Two major objectives must be achieved to treat IE effectively. The infecting  micro-organism in the vegetation must be eradicated. Also, invasive, destructive intracardiac and focal extracardiac complications of infection must be resolved if morbidity and mortality are to be minimized. The second objective often exceeds the capacity of effective antimicrobial therapy and requires cardiac or other surgical intervention. Bacteria in vegetations multiply to population densities approaching 109 to 1010 organisms per gram of tissue, become metabolically dormant, and are difficult to eradicate. Optimal therapy should use bactericidal antibiotics or antibiotic combinations rather than bacteriostatic agents.

Additionally, antibiotics reach the central area of avascular vegetations by passive diffusion. To reach effective antibiotic concentrations in vegetations, high serum concentration must be achieved, and penetration by some agents is limited even then. Parenteral antimicrobial therapy is used whenever feasible in order to achieve suitable serum antibiotic concentrations and to avoid the potentially erratic absorption or orally administered therapy.  Treatment is continued for prolonged period to ensure eradication of dormant microorganisms.

In selecting antimicrobial therapy for patients with IE, one must consider the ability of potential agents to kill the causative organism as well as the MIC (minimum inhibitory concentration) and minimum bactericidal concentration (MBC) of these antibiotics for the organism. The MIC is the lowest concentration that inhibits growth, and MBC is the lowest concentration that decreases a standard inoculum of organisms 99.9 per cent during 24 hours. For the vast majority of streptococci and staphylococci, the MIC and MBC of penicillins, cephalosporins, or vancomycin are the same or differ by only a factor of two to four. Organisms for which the MBC for these antibiotics is 10 fold or greater than the MIC are occasionally encountered. This phenomenon has been termed tolerance. Most of the tolerant strains are simply killed more slowly than non tolerant strains and with prolonged incubation (48 hours) their MICs and MBCs are similar.

Enterococci can be killed by the combined activity of selected penicillins or vancomycin and an aminoglycoside. This enhanced antibiotic activity of the combination against enterococci, if of sufficient magnitude, is called synergy or a synergistic bactericidal effect.A synergistic bactericidal effect is required for optimal therapy of enterococcal endocarditis and has been used to achieve more effective therapy or effective short-course therapy of IE caused by other organisms.