The Pharmacokinetics/Pharmacodynamics and Neurotoxicity of Tigecycline Intraventricular Injection for the Treatment of Extensively Drug-Resistant Acinetobacter baumannii Intracranial Infection

OBJECTIVE: This study aimed to provide feasible suggestions for intraventricular injection of tigecycline to treat intractable Acinetobacter baumannii intracranial infections by studying its pharmacokinetics/pharmacodynamics and neurotoxicity. METHODS: A simple and reliable two-dimensional high-performance liquid chromatography (2D-HPLC) method was used to determine tigecycline concentration. The pharmacokinetics (PK) of tigecycline in cerebrospinal fluid (CSF) was investigated by performing therapeutic drug monitoring (TDM). The pharmacodynamics (PD) of tigecycline was evaluated by its minimum inhibitory concentration (MIC) against XDR A. baumannii. CCK8 assay was used to evaluate the cytotoxicity of different concentrations of tigecycline effect on PC12 cells, and apoptosis assay was analyzed by flow cytometry. RESULTS: Tigecycline retention time in 2D-HPLC was 7.636 min. The lower limit of quantitation (LLOQ) was 0.1mg/L, which met the requirements of concentration determination for TDM. The MIC(50) and MIC(90) values of tigecycline for A. baumannii were 2 and 4 mg/L, respectively. After a dose of 5mg tigecycline, Cmax in CSF was 37.894 mg/L which was high above the MIC values. The t(1/2) of tigecycline was estimated to be 2.73 hours. Tigecycline significantly decreased cell viability as assessed and induced apoptosis of the PC12 cell. The IC(50) value of PC12 cells treated with tigecycline was about 51.35 mg/L. CONCLUSION: Intraventricular injection of tigecycline is a promising method for treating XDR A. baumannii intracranial infection. Since a high concentration of tigecycline in CSF may have potential neurotoxicity, and the t(1/2) was short, giving small doses of less than 5 mg at least twice a day may be safer and more effective. Intraventricular injection of tigecycline must be selected cautiously and best carried out under TDM.