Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'

Key Points Antimicrobial pharmacodynamics attempts to link measures of drug exposure to the observed effect. This differs from other areas of pharmacodynamics because the main indicator of effect and the site of action of the drug is the organism that causes the pathological process. Understanding antimicrobial pharmacodynamics requires the acceptance of four important ideas. First, the drug exposure achieved with a fixed drug dose varies greatly in the infected population of interest. Second, the shape of the concentration–time curve can sometimes affect the outcome. Third, only non-protein-bound drug is microbiologically active. Finally, as the measure of potency increases, the effect any fixed drug dose will cause decreases. All these ideas can be integrated by use of the Monte Carlo simulation to determine the potential use of a drug and dose for the intended population and to estimate susceptibility breakpoints. These techniques can also be used to help suppress the amplification of resistant subpopulations by identifying the drug exposure that will cause this effect and then evaluating the use of different doses for attaining the exposure target in the population of interest. These ideas can be transferred to the clinical arena. The use of optimal sampling techniques allows informative times for blood sample acquisition to be identified. Population modelling followed by Bayesian estimation allows robust estimation of the exposure achieved in a specific patient. Exposure measures relative to the MIC of the pathogen (peak/MIC ratio, AUC/MIC ratio and time > MIC) can then be linked to the desired clinical or microbiological outcome through common statistical techniques, such as logistic regression analysis, classification and regression tree (CART) analysis and Cox proportional hazards modelling. Antimicrobial pharmacodynamics is the discipline that integrates microbiology and pharmacology, with the aim of linking a measure of drug exposure, relative to a measure of drug potency for the pathogen in question, to the microbiological or clinical effect achieved. The delineation of such relationships allows the drug dose to be chosen in a rational manner, so that the desired effect (for example, the maximal bactericidal effect) can be achieved in a large proportion of the intended patient population. Ultimately, the goal of any anti-infective therapy is to administer a dose of drug that has an acceptably high probability of achieving the desired therapeutic