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Difference in persistent tuberculosis bacteria between in vitro and sputum from patients: implications for translational predictions

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dc.contributor.authorFaraj, Alan
dc.contributor.authorClewe, Oskar
dc.contributor.authorSvensson, Robin J.
dc.contributor.authorMukamolova, Galina V.
dc.contributor.authorBarer, Michael R.
dc.contributor.authorSimonsson, Ulrika S. H.
dc.contributor.funderEuropean Commissionen
dc.date.accessioned2021-06-29T09:23:59Z
dc.date.available2021-06-29T09:23:59Z
dc.date.issued2020-09-23
dc.description.abstractThis study aimed to investigate the number of persistent bacteria in sputum from tuberculosis patients compared to in vitro and to suggest a model-based approach for accounting for the potential difference. Sputum smear positive patients (nā€‰=ā€‰25) provided sputum samples prior to onset of chemotherapy. The number of cells detected by conventional agar colony forming unit (CFU) and most probable number (MPN) with Rpf supplementation were quantified. Persistent bacteria was assumed to be the difference between MPNrpf and CFU. The difference in persistent bacteria between in vitro and human sputum prior to chemotherapy was quantified using different model-based approaches. The persistent bacteria in sputum was 17% of the in vitro levels, suggesting a difference in phenotypic resistance, whereas no difference was found for multiplying bacterial subpopulations. Clinical trial simulations showed that the predicted time to 2 log fall in MPNrpf in a Phase 2a setting using in vitro pre-clinical efficacy information, would be almost 3 days longer if drug response was predicted ignoring the difference in phenotypic resistance. The discovered phenotypic differences between in vitro and humans prior to chemotherapy could have implications on translational efforts but can be accounted for using a model-based approach for translating in vitro to human drug response.en
dc.description.sponsorshipThis project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 853989. The JU receives support from the European Unionā€™s Horizon 2020 research and innovation programme and EFPIA and Global Alliance for TB Drug Development non profit organisation, Bill & Melinda Gates Foundation and University of Dundee. The authors also would like to acknowledge the patients involved in the trial for their contribution to the research.en
dc.format.extent10
dc.identifier.bibliographicCitationFaraj, A., Clewe, O., Svensson, R. J., Mukamolova, G. V., Barer, M. R. & Simonsson, U. S. H. (2020). Difference in persistent tuberculosis bacteria between in vitro and sputum from patients: implications for translational predictions. Scientific Reports, 10(1), 15537.en
dc.identifier.doihttps://doi.org/10.1038/s41598-020-72472-y
dc.identifier.issn2045-2322
dc.identifier.publicationfirstpage1
dc.identifier.publicationissue15537
dc.identifier.publicationlastpage10
dc.identifier.publicationtitleScientific Reportsen
dc.identifier.publicationvolume10
dc.identifier.urihttps://hdl.handle.net/10016/32951
dc.language.isoeng
dc.publisherNature Researchen
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/853989/ERA4TB
dc.rightsĀ© The Author(s) 2020en
dc.rightsAtribuciĆ³n 3.0 EspaƱa*
dc.rights.accessRightsopen accessen
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subject.ecienciaBiologĆ­a y Biomedicinaes
dc.subject.ecienciaMedicinaes
dc.subject.otherBiomarkersen
dc.subject.otherPharmacodynamicsen
dc.subject.otherTuberculosisen
dc.titleDifference in persistent tuberculosis bacteria between in vitro and sputum from patients: implications for translational predictionsen
dc.typeresearch article*
dc.type.hasVersionVoR*
dspace.entity.typePublication
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