Pharmacologic considerations in antimicrobial therapy, with emphasis on pharmacokinetics and pharmacodynamics: reviews for the practicing clinician

For all types of infection—bacterial, mycobacterial, fungal, parasitic, and viral—it has become increasingly clear that integration of the principles of antimicrobial pharmacology and the pharmacokinetic parameters of an individual patient is necessary to provide a rational assessment of the interactions between pathogen, host, and antibiotic. This series of four review articles by authorities in the field is designed to address the many factors a clinician must consider when selecting an antimicrobial agent and appropriate dosing regimen for the treatment of various infections. The objective of these reviews is to present selected concepts that should be considered when using agents to treat bacterial [1], mycobacterial [2], fungal [3], and parasitic [4] infections. The authors highlight the importance of pharmacokinetic and pharmacodynamic principles that may assist in optimizing efficacy while minimizing the risk of drug-related toxicity. Pharmacokinetics describes the fundamental processes of absorption, distribution, metabolism, and elimination and the resulting concentration-versus-time profile of an agent administered in vivo. Pharmacodynamics is the study of the relationships between drug concentration and effect and describes what effects the drug imparts on human cells (toxicity) and the microorganism (killing activity). Several factors are important regarding pharmacokinetic and pharmacodynamic relationships. First, the same dose does not always produce the same plasma concentration of drug. For some agents (e.g. aminoglycosides, protease inhibitors), the considerable intersubject variation in pharmacokinetics supports the measurement of plasma concentrations to guide dose adjustments. Similarly, a given concentration will provide different killing activity dependent on the susceptibility of the offending microorganism. For each class of agent, appreciation of the different approaches to maximize microbial killing will allow for optimal clinical efficacy and reduction in risk of development of resistance while avoiding excessive exposure and minimizing risk of toxicity. Appropriate use of antimicrobial agents requires an understanding of the characteristics of the drug, the host factors, and the pathogen, all of which impact selection of the antibiotic agent and dose. Other important considerations beyond efficacy and safety include pharmacologic properties such as tissue penetration, protein binding, metabolism, and elimination characteristics, which will affect the resulting pharmacokinetic profile. In the treatment of infectious diseases described in this compilation of reviews, there are frequently more similarities than differences. Microbial inoculum is an important consideration in the treatment of bacterial, viral, and parasitic infections. Testing for susceptibility and the development of resistance is essential to guide therapies for all classes of agents. Lastly, combination therapies are often necessary to improve killing activity and to optimize clinical cure rates. With the emergence of resistant microorganisms, the appearance of a multitude of new antimicrobial agents, and the economic pressures on healthcare systems, these four reviews are especially pertinent. We hope the readers of the European Journal of Clinical Microbiology & Infectious Diseases find these reviews useful in their practice.