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Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation

To evaluate the resistance mechanisms among Pseudomonas aeruginosa clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). P. aeruginosa clinical isolates collected in US hospitals from 2014 to 2019 were susceptibility tested. Whole-genome and transcriptome s...

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Autores principales: Castanheira, Mariana, Doyle, Timothy B., Hubler, Cory M., DeVries, Sean, Shortridge, Dee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597463/
https://www.ncbi.nlm.nih.gov/pubmed/37768064
http://dx.doi.org/10.1128/msphere.00162-23
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author Castanheira, Mariana
Doyle, Timothy B.
Hubler, Cory M.
DeVries, Sean
Shortridge, Dee
author_facet Castanheira, Mariana
Doyle, Timothy B.
Hubler, Cory M.
DeVries, Sean
Shortridge, Dee
author_sort Castanheira, Mariana
collection PubMed
description To evaluate the resistance mechanisms among Pseudomonas aeruginosa clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). P. aeruginosa clinical isolates collected in US hospitals from 2014 to 2019 were susceptibility tested. Whole-genome and transcriptome sequencing were performed. Results were analyzed for strain typing, acquired β-lactamases, and mutations in chromosomal genes; gene expression was measured for known β-lactam resistance contributors. Results were compared to a control group of 10 P. aeruginosa isolates displaying MIC values at 8 mg/L for meropenem ± vaborbactam (MEM = MEV). Out of 88 isolates displaying MEM > MEV, 33 (37.5%) isolates had reproducibly lower MIC values for meropenem-vaborbactam compared to meropenem when retested. The expression of mexX, mexY, mexZ, and ampC was significantly greater among a higher percentage of the MEM > MEV isolates. Furthermore, the association of mexXY and ampC overexpression was detected in 17/33 MEM > MEV isolates and only 1/10 MEM = MEV isolate. In addition, the Pseudomonas-derived cephalosporinase amino acid substitution R79Q was detected among 33.3% of the isolates displaying MEM > MEV, and none of the isolates displayed MEM = MEV. Other resistance mechanisms were not observed or were equally observed in both groups. In rare cases, vaborbactam plays a role in lowering the meropenem MIC values in P. aeruginosa clinical isolates likely due to the inhibition of the AmpC gene that was overexpressed in the presence of upregulation of MexXY with or without alterations in the AmpC gene. IMPORTANCE: Pseudomonas aeruginosa isolates are intrinsically resistant to multiple antimicrobial agents and meropenem is an important therapeutic option to treat infections caused by this organism. Meropenem-vaborbactam activity is similar to that of meropenem alone against P. aeruginosa isolates. Isolates belonging to this species that display lower meropenem-vaborbactam compared to meropenem are rare. We initiated this study to understand the resistance mechanisms that could lead to lower meropenem-vaborbactam MIC values when compared to meropenem alone. We documented that isolates displaying lower meropenem-vaborbactam exhibited overexpression of MexXY and AmpC. In addition, isolates displaying the R79Q PDC (AmpC) mutation were more likely to display lower meropenem-vaborbactam when compared to isolates displaying the same MIC values for these agents.
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spelling pubmed-105974632023-10-25 Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation Castanheira, Mariana Doyle, Timothy B. Hubler, Cory M. DeVries, Sean Shortridge, Dee mSphere Research Article To evaluate the resistance mechanisms among Pseudomonas aeruginosa clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). P. aeruginosa clinical isolates collected in US hospitals from 2014 to 2019 were susceptibility tested. Whole-genome and transcriptome sequencing were performed. Results were analyzed for strain typing, acquired β-lactamases, and mutations in chromosomal genes; gene expression was measured for known β-lactam resistance contributors. Results were compared to a control group of 10 P. aeruginosa isolates displaying MIC values at 8 mg/L for meropenem ± vaborbactam (MEM = MEV). Out of 88 isolates displaying MEM > MEV, 33 (37.5%) isolates had reproducibly lower MIC values for meropenem-vaborbactam compared to meropenem when retested. The expression of mexX, mexY, mexZ, and ampC was significantly greater among a higher percentage of the MEM > MEV isolates. Furthermore, the association of mexXY and ampC overexpression was detected in 17/33 MEM > MEV isolates and only 1/10 MEM = MEV isolate. In addition, the Pseudomonas-derived cephalosporinase amino acid substitution R79Q was detected among 33.3% of the isolates displaying MEM > MEV, and none of the isolates displayed MEM = MEV. Other resistance mechanisms were not observed or were equally observed in both groups. In rare cases, vaborbactam plays a role in lowering the meropenem MIC values in P. aeruginosa clinical isolates likely due to the inhibition of the AmpC gene that was overexpressed in the presence of upregulation of MexXY with or without alterations in the AmpC gene. IMPORTANCE: Pseudomonas aeruginosa isolates are intrinsically resistant to multiple antimicrobial agents and meropenem is an important therapeutic option to treat infections caused by this organism. Meropenem-vaborbactam activity is similar to that of meropenem alone against P. aeruginosa isolates. Isolates belonging to this species that display lower meropenem-vaborbactam compared to meropenem are rare. We initiated this study to understand the resistance mechanisms that could lead to lower meropenem-vaborbactam MIC values when compared to meropenem alone. We documented that isolates displaying lower meropenem-vaborbactam exhibited overexpression of MexXY and AmpC. In addition, isolates displaying the R79Q PDC (AmpC) mutation were more likely to display lower meropenem-vaborbactam when compared to isolates displaying the same MIC values for these agents. American Society for Microbiology 2023-09-28 /pmc/articles/PMC10597463/ /pubmed/37768064 http://dx.doi.org/10.1128/msphere.00162-23 Text en Copyright © 2023 Castanheira et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Castanheira, Mariana
Doyle, Timothy B.
Hubler, Cory M.
DeVries, Sean
Shortridge, Dee
Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation
title Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation
title_full Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation
title_fullStr Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation
title_full_unstemmed Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation
title_short Vaborbactam increases meropenem susceptibility in Pseudomonas aeruginosa clinical isolates displaying MexXY and AmpC upregulation
title_sort vaborbactam increases meropenem susceptibility in pseudomonas aeruginosa clinical isolates displaying mexxy and ampc upregulation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597463/
https://www.ncbi.nlm.nih.gov/pubmed/37768064
http://dx.doi.org/10.1128/msphere.00162-23
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