Animal models in the evaluation of antimicrobial agents.

The testing of potential antimicrobial agents in animal models of infectious disease is a long-established practice and is acknowledged as an essential prerequisite of antiinfective therapy, but the ultimate utility of such experiments in the development of antimicrobial agents is still debated. Although there are guidelines specifying appropriate models and relevant parameters for evaluating the safety of antibiotics, no clear guidelines exist for the evaluation of their efficacies in animals. This deficit appears to reflect the recognized difficulties in the design and interpretation of such experiments. Animal models of infectious disease bridge the gap between the in vitro characterization and the clinical evaluation of antimicrobial agents. In contrast to in vitro testing, which determines the inherent susceptibilities of microorganisms to chemical agents (7), in vivo testing places antimicrobial agents into a realm where their in vitro activities are altered by a variety of host factors, most critically by metabolic processes and anti-infective defense mechanisms. The majority of agents active in vitro are devoid of significant activity in vivo, and while some may also exert demonstrable effects in vivo, the correlation is generally considered poor (49). Although the final judgment of the efficacies of antimicrobial agents must depend on the results of controlled clinical trials, the findings made in experimental models can permit reasonably accurate predictions of clinical efficacy, provided that the limitations of these models are clearly realized. This review outlines the role that animal experimentation can play in the evaluation of antimicrobial (largely antibacterial) therapy, with emphasis on the assessment of efficacy, and indicates the restrictions, which, if ignored, will compromise the conclusions that are reached. Experimental details already dealt with in previous, more extensive reviews (1, 3, 7, 20, 21, 28, 31-33, 39, 45-52) are omitted.