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

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dc.contributor.author Faraj, Alan
dc.contributor.author Clewe, Oskar
dc.contributor.author Svensson, Robin J.
dc.contributor.author Mukamolova, Galina V.
dc.contributor.author Barer, Michael R.
dc.contributor.author Simonsson, Ulrika S. H.
dc.date.accessioned 2021-06-29T09:23:59Z
dc.date.available 2021-06-29T09:23:59Z
dc.date.issued 2020-09-23
dc.identifier.bibliographicCitation Faraj, 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.
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10016/32951
dc.description.abstract This 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 (n = 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.
dc.description.sponsorship This 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 Union’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.
dc.format.extent 10
dc.language.iso eng
dc.publisher Nature Research
dc.rights © The Author(s) 2020
dc.rights Atribución 3.0 España
dc.rights.uri http://creativecommons.org/licenses/by/3.0/es/
dc.subject.other Biomarkers
dc.subject.other Pharmacodynamics
dc.subject.other Tuberculosis
dc.title Difference in persistent tuberculosis bacteria between in vitro and sputum from patients: implications for translational predictions
dc.type article
dc.subject.eciencia Biología y Biomedicina
dc.subject.eciencia Medicina
dc.identifier.doi https://doi.org/10.1038/s41598-020-72472-y
dc.rights.accessRights openAccess
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/853989/ERA4TB
dc.type.version publishedVersion
dc.identifier.publicationfirstpage 1
dc.identifier.publicationissue 15537
dc.identifier.publicationlastpage 10
dc.identifier.publicationtitle Scientific Reports
dc.identifier.publicationvolume 10
dc.contributor.funder European Commission
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