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Biotech / Medical : Microcide Pharmaceuticals (MCDE)
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To: scaram(o)uche who wrote (163)8/29/1999 1:52:00 PM
From: scaram(o)uche   of 186
 
Session: Inhibitors of Bacterial and Fungal Efflux Pumps
Location:
Exhibit Hall
Session Date:
Monday, 9/27/99
Session Time:
3:00 pm - 4:30 pm

Pharmacodynamic Assessment of Efflux- and Target-Based Resistance to Fluconazole (FLU) on
Efficacy against C. albicans in a Mouse Kidney Infection Model

K. Sorensen, E. Corcoran, S. Chen, D. Clark, V. Tembe, O. Lomovskaya, M. Dudley
Microcide Pharmaceuticals, Inc.: Mountain View, CA

Mechanisms for reduced in vitro susceptibility of C. albicans to azoles include target- or efflux-based
mechanisms. It is not known whether these mechanisms working alone or in combination result in similar levels of
resistance to FLU in vivo. Strains of C. albicans with a >2,000-fold range in susceptibility to FLU due to drug
efflux or target over-expression/modification were tested in neutropenic CFW mice. An inoculum of ca. 104 CFU
was administered IV followed 2h later by a single dose of FLU. Kidneys were harvested at 24h and CFU/kidney
determined. Results (see table) showed that reduction in CFU with comparable FLU dose:MIC
Efflux Pump/Target Status of Test
Strain
FLU MICs
mg/ml)
Difference in Log CFU/kidney vs. No Rx
According to Indicated Dose:MIC Ratio:
<1 to 5
6 to 25
>25
D CDR1/D CDR2/D BEN/D FLU1
0.06
no data
-0.99
-1.75
D CDR1/D CDR2
0.125
-0.49
-1.90
-2.02
Wild-type
0.25-1
0.08 to -1.93
-0.98 to -2.18
-1.99 to -2.69
BEN over-expression
8
-0.46 to -0.48
-1.43
no data
BEN over-expression/target modification
64
0.06 to -0.40
no data
no data
CDR1/CDR2 over-expression
128
0.01 to -0.12
no data
no data

(or AUC:MIC) ratios did not vary according to resistance mechanism. These data show that reduced in vitro
susceptibility due to efflux- and/or target-based mechanisms is associated with diminished FLU efficacy in vivo;
however, similar levels of efficacy in vivo can be restored by a proportional increase in FLU dose to attain target
dose (or AUC):MIC ratios. These data have implications for combination therapy with agents that potentiate
azole activity against drug-resistant strains.
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