. Phylogenetic analysis indicated that linezolid resistance developed in ST5 or ST105 backgrounds. Three individuals had linezolid resistant S. aureus with a G2576T mutation in 23S rRNA. One of these subjects additionally had a mutS- mutL- hypermutating S. aureus that produced 5 resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear. Conclusions Linezolid resistance evolved in 4 of 111 patients in this study. Linezolid resistance occurred by multiple genetic mechanisms. All resistant strains developed in ST5 or ST105 MRSA backgrounds.

Details

Title: Subtitle: Parallel Evolution of Linezolid Resistant Staphylococcus aureus in Patients with Cystic Fibrosis
Creators: Nicholas J. Pitcher - University of Iowa
Andries Feder - Children's Hospital of Philadelphia
Nicholas Bolden - University of Pennsylvania
Christian F. Zirbes - University of Iowa
Anthony J. Pamatmat - University of Iowa
Linda Boyken - University of Iowa
Jared J. Hill - University of Iowa
Andrew L. Thurman - University of Iowa
Valérie C. Reeb - University of Iowa
Harry S. Porterfield - National Institutes of Health Clinical Center
Ahmed M. Moustafa - Children's Hospital of Philadelphia
Paul J. Planet - Children's Hospital of Philadelphia
Anthony J. Fischer - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2023.05.02.539145
PMID: 37205485
PMCID: PMC10187253
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 05/02/2023
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics; Hygienic Laboratory - Bdc; Pathology; Internal Medicine
Record Identifier: 9984410793902771

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