Optimizing Individualized Antimicrobial Dosing in Pediatric Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Abstract

Background: Therapeutic drug monitoring (TDM) and target concentration intervention (TCI) represent significant advancements in individualized medicine, aiming to tailor dosages based on patient-specific characteristics. These approaches account for intra- and inter-individual physiological and clinical variability, with the goal of improving target attainment and clinical remission while reducing treatment failure and adverse effects.

Objectives: The objective is to assess and enhance the current body of randomized controlled trials (RCTs) that have investigated alternative personalized dosing strategies, such as TDM and TCI, in terms of their efficacy and safety for individualized antimicrobial dosing in pediatric populations. Only studies that compared different dosing regimens and reported plasma concentrations were included in the analysis.

Methods: Databases such as MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until January 3rd, 2024. Only published, peer-reviewed RCTs were considered for inclusion. The study focused on human subjects aged < 18 years who were receiving an antimicrobial drug. The interventions compared experimental dosing versus standard dosing with TDM or TCI. The risk of bias was assessed using version 2 of the Cochrane risk-of-bias tool for randomized trials. The primary outcome was the attainment of target concentrations, while secondary outcomes included adverse effects, clinical remission, and treatment failure. Data synthesis was performed using the restricted maximum likelihood method, and the risk ratio (RR) was used as the measure of effect size.

Results: Only 11 TDM-based RCTs were included in the study [experimental vs standard doses: 592 (51.3%) patients vs 563 (48.7%) patients]. Experimental dose was significantly associated with improvement in target attainment (RR 1.2587, OR 1.0717-1.4786; p = 0.0051). However, experimental antimicrobial dose optimization was non-significantly associated with a numerical decrease in treatment failure (RR 0.8966, OR 0.7749-1.0374; p = 0.1424). In addition, it was not significant associated with higher adverse effects [RR 1.3408, odds ratio (OR) 0.1783-10.0825; p = 0.7757] and clinical remission rates (RR 4.0589, OR 0.2494-66.0558; p = 0.3250).

Conclusions: This meta-analysis showed that only target attainment using TDM was significantly improved in pediatric patients treated with experimental doses of antimicrobials compared to standard doses. Larger TCI-focused RCTs are needed to significantly improve treatment failure, adverse effects, and clinical remission.