Pharmacodynamics of Razupenem (PZ601) Studied in anIn VitroPharmacokinetic Model of Infection

Abstract

ABSTRACTSimulations of administration of razupenem at 1 g every 12 h by 1-h intravenous (i.v.) infusion were performed in anin vitropharmacokinetic model of infection. The antibacterial effect of this razupenem dosing regimen against six strains ofStaphylococcus aureus(one methicillin-sensitiveS. aureus[MSSA] strain [MIC, 0.015 μg/ml] and five methicillin-resistantS. aureus[MRSA] strains [MIC range, 0.09 to 3 μg/ml]) and five strains ofEnterobacteriaceae(threeEscherichia colistrains [two containing extended-spectrum β-lactamases {ESBLs}] and twoEnterobactersp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 μg/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 2× MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 μg/ml) and at 120 h with strain 27706 (MIC, 1.5 μg/ml). AgainstE. coliandEnterobacterspp., razupenem produced a >3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 μg/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except forEnterobacterstrain 34425 (MIC, 6.0 μg/ml), where colonies were recovered from media containing 2×, 4×, and 8× 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 2× MIC recovery medium atfT>MIC values of 1 to 35% but not at a value of >35%. In a similar set of experiments withEnterobacteriaceae, thefT>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 2×, 4×, and 8× MIC atfT>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 μg/ml andEnterobacteriaceaewith MICs of ≤0.4 μg/ml.fT>MIC targets of ≥35% for MRSA and ≥70% forEnterobacteriaceaeshould provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles.