RT Journal Article
T1 Difference in persistent tuberculosis bacteria between in vitro and sputum from patients: implications for translational predictions
A1 Faraj, Alan
A1 Clewe, Oskar
A1 Svensson, Robin J.
A1 Mukamolova, Galina V.
A1 Barer, Michael R.
A1 Simonsson, Ulrika S. H.
AB 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.
PB Nature Research
SN 2045-2322
YR 2020
FD 2020-09-23
LK https://hdl.handle.net/10016/32951
UL https://hdl.handle.net/10016/32951
LA eng
NO 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.
DS e-Archivo
RD 18 may. 2024