Assessment of bactericidal drug activity and treatment outcome in a mouse tuberculosis model using a clinical Beijing strain [PublishAheadOfPrint]

Objectives: Mycobacterium tuberculosis Beijing strains are associated with lower treatment success rates in tuberculosis patients. In contrast, laboratory strains such as H37Rv are often used in preclinical tuberculosis models. Therefore, we explored the impact of using a clinical Beijing strain on treatment outcome in our mouse tuberculosis model. Additionally, the predictive value of bactericidal activity on treatment outcome was assessed.

Methods: BALB/c mice were infected with a Beijing strain and treated with one of ten different combinations of conventional anti-TB drugs. Bactericidal activity was assessed by determining reductions in mycobacterial load after 7, 14 and 28 days and after 2, 3 and 6 months of treatment. Treatment outcome was evaluated after a 6-months treatment-course and was based on lung culture-status 3 months post-treatment.

Results: None of the anti-TB drug regimens tested could achieve 100% treatment success. Treatment outcome depended critically on rifampicin. Four non-rifampicin-containing regimens showed 0% treatment success compared to success rates ranging between 81-95% for six rifampicin-containing regimens. Bactericidal activity was only predictive for treatment outcome after 3 months of treatment.

Conclusion: Our data advocate the use of multiple mycobacterial strains, including a Beijing strain, to increase the translational value of mouse TB models evaluating treatment outcome. Additionally, our findings support the notion that bactericidal activity in the first two months of treatment, as measured in clinical phase IIa/b trials, has limited predictive value for tuberculosis treatment outcome, thus emphasizing the need for better parameters to guide future phase-IIII trials.

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