{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:44:50Z","timestamp":1789231490453,"version":"build-2803163510"},"reference-count":32,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council for Scientific and Technological Development (CNPq)","award":["#423260\/2021-9"],"award-info":[{"award-number":["#423260\/2021-9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Objective: This study aims to evaluate free vancomycin concentrations in tissues of septic patients that received empirical doses. Methods: A PBPK model was built in PK-Sim to simulate vancomycin concentrations in healthy volunteers and septic patients. Literature data were used to validate the model. A strain of MRSA (methicillin-resistant Staphylococcus aureus) was evaluated through time-kill curves. Based on the information obtained from the time-kill study, a PD model, including adaptive resistance, was developed using NONMEM. The PBPK and PD models were combined to evaluate the vancomycin effect in plasma and tissues against MRSA. Results: A PBPK model was successfully built for both healthy volunteers and septic patients. The tissue concentrations were found to be significantly lower than plasma concentrations. The studied strain of MRSA was found to have an MIC of 2 \u00b5g\/mL, and the PD model described the EC50 as 1.05 \u00b5g\/mL. The PBPK and PD models were successfully combined, and septic patients infected with MRSA strains with MIC of 2 \u00b5g\/mL had effective treatment response. However, septic patients infected with MRSA strains with MICs of 4 \u00b5g\/mL and 8 \u00b5g\/mL did not have adequate response to vancomycin treatment. Conclusions: In septic patients, response was limited against resistant MRSA strains. These findings should be considered hypothesis-generating and interpreted with caution, underscoring the need for individualized approaches and rigorous monitoring.<\/jats:p>","DOI":"10.3390\/pharmaceutics17091111","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T14:18:49Z","timestamp":1756217929000},"page":"1111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["PBPK\/PD Model of Vancomycin in Sepsis: Linking Interstitial Exposure in Perfusion-Limited Tissues to MRSA Infection"],"prefix":"10.3390","volume":"17","author":[{"given":"Laura Ben","family":"Olivo","sequence":"first","affiliation":[{"name":"Pharmacokinetics and PK\/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, 2752 Ipiranga Ave., Santana, Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9ssica Lu\u00edsa Silva","family":"de Lemos","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and PK\/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, 2752 Ipiranga Ave., Santana, Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0292-878X","authenticated-orcid":false,"given":"Vinicius Jardim","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and PK\/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, 2752 Ipiranga Ave., Santana, Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00fania Batirola","family":"Kretschmer","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Integrated Regional University of Alto Uruguai and Miss\u00f5es, 464, St. Unisersidade das Miss\u00f5es, Santo \u00c2ngelo 98802-470, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William de Avila","family":"Cruz","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Integrated Regional University of Alto Uruguai and Miss\u00f5es, 464, St. Unisersidade das Miss\u00f5es, Santo \u00c2ngelo 98802-470, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keli Jaqueline","family":"Staudt","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Integrated Regional University of Alto Uruguai and Miss\u00f5es, 464, St. Unisersidade das Miss\u00f5es, Santo \u00c2ngelo 98802-470, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-7351","authenticated-orcid":false,"given":"Pieter","family":"Annaert","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9706-0389","authenticated-orcid":false,"given":"Bibiana Verlindo","family":"de Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Pharmacokinetics and PK\/PD Modeling Laboratory, Pharmaceutical Sciences Graduate Program, Federal University of Rio Grande do Sul, 2752 Ipiranga Ave., Santana, Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","unstructured":"(2025, June 04). 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