Optimisation of antimicrobial dosing based on pharmacokinetic and pharmacodynamic principles

Abstract

While suboptimal dosing of antimicrobials has been attributed to poorer clinical outcomes, clinical cure and mortality advantages have been demonstrated when target pharmacokinetic (PK) and pharmacodynamic (PD) indices for various classes of antimicrobials were achieved to maximise antibiotic activity. Dosing optimisation requires a good knowledge of PK/PD principles. This review serves to provide a foundation in PK/PD principles for the commonly prescribed antibiotics (β-lactams, vancomycin, fluoroquinolones and aminoglycosides), as well as dosing considerations in special populations (critically ill and obese patients). PK principles determine whether an appropriate dose of antimicrobial reaches the intended pathogen(s). It involves the fundamental processes of absorption, distribution, metabolism and elimination, and is affected by the antimicrobial's physicochemical properties. Antimicrobial pharmacodynamics define the relationship between the drug concentration and its observed effect on the pathogen. The major indicator of the effect of the antibiotics is the minimum inhibitory concentration. The quantitative relationship between a PK and microbiological parameter is known as a PK/PD index, which describes the relationship between dose administered and the rate and extent of bacterial killing. Improvements in clinical outcomes have been observed when antimicrobial agents are dosed optimally to achieve their respective PK/PD targets. With the rising rates of antimicrobial resistance and a limited drug development pipeline, PK/PD concepts can foster more rational and individualised dosing regimens, improving outcomes while simultaneously limiting the toxicity of antimicrobials.