Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices

Abstract

The pharmacokinetic/pharmacodynamic (PK/PD) indices useful for predicting antimicrobial clinical efficacy are well established. The most common indices include the time free drug concentration in plasma is above the minimum inhibitory concentration (MIC) (fT(>MIC)) expressed as a percent of the dosing interval, the ratio of maximum concentration to MIC (C(max)/MIC), and the ratio of the area under the 24-h concentration-time curve to MIC (AUC(0-24)/MIC). A single PK/PD index may correlate well with an entire antimicrobial class. For example, the beta-lactams correlate well with the fT(>MIC). However, other classes may be more complex and a single index cannot be generalised to the class, e.g. the macrolides. The rationale behind which PK/PD index best correlates with efficacy depends on several factors, including the mechanism of action, the microbial kill kinetics, the degree of protein binding and the degree of tissue distribution. Studies have traditionally emphasised the first two factors, whilst the significance of protein binding and tissue distribution is increasingly appreciated. In fact, the latter two factors may partially elucidate why the magnitude of reported target indices are not always as expected. For example, tigecycline and telithromycin are clinically efficacious with average serum concentrations below their MICs over a 24-h period. Therefore, to understand more fully the PK/PD relationship of antibiotics and to better predict the clinical efficacy of antibiotic dosing regimens, assessment of free drug concentrations at the site of action is warranted.