{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T23:48:06Z","timestamp":1773100086730,"version":"3.50.1"},"reference-count":41,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T00:00:00Z","timestamp":1477958400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001868","name":"National Science Council of Taiwan","doi-asserted-by":"crossref","award":["NSC 102-2314-B-002-165"],"award-info":[{"award-number":["NSC 102-2314-B-002-165"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010304","name":"Pershing Square Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010304","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Broad Institute Tuberculosis Donor Group"},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19AI110818"],"award-info":[{"award-number":["U19AI110818"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"HHS | NIH | National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG002295"],"award-info":[{"award-number":["HG002295"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2015J01145"],"award-info":[{"award-number":["2015J01145"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"publisher","award":["2008046"],"award-info":[{"award-number":["2008046"]}],"id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Fluoroquinolones (FQs) are effective second-line drugs for treating antibiotic-resistant tuberculosis (TB) and are being considered for use as first-line agents. Because FQs are used to treat a range of infections, in a setting of undiagnosed TB, there is potential to select for drug-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n            mutants during FQ-based treatment of other infections, including pneumonia. Here we present a detailed characterization of ofloxacin-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            samples isolated directly from patients in Taiwan, which demonstrates that selection for FQ resistance can occur within patients who have not received FQs for the treatment of TB. Several of these samples showed no mutations in\n            <jats:italic>gyrA<\/jats:italic>\n            or\n            <jats:italic>gyrB<\/jats:italic>\n            based on PCR-based molecular assays, but genome-wide next-generation sequencing (NGS) revealed minority populations of\n            <jats:italic>gyrA<\/jats:italic>\n            and\/or\n            <jats:italic>gyrB<\/jats:italic>\n            mutants. In other samples with PCR-detectable\n            <jats:italic>gyrA<\/jats:italic>\n            mutations, NGS revealed subpopulations containing alternative resistance-associated genotypes. Isolation of individual clones from these apparently heterogeneous samples confirmed the presence of the minority drug-resistant variants suggested by the NGS data. Further NGS of these purified clones established evolutionary links between FQ-sensitive and -resistant clones derived from the same patient, suggesting\n            <jats:italic>de novo<\/jats:italic>\n            emergence of FQ-resistant TB. Importantly, most of these samples were isolated from patients without a history of FQ treatment for TB. Thus, selective pressure applied by FQ monotherapy in the setting of undiagnosed TB infection appears to be able to drive the full or partial emergence of FQ-resistant\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n            , which has the potential to confound diagnostic tests for antibiotic susceptibility and limit the effectiveness of FQs in TB treatment.\n          <\/jats:p>","DOI":"10.1128\/aac.00664-16","type":"journal-article","created":{"date-parts":[[2016,8,30]],"date-time":"2016-08-30T02:03:38Z","timestamp":1472522618000},"page":"6600-6608","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Genomic Analysis of the Evolution of Fluoroquinolone Resistance in Mycobacterium tuberculosis Prior to Tuberculosis Diagnosis"],"prefix":"10.1128","volume":"60","author":[{"given":"Danfeng","family":"Zhang","sequence":"first","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"},{"name":"School of Biological Science and Biotechnology, Minnan Normal University, Zhangzhou, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James E.","family":"Gomez","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung-Yien","family":"Chien","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, National Taiwan University Medical College, Taipei, Taiwan"},{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University Medical College, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Haseley","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher A.","family":"Desjardins","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashlee M.","family":"Earl","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Po-Ren","family":"Hsueh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University Medical College, Taipei, Taiwan"},{"name":"Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University Medical College, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah T.","family":"Hung","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"},{"name":"Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA"},{"name":"Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"World Health Organization","author":"World Health Organization","year":"2015","unstructured":"World Health Organization. 2015. Global tuberculosis report 2015. WHO\/HTM\/TB\/2015.22. World Health Organization. Geneva, Switzerland."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00105-15"},{"key":"e_1_3_3_4_2","volume-title":"World Health Organization","author":"World Health Organization","year":"2011","unstructured":"World Health Organization. 2011. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO\/HTM\/TB\/2011.6. World Health Organization. Geneva, Switzerland."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1314210"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1315817"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407426"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)62002-X"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/511159"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.3947\/ic.2014.46.4.226"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568026033452537"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MGM2-0009-2013"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr566"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120470"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2014.03.1388"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05905-11"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02066-13"},{"key":"e_1_3_3_18_2","volume-title":"Approved standard","author":"National Committee for Clinical Laboratory Standards","year":"2003","unstructured":"National Committee for Clinical Laboratory Standards. 2003. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes. Approved standard. National Committee for Clinical Laboratory Standards, Wayne, PA."},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.43.6.2996-2997.2005"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112963"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm061"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-5-r51"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039754"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091024"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0490-3"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2672.2003.01918.x"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2013.09.013"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1086\/598196"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268814003136"},{"key":"e_1_3_3_30_2","first-page":"159","volume-title":"Public health mycobacteriology: a guide for the level III laboratory","author":"Kent PT","year":"1985","unstructured":"Kent PT, Kubica GP. 1985. Antituberculosis chemotherapy and drug susceptibility testing, p 159\u2013184. In Kent PT, Kubica GP (ed), Public health mycobacteriology: a guide for the level III laboratory. Centers for Disease Control and Prevention, Atlanta, GA."},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.40.1.150-154.2002"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01463-09"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0144656"},{"key":"e_1_3_3_34_2","unstructured":"Boehme C. 2015. Looking ahead: the new TB diagnostic pipeline. http:\/\/www.stoptb.org\/wg\/gli\/assets\/documents\/M7\/4. BOEHME_New TB diagnostics pipeline.pdf."},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD010705.pub2"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01602-13"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mimet.2013.01.008"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3226"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(12)70277-3"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00071-7"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00466-X"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10063"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00664-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00664-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:32:39Z","timestamp":1645475559000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00664-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11]]},"references-count":41,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2016,11]]}},"alternative-id":["10.1128\/AAC.00664-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.00664-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11]]},"assertion":[{"value":"2016-03-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-08-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-10-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}