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The Effect of Anti-Tuberculosis Drugs on in vitro Stationary Phase Mycobacterium tuberculosis: Using a Multistate Tuberculosis Disease Model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
2015 (English)Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesisAlternative title
En farmakometrisk modell för effekten av anti-tuberkulära läkemedel på Mycobacterium tuberculosis i stationärfas (Swedish)
Abstract [en]

Introduction: Tuberculosis (TB), is one of the deadliest transmittable diseases in the world, and requires a lengthy treatment due to persistent non-multiplying bacteria. In hypoxia driven in vitro systems persistent or dormant Mycobacterium tuberculosis (M. tuberculosis) bacteria are thought to constitute a larger part of the bacterial population in late stationary phase compared to the initial log phase of the bacterial growth curve. A semi-mechanistic pharmacometric multistate tuberculosis disease model describing the natural growth of M. tuberculosis H37Rv, providing predictions of a fast, slow and non-multiplying bacterial state, has previously been developed. The model has further been used to describe the effect of rifampicin (RIF) on bacteria originating from log phase bacterial cultures.

Aim:  This project aimed to explore if the effect of anti-TB drugs on in vitro M. tuberculosis is independent of in which phase the bacterial culture originates from, to gain insights in the kill kinetics of the different bacterial states.

Materials and Methods: Data consisted of stationary phase M. tuberculosis incubated with different concentrations of RIF. The effect of RIF was evaluated as inhibition of growth or increased death rate of the different states using the multistate model. The final stationary phase model was compared to the log phase model and externally validated with clinical data.

Results: A model describing the effect of RIF on stationary phase bacteria was developed and included drug effect on all multiplication states. This differed from the previous develop log model.

Conclusions:  The multistate model was used to characterise the antibacterial drug effect of RIF on M. tuberculosis H37Rv. Evaluation of applying log phase data to the stationary phase model suggests that the stationary phase model can describe log phase data but not the opposite. 

Place, publisher, year, edition, pages
2015. , 31 p.
Keyword [en]
Pharmacometrics, Pharmacokinetics, Pharmacodynamics, Tuberculosis, Mycobacterium tuberculosis
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-258111OAI: oai:DiVA.org:uu-258111DiVA: diva2:844268
Educational program
Master of Science Programme in Pharmacy
Available from: 2015-08-10 Created: 2015-07-10 Last updated: 2015-08-10Bibliographically approved

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