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 药品保障中心药品保障中心临床药学室临床药学室pMRSApVREpVRSABACKGROUND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. Methicillin-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 liposomesapproved 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 infectionssuperiorityall ages liver disease poor kidney functionwith or without bacterial invasion of the bloodstreamATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.ATS/IDSA(2005) guidelines for the management of adults with HAP/VAP/HCAP血小板减少症血小板减少症 - -来自临床的声音来自临床的声音上市前临床试验上市前临床试验说明书说明书腹泻/头痛/恶心/呕吐/味觉异常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/贫血/全血细胞减少乳酸酸中毒 视神经病变周围神经病变安全性安全性&耐受性耐受性上市后监测上市后监测 文献文献主要的SAE是血小板减少其他国家 高发生率 (15.1-38.7%)中国 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究目的研究目的 ? 临床实际发生率及严重程度? 危险因素? 风险特征的预测指标 住院患者使用利奈唑胺致相关血小板减少住院患者使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) 使用利奈唑胺/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 tumorSevere 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/L)initial platelets were not recorded or less than three platelet observation points 254 were included in the analysis回顾性研究资料资料& &方法方法Thrombocytopenia in this study -lack of uniform diagnostic criteriaVariablesGenderAgeBody weightDaily dose (mg/kg) duration of linezolid administrationlaboratory data (5 factors)Alanine aminotransferase Total bilirubin Creatinine AlbuminBaseline platelet 标准 1严重标准 2轻中度platelet count less than 100 109/L25% reduction from baseline platelet count or less than 100 109/L结结 果果标准1 69/254 27.2%标准 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 / Lgrade , 25 109 / L研究对象概况血小板减少发生率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CountryCountryNumberNumberIncidenceIncidenceCriterionCriterionAutherAutherUSA1932%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% 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究结果n 轻中度血小板下降很常见（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 差异性分析差异性分析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 thrombocytopenia(n=69)Patients without thrombocytopenia (n=185)Gender(male) 44( 63.77%) 125( 67.57%) 0.5681+Age(years) 63.49(15.97) 57.45(18.06)0.0152#Weight(kg) 61.70(13.18)65.75(13.06)0.0294#Alanine aminotransferase(U/L)30.24(27.55) 35.79(47.27)0.3084*Total bilirubin(umol/L)18.01(17.52)17.76(27.30)0.3803*Creatinine clearance(mL/min)84.37(63.12)102.07(57.26)0.0087*Albumin(g/L)31.34(5.27)33.84(8.79)0.0051*Daily dose(mg/kg)20.11(4.14)18.46(4.44) 0.0016*Baseline platelet(109/L)176.96(61.97)234.14(73.68)0.0001*Treatment duration(d)10.52(5.01)9.02(5.83)0.0067*结果结果 差异性分析差异性分析Risk factors Analysis of Thrombocytopenia Criterion 2VariablesVariables25% decrease or a final platelet count 100109/L P valueP valuePatients with thrombocytopenia(n=131)Patients without thrombocytopenia(n=123)Gender(male)84( 64.12%) 85( 69.11%)0.4002+Age(years)61.85(17.25)56.16(17.75)0.0102#Weight(kg)62.08(12.48)67.38(13.42)0.0013#Alanine aminotransferase(U/L)33.35(42.54)35.27(43.27)0.1388*Total bilirubin(umol/L)19.85(31.38)15.63(14.94)0.5476*Creatinine clearance(mL/min)85.96(58.90)109.37(57.56)0.0005*Albumin(g/L)31.77(5.10)34.66(10.17)0.0026*Daily dose(mg/kg)20.01(4.17)17.74(4.38)0.0001*Baseline platelet(109/L)212.44(76.78)225.17(72.87)0.1069*Treatment duration(d)10.35(5.79) 8.45(5.33)0.0015*+ chi-square test # t-test * Mann-Whitney U-test结果结果 单因素分析单因素分析Risk factors for thrombocytopenia selected by logistic regression univariate analysisRisk factors25% decrease or a final platelet count 100109/L a final platelet count 100109/L Odds ratio95%CIP valueOdds ratio95%CIP valueAge(years)1.021.00-1.030.01121.021.00-1.040.0165Weight(kg)0.970.95-0.990.00180.980.95-1.000.0308Creatinine clearance(mL/min)0.990.99-1.000.00220.990.99-1.000.0361Albumin(g/L)0.930.89-0.980.00310.940.89-0.990.0131Daily dose(mg/kg)1.141.07-1.210.00011.091.02-1.160.0088Baseline platelet(109/L)1.00 0.99-1.000.17710.990.98-0.990.0000 Treatment duration(d)1.071.02-1.120.00881.051.00-1.100.0632Criterion 2Criterion 1Multivariate AnalysisRisk factors25% decrease or a final platelet count 100109/L a final platelet count 100109/L Odds ratio95%CIP valueOdds ratio95%CIP valueCreatinine clearance(mL/min)0.9950.990-1.0000.0351Albumin(g/L)0.9490.904-0.9960.0323Daily dose(mg/kg)1.121.047-1.1980.0010 1.0811.007-1.1610.0308Baseline platelet(109/L)0.9870.982-0.9920.0001Treatment duration(d)1.0611.005-1.1200.0317结果结果 多因素分析多因素分析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 ： 181109 /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/dPLT 20010PLT 200109 9 /L /LCcr 30 mL/minCcr 30 mL/minCcr 50 mL/min Ccr 50 mL/min duration duration 14 14 dsensitivity65.22%Specificity77.84%Sensitivity63.07%Specificity73.95%每日剂量每日剂量 prisk increasedaily dose 18.75 mg/kg/d body weight 64kgpa protective factor of thrombocytopenia : body weightphigher drug exposure induced thrombocytopeniaindependent risk factor for mild&severe PLT decreasenlinezolid-related thrombocytopenia is characterized as drug concentration-dependentndosage adjustment according 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pbaseline 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) to 4.1% (19/461)p ROC cut-off point (Criterion 1 ):10 daysindependent risk factor for severe thrombocytopeniapconfirmed the findings of reports& drug instructionplonger treatment need more clinical blood tests 肌苷清除率肌苷清除率nWu VC et al. A retrospective case-control studyTwo groups:end-stage or non-end-stage renal diseases incidence of thrombocytopenia is higher in the group with end-stage renal diseasenBrier et al. the clinical significance of accumulation of two metabolites PNU-142586 PMU-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 impairment pCreatinine clearance as the indicator of renal functionthe ROC cut-off point (Criterion 2)creatinine clearance 88.39 mL/minpMild PLT decrease may occur when creatinine clearance rate is at its lower limit, while there is still no sign of renal insufficiency.pCcr30 severe renal impairment (48% 15/31 vs. 24% 54/222, P=0.005,OR=2.92 95%CI1.396.14）结结 论论nSituation in Chinese patientsactual incidence is much higher than in drug instructionshemorrhagic tendencynRisk factors low pre-treatment platelet valueslow body weightlow serum albumin long time of administrationAdvanced agerenal impairment nPredictorsbaseline platelet 181109/Ldaily dose 18.75 mg/kgduration of linezolid therapy 10 d nStrategystrengthen monitoring frequency according to risk factorsdosage adjustment according to body weight(PK/PD)Thank you for your attention