利奈唑胺相關(guān)血小板減少ppt課件

1、利奈唑胺相關(guān)性血小板減少利奈唑胺相關(guān)性血小板減少陳陳 超超解放軍總醫(yī)院解放軍總醫(yī)院 藥品保證中心藥品保證中心臨床藥學(xué)室臨床藥學(xué)室p MRSAp VREp VRSABACKGROUND萬古霉素 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、血小板減少癥血小板減少癥 - -來自臨床的來自臨床的聲音聲音上市前臨床實驗上市前臨床實驗闡明書闡明書腹瀉腹瀉/頭痛頭痛/惡心惡心/嘔吐嘔吐/味覺異味覺異常常骨髓抑制骨髓抑制血小板減少血小板減少 2.4%0.3%-10.0%/白細(xì)胞減少白細(xì)胞減少/貧血貧血/全血細(xì)胞全血細(xì)胞減少減少乳酸酸中毒乳酸酸中毒 視神經(jīng)病變視神經(jīng)病變周圍神經(jīng)病變周圍神經(jīng)病變平安性平安性&耐受性耐受性上市后監(jiān)測上市后監(jiān)測 文獻(xiàn)文獻(xiàn)主要的主要的SAE是血小板減少是血小板減少其他國家其他國家 高發(fā)生率高發(fā)生率 15.1-38.7%中國中國 個案報道個案報道 沒有大樣本人群的發(fā)生率沒有大樣本人群的發(fā)生率研討目的研討目的 ? 臨床實

6、踐發(fā)生率及嚴(yán)重程度? 危險要素? 風(fēng)險特征的預(yù)測目的 住院患者運用利奈唑胺致相關(guān)血小板減少住院患者運用利奈唑胺致相關(guān)血小板減少資料資料& &方法方法數(shù)據(jù)來源解放軍總醫(yī)院 4,000 beds 運用利奈唑胺/口服/靜注/序貫電子醫(yī)療記錄 512 Patients were screened7 Patients were excluded due to younger than 18 years old血小板減少癥評價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回想性研討資料資料& &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、規(guī)范 1嚴(yán)重規(guī)范 2輕中度platelet count less than 100 109/L25% reduction from baseline platelet count or less than 100 109/L結(jié)結(jié) 果果規(guī)范1 69/254 27.2%規(guī)范 2 131/254 51.6% & IV 度血小板下降 27/254 10.6%輸血或輸注血小板 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研討對象概略血小板減少發(fā)生率 169 男性 /85 女性 平均年齡 59.0 17.7 range 18-95 歲 平均用藥時間 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 結(jié)果與國外文獻(xiàn)報道相近 n 顯著高于產(chǎn)品資料所報道的期臨床研討結(jié)果n 輕中度血

12、小板下降很常見10%n 存在出血傾向血小板下降常見血小板下降常見結(jié)果結(jié)果 差別性分析差別性分析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*結(jié)果結(jié)果 差別性分析差別性分析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結(jié)果結(jié)果 單要素分析單要素分析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結(jié)果結(jié)果 多要素分析多要素分析Risk factors for thrombocytopenia selected by logistic regression Criterion 2Criterion 1結(jié)果結(jié)果 ROC 曲線曲線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%每日劑量每日劑量 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基線血小板基線血小板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