This loss of penicillin-binding proteins during stationary-phase growth may be responsible in part for the inoculum effect observed in vivo and may account for the failure of penicil- lin in both experimental and human cases of severe strep- Importantly, fluoroquinolones and aminoglycoside antibiotics are less affected by the size of the inoculum because of their different mechanisms of bac- An inoculum effect also occurs with -lactamase susceptible -lactam antibiotics versus -lactamase producing bacteria, presumably because more -lactamase is present in denser -lactamase producing bacterial populations, as observed in vitro with some enterococci,83 and Gram- ; in animal models of experimental IE86,87 ; High inocula are also more likely to have antibiotic-resis- tant subpopulations that can emerge in the setting of antibiotic therapy. For example, in an in vitro PD model, the activity of vancomycin against heterogeneous vancomycin-intermediate S aureus (hVISA) and non-hVISA isolates was reduced in the presence of a high inoculum amount (108 colony-forming units per milliliter).75 Bactericidal Drugs Data from animal models of IE and clinical investigations support the need for bactericidal antibiotics to sterilize veg- etations in IE with high bacterial densities.89 For enterococci, bactericidal activity can be achieved by the combination of certain -lactam antibiotics (eg, penicillin, ampicillin, and piperacillin) with an aminoglycoside. The bactericidal effect achieved by a combination of antibacterial drugs that alone only inhibit bacterial growth is called synergy. The rate of bactericidal activity against some other organisms can also be enhanced by a combination of a -lactam antibiotic plus an aminoglycoside. Duration of Antimicrobial Therapy The duration of therapy in IE must be sufficient to ensure complete eradication of microorganisms within vegetations. Prolonged therapy is necessary because of the high bacterial densities within vegetations and the relatively slow bacteri- cidal activity of some antibiotics such as -lactams and van- comycin. 