The Pharmacokinetics Study Of Norvancomycin In Cerebrospinal Fluid Of Patients With Postoperative Intracranial Infection

Part 1 Establishment of the determination method of norvancomycin in human cerebrospinal fluidObjective:To develop a high performance liquid chromatography（HPLC）method for determination of norvancomycin（NVCM）in human cerebrospinal fluid（CSF）.Methods:A diamonsil C₁₈ column（150 mm×4.6 mm,5μm）was used in this method.The mobile phase consisted of methanol-0.05 mol·L^-1 potassium dihydrogen phosphate（p H=3.2）（17:83,V/V）and the flow rate was 1.0m L·min^-1;the column temperature was maintained at 30℃;the detection wavelength was 236 nm;the sample injection size was 20μL,CSF samples were deproteimized with 6%prechlorld acid,vancomycin was used as internal standard（IS）.The specificity,linearity,limit of detection and quantitative,recovery,stability and precision were investigated.Results:It’s linear in the concentration rang of 0.25～100μg·m L^-1 and the standard curve equations were Y=0.2059X-0.0129（r=0.9999）.The peak of NVCM was not interfered by endogenous ingredients in CSF.The retention time of NVCM and IS were 11.9 min and 15.3 min,respectively.The limit of detection was 0.03μg·m L^-1 and the limit of quantitative was 0.25μg·m L^-1.The absolut and relative recovery were 92.44%～97.43%and 93.50%～101.2%,respectively.The relative standard deviation of inter-day and intra-day precisions were both less than 15%.CSF samples were stable when under freeze-thaw cycles,placed 8h at room temperature after processed and stored at-40℃for 90 days.Conclusions:This HPLC method for the determinnation of NVCM concentration in CSF established in this study is simple,specificity,sensitive and well recovery.It can be used for the detection of NVCM in patients CSF.Part 2 Pharmacokinetics study of norvancomycin in cerebrospinal fluid:intravenous infusion versus intrathecal injectionObjective:To performe a comparative analysis of NVCM’s PK,safety as well as clinical efficacy on intravenous only versus combined intravenous and intrathecal administration.Methods:Twenty-four patients suffering from MRSA intracranial infection after craniotomy were randomly divided into two groups:twelve patients in the control group were intravenously infused with 800 mg of NVCM for 2 h every 12 h;other twelve patients in the test group received an intrathecal injection of 16 mg of NVCM per day in addition to the intravenous dose used in the control group.CSF samples were collected at various time-points for determining NVCM levels following injection.A comparative analysis was performed on the PK parameters,safety as well as clinical efficacy between the two groups.Results:In the test group,the maximum CSF levels were 828.7±238.5 were 1.1±0.7μg·m L^-1 in the control group;significant differences between the two groups were observed（P<0.05）.The AUC_0-24h/MIC in the test group(AUC_0-24h/MIC:2307±928.6)were significantly higher than those in the control group(AUC_0-24h/MIC:46.8±27.5),（P<0.05）.The average cure time of the test group（9.4 d,n=10）was significantly shorter than that of the control group（14.0 d,n=9）,（P<0.05）.Two patients in the test group displayed nerve root irritation symptoms;the symptoms were relieved once the injection speed was slowed down.No other adverse effects were found in either of the two groups throughout the treatment course.Conclusions:Combined intravenous and intrathecal injection led to an increase in NVCM concentrations in CSF and AUC_0-24h/MIC ratios,the cure time is shortened and the safety is better.Combined intravenous and intrathecal injection of NVCM can effectively treat intracranial infection.