BRII-693 is a next-generation synthetic macrocyclic peptide antibiotic for infections caused by drug-resistant gram-negative pathogens. This study evaluated the pharmacodynamic activity of BRII-693 against common gram-negative pathogens using neutropenic mouse thigh (11 strains) and lung (15 strains) infection models. BRII-693 exhibited dose-dependent increases in pharmacokinetic exposure in both plasma and epithelial lining fluid (ELF). Due to its prolonged elimination half-life within ELF, the ELF area under the curve (AUC) was higher than plasma AUC on a mg/kg basis. In dose-ranging PK/PD studies, BRII-693 demonstrated dose-dependent antibacterial activity. In both the thigh and lung models, bacterial stasis was achieved at 24 h plasma AUC/MIC values of 1-19 for Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and 1-log kill required only modestly higher targets given the steep exposure-response relationships. Higher target exposures were noted for Pseudomonas aeruginosa studies. In the lung model, BRII-693 achieved robust cidal endpoints against all tested organisms. Maximal effect (3-4 log reduction in bacterial burden) converged at a 24 h plasma AUC/MIC value of 50. These findings demonstrate robust PK/PD profile and in vivo efficacy of BRII-693 against clinically relevant gram-negative pathogens, supporting its potential as a next-generation macrocyclic peptide antibiotic.
Lepak et al. (Thu,) studied this question.