Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Kill Curves versus MIC

Abstract

The success of antimicrobial therapy is determined by complex interactions between an administered drug, a host, and an infecting agent. In a clinical situation, the complexity of these interactions is usually reflected by a high variability in the dose-response relationship. Therefore, to minimize the dose-response variability, key characteristics of the drug, the infecting agent and the host have to be taken into account for selecting an appropriate antibiotic and an appropriate dose. Failure to do so may result in either therapeutic failure or emergence of resistant strains. To date, dose and drug selection is mostly based on a static in vitro parameter, the MIC and on the drug′s serum concentration as a pharmacokinetic parameter. In practice, however, a pharmacodynamic effect in vivo is rather the result of a dynamic exposure of the infective agent to the unbound antibiotic drug fraction at the relevant effect site. Thus, static conditions in an in vitro setting hardly reflect a dynamic situation in a target organ under in vivo conditions. Furthermore, serum concentrations do not reflect the unbound concentrations at the target site. In recent years substantial efforts were devoted to systematically elucidate the dynamic relationship between pharmacokinetic and pharmacodynamic variables. The main concept of this pharmacokinetic-pharmacodynamic approach is to use the concentration-effect relationship of the drug of interest in dosage adjustment and product development in a logical way and minimize trial-and-error approaches (29, 80). This approach can potentially result in substantial savings of time and expenses and may help to avoid unnecessary and, hence, unethical clinical studies (97). Thus, dosages and dosing intervals of antimicrobial agents should be designed with reference to dynamic pharmacokinetic and pharmacodynamic parameters. Accordingly, several efficacy indices or surrogate markers that take into account both pharmacokinetic and pharmacodynamic information have been defined and used by different authors to describe the antibacterial activity of various classes of antimicrobial agents (100, 106, 59). Currently there are two main trends for antibiotic pharmacokinetic-pharmacodynamic models; those based on the MIC and those based on a kill-curve approach, both of which will be described in detail in the following.