利奈唑胺相关血小板减少.pptx

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,#,利奈唑胺相关血小板减少,利奈唑胺相关血小板减少,第1页,MRSA,VRE,VRSA,BACKGROUND,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.,利奈唑胺相关血小板减少,第2页,Linezolid,oxazolidinone antibiotics,FDA,SFDA,unique mechanism of the antibacterial action,inhibition of protein synthesis in bacterial liposomes,approved indications for linezolid use,vancomycin-resistant Enterococcus infection and comorbid with bacteremia,hospital,-acquired pneumonia,complicated skin and skin structure infections,community-acquired pneumonia,and comorbid with bacteremia,uncomplicated skin and soft tissue infections,superiority,all ages,liver disease,poor kidney function,with or without,bacterial invasion of the bloodstream,Efficacy of linezolid on HAP and VAP caused by MRSA is better than vancomycin,ATS/IDSA.Am J Respir Crit Care Med.;171:388-416.,ATS/IDSA()guidelines for the management of adults with HAP/VAP/HCAP,利奈唑胺相关血小板减少,第3页,血小板降低症,-,来自临床声音,上市前临床试验,说明书,腹泻,/,头痛,/,恶心,/,呕吐,/,味觉异常,骨髓抑制,血小板降低,2.4%,(0.3%-10.0%),/,白细胞降低,/,贫血,/,全血细胞降低,乳酸酸中毒,视神经病变,周围神经病变,安全性,&,耐受性,上市后监测,文件,主要,SAE,是血小板降低,其它国家,高发生率,(15.1-38.7%),中国,个案报道,没有大样本人群发生率,利奈唑胺相关血小板减少,第4页,研究目标,临床实际发生率及严重程度,危险原因,风险特征预测指标,住院患者使用利奈唑胺致相关血小板降低,利奈唑胺相关血小板减少,第5页,资料,&,方法,数据起源,解放军总医院,(4,000 beds),使用利奈唑胺,/,口服,/,静注,/,序贯,电子医疗统计,512 Patients were screened,7,Patients,were excluded due to,younger than 18 years old,血小板降低症评价,505,85,were excluded due to diagnosis and drugs,Hematological disorders,Chemotherapy on tumor,Severe pancreatitis,Hepatoblastoma,Systemic Lupus Erythmatosus,antiplatelet agent,425 were eligible and consented,171,were excluded due to platelet count,baseline platelet anomalies,(less than 10010,9,/L or more than 40010,9,/L),initial platelets were not recorded or less than three platelet observation points,254 were included,in the analysis,回顾性研究,利奈唑胺相关血小板减少,第6页,资料,&,方法,Thrombocytopenia in,this,study,-,lack of,uniform diagnostic criteria,Variables,Gender,Age,Body weight,Daily dose(mg/kg),duration of linezolid administration,laboratory data(5 factors),Alanine aminotransferase,Total bilirubin,Creatinine,Albumin,Baseline platelet,标准,1,严重,标准,2,轻中度,platelet count less than 100 10,9,/L,25%reduction from baseline platelet count or less than 100 10,9,/L,利奈唑胺相关血小板减少,第7页,结 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/L,grade,25 109/L,研究对象概况,血小板降低发生率,169,男性,/85,女性,平均年纪,59.0 17.7(range 18-95),岁,平均用药时间,9.43 5.63(range 2-35.5),天,利奈唑胺相关血小板减少,第8页,Country,Number,Incidence,Criterion,Auther,USA,19,32%,platelet count less than 10010,9,/L,Attassi et al,USA,48,48%,30%reduction,Orrick et al,19%,platelet count less than 10010,9,/L,Janpan,42,16.7%,defined as a 10010,9,/L decrease from the baseline or a 25%reduction,Niwa et al,Janpan,331,38.7%,defined as a 10010,9,/L decrease from the baseline or a 30%reduction,Yoshiko takahashi et al,Chinese,254,27.2%,platelet count less than 10010,9,/L,this study,51.6%,defined as a 10010,9,/L decrease from the baseline or a 25%reduction,结果与国外文件报道相近,显著高于产品资料所报道,期临床研究结果,轻中度血小板下降很常见（,10%,）,存在出血倾向,血小板下降常见,利奈唑胺相关血小板减少,第9页,结果,差异性分析,Risk factors Analysis of Thrombocytopenia,Criterion 1,+chi-square test#t-test *Mann-Whitney U-test,Variables,a final platelet count,10010,9,/L,P value,Patients 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*,利奈唑胺相关血小板减少,第10页,结果,差异性分析,Risk factors Analysis of Thrombocytopenia,Criterion 2,Variables,25%decrease or a final platelet count,100109/L,P value,Patients 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,利奈唑胺相关血小板减少,第11页,结果,单原因分析,Risk factors for thrombocytopenia selected by logistic regression,univariate analysis,Risk factors,25%decrease or a final platelet count,100109/L,a final platelet count,100109/L,Odds ratio,95%CI,P value,Odds ratio,95%CI,P value,Age(years),1.02,1.00-1.03,0.0112,1.02,1.00-1.04,0.0165,Weight(kg),0.97,0.95-0.99,0.0018,0.98,0.95-1.00,0.0308,Creatinine clearance(mL/min),0.99,0.99-1.00,0.0022,0.99,0.99-1.00,0.0361,Albumin(g/L),0.93,0.89-0.98,0.0031,0.94,0.89-0.99,0.0131,Daily dose(mg/kg),1.14,1.07-1.21,0.0001,1.09,1.02-1.16,0.0088,Baseline platelet(109/L),1.00,0.99-1.00,0.1771,0.99,0.98-0.99,0.0000,Treatment duration(d),1.07,1.02-1.12,0.0088,1.05,1.00-1.10,0.0632,Criterion 2,Criterion 1,利奈唑胺相关血小板减少,第12页,Multivariate Analysis,Risk factors,25%decrease or a final platelet count,100109/L,a final platelet count,100109/L,Odds ratio,95%CI,P value,Odds ratio,95%CI,P value,Creatinine clearance(mL/min),0.995,0.990-1.000,0.0351,Albumin(g/L),0.949,0.904-0.996,0.0323,Daily dose(mg/kg),1.12,1.047-1.198,0.0010,1.081,1.007-1.161,0.0308,Baseline platelet(109/L),0.987,0.982-0.992,0.0001,Treatment duration(d),1.061,1.005-1.120,0.0317,结果,多原因分析,Risk factors for thrombocytopenia selected by logistic regression,Criterion 2,Criterion 1,利奈唑胺相关血小板减少,第13页,结果,ROC,曲线,Clinical,features of thrombocytopenia,predicated,by,ROC curves,Criterion 1,Youden index,：,0.4306,area under ROC curve,：,0.757,baseline platelet value,：,18110,9,/L,daily dose,：,18.75 mg/kg/d,duration of medication,：,10 d,Criterion 2,Youden index,：,0.3703,area under ROC curve,：,0.706,creatinine clearance,：,88.39 mL/min,serum albumin,：,33.5 g/L,daily dose,：,18.46 mg/kg/d,PLT 20010,9,/L,Ccr 30 mL/min,Ccr 50 mL/min duration,14,d,sensitivity65.22%,Specificity77.84%,Sensitivity63.07%,Specificity73.95%,利奈唑胺相关血小板减少,第14页,每日剂量,risk increase,daily dose 18.75 mg/kg/d,body weight 64kg,a protective factor of thrombocytopenia:body weight,higher drug exposure induced thrombocytopenia,independent risk factor for mild&severe PLT decrease,linezolid-related thrombocytopenia is characterized as,drug concentration-dependent,dosage adjustment according to body weight,may help to reduce the risk of linezolid-related thrombocytopenia in Chinese population,利奈唑胺相关血小板减少,第15页,基线血小板,baseline platelet,18110,9,/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),ROC cut-off point(Criterion 1):10 days,independent risk factor for,severe,thrombocytopenia,confirm,ed,the findings of reports&drug instruction,longer treatment need more clinical blood tests,利奈唑胺相关血小板减少,第17页,肌苷去除率,Wu VC et al.,A retrospective case-control study,Two groups:end-stage,or,non-end-stage renal disease,s,incidence of thrombocytopenia is higher in the group with,end-stage renal disease,Brier et al.the clinical significance of accumulation of two,metabolites,PNU-142586,PMU-142300,Wu VC et al.Clin Infect Dis;42:66-72.,Brier et al.Antimicrob Agents Chemother;47:2775-80.,Higher incidence in the group with,severe renal,impairment,Creatinine clearance as the indicator of renal function,the ROC cut-off point(Criterion 2)creatinine clearance 88.39 mL/min,Mild PLT decrease may occur when creatinine clearance rate is at its lower limit,while there is still no sign of renal insufficiency.,Ccr30 severe renal impairment,(48%15/31 vs.24%54/222,P=0.005,OR=2.92,95%CI1.396.14,）,利奈唑胺相关血小板减少,第18页,结 论,Situation in Chinese patients,actual incidence is much higher than in drug instructions,hemorrhagic tendency,Risk factors,low pre-treatment platelet values,low body weight,low serum albumin,long time of administration,Advanced age,renal impairment,Predictors,baseline platelet 18110,9,/L,daily dose 18.75 mg/kg,duration of linezolid therapy 10 d,Strategy,strengthen monitoring frequency according to risk factors,dosage adjustment according to body weight(PK/PD),利奈唑胺相关血小板减少,第19页,