Subtherapeutic concentrations of first-line antitubercular agents in pediatric patients and its association with tuberculosis treatment outcome: protocol for a systematic review and meta-analysis

Pediatric tuberculosis is a neglected disease that is receiving more attention lately. Some studies found that serum levels of first line antituberculosis drugs do not reach reference concentrations in children. However, these reference ranges were validated in an adult sample. Thus, we do not know if subtherapeutic concentrations of antitubercular agents in children is associated with negative outcomes. ObjectiveTo estimate the association between subtherapeutic concentrations of first-line antitubercular drugs with clinical outcomes of treatment. MethodsWe propose to do a systematic review and meta-analysis. In order to do so, we will perform an electronic search in Medline, SCOPUS, Web of Science. There will be no restriction of language nor date of publication. First, we will screen titles and abstracts; then we will screen through the full text of the article. Both phases will be done by 2 independent authors. Data extraction will be performed using a data abstraction form by two independent authors. The quality of the studies will be checked with standardized tools according to the design of the study, and will also be performed by duplicate. We will present the main characteristics of each included study through tables. The heterogeneity between studies will be assessed through the I2 statistic. If appropriate, we will use the random-effects model to calculate the pooled estimate. We will evaluate the publication bias through visual inspection of the funnel plot and Eggers test. Pre-arranged subgroup and sensitivity analysis will be performed. ResultsWe will publish the results of this systematic review in a peer-reviewed journal. ConclusionsThis systematic review will provide up-to-date evidence regarding serum concentration in pediatric patients and its association with outcomes. With the analysis we plan, we will offer important recommendations regarding the dosage of the first line antitubercular agents in children, and the modifications that may be needed.