Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward

Abstract

Within a few years after the first successful clinical use of penicillin, investigations were conducted in animal infection models to explore a range of factors that were considered likely to influence the antibacterial response to the drug. Those studies identified that the response was influenced by not only the total daily dose but also the interval between individual doses across the day, and whether penicillin was administered in an intermittent or continuous manner. Later, as more antibiotics were discovered and developed, antimicrobial pharmacologists began to measure antibiotic concentrations in biological fluids. This enabled the linking of antibacterial response at a single time point in an animal or in vitro infection model with one of three summary pharmacokinetic (PK) measures of in vivo exposure to the antibiotic. The summary PK exposure measures were normalised to the minimum inhibitory concentration (MIC), an in vitro measure of the pharmacodynamic (PD) potency of the drug. The three PK-PD indices (ratio of maximum concentration to MIC, ratio of area under the concentration-time curve to MIC, time concentration is above MIC) have been used extensively since the 1980s. While these MIC-based summary PK-PD metrics have undoubtedly facilitated the development of new antibiotics and the clinical application of both new and old antibiotics, it is increasingly recognised that they have a number of substantial limitations. In this article we use a historical perspective to review the origins of the three traditional PK-PD indices before exploring in detail their limitations and the implications arising from those limitations. Finally, in the interests of improving antibiotic development and dosing in patients, we consider a model-based approach of linking the full time-course of antibiotic concentrations with that of the antibacterial response. Such an approach enables incorporation of other factors that can influence treatment outcome in patients and has the potential to drive model-informed precision dosing of antibiotics into the future.