Combination therapy with penicillin or ceftriaxone and an aminoglycoside for 2 weeks is highly effective in viridans group streptococci (VGS) IE90 in very select patients with uncomplicated infection. Both -lactam therapy alone and combination therapy with nafcil- lin and an aminoglycoside for only 2 weeks have been effec- tive in patients with uncomplicated right-sided IE caused by S ; monotherapy with a -lactam would be selected for use in cases of uncomplicated IE.92 Of interest, right-sided vegetations tend to have lower bacterial densities, which may result from host defense mech- anisms, including polymorphonuclear activity or platelet- derived antibacterial cationic peptides.90,91,93 Drug Penetration The penetration of antibiotics is a significant issue in the treatment of IE because cardiac vegetations, which are com- posed of layers of fibrin and platelets, pose a considerable mechanical barrier between the antibiotic and the embedded The efficacy of antimicrobial drugs varies, depending on the degree of penetration into the vegetation, pattern of distribution within the vegetation, and Patterns of diffusion differ by class of anti- biotic, which may have implications for therapeutic outcomes in patients being treated for IE.98 100 PK/PD and Dosing Implications in IE In the design of dose regimens for the treatment of IE, it is important to fully optimize the PK/PD parameter for the selected antibiotic to increase the likelihood of success and to decrease the potential for developing resistance.101 Antibiotic PK/PD is related to both PK and microorganism susceptibility to the drug.102 With the use of in vitro and in vivo evaluations, antibiotics are categorized on the basis of whether they possess concentration-dependent or time- dependent effects on microorganisms and on the basis of 4 common PK/PD parameters that predict antibiotic efficacy: the ratio of the maximum serum concentration to the MIC, the ratio of the area under the 24-hour plasma concentra- tion-time curve to the MIC (AUC24 /MIC), the duration of time that the serum concentration exceeds the MIC, and the duration of the postantibiotic effect.101,103 More detailed discussion of the calculation of these parameters has been Whereas both the ratio of maximum serum concentra- tion to MIC and the AUC24 /MIC ratio have been shown to predict efficacy as the optimized PD parameters for ami- noglycoside, fluoroquinolone, and daptomycin therapy, the /MIC is the optimized PD activity for glycopeptides such as vancomycin, teicoplanin, telavancin, oritavancin, and lipopeptides such as daptomycin. 