Pharmacodynamics of SMP-601 (PTZ601) against Vancomycin-Resistant Enterococcus faecium and Methicillin-Resistant Staphylococcus aureus in Neutropenic Murine Thigh Infection Models

Abstract

ABSTRACT SMP-601 (also known as PTZ601, PZ-601, or SM-216601) is a novel parenteral carbapenem with potent activity against multidrug-resistant gram-positive pathogens, including vancomycin-resistant Enterococcus faecium (VREF) and methicillin-resistant Staphylococcus aureus (MRSA). The pharmacodynamics of SMP-601 against VREF and MRSA were investigated in neutropenic murine thigh infection models. The percentage of the dosing interval that the unbound SMP-601 concentration exceeded the MIC ( f % T >MIC) was the pharmacokinetic-pharmacodynamic parameter that correlated most closely with efficacy with R 2 values of 0.81 to 0.84 for two strains of VREF and 0.92 to 0.93 for two strains of MRSA, whereas the R 2 values for the area under the concentration-time curve from 0 to 24 h divided by the MIC were 0.12 to 0.89, and the R 2 values for the peak level divided by the MIC were 0 to 0.22. The f % T >MIC levels required for static or killing efficacy against two strains of VREF (9 to 19%) apparently were lower than those against two strains of MRSA (23 to 37%). These results suggested that SMP-601 showed time-dependent in vivo efficacy against VREF and MRSA, and SMP-601 had a sufficient therapeutic effect against VREF infections at lower exposure conditions compared to those for with MRSA infections.