Analysis Of Influence Factors On Effectiveness Of Vancomycin And Population Pharmacokinetics Study

Background:Vancomycin,one of the glycopeptide antibiotics,which has been used for more than half a century,is the first-line treatment for Methicillin Resistant Staphylococcus Aureus?MRSA?infection.The use of vancomycin in MRSA infection has been agreed by the American Association of Health System pharmacists,the American Association of Infectious Diseases and the Chinese Association of Infectious Disease pharmacists.The Chinese expert consensus on the clinical application of vancomycin,published in 2011,also clearly pointed out that vancomycin was the preferred drug for the treatment of MRSA infection.Vancomycin has obvious advantages in price and clinical cure rate compared with other new drugs to treat MRSA infection in recent years.With the wide application of vancomycin in MRSA treatment,its rational use is getting more and more attention.In order to reduce the occurrence of vancomycin resistant bacteria and reduce the nephrotoxicity induced by vancomycin,the guidelines for the application of vancomycin recommended the serum trough concentration range of vancomycin was 10-20?g/mL,and 15-20?g/mL for severe infections.If the treatment dose of vancomycin is insufficient,it will cause selective pressure of bacteria,which will result in the emergence of vancomycin intermediate staphylococcus aureus and heterogeneic vancomycin intermediate staphylococcus aureus.On the contray,If the dose of vancomycin is too high,renal toxicity will occur.Therefore,during the use of vancomycin,the steady-state serum trough concentration of vancomycin(C_trough)should be monitored in the recommended range to achieve safe and reasonable use of vancomycin.Objective:In this study,the influencing factors of C_trough were analyzed and the main reasons for subtherapeutic drug concentration were investigated.Population pharmacokinetic study was performed on these patients and the main pharmacokinetic parameters were obtained for concentration prediction and dosage adjustment.The clinical efficacy and adverse reactions of different infusion methods were further evaluated by meta-analysis.All the above results provided a reference for clinical individual therapy of vancomycin.Methods:In the first part of this study,single factor analysis and ordinal classification Logistic regression were used to analyze the influencing factors of C_trough.A total of 324patients suspected or confirmed gram-positive bacterial infection and treated with vancomycin in the first affiliated hospital of China Medical University from May 2013 to October 2016 were retrospectively collected.The basic information included C_trough,routine blood,liver function and kidney function,and IBM SPSS 22.0 software was used for statistical analysis.Firstly,we analysised the correlation of C_trough and clinical information,secondly,the significant factors were carried out by single factor analysis.Thirdly,the significant factors drawn by single factor analysis were performed by ordinal classification Logistic regression.Finally,the main influencing factors of C_trough were obtained.In the second part of this study,the population pharmacokinetic model of patients with C_trough below the recommended level was established by NONMEM software.C_trough was detected by enzyme multiplied immunoassay,which could be used to determine the concentration range of 2.0-50?g/mL with strong specificity.Information of 95 patients admitted to the first affiliated hospital of China medical university from July 2013 to December 2015 with intermittent vancomycin infusion and creatinine clearance rate higher than 130 mL/min were collected retrospectively.The collected information includes:basic information of patients,C_trough,blood routine,liver function,kidney function and combined medication.Since the patients are all sparse samples,the complex model can not be supported,so the initial structural model choosed a one-compartment model.The final model was established by stepwise addition method and backward deletion method.Model was evaluated by model diagnostic plots and VPC method,and validated by Bootstrap method and NPDE method.In addition,32 C_trough data of 16patients were used for external validation of the model by software JPKD.In the third part of this study,meta-analysis was used to analyze the efficacy and adverse reactions of different vancomycin infusion method.According to the strict inclusion and exclusion criteria,the related 14 literatures,including 1658 patients,were retrieved in Pubmed,Embase,Cocharane,Web of Science,CNKI,VIP and Wanfang database.RevMan5.0 software was used for meta-analysis,Stata12.0 software was used to investigate the heterogeneity.The heterogeneity reason was analyzed.Results:In the first part of this study,the single factor analysis and ordinal classification Logistic regression indicated the main influencing factors of C_trough was CL_cr,and the secondary influencing factors were age and ALB.Weight was not the obvious factor.The results showed that age was positively correlated with C_trough?P<0.05?,and CL_cr,ALB were negatively correlated with C_trough?P<0.05?.It was found that the C_trough in ARC patients was influenced mainly by age,and was not easily up to standard concentration.In the second part of this study,the population pharmacokinetics model of vancomycin was established by collecting the data of sparse serum trough concentration in patients with augmented renal clearance?ARC?.The covariate of the final model is age.This model achieved good prediction for 93.75%patients?weight deviation<30%?.The third part of this study screened the literature on the efficacy and adverse reactions of different infusion methods in the treatment of vancomycin.The results are shown in the following five aspects,intermittent infusion of vancomycin?IIV?was lower than continuous infusion of vancomycin?CIV?in PTAs of C_m?C_t?RR=0.72,95%CI=[0.60–0.88]?,IIV was higher than CIV in nephrotoxicity?RR=1.70,95%CI=[1.34–2.14]?,and there were no significant difference between IIV and CIV in the PTAs of AUC_24h/MIC?400?RR=0.84,95%CI=[0.70–1.00]?,treatment time?SMD=0.08,95%CI=[-0.08–0.25]?and fatality?RR=0.94,95%CI=[0.72–1.25]?.Conclusion:The current results indicated that the first influencing factors of C_trough was CL_cr,the second should be the age and ALB.For the augmented renal clearance patients,age is the primary factor which affected vancomycin concentration.The population pharmacokinetic model established in this study can quickly and easily predict C_trough for patients with augmented renal clearance,which is suitable for clinical.The results of meta-analysis indicated that CIV could be considered as the better infusion method in patients whose vancomycin concentration is not easily up to the standard or renal function has been damaged.Based on the clinical application and literature search,the research has certain theoretical and practical significance,which can provide the evidence for the rational use of vancomycin in the clinical.