{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T22:25:41Z","timestamp":1780439141828,"version":"3.54.1"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Toxins produced by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) contribute to virulence. We developed a statistical approach to determine an optimum sequence of antimicrobials to treat CA-MRSA infections based on an antimicrobial\u2019s ability to reduce virulence. In an in vitro pharmacodynamic hollow fiber model, expression of six virulence genes (lukSF-PV, sek, seq, ssl8, ear, and lpl10) in CA-MRSA USA300 was measured by RT-PCR at six time points with or without human-simulated, pharmacokinetic dosing of five antimicrobials (clindamycin, minocycline, vancomycin, linezolid, and trimethoprim\/sulfamethoxazole (SXT)). Statistical modeling identified the antimicrobial causing the greatest decrease in virulence gene expression at each time-point. The optimum sequence was SXT at T0 and T4, linezolid at T8, and clindamycin at T24\u2013T72 when lukSF-PV was weighted as the most important gene or when all six genes were weighted equally. This changed to SXT at T0\u2013T24, linezolid at T48, and clindamycin at T72 when lukSF-PV was weighted as unimportant. The empirical p-value for each optimum sequence according to the different weights was 0.001, 0.0009, and 0.0018 with 10,000 permutations, respectively, indicating statistical significance. A statistical method integrating data on change in gene expression upon multiple antimicrobial exposures is a promising tool for identifying a sequence of antimicrobials that is effective in sustaining reduced CA-MRSA virulence.<\/jats:p>","DOI":"10.3390\/toxins12020069","type":"journal-article","created":{"date-parts":[[2020,1,27]],"date-time":"2020-01-27T07:41:11Z","timestamp":1580110871000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Modeling of Effective Antimicrobials to Reduce Staphylococcus aureus Virulence Gene Expression Using a Two-Compartment Hollow Fiber Infection Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Sanjay K.","family":"Shukla","sequence":"first","affiliation":[{"name":"Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2107-7838","authenticated-orcid":false,"given":"Tonia C.","family":"Carter","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhan","family":"Ye","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhulatha","family":"Pantrangi","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren E.","family":"Rose","sequence":"additional","affiliation":[{"name":"Pharmacy Practice Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/S0140-6736(02)08713-5","article-title":"Genome and virulence determinants of high virulence community-acquired MRSA","volume":"359","author":"Baba","year":"2002","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5587","DOI":"10.1073\/pnas.0912403107","article-title":"Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury","volume":"107","author":"Diep","year":"2010","journal-title":"Proc. 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