| Objective: To establish a sensitive and specific method for determination of Linezolid in human serum, the research on the pharmacokinetics and the clinical evaluation under the guidance by PK-PD model in severe infection patients were treated with Linezolid. At the same time, to study the risk factors and to predict the risks of Linezolid-associated thrombocytopenia.Methods: 9 cases of ICU in our hospital treated patients and application of Linezolid Injection, according to whether patients undergoing hemodialysis, divided into dialysis group(n = 3) and non dialysis group(n = 6). Blood samples were collected before and after treatment for determination of drug concentration, then through the DAS 2.0software to calculate the PK-PD parameters of drug therapy. To deduce the pharmacokinetic characteristics which combined with general information and clinical data of disease in the patients treated with Linezolid. Meanwhile, logistic regression analysis was used to the physiological characteristics, clinical indicators during treatment,treatment results, characteristics of drug monitoring infection type and the combined use of these five aspects of patient treatment, of Linezolid in the treatment of severe infection were independent risk factors in patients with thrombocytopenia.To predict the risks of Linezolid-thrombocytopenia by logistic model and receiver operating characteristic curves in severe infection patients.Results: We had established a sensitive and specific method for determination of Linezolid in human serum by HPLC. The standard curve was linear in the range of0.1mg/L and 30.0 mg/L(As =18789.925×C +93.712, r=0.9997).The relative standard deviation of intra-day and inter-day was smaller than 10%.The absolute recoveries of linezolid were between 75.4% and 84%.The characteristic of Linezolid pharmacokinetics in patients of severe infection which present one-compartment linear elimination model. The main parameters ofPK( Vd 、CL、AUC0–12) in non dialysis group and dialysis patients were [36.68 ± 13.63 L vs 47.54 ± 5.95 L ]、[8.02 ± 5.59 L/h vs 11.75 ± 1.35 L/h ]、[98.99 ± 55.79 mg/L*h vs72.34 ± 10.26 mg/L*h ] respectively. Compared with non dialysis patients, hemodialysis in patients with T1/2 significantly decreased the [2.14 ± 0.81 h vs 4.23 ± 1.97 h, p =0.03 ].For the first time of the trough concentration of doses, non dialysis patients were significantly higher than that in dialysis patients [5.29 ± 3.54 mg/L vs 1.31 ± 0.72 mg/L,p < 0.05 ]. After that, non dialysis group concentration is much higher than that of dialysis patients.The patient under the routine treatment of Linezolid therapy, success rate of dialysis group and non dialysis group were [ 33.3% vs 71.4% ]. 7 patients in 9 cases of PK-PD parameters can accurately reflect the antibacterial efficacy of Linezolid efficacy, the relevant parameters of PK-PD standards are consistent with the results of actual clinical treatment. However, the other 2 cases of PK-PD parameters were contrast with the actual clinical effect.108 patients(65 males, 43 females) were included in the study, and thrombocytopenia occurred in 30 patients.Based on a multivariate logistic regression analysis, only age, serum creatinine, baseline platelet counts and trough concentration,were significant risks for Linezolid-associated thrombocytopenia. Based on the above independent risk factors, Logistic regression equation was established:Logit(P) = 0.056 × XC- 0.094 × XPLT + 0.086 × XScr- 0.082 × XAge + 1.927; By constructing the ROC curve of the combined forecasting factor, the Logistic regression equation is transformed to obtain the calculation formula of the joint prediction factor :Y联合= XC- 1.678 × XPLT + 1.535 × XScr- 1.464 × XAge.Conclusions: Patients with severe infection of Linezolid in the treatment of routine drug treatment, treatment failure may occur in vivo drug exposure caused by insufficient.Patients with renal replacement therapy(such as hemodialysis), the application of loading does and extending administration time of Linezolid injection toavoid the increased drug clearance caused by high-throughput circulation in vitro.Therapeutic drug monitoring in the severe infection patients,it is not enough to infer the drug concentration in target site according to the concentration in vein blood. This issue can be solved by the following two ways: one is to adopt the method of direct determination of free drug concentration; the two part is the quantitative detection of drug concentration in the target site, such as cerebrospinal fluid and alveolar epithelial lining fluid, pancreatic juice, etc In clinical practice, we could calculate the joint predictor by the age, serum creatinine, baseline platelet counts and trough concentration of the patients. Using calculation formula( Y = XC- 1.678 * XPLT + 1.535 * XScr- 1.464 * XAge), If the calculated results in less than 520.62(ROC best critical value),the patient during treatment appear thrombocytopenia have a higher risk of disease., then it should be strictly monitoring of patients with hematological indexes, and take withdrawal and symptomatic treatment when necessary... |
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