THE IMPORTANCE OF PHARMACOKINETIC-PHARMACODYNAMIC SURROGATE MARKERS TO OUTCOME - FOCUS ON ANTIBACTERIAL AGENTS

Pharmacokinetic/pharmacodynamic surrogate relationships have been used to describe the antibacterial activity of various classes of antimicr obial agents. Studies that have evaluated these relationships were rev iewed to determine which of these surrogate markers were further depen dent on antimicrobial class. The fluoroquinolone and aminoglycoside ag ents exhibit concentration-dependent killing. Studies have demonstrate d that peak serum concentration: minimum inhibitory concentration (MIC ) and area under the serum concentration-time curve (AUG):MIC ratios a re important predictors of outcome for these antimicrobial agents. Are a under the inhibitory concentration-time curve (AUIC(24)) [i.e. AUC(2 4)/MIC] is a useful parameter for describing efficacy for these agents , while an adequate peak concentration:MIC ratio seems necessary to pr event selection of resistant organisms. For beta-lactam antibiotics, t he duration of time that the serum concentration exceeds the MIC (T > MIG) was the significant pharmacokinetic/pharmacodynamic surrogate in cases where the bacterial inoculum was low, or where very sensitive or ganisms were tested. However, in studies using more resistant organism s or larger inoculum sizes there is some concentration-dependence to t he observed effect. Studies using reasonable dosage intervals have dem onstrated covariance between T > MIC and AUC/MIC ratio for beta-lactam antibiotics. Since glycopeptide antibiotics display relatively slow b ut concentration-independent killing, and are cell wall active agents similar to beta-lactams, it has been presumed that T > MTC is the impo rtant pharmacokinetic surrogate related to efficacy for these agents. Some studies have shown that a concentration multiple of the MIC may b e necessary for successful outcome with vancomycin. AUIC(24) may prove to be an important pharmacokinetic surrogate if both time and concent ration are indeed important parameters. To select an appropriate antim icrobial agent, the clinician must consider many patient-specific as w ell as organism-specific factors. Utilisation of known pharmacokinetic /pharmacodynamic surrogate relationships should help to optimise treat ment outcome.