利奈唑胺相关血小板减少.ppt

利奈唑胺相关性血小板减少,陈 超 解放军总医院 药品保障中心 临床药学室,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.,Linezolid,oxazolidinone antibiotics 2000 FDA 2007 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. 2005;171:388-416. ATS/IDSA(2005) guidelines for the management of adults with HAP/VAP/HCAP,血小板减少症 -来自临床的声音,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&耐受性,上市后监测 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,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,资料&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 screened,7 Patients were excluded due to younger than 18 years old,血小板减少症评价,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 100×109/L or more than 400×109/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&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 ×109/L,25% reduction from baseline platelet count or less than 100 ×109/L,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,结果与国外文献报道相近 显著高于产品资料所报道的期临床研究结果 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,结果 差异性分析,Risk factors Analysis of Thrombocytopenia Criterion 1,+ chi-square test # t-test * Mann-Whitney U-test,结果 差异性分析,Risk factors Analysis of Thrombocytopenia Criterion 2,+ chi-square test # t-test * Mann-Whitney U-test,结果 单因素分析,Risk factors for thrombocytopenia selected by logistic regression,Criterion 2,Criterion 1,结果 多因素分析,Risk factors for thrombocytopenia selected by logistic regression,Criterion 2,Criterion 1,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 ： 181×109 /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 200×109 /L Ccr 30 mL/min Ccr 50 mL/min duration 14 d,sensitivity65.22% Specificity77.84%,Sensitivity63.07% Specificity73.95%,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,基线血小板,baseline platelet 181×109/L are more likely to suffer from thrombocytopenia than others (45.9% 39/85 vs. 17.8% 30/169, P0.001) OR=3.93，95%CI 2.246.90 N=254,independent risk factor for severe thrombocytopenia,Grau et al. show that thrombocytopenia is more likely to occur in patients with baseline platelet 240.7×109 /L (8/18, 44.4%) compared with that in other patients (4/31, 12.9%, P=0.018) OR=2，95%CI 0.557.33 N=49,用药时间,Drug instruction the recommended duration : 10-14 days Gerson SL et al. -prolonged use of linezolid ( 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,confirmed the findings of reports& drug instruction longer treatment need more clinical blood tests,肌苷清除率,Wu VC et al. A retrospective case-control study Two groups:end-stage or non-end-stage renal diseases 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 2006; 42: 66-72. Brier et al. Antimicrob Agents Chemother 2003; 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）,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 181×109/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),Thank you for your attention,