Pharmacodynamics of Razupenem (PZ601) Studied in an In Vitro Pharmacokinetic Model of Infection

Simulations of administration of razupenem at 1 g every 12 h by 1-h intravenous (i.v.) infusion were performed in an in vitro pharmacokinetic model of infection. The antibacterial effect of this razupenem dosing regimen against six strains of Staphylococcus aureus (one methicillin-sensitive S. aureus [MSSA] strain [MIC, 0.015 mu g/ml] and five methicillin-resistant S. aureus [MRSA] strains [MIC range, 0.09 to 3 mu g/ml]) and five strains of Enterobacteriaceae (three Escherichia coli strains [two containing extended-spectrum beta-lactamases {ESBLs}] and two Enterobacter sp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 mu g/ml]) was assessed. Against the MSSA and MRSA strains, razupenem produced a > 3.5-log-unit reduction in viable count after 24 h. There were no changes in population profiles. In a second series of experiments, over 5 days there was rapid initial clearance of MRSA from the model followed by regrowth after 48 h. MRSA colonies appeared on 2x MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 mu g/ml) and at 120 h with strain 27706 (MIC, 1.5 mu g/ml). Against E. coli and Enterobacter spp., razupenem produced a > 3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 mu g/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except for Enterobacter strain 34425 (MIC, 6.0 mu g/ml), where colonies were recovered from media containing 2x, 4x, and 8x MIC. In dose-ranging studies with MRSA strains, the percentage of the dosing interval that the free drug concentration remained higher than the pathogen MIC (fT > MIC) for a 24-h bacteriostatic effect was 5.0% +/- 1.4%, and that for a 1-log-unit reduction in count was 12.5% +/- 5.8%. Population profiles indicated growth on 2x MIC recovery medium at fT > MIC values of 1 to 35% but not at a value of > 35%. In a similar set of experiments with Enterobacteriaceae, the fT > MIC for a 24-h bacteriostatic effect was 34.2% +/- 7.6% and that for a 1-log-unit reduction in count was 42.5% +/- 7.8%. Population analysis profiles indicated growth on recovery media with 2x, 4x, and 8x MIC at fT > MICs in the range of 1 to 69% but rarely at values of >= 70%. In conclusion, razupenem at simulated human doses of 1 g i.v. every 12 h has a marked antibacterial effect on MSSA and MRSA strains with MICs of <= 3.0 mu g/ml and Enterobacteriaceae with MICs of <= 0.4 mu g/ml. fT > MIC targets of >= 35% for MRSA and >= 70% for Enterobacteriaceae should provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles.