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dc.contributor.authorZhang, Danfeng
dc.contributor.authorGomez, James
dc.contributor.authorChien, Jung-Yien
dc.contributor.authorHaseley, Nathan
dc.contributor.authorDesjardins, Christopher
dc.contributor.authorEarl, Ashlee
dc.contributor.authorHsueh, Po-Ren
dc.contributor.authorHung, Deborah
dc.date.accessioned2019-10-13T16:03:23Z
dc.date.issued2016
dc.identifier.citationZhang, Danfeng, James E. Gomez, Jung-Yien Chien, Nathan Haseley, Christopher A. Desjardins, Ashlee M. Earl, Po-Ren Hsueh, and Deborah T. Hung. 2016. “Genomic Analysis of the Evolution of Fluoroquinolone Resistance in Mycobacterium Tuberculosis Prior to Tuberculosis Diagnosis.” Antimicrobial Agents and Chemotherapy 60 (11): 6600–6608. doi:10.1128/AAC.00664-16.
dc.identifier.issn0066-4804
dc.identifier.issn1098-6596
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41542800*
dc.description.abstractFluoroquinolones (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 Mycobacterium tuberculosis mutants during FQ-based treatment of other infections, including pneumonia. Here we present a detailed characterization of ofloxacin-resistant M. tuberculosis 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 gyrA or gyrB based on PCR-based molecular assays, but genome-wide next-generation sequencing (NGS) revealed minority populations of gyrA and/ or gyrB mutants. In other samples with PCR-detectable gyrA 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 de novo 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 M. tuberculosis, which has the potential to confound diagnostic tests for antibiotic susceptibility and limit the effectiveness of FQs in TB treatment.
dc.language.isoen_US
dc.publisherAmerican Society for Microbiology
dash.licenseLAA
dc.titleGenomic Analysis of the Evolution of Fluoroquinolone Resistance in Mycobacterium tuberculosis Prior to Tuberculosis Diagnosis
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalAntimicrobial Agents and Chemotherapy
dash.depositing.authorHung, Deborah Tan::45968263d9ae67f8c1970987265073e7::600
dc.date.available2019-10-13T16:03:23Z
dash.workflow.comments1Science Serial ID 15339
dc.identifier.doi10.1128/AAC.00664-16
dash.source.volume60;11
dash.source.page6600


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