{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:25:01Z","timestamp":1792794301771,"version":"4.5.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T00:00:00Z","timestamp":1633305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"UCSF Fletcher Jones Fellowship and Institutional T32 Kirschstein-NRSA Fellowship","award":["5T32HL007185-43"],"award-info":[{"award-number":["5T32HL007185-43"]}]},{"name":"Australia\u2019s Department of Foreign Affairs and Trade","id":[{"id":"https:\/\/ror.org\/023wsvq95","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Germany\u2019s Federal Ministry of Education and Research","id":[{"id":"https:\/\/ror.org\/04pz7b180","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Disease","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Netherlands Ministry of Foreign Affairs","id":[{"id":"https:\/\/ror.org\/03rx2ty86","id-type":"ROR","asserted-by":"crossref"}]},{"name":"United Kingdom\u2019s Foreign"},{"name":"Commonwealth and Development Office"},{"DOI":"10.13039\/100000200","name":"US Agency for International Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000200","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1129600"],"award-info":[{"award-number":["OPP1129600"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. .<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as\u2005\u2265\u2005grade 3 adverse events according to the NIAID Division of Microbiology and Infectious Disease Adult Toxicity table.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Predicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [CI], 17%\u201322% vs 5%, 4%\u20137%) and severe anemia (15%, 12%\u201317% vs 1%, 0%\u20132%) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median, &amp;lt;1% for both daily doses). Generally, neuropathy occurred after 3 to 6 months of treatment and, with protocol-specified management, reversed within 15 months after onset. Simulations indicated that a &amp;gt;10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the dose from 1200 to 600 mg triggered by this marker may prevent 60% (90% CI, 45%\u201372%) of severe anemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm the benefit-to-risk ratio.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciab699","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T15:10:41Z","timestamp":1628867441000},"page":"1736-1747","source":"Crossref","is-referenced-by-count":58,"title":["Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis"],"prefix":"10.1093","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7434-3012","authenticated-orcid":false,"given":"Marjorie Z","family":"Imperial","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California , San Francisco,California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry R","family":"Nedelman","sequence":"additional","affiliation":[{"name":"TB Alliance , New York, New York , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Conradie","sequence":"additional","affiliation":[{"name":"Clinical HIV Research Unit, University of Witwatersrand , Johannesburg , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R M","family":"Savic","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California , San Francisco,California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,4]]},"reference":[{"key":"2022053122503479100_CIT0001","volume-title":"Global tuberculosis report 2019. Licence: CC BY-NC-SA 3.0 IGO","year":"2019"},{"key":"2022053122503479100_CIT0002","volume-title":"Meeting report of the WHO expert consultation on the definition of extensively drug-resistant tuberculosis. Licence: CC BY-NC-SA 3.0 IGO","year":"2021"},{"key":"2022053122503479100_CIT0003","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1080\/14787210.2016.1225498","article-title":"Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index","volume":"14","author":"Wasserman","year":"2016","journal-title":"Expert Rev Anti Infect Ther"},{"key":"2022053122503479100_CIT0004","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S0140-6736(18)31644-1","article-title":"Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis","volume":"392","author":"Ahmad","year":"2018","journal-title":"Lancet"},{"key":"2022053122503479100_CIT0005","volume-title":"Rapid communication: key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR\/RR-TB). Licence: CC BY-NC-SA 3.0 IGO","year":"2018"},{"key":"2022053122503479100_CIT0006","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1056\/NEJMoa1901814","article-title":"Treatment of highly drug-resistant pulmonary tuberculosis","volume":"382","author":"Conradie","year":"2020","journal-title":"N Engl J Med"},{"key":"2022053122503479100_CIT0007"},{"key":"2022053122503479100_CIT0008","volume-title":"Rapid communication: key changes to treatment of drug-resistant tuberculosis. Licence: CC BY-NC-SA 3.0 IGO","year":"2019"},{"key":"2022053122503479100_CIT0009","author":"European Medicine Agency: EMEA\/H\/C\/005167- Dovprela (previously Pretomanid FGK)."},{"key":"2022053122503479100_CIT0010","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1128\/AAC.01411-05","article-title":"Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones","volume":"50","author":"McKee","year":"2006","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122503479100_CIT0011","first-page":"603","article-title":"Systematic review and meta-analysis of the efficacy and safety of therapy with linezolid containing regimens in the treatment of multidrug-resistant and extensively drug-resistant tuberculosis","volume":"7","author":"Zhang","year":"2015","journal-title":"J Thorac Dis"},{"key":"2022053122503479100_CIT0012","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/j.ebiom.2015.09.051","article-title":"Linezolid trough concentrations correlate with mitochondrial toxicity-related adverse events in the treatment of chronic extensively drug-resistant tuberculosis","volume":"2","author":"Song","year":"2015","journal-title":"EBioMedicine"},{"key":"2022053122503479100_CIT0013","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.1128\/AAC.01378-08","article-title":"Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis","volume":"53","author":"McGee","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122503479100_CIT0014","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1128\/AAC.01885-13","article-title":"Clinical population pharmacokinetics and toxicodynamics of linezolid","volume":"58","author":"Boak","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122503479100_CIT0015","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1128\/AAC.01185-10","article-title":"Population pharmacokinetic and pharmacodynamic analysis of linezolid and a hematologic side effect, thrombocytopenia, in Japanese patients","volume":"55","author":"Sasaki","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122503479100_CIT0016","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1128\/AAC.47.2.548-553.2003","article-title":"Population pharmacokinetics of linezolid in patients treated in a compassionate-use program","volume":"47","author":"Meagher","year":"2003","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122503479100_CIT0017","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1124\/dmd.106.013755","article-title":"Does linezolid inhibit its own metabolism? 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tolerability in multidrug-resistant tuberculosis: a retrospective study","volume":"46","author":"Bolhuis","year":"2015","journal-title":"Eur Respir J"},{"key":"2022053122503479100_CIT0033","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12941-016-0156-y","article-title":"Efficacy and safety profile of linezolid in the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic review and meta-analysis","volume":"15","author":"Agyeman","year":"2016","journal-title":"Ann Clin Microbiol Antimicrob"},{"key":"2022053122503479100_CIT0034","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.3201\/eid2608.191499","article-title":"Linezolid-associated neurologic adverse events in patients with multidrug-resistant tuberculosis, France","volume":"26","author":"Jaspard","year":"2020","journal-title":"Emerg Infect 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