The Importance of Pharmacokinetic/Pharmacodynamic Surrogate Markers to Outcome

Abstract

Pharmacokinetic/pharmacodynamic surrogate relationships have been used to describe the antibacterial activity of various classes of antimicrobial agents. Studies that have evaluated these relationships were reviewed to determine which of these surrogate markers were further dependent on antimicrobial class. The fluoroquinolone and aminoglycoside agents exhibit concentration-dependent killing. Studies have demonstrated that peak serum concentration: minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC): MIC ratios are important predictors of outcome for these antimicrobial agents. Area under the inhibitory concentration-time curve (AUIC24) [i.e. AUC24/MIC] is a useful parameter for describing efficacy for these agents, while an adequate peak concentration: MIC ratio seems necessary to prevent selection of resistant organisms. For beta-lactam antibiotics, the duration of time that the serum concentration exceeds the MIC (T > MIC) was the significant pharmacokinetic/pharmacodynamic surrogate in cases where the bacterial inoculum was low, or where very sensitive organisms were tested. However, in studies using more resistant organisms or larger inoculum sizes there is some concentration-dependence to the observed effect. Studies using reasonable dosage intervals have demonstrated covariance between T > MIC and AUC/MIC ratio for beta-lactam antibiotics. Since glycopeptide antibiotics display relatively slow but concentration-independent killing, and are cell wall active agents similar to beta-lactams, it has been presumed that T > MIC is the important pharmacokinetic surrogate related to efficacy for these agents. Some studies have shown that a concentration multiple of the MIC may be necessary for successful outcome with vancomycin. AUIC24 may prove to be an important pharmacokinetic surrogate if both time and concentration are indeed important parameters. To select an appropriate antimicrobial agent, the clinician must consider many patient-specific as well as organism-specific factors. Utilisation of known pharmacokinetic/pharmacodynamic surrogate relationships should help to optimise treatment outcome.