28 Current Pharmaceutical Biotechnology, 2010, 11, 28-47 1389-2010/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. Phage Therapy Pharmacology Stephen T. Abedon* and Cameron Thomas-Abedon Department of Microbiology, The Ohio State University, 1680 University Dr., Mansfield, OH 44906, USA Abstract: Phage therapy—application of bacteria-specific viruses to reduce densities of pathogenic or nuisance bacte- ria—is a two-step process involving phage penetration to target bacteria followed by bacteria killing. Any analysis of these steps is inherently ecological as they represent phage-environment interactions, i.e., between phages and bacteria as well as between phages and body tissues. In considering phages more generically, as selectively toxic antibacterial agents employed to treat bacterial infections, the term “ecology” may be fairly cleanly replaced with the term “pharmacology”. Pharmacology, in turn, may be distinguished into two major components: pharmacokinetics and pharmacodynamics. Pharmacokinetics is explicitly a description of the body’s impact on a drug (e.g., movement through and between body compartments) whereas pharmacodynamics is a description of a drug’s impact on the body. “Body” includes both body tissues and microbial flora, so an important component of antibacterial pharmacodynamics is inhibition of the growth of target bacteria. Our guiding premise is that phage therapy may be rationally improved through a better understanding of phage pharmacokinetics and pharmacodynamics. Our primary conclusions are (i) that the principle advantages of phages, over antibiotics, are the former’s relative safety and ease of discovery; (ii) that phage therapy efficacy is highly dependent on attaining relatively high phage “killing titers”; (iii) that attainment of sufficient titers solely via in situ phage replication should, in some or many circumstances, not be counted upon; and (iv) that phage replication nonetheless may provide a “margin of safety” toward attaining phage therapy efficacy. Keywords: Bacteriophages, ecology, pharmacodynamics, pharmacokinetics. INTRODUCTION Homeostasis is the body’s ability to maintain a general state of health without an imposition of external control. When health declines, however, external control can become necessary. In medical practice one common augmentation of homeostasis involves the application of bioactive chemot- herapeutics, also known as drugs. Drugs act both outside of and within homeostasis. That is, while providing an extra- homoeostatic modification of the body’s physiology, drugs and their effects are modified by the body, that is, by homeo- static mechanisms. Successful chemotherapy consequently requires a detailed understanding of these modification proc- esses. Pharmacology, generally, is the study of such drug- body interactions. Here we provide an overview of phage therapy pharma- cology that we explicitly target toward phage therapy re- search and development, focusing especially on the impact of phages on bacteria (particularly, the positive pharmacody- namic effects) and the impact of bacteria on phages (meta- bolic pharmacokinetic effects, especially phage replication). Though not emphasized as such, many of these considera- tions are relevant also to non-medical phage application as bacteria biocontrol agents [1]. Because clinical application requires case-by-case experimental verification, we stress the need for pharmacologically informed modeling and devel- opment of approaches—theoretically and in vitro as well as in vivo using appropriate animal models—prior to medical implementation. *Address correspondences to this author at the Department of Microbiology, The Ohio State University, 1680 University Dr., Mansfield, OH 44906, USA; Tel: +1-419-755-4343; E-mail: abedon.1@osu.edu Pharmacology Basics Pharmacology traditionally is distinguished into two fun- damental components: pharmacodynamics and pharmacoki- netics. Pharmacodynamics is the study of drug impact on the body. Impacts can be either positive (i.e., maintaining or restoring health) or negative (i.e., effecting toxic side ef- fects). Pharmacokinetics considers instead the body’s impact upon the drug. Generally pharmacokinetics can be distin- guished into four categories: drug absorption, drug distribu- tion, drug metabolism, and drug excretion. Both absorption and distribution concern drug movement throughout the body, initially to the blood (absorption) and then (or instead) beyond the blood (distribution). Absorption and distribution also can be viewed in terms of drug density increase within body locations, such as specific tissues or compartments. Drug metabolism and often excretion often refer, in contrast, to declines in drug density, though with two prominent ex- ceptions. These are when drugs are converted to their active form by metabolic processes or when drugs are delivered to their site of activity via excretion. In considering both phar- macodynamics and pharmacokinetics, “body” is defined to include both body tissues and associated microbial flora (mi- crobiome). Thus, drug action on the “body” can include drug action against, for example, bacterial pathogens. To be efficacious, a drug must be delivered to its site of action, be present there at sufficient densities for sufficient lengths of time, and, as it is maintained at these therapeutic levels, it must not simultaneously cause substantial harm to the patient. Since drugs typically will decline in density as a consequence of metabolism and excretion, the “trick” to suc- cessful chemotherapy is to deliver drugs sufficiently often