Pharmacokinetics and Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a Murine Thigh Infection Model Against Staphylococcus aureus

Peng He,1 Xin Li,2 Xiaohan Guo,1 Xingchen Bian,1 Rui Wang,1 Yue Wang,1 Sijing Huang,1 Mengya Qi,1 Yuanxia Liu,3 Meiqing Feng1 1Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, People’s Republic of China; 2Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Department of Pathology, Shanghai, People’s Republic of ChinaCorrespondence: Meiqing Feng, Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, People’s Republic of China, Tel +86 21 51980035, Email fmq@fudan.edu.cn Yuanxia Liu, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Department of Pathology, Shanghai, People’s Republic of China, Email lyuyx@126.comIntroduction: LYSC98 is a novel vancomycin derivative used for gram-positive bacterial infections. Here we compared the antibacterial activity of LYSC98 with vancomycin and linezolid in vitro and in vivo. Besides, we also reported the pharmacokinetic/pharmacodynamic (PK/PD) index and efficacy-target values of LYSC98.Methods: The MIC values of LYSC98 were identified through broth microdilution method. A mice sepsis model was established to investigate the protective effect of LYSC98 in vivo. Single-dose pharmacokinetics of LYSC98 was studied in thigh-infected mice and liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was used to determine LYSC98 concentration in plasma. Dose fractionation studies were performed to evaluate different PK/PD indices. Two methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used in the dose ranging studies to determine the efficacy-target values.Results: LYSC98 showed a universal antibacterial effect in Staphylococcus aureus with a MIC range of 2– 4 μg/mL. In vivo, LYSC98 demonstrated distinctive mortality protection in mice sepsis model with an ED50 value of 0.41– 1.86 mg/kg. The pharmacokinetics results displayed maximum plasma concentration (Cmax) 11,466.67− 48,866.67 ng/mL, area under the concentration–time curve from 0 to 24 h (AUC0– 24) 14,788.42− 91,885.93 ng/mL·h, and elimination half-life (T1/2) 1.70– 2.64 h, respectively. Cmax/MIC (R2 0.8941) was proved to be the most suitable PK/PD index for LYSC98 to predict its antibacterial efficacy. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log 10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively.Conclusion: Our study demonstrates that LYSC98 is more effective than vancomycin either in killing vancomycin-resistant Staphylococcus aureus (VRSA) in vitro or treating S. aureus infections in vivo, making it a novel and promising antibiotic. The PK/PD analysis will also contribute to the LYSC98 Phase I dose design.Keywords: LYSC98, vancomycin derivative, pharmacokinetics and pharmacodynamics, Staphylococcus aureus, murine thigh infection model