肝硬化患者合并曲霉菌感染患者医学PPT

重度肝硬化合并曲霉菌感染患者使用伏立康唑剂量的调整,患者男，56岁，身高176cm，体质量100kg，因HBsAg阳性6年，乏力、尿黄1月余，发热伴咯血3天入院。检查提示：ALT218UL，AST167UL，总胆红素409mol/L。双肺CT平扫：双肺多发大小不等类圆形高密度影，其内可见空洞。临床诊断：1、乙型病毒性肝炎、肝炎肝硬化；2、急性肝功能衰竭；3肺部感染；4慢性肾功能不全。给予护肝、降酶、退黄、哌拉西林他唑巴坦抗感染治疗、免疫等对症治疗。住院期间2次痰培养均为烟曲霉菌，给予卡泊芬净治疗1周后患者咳痰增多，发热，最高达392。外院专家会诊建议加用伏立康唑治疗。,肝功能损害者用药,急性肝损害者（ALT、AST增高）：无需调整剂量，但监测肝功能。轻度到中度肝硬化患者（Child-Pugh A 和B）：建议伏立康唑的负 荷剂量（6mg/kg）不变，但维持剂量减半。 重度肝硬化者（Child-Pugh C）：目前尚无研究。,ABX指南肝功能受损时剂量：轻中度肝功能不全：6mg/kg q12h(负荷量)，其后2mg/kg iv q12h，监测血药浓度。抗微生物治疗指南（热病41版）IV:6mg/kg q12h治疗侵袭性曲霉菌病和严重霉菌感染：4mg/kg q12h,有中度肝脏损伤者，维持剂量减半。,检索文献,检索工具： 数据库：CNKI、Pubmed 检索途径：高级检索 关键检索词：伏立康唑、肝功能异常 （Voriconazolen、 Liver Cirrhosis、severe liver dysfunction ） 检索时间：2005-2017年检索结果：中文文献（38篇）、英文文献（24篇）文献筛选原则：研究内容的有效性、文献类型（系统评 价或meta分析、RCT、综述等）、新颖度、质量等文献筛选结果：4篇,Altered Pharmacokinetics of Voriconazolen a Patient with Liver Cirrhosis,A 45-year-old male (body weight, 100 kg) Fatty-liver cirrhosis (Child-Pugh class C; model of end-stage liver disease score, 20) who was listed for liver transplantation and showed signs of portal hypertension (esophageal varices and ascites) and cholestasis (plasma bilirubin level, 20.26 mg/dl, or 346 mol/liter) Received 2 mg of VRC/kg of body weight orally twice a day because of suspected pulmonary aspergillosis. At day 30 of clinical treatment with VRC, he was transferred to the ICU because of unconsciousness (Glasgow Coma Scale score, 5 of 15) and hyperventilation.,文献1：肝硬化患者使用伏立康唑的药代动力学变化,半衰期：4.7h,53.1h,清除率：253.9 1.4mg/h/kg,文献1：肝硬化患者使用伏立康唑的药代动力学变化,conclusions：In patients with moderate liver cirrhosis (Child-Pugh class B),a reduction of the maintenance dose by 50% is recommended for patients with mild to moderate hepatic insufficiency.For patients with severely impaired liver function, a dose reduction of more than 50% appears to be required, and therapeutic drug monitoring will greatly improve therapeutic safety.,文献1：肝硬化患者使用伏立康唑的药代动力学变化,Between 1999 and 2009, we screened all adult patients admitted to the Liver Intensive Therapy Unit (LITU) at Kings College Hospital in London and identified patients who had a Model for End Stage Liver Disease (MELD) greater than 9 and had received at least 4 doses of voriconazole.,文献2：伏立康唑在严重肝功能障碍患者的肝毒性,文献2：伏立康唑在严重肝功能障碍患者的肝毒性,给予负荷剂量的患者有13人（44.8%），其余16人直接给予治疗剂量。平均负荷剂量：30245.9mg/day or 4.60.7mg/kg/day (200-400mg/day; 3.3-5.5mg/kg/day)治疗剂量：218.641.4mg/day or 3.630.7mg/kg/day (160-300mg/day; 2.58-4.33mg/kg/day)给药次数：25人为Qd，4人为Bid平均治疗天数：39.751.7days（5-180days）,文献2：伏立康唑在严重肝功能障碍患者的肝毒性,文献2：伏立康唑在严重肝功能障碍患者的肝毒性,69% of patients treated with voriconazole showed changes in liver functiontests (LFTs) during therapy. The control group developed alterations in the LFTs in only 10.3% of patients.They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p 0.001).,Voriconazole hepatotoxicity in severe liver Dysfunction. Journal of Infection (2013) 66, 80-86,文献2：伏立康唑在严重肝功能障碍患者的肝毒性,文献3 伏立康唑联合卡泊芬净成功治疗2例肝功能衰竭 合并侵袭性肺曲霉菌病,说明卡泊芬净与伏立康唑联用有一定的协同作用,Li D，Chert L，Ding X，et a1Hospitalacquired invasive pulmonary aspergillosis in patients with hepatic failureJBMC Gastroenterol，2008，31：32,本研究中2例患者均采用了伏立康唑+卡泊芬净静脉应用和两性霉素B脂质体雾化吸入的三联抗曲霉菌治疗，未出现因药物因素导致的肝功能和(或)肾功能进一步加重的表现，耐受性较好，并于联合用药后感染得到控制并逐渐好转。,文献4、末期肝病或急性肝衰竭患者曲霉菌感染,Treatment of IA is challenging in patients with severe liver disease. The drug of choice is voriconazole, but this drug is potentially hepatotoxic and is metabolized by cytochrome P-450 isoenzymes causing important drug interactions . Thus, it should be used with caution in patients with severe hepatic failure. The alternative options are represented by lipid-formulations of AMB, which are less nephrotoxic than AMB deoxycholate.,Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. J Hepatol 2008; 48 (Suppl. 1):S93 103,文献三,文献4、末期肝病或急性肝衰竭患者曲霉菌感染,1、关于重度肝功能异常患者使用伏立康唑研究目前甚少，且具体给药剂量调整无法统一，今后仍需更多研究以评估和指导临床应用。2、目前研究的文献量数量少，局限性大，缺乏大规模的药动学、安全性等方面的研究。3、目前研究无法明确种族、基因型的差别对伏立康唑药动学及药效学的影响，有待临床进一步研究，明确并指导临床合理用药。,体会与建议,对于重度肝功能异常患者可用伏立康唑，应监测肝功 能变化和血药浓度，提高治疗的安全性和有效性。对于重度肝功能异常患者使用伏立康唑负荷剂量应小于300mg(4.5 mg/kg) ，维持剂量应减少高于50% 。棘白菌素类与唑类联合使用有一定的协同作用，对于侵袭性肺曲霉菌患者，也可以选择两性霉素B脂质体作为替代药物。,体会与建议,Altered Pharmacokinetics of Voriconazole in a Patient with Liver CirrhosisJ. Antimicrobial agents and chemotheray，Sept. 2007, 3459-3460Paniagua Martin MJ，Marzoa Rivas R，Barge Caballero E，eta1Efficacy and tolerance of different types of prophylaxis for prevention of early aspergillosis after heart transplantationJTransplant Proc，2010，42：3014-3016Invasive aspergillosis in patients with liver diseaseJ. Med Mycol2011 May;49 (4): 406-13王玮，赵