Session: Pharmacodynamic Studies of Drug-resistant Bacteria (with
minilecture)
Location:
132/133
Session Date:
Wednesday, 9/29/99
Session Time:
8:30 am - 11:00 am
Presentation Time:
9:30 am - 9:45 am
Pharmacokinetic-Pharmacodynamic (PK-PD) Indices for Vancomycin (V)
Treatment of Susceptible (VSSA) and Intermediate (VISA) S. aureus in the
Neutropenic Mouse Thigh Model
M. Dudley, D. Griffith, E. Corcoran, C. Liu, K. Sorensen, V. Tembe, D. Cotter, S.
Chamberland, S. Chen
Microcide Pharmaceuticals, Inc.: Mountain View, CA
Recent infections with VISA in the clinic have raised questions concerning the adequacy
of current V regimens to treat these strains. We compared the PK-PD indices associated
with bacterial killing of strains of VISA and VSSA over 24h in the neutropenic mouse
thigh model. V doses of 7.5-1,200mg/d were given in 2-12 divided doses (i.e., 14
regimens/strain) over 24h. PK-PD indices for free drug AUC:MIC; % of 24h free serum
V concentrations exceed MIC (%T>MIC) and Cmax:MIC were determined for each
strain and modeled to change in log CFU/thigh at 24h using the modified Hill equation. All
strains grew well in mice, with subpopulations of VISA maintained in untreated mice over
24h. Reduction in log CFU/thigh was best described using either V AUC:MIC or
Cmax:MIC as independent variables (see Table). The maximum extent of killing (Emax) by
V of
PK:PD Indices
VSSA (n=3)
(MIC=0.5-1mg/L)
VISA (n=2)
(MIC=8)
For AUC:MIC Modeling:
Emax , D Log CFU/thigh vs. no Rx
0.72 to 3.3
1.0, 2.4
AUC:MIC @50% Emax
86 to 460
23, 32
For Cmax:MIC Modeling:
Emax , D Log CFU/thigh vs. no Rx
0.59 to 4.0
2.5, 3.1
Cmax:MIC @50% Emax
15 to 91
4.4, 9.5
VISA strains occurred at lower values of AUC:MIC and Cmax:MIC than that for VSSA.
These data show that although V MICs are elevated in VISA strains, comparable levels
of bacterial killing of VISA by V in this model are obtained at a lower PK-PD intensity
than with VSSA. These findings may have implications for the management of infections
due to VISA. |
