The population pharmacokinetic parameters of vancomycin obtained here can be used to individualize the dosage of vancomycin in institutions with similar patient population characteristics.

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Listeriolysin O (LLO), a cholesterol-binding cytolysin of Listeria monocytogenes, exhibits cytokine-inducing and cytolytic activities. Because the cytolytic activity was abolished by cholesterol treatment but the cytokineinducing activity was not, these activities appeared to be linked to different domains of the LLO molecule. In this study, we constructed recombinant full-length LLO (rLLO529) and various truncated derivatives and examined their cytolytic, cholesterol-binding, and gamma interferon (IFN-␥)-inducing activities. rLLO529 exhibited both IFN-␥-inducing and cytolytic activities. Four truncated rLLOs possessing different C termini, which did not exert either cytolytic or cholesterol-binding activity, stimulated IFN-␥ production in normal spleen cells. However, a truncated rLLO corresponding to domain 4 (rLLO416-529) did not exhibit IFN-␥-inducing activity, whereas it did bind to immobilized cholesterol. In addition, though the hemolysis induced by rLLO529 was inhibited by rLLO416-529, such inhibition was not detected upon rLLO529-induced IFN-␥ production. These data indicated that domain 4 was responsible for binding of LLO to membrane cholesterol followed by oligomerization and pore formation by the entire LLO molecule. In contrast, the other part of LLO, corresponding to domain 1-3, was essential for IFN-␥-inducing activity. These findings implied a novel aspect of the function of LLO as a bacterial modulin.Listeria monocytogenes is a gram-positive, facultative intracellular bacterium which is responsible for sporadic but severe infections in humans and other animal species (18, 28). The major virulence factor of this bacterium essential for intracellular survival inside professional phagocytes is listeriolysin O (LLO), a pore-forming cytolysin (15). Based on the loss of escape from the phagosomal compartment into the cytosolic space of macrophages in LLO-deficient mutants, LLO is believed to lyse the phagosomal membrane and enable L. monocytogenes to gain access to the cytosol, resulting in intracellular parasitism (6,17,25).LLO has been purified from culture supernatant of L. monocytogenes as a homogenous protein of approximately 60 kDa (10,14). The gene encoding LLO, hly, has been cloned and sequenced, and the amino acid sequence of LLO has been determined (8,19). LLO is a member of the family of thiolactivated cytolysins (TACYs), including streptolysin O (SLO), pneumolysin (PLY), and perfringolysin O (PFO) (1). An important feature of the TACYs is the presence of a highly conserved undecapeptide sequence (ECTGLAWEWWR) in the C-terminal region that is believed to be essential for the hemolytic activity. Conversion of the unique cysteine residue located within the undecapeptide of SLO (24), PLY (27), and LLO (20) to alanine by site-directed mutagenesis resulted in a minor loss of activity. In addition, pyolysin, a TACY from Arcanobacterium pyogenes, is reported to contain no cysteine residue in the undecapeptide (5). In contrast, a drastic decrease in hemolytic activity was observed after replacemen...

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