{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T05:52:28Z","timestamp":1789883548059,"version":"4.0.1"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T00:00:00Z","timestamp":1456790400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI111990"],"award-info":[{"award-number":["R01AI111990"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Staphylococcus aureus<\/jats:named-content>\n            possesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined the\n            <jats:italic>in vitro<\/jats:italic>\n            evolution of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>\n            in response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (10\n            <jats:sup>8<\/jats:sup>\n            CFU\/ml) of methicillin-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>\n            (MRSA) USA300 and USA400. Host-pathogen interactions using\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Galleria mellonella<\/jats:named-content>\n            and accessory gene regulator (\n            <jats:italic>agr<\/jats:italic>\n            ) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (\n            <jats:italic>f<\/jats:italic>\n            AUC\/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereas\n            <jats:italic>f<\/jats:italic>\n            AUC\/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">G. mellonella<\/jats:named-content>\n            mortality (\n            <jats:italic>P<\/jats:italic>\n            = 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases in\n            <jats:italic>agr<\/jats:italic>\n            expression and virulence during therapy may be an adaptive mechanism of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>\n            persistence.\n          <\/jats:p>","DOI":"10.1128\/aac.02657-15","type":"journal-article","created":{"date-parts":[[2015,12,29]],"date-time":"2015-12-29T03:23:15Z","timestamp":1451359395000},"page":"1584-1591","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic\/Pharmacodynamic Targets for Vancomycin Exposure"],"prefix":"10.1128","volume":"60","author":[{"given":"Justin R.","family":"Lenhard","sequence":"first","affiliation":[{"name":"Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"},{"name":"New York State Center of Excellence in Life Sciences and Bioinformatics, University at Buffalo, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Brown","sequence":"additional","affiliation":[{"name":"Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"},{"name":"New York State Center of Excellence in Life Sciences and Bioinformatics, University at Buffalo, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Rybak","sequence":"additional","affiliation":[{"name":"Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin J.","family":"Meaney","sequence":"additional","affiliation":[{"name":"Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"},{"name":"New York State Center of Excellence in Life Sciences and Bioinformatics, University at Buffalo, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas B.","family":"Norgard","sequence":"additional","affiliation":[{"name":"Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zackery P.","family":"Bulman","sequence":"additional","affiliation":[{"name":"Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"},{"name":"New York State Center of Excellence in Life Sciences and Bioinformatics, University at Buffalo, Buffalo, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Brazeau","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of New England, Portland, Maine, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian T.","family":"Tsuji","sequence":"additional","affiliation":[{"name":"Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA"},{"name":"New York State Center of Excellence in Life Sciences and Bioinformatics, University at Buffalo, Buffalo, New York, 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Vancomycin: the tale of the vanquisher and the pyrrhic victory. 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