Combatting the Rising Tide of Antimicrobial Resistance: Pharmacokinetic/Pharmacodynamic Dosing Strategies for Maximal Precision.

OBJECTIVE:Antimicrobial pharmacokinetics/pharmacodynamics (PK/PD) principles and PK/PD models have been essential in characterizing the mechanism of antibiotic bacterial killing and determining the most optimal dosing regimen that maximizes clinical outcomes. This review summarized the fundamentals of antimicrobial PK/PD and the various types of PK/PD experiments that shaped the utilization and dosing strategies of antibiotics today. METHODS:Multiple databases - including PubMed, Scopus, and EMBASE - were searched for published articles that involved PK/PD modelling and precision dosing. Data from in vitro, in vivo and mechanistic PK/PD models were reviewed as a basis for compiling studies that guide dosing regimens used in clinical trials. RESULTS:Literature regarding the utilization of exposure-response analyses, mathematical modelling and simulations that were summarized are able to provide a better understanding of antibiotic pharmacodynamics that influence translational drug development. Optimal pharmacokinetic sampling of antibiotics from patients can lead to personalized dosing regimens that attain target concentrations while minimizing toxicity. Thus the development of a fully integrated mechanistic model based on systems pharmacology can continually adapt to data generated from clinical responses, which can provide the framework for individualized dosing regimens. CONCLUSIONS:The promise of what PK/PD can provide through precision dosing for antibiotics has not been fully realized in the clinical setting. Antimicrobial resistance, which has emerged as a significant public health threat, has forced clinicians to empirically utilize therapies. Future research focused on implementation and translation of PK/PD-based approaches integrating novel approaches that combine knowledge of combination therapies, systems pharmacology and resistance mechanisms are necessary. To fully realize maximally precise therapeutics, optimal PK/PD strategies are critical to maximize antimicrobial efficacy against extremely-drug-resistant organisms, while minimizing toxicity.