{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T04:46:04Z","timestamp":1782794764533,"version":"3.54.5"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Linezolid is a cornerstone therapy for multidrug-resistant Gram-positive infections. While prolonged intermittent infusion (PII) or continuous infusion (CI) can optimize the efficacy of time-dependent antibiotics, their application to linezolid remains controversial. Specifically, it is debated whether the theoretical efficacy gains of CI are negated by the elimination of the concentration nadir, which may trigger accumulation-related toxicity. Quantitative evidence dissecting this delicate trade-off is currently absent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aimed to quantify the interplay between infusion duration, efficacy, and toxicity. By developing a population pharmacokinetic (PopPK) model and employing a \u201ccomposite efficacy-safety target\u201d, we sought to identify precision dosing strategies for critically ill patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Plasma concentration-time data obtained from 20 critically ill patients were used to develop a PopPK model using nonlinear mixed-effects modeling (NONMEM v7.5). Based on final model parameters, Monte Carlo simulations were performed for 1,000 virtual patients. A composite target was established comprising a pharmacodynamic efficacy threshold (AUC\n                      <jats:sub>24<\/jats:sub>\n                      ,ss\/minimum inhibitory concentration \u2265100 and %T &amp;gt; MIC \u226585%) and a safety threshold (steady-state trough concentration, C\n                      <jats:sub>min,ss<\/jats:sub>\n                      &amp;lt; 8\u00a0mg\/L). Probability of Target Attainment (PTA) was evaluated across 7 dosing regimens (300, \u2026 , 900\u00a0mg q12\u00a0h) and 13 infusion durations (0.5, 1, 2, \u2026 , 12\u00a0h).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The pharmacokinetics were best described by a one-compartment model, with body weight (WT) and creatinine clearance (CLcr) identified as critical determinants of distribution volume (V) and clearance (CL), respectively. Simulations revealed a non-linear relationship between infusion duration and composite PTA. While prolonged intermittent infusion enhanced efficacy by improving % T &amp;gt; MIC, indiscriminate extension to CI, particularly at moderate-to-high doses, resulted in a systematic breach of the safety threshold (C\n                      <jats:sub>min,ss<\/jats:sub>\n                      \u2265 8\u00a0mg\/L). Consequently, composite PTA declined due to toxic over-exposure. Notably, for refractory pathogens (MIC \u22652\u00a0mg\/L), traditional CI yielded near-zero success rates due to high toxicity risks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In critically ill patients, the optimal infusion duration for linezolid exhibits a non-linear dependency on dose and MIC. For high-MIC pathogens requiring intensified dosing (e.g., 900\u00a0mg q12\u00a0h), a prolonged infusion of 2\u20135\u00a0h optimizes the therapeutic index, synergizing maximal efficacy with a necessary elimination phase to mitigate toxicity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1766346","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T04:24:16Z","timestamp":1782793456000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimization of linezolid infusion duration in critically ill patients: a population pharmacokinetic analysis of the trade-off between efficacy and toxicity"],"prefix":"10.3389","volume":"17","author":[{"given":"Chenchen","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Computer and Information Engineering, Anhui University of Finance and Economics","place":["Bengbu, Anhui, China"]},{"name":"Anhui Xiangyuan Technology Co., Ltd.","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Emergency Medicine, The Third The People\u2019s Hospital of Bengbu","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingti","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1007\/s00134-020-06050-1","article-title":"Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper","volume":"46","author":"Abdul-Aziz","year":"2020","journal-title":"Intensive Care Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1177\/0091270009337947","article-title":"Population pharmacokinetic analysis of linezolid in patients with infectious disease: application to lower body weight and elderly patients","volume":"49","author":"Abe","year":"2009","journal-title":"J. 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