Individualized antimicrobial dose optimization: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Therapeutic drug monitoring and Model-informed precision dosing allow dose individualization to increase drug effectivity and reduce toxicity.

Objectives: To evaluate the available evidence on the clinical efficacy of individualized antimicrobial dosing optimization.

Methods: Data sources: PubMed, Embase, Web of Science, and Cochrane Library databases from database inception to 11 November 2022.

Study eligibility criteria: Published peer-reviewed randomized controlled trials.

Participants: Human subjects aged ≥18 years receiving an antibiotic or antifungal drug.

Interventions: Patients receiving individualized antimicrobial dose adjustment.

Assessment of risk of bias: Cochrane risk-of-bias tool for randomized trials.

Methods of data synthesis: The primary outcome was the risk of mortality. Secondary outcomes included target attainment, treatment failure, clinical and microbiological cure, length of stay, treatment duration, and adverse events. Effect sizes were pooled using a random-effects model. Statistical heterogeneity was assessed by inconsistency testing (I²).

Results: Ten randomized controlled trials were included in the meta-analysis (1241 participants; n = 624 in the individualized antimicrobial dosing group and n = 617 in the control group). Individualized antimicrobial dose optimization was associated with a numerical decrease in mortality (risk ratio [RR] = 0.86; 95% CI, 0.71-1.05), without reaching statistical significance. Moreover, it was associated with significantly higher target attainment rates (RR = 1.41; 95% CI, 1.13-1.76) and a significant decrease in treatment failure (RR = 0.70; 95% CI, 0.54-0.92). Individualized antimicrobial dose optimization was associated with improvement, but not significant in clinical cure (RR = 1.33; 95% CI, 0.94-1.33) and microbiological outcome (RR = 1.25; CI, 1.00-1.57), as well as with a significant decrease in the risk of nephrotoxicity (RR = 0.55; 95% CI, 0.31-0.97).

Conclusions: This meta-analysis demonstrated that target attainment, treatment failure, and nephrotoxicity were significantly improved in patients who underwent individualized antimicrobial dose optimization. It showed an improvement in mortality, clinical cure or microbiological outcome, although not significant.

Keywords: Antibiotic; Antifungal; Antimicrobial; Dose individualization; Dose optimisation; Drug management; MIPD; Model-Informed precision dosing; TDM; Therapeutic drug monitoring.