利奈唑胺相关血小板减少ppt课件

1、利奈唑胺相关性血小板减少利奈唑胺相关性血小板减少陈陈 超超解放军总医院解放军总医院 药品保证中心药品保证中心临床药学室临床药学室p MRSAp VREp VRSABACKGROUND万古霉素 vancomycin利奈唑胺 linezolid Antimicrobial resistance in China has become a serious healthcare problem, with high resistance rates of most common bacteria to clinically important antimicrobial agents. Methici

2、llin-resistant S. aureus, ESBL-producing Enterobacteriaceae and carbapenem-resistant Acinetobacter baumannii represent more than 50% of microbial isolates.Linezolidoxazolidinone antibiotics2000 FDA2007 SFDAunique mechanism of the antibacterial actioninhibition of protein synthesis in bacterial lipos

3、omesapproved indications for linezolid usevancomycin-resistant Enterococcus infection and comorbid with bacteremiahospital -acquired pneumonia complicated skin and skin structure infections community-acquired pneumonia and comorbid with bacteremiauncomplicated skin and soft tissue infectionssuperior

4、ityall ages liver disease poor kidney functionwith or without bacterial invasion of the bloodstreamEfficacy of linezolid on HAP and VAP caused by MRSA is better than vancomycinATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.ATS/IDSA2005 guidelines for the management of adults with HAP/VAP/HCAP

5、血小板减少症血小板减少症 - -来自临床的来自临床的声音声音上市前临床实验上市前临床实验阐明书阐明书腹泻腹泻/头痛头痛/恶心恶心/呕吐呕吐/味觉异味觉异常常骨髓抑制骨髓抑制血小板减少血小板减少 2.4%0.3%-10.0%/白细胞减少白细胞减少/贫血贫血/全血细胞全血细胞减少减少乳酸酸中毒乳酸酸中毒 视神经病变视神经病变周围神经病变周围神经病变平安性平安性&耐受性耐受性上市后监测上市后监测 文献文献主要的主要的SAE是血小板减少是血小板减少其他国家其他国家 高发生率高发生率 15.1-38.7%中国中国 个案报道个案报道 没有大样本人群的发生率没有大样本人群的发生率研讨目的研讨目的 ? 临床实

6、践发生率及严重程度? 危险要素? 风险特征的预测目的 住院患者运用利奈唑胺致相关血小板减少住院患者运用利奈唑胺致相关血小板减少资料资料& &方法方法数据来源解放军总医院 4,000 beds 运用利奈唑胺/口服/静注/序贯电子医疗记录 512 Patients were screened7 Patients were excluded due to younger than 18 years old血小板减少症评价50585 were excluded due to diagnosis and drugsHematological disordersChemotherapy on tumorS

7、evere pancreatitisHepatoblastomaSystemic Lupus Erythmatosusantiplatelet agent 425 were eligible and consented171 were excluded due to platelet count baseline platelet anomalies less than 100109/L or more than 400109/Linitial platelets were not recorded or less than three platelet observation points

8、254 were included in the analysis回想性研讨资料资料& &方法方法Thrombocytopenia in this study -lack of uniform diagnostic criteriaVariablesGenderAgeBody weightDaily dose mg/kg duration of linezolid administrationlaboratory data 5 factorsAlanine aminotransferase Total bilirubin Creatinine AlbuminBaseline platelet

9、规范 1严重规范 2轻中度platelet count less than 100 109/L25% reduction from baseline platelet count or less than 100 109/L结结 果果规范1 69/254 27.2%规范 2 131/254 51.6% & IV 度血小板下降 27/254 10.6%输血或输注血小板 17/254 6.7%WHO assessment of acute and subacute adverse performance and indexing standards grade , 26-49 109 / Lgra

10、de , 25 109 / L研讨对象概略血小板减少发生率 169 男性 /85 女性 平均年龄 59.0 17.7 range 18-95 岁 平均用药时间 9.43 5.63 range 2-35.5 天USA1932%platelet count less than 100109 /LAttassi et alUSA4848%30% reductionOrrick et al19%platelet count less than 100109 /LJanpan4216.7%defined as a 100109 /L decrease from the baseline or a 25%

11、 reductionNiwa et alJanpan 331 38.7%defined as a 100109 /L decrease from the baseline or a 30% reductionYoshiko takahashi et alChinese25427.2%platelet count less than 100109 /Lthis study51.6%defined as a 100109 /L decrease from the baseline or a 25% reductionn 结果与国外文献报道相近 n 显著高于产品资料所报道的期临床研讨结果n 轻中度血

12、小板下降很常见10%n 存在出血倾向血小板下降常见血小板下降常见结果结果 差别性分析差别性分析Risk factors Analysis of Thrombocytopenia Criterion 1+ chi-square test # t-test * Mann-Whitney U-testVariablesVariables a final platelet count 100109/L P valuePatients with thrombocytopenian=69Patients without thrombocytopenia n=185Gendermale 44 63.77%

13、125 67.57% 0.5681+Ageyears 63.4915.97 57.4518.060.0152#Weightkg 61.7013.1865.7513.060.0294#Alanine aminotransferaseU/L30.2427.55 35.7947.270.3084*Total bilirubinumol/L18.0117.5217.7627.300.3803*Creatinine clearancemL/min84.3763.12102.0757.260.0087*Albuming/L31.345.2733.848.790.0051*Daily dosemg/kg20

14、.114.1418.464.44 0.0016*Baseline platelet109/L176.9661.97234.1473.680.0001*Treatment durationd10.525.019.025.830.0067*结果结果 差别性分析差别性分析Risk factors Analysis of Thrombocytopenia Criterion 2VariablesVariables25% decrease or a final platelet count 100109/L P valueP valuePatients with thrombocytopenian=13

15、1Patients without thrombocytopenian=123Gendermale84 64.12% 85 69.11%0.4002+Ageyears61.8517.2556.1617.750.0102#Weightkg62.0812.4867.3813.420.0013#Alanine aminotransferaseU/L33.3542.5435.2743.270.1388*Total bilirubinumol/L19.8531.3815.6314.940.5476*Creatinine clearancemL/min85.9658.90109.3757.560.0005

16、*Albuming/L31.775.1034.6610.170.0026*Daily dosemg/kg20.014.1717.744.380.0001*Baseline platelet109/L212.4476.78225.1772.870.1069*Treatment durationd10.355.79 8.455.330.0015*+ chi-square test # t-test * Mann-Whitney U-test结果结果 单要素分析单要素分析Risk factors for thrombocytopenia selected by logistic regression

17、 univariate analysisRisk factors25% decrease or a final platelet count 100109/L a final platelet count 100109/L Odds ratio95%CIP valueOdds ratio95%CIP valueAgeyears1.021.00-1.030.01121.021.00-1.040.0165Weightkg0.970.95-0.990.00180.980.95-1.000.0308Creatinine clearancemL/min0.990.99-1.000.00220.990.9

18、9-1.000.0361Albuming/L0.930.89-0.980.00310.940.89-0.990.0131Daily dosemg/kg1.141.07-1.210.00011.091.02-1.160.0088Baseline platelet109/L1.00 0.99-1.000.17710.990.98-0.990.0000 Treatment durationd1.071.02-1.120.00881.051.00-1.100.0632Criterion 2Criterion 1Multivariate AnalysisRisk factors25% decrease

19、or a final platelet count 100109/L a final platelet count 100109/L Odds ratio95%CIP valueOdds ratio95%CIP valueCreatinine clearancemL/min0.9950.990-1.0000.0351Albuming/L0.9490.904-0.9960.0323Daily dosemg/kg1.121.047-1.1980.0010 1.0811.007-1.1610.0308Baseline platelet109/L0.9870.982-0.9920.0001Treatm

20、ent durationd1.0611.005-1.1200.0317结果结果 多要素分析多要素分析Risk factors for thrombocytopenia selected by logistic regression Criterion 2Criterion 1结果结果 ROC 曲线曲线Clinical features of thrombocytopenia predicated by ROC curvesCriterion 1Youden index ：0.4306 area under ROC curve： 0.757 baseline platelet value ： 1

21、81109 /Ldaily dose：18.75 mg/kg/dduration of medication ： 10 dCriterion 2Youden index ：0.3703 area under ROC curve： 0.706creatinine clearance ：88.39 mL/minserum albumin： 33.5 g/Ldaily dose：18.46 mg/kg/dsensitivity65.22%Specificity77.84%Sensitivity63.07%Specificity73.95%每日剂量每日剂量 p risk increasep daily

22、 dose 18.75 mg/kg/d p body weight 64kgp a protective factor of thrombocytopenia : body weightp higher drug exposure induced thrombocytopeniaindependent risk factor for mild&severe PLT decreasen linezolid-related thrombocytopenia is characterized as drug concentration-dependentn dosage adjustment acc

23、ording to body weight may help to reduce the risk of linezolid-related thrombocytopenia in Chinese population基线血小板基线血小板p baseline platelet 181109/L are more likely to suffer from thrombocytopenia than others 45.9% 39/85 vs. 17.8% 30/169, P 14 d has increased the risk of thrombocytopenia 2.9% 36/1243

24、 to 4.1% 19/461p ROC cut-off point Criterion 1 :10 daysindependent risk factor for severe thrombocytopeniap confirmed the findings of reports& drug instructionp longer treatment need more clinical blood tests 肌苷去除率肌苷去除率nWu VC et al. A retrospective case-control studynTwo groups:end-stage or non-end-

25、stage renal diseases nincidence of thrombocytopenia is higher in the group with end-stage renal diseasenBrier et al. the clinical significance of accumulation of two metabolites nPNU-142586 nPMU-142300Wu VC et al .Clin Infect Dis 2006; 42: 66-72.Brier et al. Antimicrob Agents Chemother 2003; 47: 2775-80.Higher incidence in the group with severe renal impair