Methods: MICs for MER alone and with RPX7009 at various concentrations (CONs) were examined against 315 KPC producing strains of ENT (KPC-ENT). Resistance development (RD) studies with 10 KPC-ENT were performed at multiple CONs of both MER and RPX7009. Efficacy in a mouse thigh infection model against 12 KPC-ENT were determined at different exposures (EXPs) of MER and RPX7009. Prevention of RD was examined with 10 strains in an in vitro hollow fiber pharmacodynamics (HF-PD) model using various EXPs of both MER and RPX7009 simulated based on human PK determined in Phase 1 studies.
Results: 96% of KPC-ENT were inhibited by MER 2 mg/L with RPX7009 at 8 mg/L. Previously described porin-based resistance to MER was prevented by RPX7009 at 8 mg/L combined with 8 mg/L of MER. Both mouse and in vitro HF-PD models showed maximal bacterial killing and prevention of RD against strains with MER MIC’s up to 8 mg/L with MER/RPX7009 EXPs with doses of 2g q8h by 3 hr infusion.
Conclusion: Based on the non-clinical studies of RD and PK-PD studies along with Phase 1 studies in healthy volunteers, a dose of 2g MER plus 2g of RPX7009 by 3 hr infusion every 8 hours was selected for pivotal studies with CVC. MER MICs determined with 8 mg/L of RPX7009 were the best predictor of efficacy in the in vitro HF-PD model.
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