Abstract
Proper characterization of drug effects on Mycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure–response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of in vitro and in vivo phenotypic resistance i.e. persisters, using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated based on bacterial cultures grown with and without drug exposure using CFU alone or CFU plus MPN data. Phenotypic resistance and total bacterial number in in vitro natural growth observations, i.e. without drug, was well predicted by the MTP model using only CFU data. Capturing the murine in vivo total bacterial number and persisters during natural growth did however require re-estimation of model parameter using both the CFU and MPN observations implying that the ratio of persisters to total bacterial burden is different in vitro compared to murine in vivo. The evaluation of the in vitro rifampicin drug effect revealed that higher resolution in the persister drug effect was seen using CFU and MPN compared to CFU alone although drug effects on the other bacterial populations were well predicted using only CFU data. The ratio of persistent bacteria to total bacteria was predicted to be different between in vitro and murine in vivo. This difference could have implications for subsequent translational efforts in tuberculosis drug development.
Highlights
Tuberculosis (TB) is ranked as the leading cause of death due to an infectious disease worldwide and has been identified by the World Health Organization as ‘‘a global priority for research and development’’ based on the high lethality and the ‘‘seriously underfunded’’ TB drug researchElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.and development [1]
The evaluation of the in vitro rifampicin drug effect revealed that higher resolution in the persister drug effect was seen using colony forming unit (CFU) and most probable number (MPN) compared to CFU alone drug effects on the other bacterial populations were well predicted using only CFU data
Predictions of in vitro and in vivo phenotypic resistance using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated using M. tuberculosis H37Rv cultures subjected to culture supernatant containing RPFs
Summary
Current research efforts relating to optimization of existing treatment including increased doses of rifampicin [2,3,4,5,6], which has proven effect against persistent Mycobacterium tuberculosis (M. tuberculosis) [7,8,9], and the re-evaluation of clofazimine [10] are good examples of how improved understanding and usage of modern approaches for pharmacokinetic and pharmacodynamic (PKPD) characterisation has the potential to improve the treatment of TB. For disease areas as TB, where the incitement for investing in drug development is low, these methods are very important as they represent rational and informative methods that has the power of identifying the most efficient treatment regimens to patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
