Study On The Efficacy Suppression And Its Mechanism Of Teicoplanin By Low Plasma Protein In Enterococcal Infection

Aim1 Investigate the effect of Albumin(ALB)on the concentration of teicoplanin(TEIC).2 To investigate the changes in total(Ct)and free(Cf)concentrations of TEIC,as well as the efficacy and adverse reactions of the drug administered with different therapeutic doses under the condition of infection with hypoproteinemia,to provide a reference for determining the dosage of TEIC in the safe and effective treatment of hypoproteinemia patients with bacterial infection.Methods1 Construct an animal model of hypoproteinemiaA low-protein diet controlled feeding plus plasma exchange method was used to construct a New Zealand rabbit model of hypoproteinemia.The content of serum albumin decreased by 20%-35%in mild-moderate hypoalbuminemia,and by more than45%in moderate-severe hypoalbuminemia.2 Construct an animal model of bloodstream infectionAn animal model of bloodstream infection was constructed by injecting 1ml/kg enterococci bacterial fluid with an OD value of 0.9 through a rabbit ear marginal vein.3 Groups and drug intervention3.1 Plasma protein groupAccording to different levels of serum albumin,it was divided into normal protein group,mild to moderate hypoproteinemia group(protein content decreased by20%-35%)and moderate to severe hypoproteinemia group(protein content decreased by more than 45%)3.2 Administration groupDifferent levels of hypoproteinemia group were set up with negative control group(injected with the same amount of normal saline),positive control group(injected with bacterial solution only),and high dose group(Bacterial injection+TEIC:36.96 mg/kg q12h*3 loaddose+36.96 mg/kgqd maintain),medium dose group(Bacterial injection+TEIC:18.48mg/kg q12h*3 load dose+18.48 mg/kg qd maintain),low dose group(Bacterial injection+TEIC:9.24mg/kg q12h*3 load dose+9.24mg/kg qd maintain).4 Measurements4.1 Establish a High-performance liquid chromatography(HPLC)method to determine the total concentration and free concentration of TEIC in plasma.4.2 Automated biochemical detector for detection of total blood protein(TP),albumin(ALB),serum creatinine(CREA),C-reactive protein(CRP),procalcitonin(PCT);4.3 Automatic blood cell analyzer for cell sorting and counting;4.4 Detect blood creatinine to assess renal function;4.5 Record the body temperature of the rabbit,observe the changes in mental state;4.6 Based on the above data of hemogram,biochemical index and body temperature,the efficacy and adverse reactions of the drug were evaluated.Results1 The free concentration of TEIC was linear within 0.5-50μg/m L(y=12801x-2574.1,r~2=0.9998),the lower limit of quantification was 0.5μg/m L,and the method recovery rate was 94.63%-103.72%.Relative standard deviation(RSD)of intra-day and inter-day precisionwere all less than 4.00%;the linearity is good within the total concentration of 1.5625-100μg/m L(y=10576x+9950.1,r~2=0.999 8),the lower limit of quantification is 1.5625μg/m L,the method recovery rate is94.55%-99.59%,RSD of intra-day and inter-day precisionwere all less than 4.00%.The TEIC was all stability at the conditions of maintaining at room temperature for 10 h,after freeze-thaw cycle and keeping at 4℃for 72h.2 After treatment,the white blood cell(WBC),body temperature,CRP,and PCT of each treatment group were significantly decreased(P<0.05);the therapeutic effect of normal protein group was dose-dependentat 120h,white blood cells,body temperature,and CRP all returned to normal levels.The body temperature of mild to moderate hypoproteinemia and moderate to severe hypoproteinemia was normal after teic high dose treatment,but WBC,PCT and CRP did not return to the level before modeling(P<0.05).The experimental rabbit leukocytes,body temperature,PCT and CRP will change with time because of different treatment methods.3 After 24h,48h,72h and 120h of treatment,the total TEIC concentration and protein binding rate of the mild to moderate hypoproteinemia group and the moderate to severe hypoproteinemia group decreased.ALB significantly affected the total concentration and free concentration of teicoplanin.4 No adverse reactions(ADR)such as skin rashes and renal impairment were observed after high,medium and low doses administration.Conclusions1 Hypoproteinemia can reduce the therapeutic effect of TEIC high-dose regimen(36.96 mg/kg q12h*3 dose load+36.96 mg/kg qd maintenance).It is recommended to increase the dose to obtain good therapeutic effect.2 The total concentration and free concentration of TEIC are obviously affected by ALB.It is suggested that the dosage should be adjusted by monitoring the free concentration of teic in hypoalbuminemia to obtain good effect.