Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: The isothiazoloquinolone ACH-702 displays rapid bactericidal activity against MQRSA in vitro and a low propensity to select resistant mutants. However, the relationship between ACH-702 PK/PD and the emergence of resistance in MQRSA is not known. Methods: Log-phase cultures (8 log CFU/ml) of two ACH-702-susceptible (MIC 0.125 µg/ml) MQRSA strains, 8043 C96-7 (S80F grlA, S84L gyrA) and 8282 L96-22 (S80F/P144S grlA, E422D grlB, S84L gyrA), were exposed for 96 h in a hollow fiber IVM to an ACH-702 PK profile designed to achieve a target free-drug (f) AUC/MIC of 30, based on the proposed PK/PD breakpoint for quinolone efficacy against S. aureus. The ACH-702 t1/2 simulated was 6 h based on allometric scaling estimates of human clearance derived from animal studies, and the drug was given every 12 h. The development of resistance was evaluated by population analysis profiling, and the resistance phenotypes/genotypes of resistant subpopulations that emerged were characterized. Results: When exposed to ACH-702 fAUC/MICs of 31.6 and 31.2 and Cmax/MIC of 2.0 and 1.9, viable counts of 8043 C96-7 and 8282 L96-22 declined initially to 3 and 5 log CFU/ml at 72 and 36 h, respectively, and then increased. Subpopulations of both strains that were resistant to ACH-702 concentrations of ≥ 0.25 µg/ml were selectively enriched and the ACH-702 MICs for both strains increased 4-fold by 96 h. The MICs of post exposure isolates were lowered 4-fold by reserpine. Resistant bacteria recovered following the 96-h exposure had no additional mutations in the quinolone resistance-determining regions of grlA/B or gyrA, and no new mutations in gyrB. Conclusion: ACH-702 fAUC/MIC ratios of ~30 and Cmax/MIC of ~2 are not sufficient to prevent the selection of low-level resistant variants present in susceptible MQRSA populations.