There are many reasons for employing animal models of infection. These include the ability to establish a range of infections caused by a variety of pathogens at different host sites, to understand how in vitro antibiotic sensitivity or resistance correlates to therapy failure in vivo, to control the virulence of the infecting organism as well as the timing and route of infection, and to study drug pharmacokinetics (Bergeron, 1978;Andes and Craig, 2002;Dagan, 2003;Jacobs, 2003). The challenge to the scientist is to utilize or develop an animal infection model that closely approximates human disease and that can reliably predict clinical efficacy. The goal is to compare the effectiveness of a novel drug with an established agent by demonstrating either increased survival due to protection from a lethal pathogen, or reduction of bacterial numbers at a specific site in the host. There is a complex relationship between the drug, the host, and the pathogen that can only be addressed in the context of a whole animal. As such, it is imperative that the scientist understands, or is able to gain information on, the virulence of the pathogen, the pharmacokinetics of the new chemical entity (NCE) and its possible metabolites, any potential toxicity associated with the test agent, and host defenses, in order to make these studies ethically justifiable as well as scientifically robust.Some investigators have found it useful to divide infection models into four classes: basic, or primary screening models; ex vivo models; mono-parametric models; and discriminative models (Bergeron, 1978;Zak and O'Reilly, 1991). The basic screening models are most useful for obtaining a rough approximation of the efficacy of a potential new drug, while optimizing the route of administration and dosing regimen and identifying associated toxicity (Zak and O'Reilly, 1991). These are generally single-step, simple infections, with a short duration and easily interpretable results, usually lethality. The dose of test compound that protects 50% of infected animals is the protective dose, or PD 50 . This value is useful for directly comparing the efficacy of agents against a pathogenic organism.This unit describes three primary infection models routinely used to evaluate antibacterial efficacy. All three share the features of being simple to perform, utilize outbred mice, are compound-sparing, reproducible, and have easily interpretable outcomes (Zak and O'Reilly, 1991). In two of the models, the efficacy of potential antibacterial compounds can be evaluated either by monitoring survival or by enumerating bacterial numbers at the site of infection.Probably the most commonly used infection model is the murine acute systemic infection model, which is also called murine peritonitis or septicemia (see Basic Protocol 1; Zak and Sande, 1999). This model is most useful for demonstrating the relationship between the in vitro potency and the in vivo activity of a compound (Zak and Sande, 1999), and is important for the early demonstration of potential anti-bacte...