Pharmacodynamics of SMP-601 (PTZ601) against Vancomycin-ResistantEnterococcus faeciumand Methicillin-ResistantStaphylococcus aureusin Neutropenic Murine Thigh Infection Models

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.