{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:21:27Z","timestamp":1790882487003,"version":"4.1.0"},"reference-count":22,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100016956","name":"Melinta Therapeutics","doi-asserted-by":"crossref","award":["21-MEL-03"],"award-info":[{"award-number":["21-MEL-03"]}],"id":[{"id":"10.13039\/100016956","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2023,10,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            To evaluate the resistance mechanisms among\n            <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n            clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV).\n            <jats:italic>P. aeruginosa<\/jats:italic>\n            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 \u03b2-lactamases, and mutations in chromosomal genes; gene expression was measured for known \u03b2-lactam resistance contributors. Results were compared to a control group of 10\n            <jats:italic>P<\/jats:italic>\n            .\n            <jats:italic>aeruginosa<\/jats:italic>\n            isolates displaying MIC values at 8 mg\/L for meropenem \u00b1 vaborbactam (MEM = MEV). Out of 88 isolates displaying MEM &gt; MEV, 33 (37.5%) isolates had reproducibly lower MIC values for meropenem-vaborbactam compared to meropenem when retested. The expression of\n            <jats:italic>mexX<\/jats:italic>\n            ,\n            <jats:italic>mexY<\/jats:italic>\n            ,\n            <jats:italic>mexZ<\/jats:italic>\n            , and\n            <jats:italic>ampC<\/jats:italic>\n            was significantly greater among a higher percentage of the MEM &gt; MEV isolates. Furthermore, the association of\n            <jats:italic>mexXY<\/jats:italic>\n            and\n            <jats:italic>ampC<\/jats:italic>\n            overexpression was detected in 17\/33 MEM &gt; MEV isolates and only 1\/10 MEM = MEV isolate. In addition, the\n            <jats:italic>Pseudomonas<\/jats:italic>\n            -derived cephalosporinase amino acid substitution R79Q was detected among 33.3% of the isolates displaying MEM &gt; 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\n            <jats:italic>P. aeruginosa<\/jats:italic>\n            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.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n              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\n              <jats:italic>P. aeruginosa<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00162-23","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T13:03:52Z","timestamp":1695906232000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Vaborbactam increases meropenem susceptibility in\n            <i>Pseudomonas aeruginosa<\/i>\n            clinical isolates displaying MexXY and AmpC upregulation"],"prefix":"10.1128","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0126-1782","authenticated-orcid":false,"given":"Mariana","family":"Castanheira","sequence":"first","affiliation":[{"name":"JMI Laboratories , North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy B.","family":"Doyle","sequence":"additional","affiliation":[{"name":"JMI Laboratories , North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory M.","family":"Hubler","sequence":"additional","affiliation":[{"name":"JMI Laboratories , North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"DeVries","sequence":"additional","affiliation":[{"name":"JMI Laboratories , North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1215-5216","authenticated-orcid":false,"given":"Dee","family":"Shortridge","sequence":"additional","affiliation":[{"name":"JMI Laboratories , North Liberty, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz830"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00031-19"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01004-09"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00036-08"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.12.3322-3327.2000"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.5.1633-1641.2006"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku048"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01645-10"},{"key":"e_1_3_2_10_2","unstructured":"EUCAST\n. 2022. Breakpoint tables for interpretation of MICs and zone diameters. Vesion 12.0 January 2022. Available from: https:\/\/www.eucast.org\/fileadmin\/src\/media\/PDFs\/EUCAST_files\/Breakpoint_tables\/v_12.0_Breakpoint_Tables.pdf"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2092"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00567-17"},{"key":"e_1_3_2_13_2","volume-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically","author":"CLSI","year":"2018","unstructured":"CLSI . 2018. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Eleventh edition M07. Clinical and Laboratory Standards Institute, Wayne, PA.","edition":"07"},{"key":"e_1_3_2_14_2","volume-title":"M100Ed31. Performance standards for antimicrobial susceptibility testing: 31st informational supplement","author":"CLSI","year":"2021","unstructured":"CLSI . 2021. M100Ed31. Performance standards for antimicrobial susceptibility testing: 31st informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA."},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2012.0021"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-10-421"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01951-19"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.4137\/EBO.S11250"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01410-08"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr232"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/43.4.523"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02130-21"}],"container-title":["mSphere"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00162-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00162-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T16:35:55Z","timestamp":1698165355000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/msphere.00162-23"}},"subtitle":[],"editor":[{"given":"Patricia A.","family":"Bradford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,24]]},"references-count":22,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,10,24]]}},"alternative-id":["10.1128\/msphere.00162-23"],"URL":"https:\/\/doi.org\/10.1128\/msphere.00162-23","relation":{},"ISSN":["2379-5042"],"issn-type":[{"value":"2379-5042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,24]]},"assertion":[{"value":"2023-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00162-23"}}