Dataset Information

Draft Genome Sequences of Cefepime-Resistant and -Susceptible Escherichia coli Strains and Imipenem-Resistant and -Susceptible Pseudomonas aeruginosa Strains.

ABSTRACT: Draft genome sequences of Escherichia coli and Pseudomonas aeruginosa strains collected from clinical infections were used to determine the prevalence of newly emerging antibiotic resistance genes in Maine. Comparisons between cefepime-resistant and -susceptible E. coli strains and imipenem-resistant and -susceptible P. aeruginosa strains are being conducted.

SUBMITTER: Batchelder K

PROVIDER: S-EPMC8638605 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Draft Genome Sequences of Cefepime-Resistant and -Susceptible Escherichia coli Strains and Imipenem-Resistant and -Susceptible Pseudomonas aeruginosa Strains.

Batchelder Kendra K Ward Liz L Collins Elsa E Miles Caitlin C Palm Stefania S Mohamed Aisha A Feinstein Larry L

Microbiology resource announcements 20211202 48

Draft genome sequences of Escherichia coli and Pseudomonas aeruginosa strains collected from clinical infections were used to determine the prevalence of newly emerging antibiotic resistance genes in Maine. Comparisons between cefepime-resistant and -susceptible E. coli strains and imipenem-resistant and -susceptible P. aeruginosa strains are being conducted. ...[more]

PMID: 34854701

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Project description:Pseudomonas aeruginosa is an opportunistic human pathogen and a major cause of nosocomial infections. The global spread of carbapenem-resistant strains is growing rapidly and has become a major public health challenge. Imipenem-relebactam (I/R) is a novel carbapenem-beta-lactamase inhibitor combination that can overcome carbapenem resistance. In this study, we aimed to understand the mechanism underlying resistance to imipenem and imipenem-relebactam. For this purpose, we performed a genomic comparison of 40 new clinical P. aeruginosa strains with different antibiotic sensitivity patterns as well as the presence/absence of carbapenemases. Results indicated the presence of a reduced flexible genome (15% total) mostly represented by phages and defense mechanisms against them, showing an important role in evolution and pathogenicity. We found a high diversity of antibiotic resistance genes grouped in small clusters mobilized via integrative and conjugative elements and facilitated by the high homologous recombination detected. Ortholog genes were found in several pathogenic strains from distantly related taxa in different mobile elements with a global distribution. The microdiversity found in those strains without carbapenemases did not reveal a clear pattern that could be associated with carbapenem resistance, suggesting multiple mechanisms of resistance in the core genome. Our results provide new insight into the dynamics and high genomic plasticity by which clinical strains of P. aeruginosa acquire resistance. This knowledge can be applied to other multidrug-resistant microbes to create predictive frameworks for assessing common molecular mechanisms of antibiotic resistance and integrated into new strategies for their prevention. IMPORTANCE The growing emergence and spread of carbapenem-resistant pathogens worldwide exacerbate the clinical challenge of treating these infections. Given the importance of carbapenems for the treatment of infections caused by Pseudomonas aeruginosa, this study aimed to investigate the underlying genomic properties of the clinical isolates that exhibited resistance to imipenem and imipenem-relebactam. This information will enhance our ability to forecast traits of resistant strains and design reliable treatments against this important threat. Our results provide new insight into the dynamics and high genomic plasticity by which clinical strains of P. aeruginosa acquire resistance as well as offers a methodology that can be applied to many other opportunistic pathogens with broad antibiotic resistance.

Project description:BackgroundCefepime/taniborbactam is a cephalosporin/bicyclic boronate β-lactamase inhibitor combination in clinical development for nosocomial pneumonia due to MDR Gram-negative bacteria. A murine pneumonia model was used to characterize cefepime/taniborbactam in vivo pharmacodynamics against Enterobacterales and Pseudomonas aeruginosa strains.MethodsClinical cefepime-non-susceptible Enterobacterales and P. aeruginosa strains expressing serine carbapenemases and/or other cefepime-hydrolysing β-lactamases with cefepime/taniborbactam combination MICs of 0.12-16 mg/L were used. Cefepime and taniborbactam human-simulated regimens equivalent to clinical doses (i.e. 2/0.5 g q8h) were established in the pneumonia model. The in vivo activity of the cefepime human-simulated regimen given alone or concomitantly with escalating taniborbactam exposures against eight Enterobacterales and four P. aeruginosa strains was assessed. Taniborbactam pharmacokinetics were evaluated to determine systemic exposures of regimens used; taniborbactam fAUC0-24/MIC values required for efficacy were estimated using the Hill equation. In addition, the in vivo activity of the cefepime/taniborbactam combination human-simulated regimen was assessed against 18 strains.ResultsAmong Enterobacterales, median taniborbactam fAUC0-24/MIC values associated with stasis and 1 log kill were 0.96 and 4.03, respectively, while for P. aeruginosa, requirements were 1.35 and 3.02 for stasis and 1 log kill, respectively. The cefepime/taniborbactam human-simulated regimen produced >2 log kill in 14/18 strains and >1 log kill in 18/18 strains.ConclusionsCefepime/taniborbactam produced marked in vivo bactericidal activity against cefepime-non-susceptible Enterobacterales and P. aeruginosa isolates with cefepime/taniborbactam MICs up to and including 16 mg/L in the pneumonia model. Assessments of the probability of clinical attainment of the identified targets should be undertaken to support the selected cefepime/taniborbactam dose for treatment of nosocomial pneumonia.

Dataset Information

Draft Genome Sequences of Cefepime-Resistant and -Susceptible Escherichia coli Strains and Imipenem-Resistant and -Susceptible Pseudomonas aeruginosa Strains.

Publications

Draft Genome Sequences of Cefepime-Resistant and -Susceptible Escherichia coli Strains and Imipenem-Resistant and -Susceptible Pseudomonas aeruginosa Strains.

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