Optimization of tuberculosis treatment in children and adolescents: epidemiological and pharmacological approaches

This thesis addresses epidemiological and pharmacological approaches to optimize the treatment of tuberculosis (TB) in children and adolescents. In this thesis, we assessed the epidemiological characteristics and treatment outcomes, as well as the pharmacokinetics and safety/tolerability of first-line anti-TB drugs, in children and adolescents with TB. Through our findings, we showed that children and adolescents with TB generally have good treatment outcomes with standardized treatment approaches. To further optimize care in this population, several risk factors associated with poor outcomes have been identified for further development of early and tailored interventions to support these patients once diagnosed with TB. In patients with severe forms of the disease such as TB meningitis, substantially high rates of mortality and neurological morbidity were observed in children and adolescents. In addition, children and adolescents with TB meningitis were found to have suboptimal anti-TB drug dosages, especially for rifampicin. It is therefore important to further improve treatment outcomes among children and adolescents with TB meningitis by developing early interventions based on high-risk groups for poor outcomes, optimizing antimicrobial therapy using intensified anti-TB drug regimens containing high-dose rifampicin, and optimizing host-directed therapy beyond corticosteroids. Certain subgroups of patients who are at risk of suboptimal plasma exposures to first-line anti-TB drugs have also been identified, including young children under two years of age, those with severe malnutrition, and with HIV coinfection, among others. These may be relevant for population-specific dose adjustment or individualized therapeutic drug monitoring to further improve treatment outcomes.