Pharmacodynamic Evaluation of the Novel Vancomycin Derivative LYSC98

LYSC98 is a novel synthetic derivative from chemical modification of vancomycin. In this study, the antibacterial efficacy of LYSC98 was systematically evaluated against multiple clinically significant pathogens using Minimal Inhibitory Concentration (MIC) determination and murine systemic and neutropenic thigh infection models. LYSC98 was active against Gram-positive strains, with MICs generally higher or comparable to vancomycin against vancomycin susceptible isolates; however, it demonstrated elevated activity against vancomycin-resistant Enterococci (VRE), with MICs more than 8 folds lower than vancomycin. In both animal models, LYSC98 was active against methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), penicillin-intermediate S. pneumoniae (PISP), penicillin-resistant S. pneumoniae (PRSP), and VRE. In the systemic infection model, the median effective doses (ED₅₀s) of LYSC98 against MRSA, VISA, PISP, PRSP, and VRE strains were significantly lower than those of vancomycin, and either not significantly different from or significantly lower than those of teicoplanin. In the neutropenic thigh infection model, two intravenous administrations of LYSC98 at 2, 4, and 8 mg/kg achieved 2.30-4.93 log₁₀ CFU/thigh reductions against MRSA strains relative to the 24 h infection control, significantly greater than vancomycin at the corresponding doses; relative to the bacterial burden at the start of therapy (2 h control), net killing was achieved at 4 and 8 mg/kg against both strains, whereas at 2 mg/kg the burden remained at or above baseline. These results indicate that, within the strains, doses and models tested, LYSC98 is active against the Gram-positive species examined and is more effective than vancomycin in selected infection models.