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We performed a series of pharmacokinetic\/pharmacodynamic (PK\/PD) experiments with a potentially safer third-generation tetracycline, omadacycline, for the treatment of multidrug-resistant tuberculosis (MDR-TB).\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic>Mtb<\/jats:italic>\n                    ) H37Rv and an MDR-TB clinical strain (16D) were used in the minimum inhibitory concentration (MIC) and static concentration-response studies in test tubes, followed by a PK\/PD study using the hollow fiber system model of TB (HFS-TB) that examined six human-like omadacycline doses. The inhibitory sigmoid maximal effect (\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) model and Monte Carlo experiments (MCEs) were used for data analysis and clinical dose-finding, respectively. The omadacycline MIC for both\n                    <jats:italic>Mtb<\/jats:italic>\n                    H37Rv and MDR-TB clinical strain was 16 mg\/L but dropped to 4 mg\/L with daily drug supplementation to account for omadacycline degradation. The Mycobacteria Growth Indicator Tube MIC was 2 mg\/L. In the test tubes, omadacycline killed 4.39 log\n                    <jats:sub>10<\/jats:sub>\n                    CFU\/mL in 7 days. On Day 28 of the HFS-TB study, the\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    was 4.64 log\n                    <jats:sub>10<\/jats:sub>\n                    CFU\/mL, while exposure mediating 50% of\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    (EC\n                    <jats:sub>50<\/jats:sub>\n                    ) was an area under the concentration-time curve to MIC (AUC\n                    <jats:sub>0\u201324<\/jats:sub>\n                    \/MIC) ratio of 22.86. This translates to PK\/PD optimal exposure or EC\n                    <jats:sub>80<\/jats:sub>\n                    as AUC\n                    <jats:sub>0\u201324<\/jats:sub>\n                    \/MIC of 26.93. The target attainment probability of the 300-mg daily oral dose was 90% but fell at MIC \u22674 mg\/L. Omadacycline demonstrated efficacy and potency against both drug-susceptible and MDR-TB. Further studies are needed to identify the omadacycline effect in combination therapy for the treatment of both drug-susceptible and MDR-TB.\n                  <\/jats:p>","DOI":"10.1128\/aac.01080-23","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T08:34:58Z","timestamp":1703234098000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Omadacycline pharmacokinetics\/pharmacodynamics and efficacy against multidrug-resistant\n                    <i>Mycobacterium tuberculosis<\/i>\n                    in the hollow fiber system model"],"prefix":"10.1128","volume":"68","author":[{"given":"Sanjay","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7592-8012","authenticated-orcid":true,"given":"Tawanda","family":"Gumbo","sequence":"additional","affiliation":[{"name":"Quantitative Preclinical and Clinical Sciences Department, Praedicare Inc., Dallas, Texas, USA"},{"name":"Hollow Fiber System and Experimental Therapeutics Laboratories, Praedicare Inc., Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunavanthi D.","family":"Boorgula","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania A.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie V.","family":"Philley","sequence":"additional","affiliation":[{"name":"Section of Pulmonary and Critical Care, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8786-8851","authenticated-orcid":false,"given":"Shashikant","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA"},{"name":"Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1164\/art.1948.58.3.335"},{"key":"e_1_3_3_3_2","article-title":"Increase in resistance of tubercle bacilli to streptomycin; a preliminary report","volume":"21","author":"Youmans GP","year":"1946","unstructured":"Youmans GP, WILLISTON EH. 1946. 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