Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration

Ghaith Aljayyoussi,Samantha Donnellan,Stephen A Ward,Giancarlo A Biagini,Alison Ardrey,Raman Sharma,Victoria A Jenkins

doi:10.1038/s41598-017-00529-6

Ghaith Aljayyoussi, Samantha Donnellan + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-00529-6

Copy DOI

Journal: Scientific Reports	Publication Date: Mar 29, 2017
Citations: 33	License type: open-access

Affiliation: Liverpool School of Tropical Medicine

Abstract

Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.

Highlights

Tuberculosis (TB) is a highly infectious disease, with one third of the world’s population being latently infected and accounting for an estimated 1.5 million deaths in 20141
The intracellular macrophage environment offers the ability to measure Mycobacterium tuberculosis (Mtb) drug dynamics within an environment that better reflects the common niche of this pathogen
Reflecting the nutritionally-constrained environment of the intracellular macrophage milieu[37], the population growth of intracellular Mtb residing within macrophages was much slower (~21 h doubling time, Table 1 and Supplementary Fig. 1) compared with Mtb grown in stirred liquid culture which has a doubling time of approximately 9 h24, 25 (Table 1 and Supplementary Fig. 1)

Summary

Introduction

Tuberculosis (TB) is a highly infectious disease, with one third of the world’s population being latently infected and accounting for an estimated 1.5 million deaths in 20141. A major challenge to TB drug development is the lack of validated predictive in vitro and in vivo pre-clinical tools that can be used to identify potential new drug candidates or drug combinations/regimens that confidently translate to shorter treatments in the clinic[2, 3]. In the case of moxifloxacin (MOX) for example, efficacy data acquired using current in vitro and in vivo models predicted the potential for a shortened treatment regimen[4,5,6] These pre-clinical model end points did not translate to humans and in a recent clinical trial in which MOX replaced either ethambutol (EMB) or isoniazid (INH), MOX did not shorten the standard 6 month TB treatment to 4 months[7]. It is clear that demonstration of efficacy against intracellular Mtb must be a critical PD feature for any anti-tubercular drug under development[20]

Methods

Results

Conclusion