PHARMACODYNAMIC EVALUATION OF A NEW GLYCOPEPTIDE, LY333328, AND IN-VITRO ACTIVITY AGAINST STAPHYLOCOCCUS-AUREUS AND ENTEROCOCCUS-FAECIUM

The objectives of the present study were to compare the in vitro activ ity of LY333328 (LY) to that of vancomycin (V) alone and in combinatio n with gentamicin (G) and rifampin (R) against methicillin-resistant S taphylococcus aureus (MRSA) and V-resistant Enterococcus faecium (VREF ), by using the killing curve methods. In addition, the effect of the inoculum size and protein on LY's activity was evaluated by using MICs and killing curves, MICs, MBCs, and killing curves were determined wi th supplemented Mueller-Hinton broth (B), B with albumin (4 g/dl) (A), and B with 50% pooled human serum (S). For MRSA, time to 99.9% killin g after exposure to LY at four times the MIC (4x MIC) was achieved at 0.5 +/- 0 h (mean +/- standard deviation) and was significantly faster than that by V (8.54 +/- 0.10 h; P = 0.001). Against VREF, LY decreas ed the inoculum by 2.2 log(10) CFU/ml at 24 h (P = 0.002). With a larg e inoculum of MRSA, the activity of LY and V at 4x MIC was decreased c ompared to that with the standard inoculum (P = 0.0003) and regrowth o ccurred at 24 h. The reduction in the number of CFU per milliliter at 24 h to 2 log(10) CFU/ml was restored by increasing the LY concentrati on to at least 16x MIC. At 24 h, the combinations of LY and G, LY and R, LY and V, and V and G were better than either LY or V alone against a large inoculum of MRSA (P = 0.0002). LY and G achieved 99.9% killin g at 1.01 +/- 0.03 h and was more rapid (P < 0.007) than all the other regimens studied except for V and G, which achieved 99.9% killing at 3.59 +/- 0.01 h. Killing curves determined with different media agains t a standard inoculum of MRSA did not demonstrate a significant differ ence between LY and V at 24 h. Time to 99.9% killing was more rapid wi th LY than with V in B, A, and S (P = 0.0002). Times to 99.9% killing by LY in B, A, and S were not significantly different from each other, Against VREF, LY killed better than V in B, A, or S at 24 h (P = 0.00 02). LY in B was more active than LY in A or S (P = 0.0002). LY is a n ew potent glycopeptide with a unique activity profile. It has a greate r activity than that of V against MRSA and has activity against VREF, LY demonstrated synergism in combination with gentamicin against MRSA. LY was affected by large inoculum sizes and proteins in time-kill stu dies. However, the effect was compensated for by increasing the drug c oncentration to 16x MIC.