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dc.contributor.authorYu, Xiaen
dc.contributor.authorWang, Guirongen
dc.contributor.authorChen, Sutingen
dc.contributor.authorWei, Guomeien
dc.contributor.authorShang, Yuanyuanen
dc.contributor.authorDong, Linglingen
dc.contributor.authorSchön, Thomasen
dc.contributor.authorMoradigaravand, Daneshen
dc.contributor.authorParkhill, Julianen
dc.contributor.authorPeacock, Sharonen
dc.contributor.authorKöser, Claudio Uen
dc.contributor.authorHuang, Hairongen
dc.date.accessioned2016-07-08T13:38:22Z
dc.date.available2016-07-08T13:38:22Z
dc.date.issued2016-06-20en
dc.identifier.issn0066-4804
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/256683
dc.description.abstractAntofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its in vitro activity. We determined the wild-type and non-wild-type range MICs for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX) using the microplate alamar blue assay of 126 clinical Mycobacterial tuberculosis strains from Beijing (China), of which 48 were OFX resistant based on drug-susceptibility testing on Löwenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance determining regions of gyrA (Rv0006) and gyrB (Rv0005). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX, but higher than LFX and MFX based on the tentative epidemiological cut-off values (ECOFFs) determined in this study. All strains with non-wild-type MICs to AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration for OFX for Löwenstein-Jensen that was recently revised by the World Health Organization might be too high, resulting in misclassification of non-wild-type strains with known resistance mutations as wild-type. Based on our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.
dc.description.sponsorshipThe work was supported by the research funding from Infectious Diseases Special Project, Minister of Health of China (2016ZX10003001-12) and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201304). The strains used in this project were obtained from the ‘Beijing Bio-Bank of clinical resources on Tuberculosis’ (D09050704640000), Beijing Chest Hospital. In addition, this study was supported by the Health Innovation Challenge Fund (HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and Wellcome Trust. T. S. was supported by grants from the Swedish Heart and Lung Foundation and Marianne and Marcus Wallenberg Foundation. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health, Public Health England, or the Wellcome Trust. C. U. K. is a Junior Research Fellow at Wolfson College, Cambridge.
dc.languageEnglishen
dc.language.isoenen
dc.publisherAmerican Society for Microbiology
dc.rightsAttribution 4.0 International*
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmycobacterium tuberculosisen
dc.subjectantofloxacinen
dc.subjectofloxacinen
dc.subjectlevofloxacinen
dc.subjectmoxifloxacinen
dc.subjectepidemiological cut-off valueen
dc.titleWild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacinen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from American Society for Microbiology at http://dx.doi.org/10.1128/AAC.00393-16.en
prism.endingPage5237
prism.publicationDate2016en
prism.publicationNameAntimicrobial Agents and Chemotherapyen
prism.startingPage5232
prism.volume60en
dc.identifier.doi10.17863/CAM.618
dcterms.dateAccepted2016-06-10en
rioxxterms.versionofrecord10.1128/AAC.00393-16en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-06-20en
dc.contributor.orcidParkhill, Julian [0000-0002-7069-5958]
dc.contributor.orcidPeacock, Sharon [0000-0002-1718-2782]
dc.identifier.eissn1098-6596
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (098600/Z/12/Z)
cam.orpheus.successThu Jan 30 12:57:39 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International