An inoculum effect has been demonstrated with penicillin versus streptococci in both in vitro and animal models. For example, the curative dose of penicillin for streptococcal infections in animal models has been shown to increase markedly with the number of organisms inoculated and the duration of the infection, presumably because of the interim increase in the number of organisms in the infected In addition, the stationary growth-phase conditions make it less likely that bacterial cell wall active antibiotics ( -lactams and glycopeptides) are optimally effective.77 79 Stationary-phase organisms have been associated with a loss of penicillin-binding proteins that are the active tar- get sites required for -lactam antibacterial activity. 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. 