Evaluation Study Of Therapeutic Effect And Acute Kidney Injury Based On The Peak-trough Concentration And AUC Of Vancomycin

Vancomycin is widely used in clinical practice in recent years,nephrotoxicity is an important problem in the use of vancomycin which cannot be ignored.However,the optimal strategy for monitoring vancomycin therapy has not been clarified yet.Clinical data were collected from patients who used vancomycin and monitored blood concentration during hospitalization in Changhai Hospital Affiliated to Navy Medical University（Second Military Medical University）.These data were used to explore the correlation and rule of valley concentration(C_min)and peak concentration(C_peak)with curative effect and acute kidney injury（AKI）.Meanwhile,in view of the doubts on the rationality of using C_minas an alternative indicator of AUC to evaluate the clinical effect was proposed in the Consensus Guidelines for Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections（March2020）.This study prospectively included patients who received vancomycin during hospitalization,collected clinical data and medication information,and conducted external verification of the accuracy of vancomycin PPK model published for Chinese population at present.We selected the model with the best prediction performance and used Bayesian method to estimate AUC,and explored the rationality of C_minas an alternative indicator of AUC and the effectiveness of AUC as a pharmacokinetic indicator of vancomycin in evaluating clinical efficacy and the incidence of AKI.The study consisted of three parts:First part:To explore the clinical factors affecting the blood concentration distribution of vancomycin and study on therapeutic effect and acute kidney injury based on peak-trough concentration of vancomycin.Vancomycin was used in Changhai Hospital from November 2015 to April 2019 and at least once vancomycin C_minor C_peakwas determined by blood concentration.Three groups were divided according to plasma concentration:C_min<10 mg/L,10～20 mg/L,>20 mg/L;C_peakwas divided into three groups:<25 mg/L,25～40 mg/L,>40 mg/L.The results showed that the C_minand C_peakof vancomycin were affected by creatinine clearance before administration（CLcr）and urea nitrogen（BUN）.At routine clinical doses,the high concentration group increased the risk of AKI occurrence,and the incidence of AKI was correlated with vancomycin blood concentration.There was no significant difference in the curative effect between each concentration group,there was no correlation between the therapeutic effect and the blood concentration of vancomycin.The second part:The accuracy of vancomycin PPK models published in China were verified externally.Patients admitted to Changhai Hospital and treated with vancomycin between November 2018 and April 2019 were prospectively included,to monitor the blood concentration of vancomycin,accurate collection of patient medication information.By searching the literature on population pharmacokinetics（PPK）in the Chinese population published in the last five years,we identified four published articles which the studies included the similar pharmacokinetic parameters,extract the model from the corresponding article,external validation of the model using clinical data from patients included in this study,to evaluate and compare the predictive efficacy of the inclusion model for initial and adjusted concentrations and to investigate the difference between the predictive efficacy of neurosurgery patients and ordinary adult patients.Turns out,when each model predicts initial concentration,Kai Shen et al.is a modeloptimization model.When adjusting for concentration prediction,Smart Dose AD model and Kai Shen et al.model are better predictive performance.For ordinary adults patients,when the initial concentration was predicted,Kai Shen et al.group had the best predictive efficiency;For neurosurgical patients,Smart Dose NE model is recommended for initial concentration prediction.The third part:Verify and analyze the correlation between AUC and efficacy and AKI,we explore the guidance range of AUC suitable for our patient population,and then evaluate the rationality of using C_minas an alternative indicator of AUC.Select the model of optimal prediction efficiency,that is,Kai Shen et al.model,and adopt the NONMEM software estimate the AUC_0-24hand AUC_0-48hof patients included by using C_min（MIC is assumed to be 1mg/L）,the data of our patients were used to a study found that AUC_0-24hand AUC_0-48hwere critical values for the incidence of renal toxicity,AUC_0-48hhas a stronger correlation with AKI.The incidence of AKI was time and concentration dependent.AUC_0-24hwas correlated with the efficacy and the threshold value of AUC_0-24hfor efficacy was 356.84mg·h/L,when AUC_0-24h>356.84mg·h/L,C_minwas still lower than10mg/L in half of the patients.Therefore,AUC is more suitable for the evaluation of the clinical efficacy of vancomycin,and C_minis not suitable for the evaluation of pharmacodynamics as the replacement of AUC.All in all,in this study,the clinical data of vancomycin were used to evaluate the effect of C_minand C_peakin predicting the efficacy and the incidence of AKI;then the appropriate PPK model was selected from published literature by external verification,and the Bayesian method was used to prospectively estimate AUC,and analyzed the correlation about the clinical efficacy and safety of AUC that was estimated by plasma concentration of vancomycin and PPK model estimation using the actual clinical data of patients.We evaluate the difference between them in guiding clinical drug use and predicting efficacy and safety.As a result,C_minaffected by many factors,predicting clinical effectiveness as a AUC substitute may lead to unnecessary higher vancomycin blood concentration,thus increasing the risk of nephrotoxicity.Therefore,PPK model estimation AUC clinical individualized drug use guidance is more reasonable and reliable.Based on practice and comprehensive use of clinical real-world data and literature research results,this paper makes a useful exploration on how to correctly select pharmacokinetic indexes and use PPK auxiliary tools in clinical work.It has certain theoretical and applied value.