Antibiotic pharmacokinetic/pharmacodynamic modeling: MIC, Pharmacodynamic indices, and beyond.

Abstract

The dramatic increase in antimicrobial resistance and the limited pharmacological treatment options highlight the urgent need to optimize therapeutic regimens of new and available anti-infectives. Several in vitro and in vivo infection models are employed to understand the relationship between drug exposure profiles in plasma or at the site of infection (pharmacokinetics) and the time-course of therapeutic response (pharmacodynamics), to select and optimize dosage regimens for new and approved drugs. Well-designed preclinical studies, combined with mathematical model-based pharmacokinetic/pharmacodynamic analysis and in silico simulations, are critical for the effective translation of preclinical data and design of appropriate and successful clinical trials. Integration with population pharmacokinetic modeling and simulations allows for the incorporation of interindividual variability that occurs in both pharmacokinetics and pharmacodynamics, and helps predict the probability of target attainment and treatment outcome in patients. We review the role of pharmacokinetic/pharmacodynamic approaches in the optimization of dosage regimens to maximize antibacterial efficacy while minimizing toxicity and resistance emergence, and to achieve a high likelihood of therapeutic success. An approved narrow therapeutic window drug, polymyxin B, serves as an illustrative example to highlight the importance of pharmacokinetic/pharmacodynamic modeling in conjunction with experimentation, employing static time-kill studies followed by dynamic in vitro or in vivo models or both, to learn and confirm mechanistic insights necessary for translation to the bedside.