Improving treatment outcome assessment in a mouse tuberculosis model.
Bas C. Mourik,Robin J. Svensson,Gerjo J. de Knegt,Hannelore I. Bax,Annelies Verbon,Ulrika S. H. Simonsson,Jurriaan E. M. de Steenwinkel +6 more
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TLDR
A new design for treatment outcome evaluation in a mouse TB model is provided, which provides accurate tools for assessment of the relationship between treatment length and predicted cure, allows for efficient comparison between regimens and adheres to the reduction and refinement principles of laboratory animal use.Abstract:
Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens’ treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (RpZHE), rifampicin-pyrazinamide-moxifloxacin-ethambutol (RZME) or rifampicin-pyrazinamide-moxifloxacin-isoniazid (RZMH). Treatment outcome was assessed in n = 3 mice after 9 different treatment lengths between 2–6 months. Next, we created a mathematical model that best fitted the observational data and used this for inter-regimen comparison. The observed data were best described by a sigmoidal Emax model in favor over linear or conventional Emax models. Estimating regimen-specific parameters showed significantly higher curative potentials for RZME and RpZHE compared to RZMH. In conclusion, we provide a new design for treatment outcome evaluation in a mouse TB model, which (i) provides accurate tools for assessment of the relationship between treatment length and predicted cure, (ii) allows for efficient comparison between regimens and (iii) adheres to the reduction and refinement principles of laboratory animal use.read more
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Systematic measurement of combination-drug landscapes to predict in vivo treatment outcomes for tuberculosis
Jonah Larkins-Ford,Talia Greenstein,Nhi Van,Yonatan N. Degefu,Yonatan N. Degefu,Michaela C. Olson,Artem Sokolov,Bree B. Aldridge +7 more
TL;DR: In this article, the authors provide an extensible approach to rationally prioritize combination therapies for testing in in-vivo mouse models of tuberculosis, and develop classifiers predictive of multidrug treatment outcome in a mouse model of disease relapse.
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Superior efficacy of a bedaquiline, delamanid and linezolid combination regimen in a mouse-TB model.
Elise D Pieterman,Lina Keutzer,Aart van der Meijden,Sanne van den Berg,Han Wang,Matthew D. Zimmerman,Ulrika S. H. Simonsson,Hannelore I. Bax,Jurriaan E. M. de Steenwinkel +8 more
TL;DR: In this article, the authors compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid and linezolid (100mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE)
Journal ArticleDOI
Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
Pasupathy Saravanan,V. N. Azger Dusthackeer,R. S. Rajmani,B. Mahizhaveni,Christy Rosaline Nirmal,Sam Ebenezer Rajadas,Neerupma Bhardwaj,C Ponnuraja,Adhin Bhaskar,A K Hemanthkumar,Geetha Ramachandran,Srikanth Tripathy +11 more
TL;DR: In this article, a hybrid of the precursors of rifampicin and clofazimine was used for the discovery of a novel Rifaphenazine (RPZ) molecule with potent anti-TB activity.
Journal ArticleDOI
Predictive modeling to study the treatment-shortening potential of novel tuberculosis drug regimens, towards bundling of preclinical data.
Saskia E. Mudde,Rami Ayoun Alsoud,Aart van der Meijden,Anna M. Upton,Manisha U. Lotlikar,Ulrika S. H. Simonsson,Hannelore I. Bax,Jurriaan E. M. de Steenwinkel +7 more
TL;DR: In this paper, the authors explored the relationship between relapse and treatment length as well as inter-regimen differences for two novel anti-TB drug regimens using a mouse model of TB infection and mathematical modeling.
Journal ArticleDOI
Assessment of the Additional Value of Verapamil to a Moxifloxacin and Linezolid Combination Regimen in a Murine Tuberculosis Model.
Elise D. Pieterman,Lindsey H.M. te Brake,Gerjo J. de Knegt,Aart van der Meijden,Jan-Willem C. Alffenaar,Hannelore I. Bax,Rob E. Aarnoutse,Jurriaan E. M. de Steenwinkel +7 more
TL;DR: Treatment with a combination regimen of moxifloxacin and linezolid and the addition of verapamil had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing the spleen relapse rate.
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