The effect of antibiotic changes during treatment of cystic fibrosis pulmonary exacerbations

Zikic, Andrew; Ratjen, Félix; Shaw, Michelle; Tullis, Elizabeth; Waters, Valerie

doi:10.1016/j.jcf.2022.05.010

Cited by 8 publications

(13 citation statements)

References 13 publications

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“…These data suggest that hyperconcentration and accumulation of mucin and eDNA within a subject result in increased tolerance of P. aeruginosa to antibiotics. This is consistent with clinical observations of mucin and eDNA polymer concentrations and instances of antibiotic treatment failure, both increasing as a function of age, disease severity, and clinical exacerbation (11, 34, 44–48).…”

Section: Discussionsupporting

confidence: 89%

“…Increased concentrations of both eDNA and mucin have been associated with subject age, clinical exacerbation, and declining lung function (11, 42, 43). Likewise, age, acute exacerbation, and disease severity predispose individuals to higher instances of antibiotic treatment failure and chronic infections (11, 34, 44–48). Given the apparent association between mucus polymer concentration, disease severity, and treatment failure, we investigated the effects of mucin and eDNA concentrations on antibiotic recalcitrance of P. aeruginosa using a disease-relevant in vitro model system.…”

Section: Introductionmentioning

confidence: 99%

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Mucus polymer concentration andin vivoadaptation converge to define the antibiotic response ofPseudomonas aeruginosaduring chronic lung infection

Greenwald,

Meinig,

Plott

et al. 2023

Preprint

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The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, includingPseudomonas aeruginosa, which is responsible for the majority of morbidity and mortality in MADs. Despite high concentration inhaled antibiotic therapies and the absence of antibiotic resistance, antipseudomonal treatment failure in MADs remains a significant clinical challenge. Understanding the drivers of antibiotic recalcitrance is essential for developing more effective treatments that eradicate persistent infections. The complex and dynamic environment of diseased airways makes it difficult to model antibiotic efficacyin vitro. We aimed to understand how mucin and eDNA concentrations, the two dominant polymers in respiratory mucus, alter the antibiotic tolerance ofP. aeruginosa. Our results demonstrate that polymer concentration and molecular weight affectP. aeruginosasurvival post antibiotic challenge. Polymer-driven antibiotic tolerance was not explicitly associated with reduced antibiotic diffusion. Lastly, we established a robust and standardizedin vitromodel for recapitulating theex vivoantibiotic tolerance ofP. aeruginosaobserved in expectorated sputum across age, underlying MAD etiology, and disease severity, which revealed the inherent variability in intrinsic antibiotic tolerance of host-evolvedP. aeruginosapopulations.ImportanceAntibiotic treatment failure inPseudomonas aeruginosachronic lung infections is associated with increased morbidity and mortality, illustrating the clinical challenge of bacterial infection control. Understanding the underlying infection environment, as well as the host and bacterial factors driving antibiotic tolerance and the ability to accurately recapitulate these factorsin vitro, is crucial for improving antibiotic treatment outcomes. Here, we demonstrate that increasing concentration and molecular weight of mucin and host eDNA drive increased antibiotic tolerance to tobramycin. Through systematic testing and modeling, we identified a biologically relevantin vitrocondition that recapitulates antibiotic tolerance observed inex vivotreated sputum. Ultimately, this study revealed a dominant effect ofin vivoevolved bacterial populations in defining inter-subjectex vivoantibiotic tolerance and establishes a robust and translatablein vitromodel for therapeutic development.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Mucus polymer concentration andin vivoadaptation converge to define the antibiotic response ofPseudomonas aeruginosaduring chronic lung infection

Greenwald,

Meinig,

Plott

et al. 2023

Preprint

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“…Furthermore, children with both MRSA and PA who received both anti‐MRSA and anti‐PA antibiotics did not show a higher chance of returning to ≥90% or ≥100% of baseline FEV1pp or lower odds of future PEx requiring IV antibiotics within 6 months 76 . Finally, changing antibiotics during PEx treatment was not associated with improved FEV1pp response or a return to baseline lung function when the Toronto CF database was examined between 2009 and 2015 77 . These studies provide an indication for more judicious consideration of antibiotic use in PA infection.…”

Section: Pulmonologymentioning

confidence: 89%

Cystic fibrosis year in review 2022

Kim,

Lyman,

Savant

2023

Pediatric Pulmonology

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Remarkable medical advancements have been made for people with cystic fibrosis (CF) in recent years, with an abundance of research continuing to be conducted worldwide. With concern for limitations in access to highly effective CFTR modulators, as well as the recent Coronavirus Disease‐19 pandemic, there has been a consistent effort to understand and improve CF screening, disease burden, diagnosis, and management. Our aim in this review is to present articles from 2022 with an emphasis on clinically relevant studies. We hope this will serve as a broad overview of the research published in the past year.

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“…Keeping with this theme, a single-center, retrospective, cohort study analyzed the effect of changing antibiotics during treatment for PEx. They examined 399 events, 105 of which included a change of antibiotics [26] . The primary outcome was the absolute and relative change in ppFEV 1 at the end of treatment and follow-up, with the proportion of patients returning to >90% or >100% of their previous baseline as a secondary outcome.…”

Section: Pulmonary Exacerbationsmentioning

confidence: 99%