Baddour et al Infective Endocarditis in Adults 1443 Antimicrobial Therapy Therapeutic Principles The primary goal of antibiotic treatment is to eradicate infection, including sterilizing vegetations, although the unique character- istics of infected vegetations can pose a variety of challenges. These characteristics include focal infection with high bacterial density, slow rate of bacterial growth within biofilms, and low microorganism metabolic activity.72 Host characteristics such as impaired immunity also contribute to challenges in thera- peutics. In addition, antibiotics may fail to eradicate infection as a result of increased binding of the drug to serum proteins, perturbations of antibiotic penetration into the vegetation, and unique antibiotic pharmacokinetic/pharmacodynamic (PK/PD) features. Therefore, prolonged, parenteral, bactericidal therapy is required for attempted infection cure. Inoculum Effect The effect of high bacterial densities on antimicrobial activ- ity is called the inoculum effect in which certain groups of antimicrobials commonly used to treat IE such as -lactams and glycopeptides (and, to a lesser extent, lipopeptides such as daptomycin) are less active against highly dense Therefore, the effective mini- mum inhibitory concentration (MIC) at the site of infection with bacterial densities of 108 colony-forming units per 1 g tissue can be much higher than anticipated by in vitro susceptibility tests that use a standard inoculum (105.5 colony-forming units per milliliter). In addition, bacteria that are otherwise killed at low densities by bactericidal antibiotics such as penicillins can be relatively resistant to or tolerant of their bactericidal effect in dense populations. An inoculum effect has been demonstrated with penicillin versus streptococci in both in vitro and animal models. 