MRSA strains with distinct accessory genes predominate at different ages in cystic fibrosis

Porterfield, Harry S.; Maakestad, Lucas J; LaMarche, Mason; Thurman, Andrew L.; Kienenberger, Zoe; Pitcher, N.; Hansen, Alexis; Zirbes, Christian; Boyken, L.; Muyskens, Bethany L; Pezzulo, Alejandro A.; Singh, Sunil; Twait, Erik; Ford, Bradley; Diekema, Daniel J.; Reeb, Valérie; Fischer, Anthony J.

doi:10.1002/ppul.25559

Cited by 8 publications

(8 citation statements)

References 43 publications

(91 reference statements)

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“…These clonal complex 5 lineages are usually SCC mec II positive and considered hospital-associated MRSA. Collectively, these sequence types are the most prevalent MRSA lineages in our center and are associated with lower lung function in younger patients compared to clonal complex 8 MRSA lineages ( 19 ).…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether there was sharing of linezolid-resistant strains between patients, we performed phylogenetic analysis to assign closely related isolates to strains. Because some CF-associated MRSA strains exhibit hypermutation ( 19 ) or have increased SNP distance as they develop linezolid resistance ( 43 , 44 ), we did not use strict SNP cutoffs to divide isolates into strains. Instead, we used a clade-breaker approach ( 45 ).…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether there was transmission of linezolid-resistant S. aureus between patients, and to determine the molecular mechanism for resistance, all isolates were analyzed by short-read WGS as previously described ( 19 ). DNA was isolated robotically at the University of Iowa State Hygienic Laboratory.…”

Section: Methodsmentioning

confidence: 99%

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Parallel evolution of linezolid-resistant Staphylococcus aureus in patients with cystic fibrosis

Pitcher,

Feder,

Bolden

et al. 2023

Microbiol Spectr

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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). The goals of this study were to determine the incidence of linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) in CF and identify molecular mechanisms for linezolid resistance. We identified patients who cultured S. aureus resistant to linezolid with minimum inhibitory concentration (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. 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 five resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear. We conclude that linezolid resistant S. aureus can occur through multiple genetic mechanisms in patients with repeated exposure to this antibiotic. 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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Parallel evolution of linezolid-resistant Staphylococcus aureus in patients with cystic fibrosis

Pitcher,

Feder,

Bolden

et al. 2023

Microbiol Spectr

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“…However, the distributions of age, gender, CFTR theratypes, and pulmonary function among survey responses were similar to our recent reports. 32,33 Thus, the results of this survey are likely to be representative for our center.…”

Section: Limitationsmentioning

confidence: 92%

Patient and caregiver perceptions of airway clearance methods used for cystic fibrosis

Fischer

Kienenberger

Farber

et al. 2022

Preprint

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Introduction: Cystic Fibrosis Foundation guidelines recommend people with CF perform daily airway clearance. This can be difficult for patients to complete, as some find it time consuming or uncomfortable. Data comparing airway clearance methods are limited. We surveyed patients and families to understand which methods are preferred and identify obstacles performing airway clearance. Methods: We designed a REDCap survey and enrolled participants in 2021. Respondents reported information on airway clearance usage, time commitment, and medication use. They rated airway clearance methods for effectiveness, comfort, time commitment, importance, and compatibility with other treatments. Analysis included descriptive statistics and clustering. Results: 60 respondents started and 52 completed the survey. The median patient age was 20 years. Respondents experienced a median of four airway clearance methods in their lifetime, including chest wall oscillation (vest, 92%), manual chest physical therapy (CPT, 88%), huff coughing (77%), and exercise (75%). Past 30-day use was highest for exercise (62%) and vest (57%). Time commitment was generally less than 2 hours daily. Of those eligible for CFTR modulators, 53% reported decreased time commitment to airway clearance after starting treatment. On a scale of 0-100, respondents rated CFTR modulators as their most important treatment (median 99.5), followed by exercise (88). Discussion: Patients and caregivers are familiar with several methods of airway clearance for CF. They report distinct strengths and limitations of each method. Exercise and vest are the most common methods of airway clearance. Use of CFTR modulators may reduce patient-reported time commitment to airway clearance.

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“…Porterfield et al investigated 97 MRSA isolates from 74 individuals with CF from 2017 and determined that MLST types showing ST5 (n = 55), ST8 (n = 15) and ST105 (n = 14) were the most prevalent [120]. Closely related MRSA strains were only shared by family members and rarely between unrelated individuals.…”

Section: Mrsa In Cystic Fibrosis-antibiotic Resistance Persistence and Patho-adaptationmentioning

confidence: 99%

Staphylococcus aureus and Cystic Fibrosis—A Close Relationship. What Can We Learn from Sequencing Studies?

et al. 2021

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Staphylococcus aureus is next to Pseudomonas aeruginosa the most isolated pathogen from the airways of cystic fibrosis (CF) patients, who are often infected by a dominant S. aureus clone for extended periods. To be able to persist, the pathogen has to adapt to the hostile niche of the airways to counteract host defence, antibiotic therapy and the competition with coinfecting pathogens. S. aureus is equipped with many virulence factors including adhesins, toxins that are localized on the chromosome, on plasmids or are phage-related. S. aureus is especially versatile and adaptation and evolution of the pathogen occurs by the acquisition of new genes by horizontal gene transfer (HGT), changes in nucleotides (single nucleotide variations, SNVs) that can cause a selective advantage for the bacteria and become fixed in subpopulations. Methicillin-resistant S. aureus are a special threat to CF patients due to the more severe lung disease occurring in infected patients. Today, with decreasing costs for sequencing, more and more studies using S. aureus isolates cultured from CF patients are being published, which use whole genome sequencing (WGS), multilocus sequence typing (MLST) or spa-sequence typing (spa-typing) to follow the population dynamics of S. aureus, elucidate the underlying mechanisms of phenotypic variants, newly acquired resistance or adaptation to the host response in this particular niche. In the first part of this review, an introduction to the genetic make-up and the pathogenesis of S. aureus with respect to CF is provided. The second part presents an overview of recent studies and their findings using genotypic methods such as single or multilocus sequencing and whole genome sequencing, which identify factors contributing to the adaptation of S. aureus and its evolution in the airways of individuals with CF.

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MRSA strains with distinct accessory genes predominate at different ages in cystic fibrosis

Cited by 8 publications

References 43 publications

Parallel evolution of linezolid-resistant Staphylococcus aureus in patients with cystic fibrosis

Parallel evolution of linezolid-resistant Staphylococcus aureus in patients with cystic fibrosis

Patient and caregiver perceptions of airway clearance methods used for cystic fibrosis

Staphylococcus aureus and Cystic Fibrosis—A Close Relationship. What Can We Learn from Sequencing Studies?

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