Preclinical tools for the evaluation of tuberculosis treatment regimens for children.

Abstract

Tuberculosis (TB) treatment regimens have been extrapolated from adults to children. However, pediatric disease merits different treatment strategies to avoid under- or over-treatment. While animal models have been pivotal in identifying effective regimens for adult disease, pediatric TB is heterogeneous and cannot be represented by a single preclinical model. Infants and young children most commonly have disseminated disease or tuberculous meningitis (TBM), school-aged children have paucibacillary disease, and adolescents have adult-like cavitary lung disease. Models simulating these forms of pediatric TB have been developed, but their utility in assessing treatment regimens is in the early stages. Disseminated, intracellular disease can be partly reproduced by an in vitro pharmacodynamic system, TBM by a pediatric rabbit model of TBM, paucibacillary TB by the balbC mouse model, and cavitary disease by a rabbit model and a C3HeB/FeJ mouse model of pulmonary TB. Although there is no one-size-fits-all preclinical 'pediatric TB model', these models can be employed to study drug distribution to the sites of disease and, coupled with translational modeling, used to help select and optimize regimens for testing in children. Use of these models may accelerate the development of regimens for rare or hard-to-treat TB, namely drug-resistant TB and TBM.