{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:59:56Z","timestamp":1791845996453,"version":"4.3.4"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["U01AI115594"],"award-info":[{"award-number":["U01AI115594"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Rifampin-resistant and\/or multidrug-resistant tuberculosis (RR\/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Adults with pulmonary RR\/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug\u2019s area under the concentration-time curve over 24 hours (AUC0\u201324). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0\u201324\/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0\u201324\/MIC exposures.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0\u201324\/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21\u201311.56; P = .022); levofloxacin AUC0\u201324\/MIC of 118.3, clofazimine AUC0\u201324\/MIC of 50.5, and pyrazinamide AUC0\u201324 of 379 mg \u00d7 h\/L were associated with faster culture conversion (HR &amp;gt;1.0, P &amp;lt; .05). Other individual drug exposures were not predictive. Clustering by AUC0\u201324\/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Amidst multidrug regimens for RR\/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs\u2014fluoroquinolones, pyrazinamide, clofazimine\u2014were predictive and should be optimized to improve clinical outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Clinical Trials Registration<\/jats:title>\n                  <jats:p>NCT03559582.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciac511","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T18:44:52Z","timestamp":1655923492000},"page":"497-505","source":"Crossref","is-referenced-by-count":16,"title":["Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study"],"prefix":"10.1093","volume":"76","author":[{"given":"Scott K","family":"Heysell","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia , Charlottesville, Virginia , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stellah G","family":"Mpagama","sequence":"additional","affiliation":[{"name":"Kibong\u2019oto Infectious Diseases Hospital , Sanya Juu , Tanzania"},{"name":"Kilimanjaro Clinical Research Institute and Kilimanjaro Christian Medical University College , Moshi , Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg B","family":"Ogarkov","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Microbiology, Scientific Centre for Family Health and Human Reproduction Problems , Irkutsk , Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Conaway","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, University of Virginia , Charlottesville, Virginia , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahriar","family":"Ahmed","sequence":"additional","affiliation":[{"name":"International Center for Diarrheal Diseases Research, Bangladesh , Dhaka , Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Zhdanova","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Microbiology, Scientific Centre for Family Health and Human Reproduction 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Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Suzdalnitsky","sequence":"additional","affiliation":[{"name":"Irkutsk Regional Tuberculosis Referral Hospital , Irkutsk , Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Moiseeva","sequence":"additional","affiliation":[{"name":"Irkutsk Regional Tuberculosis Referral Hospital , Irkutsk , Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Zorkaltseva","sequence":"additional","affiliation":[{"name":"Irkutsk State Medical Academy of Postgraduate Education\u2013Branch of Russian Medical Academy of Continuing Professional Education , Irkutsk , Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Koshcheyev","sequence":"additional","affiliation":[{"name":"Irkutsk Regional Tuberculosis Referral Hospital , Irkutsk , Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serhiy","family":"Vitko","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia , Charlottesville, Virginia , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blandina T","family":"Mmbaga","sequence":"additional","affiliation":[{"name":"Kilimanjaro Clinical Research Institute and Kilimanjaro Christian Medical University College , Moshi , Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gibson S","family":"Kibiki","sequence":"additional","affiliation":[{"name":"Kilimanjaro Clinical Research Institute and Kilimanjaro Christian Medical University College , Moshi , Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jotam G","family":"Pasipanodya","sequence":"additional","affiliation":[{"name":"Quantitative Preclinical & Clinical Sciences Department, Praedicare Inc , Dallas, 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