中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 薛晓燕
目的 探讨临床药师在参与制定疑难侵袭性真菌感染患者抗感染治疗方案中的作用,为临床治疗侵袭性真菌感染积累经验。方法 1例隐球菌脑膜炎患者,氟康唑治疗5周后,脑脊液中仍能找到隐球菌,临床药师建议给予两性霉素B脂质体联合氟胞嘧啶的补救诱导治疗;另1例尿路来源的白念珠菌血症患者,初始卡泊芬净治疗效果不佳,临床药师建议换用在尿液中有较高浓度的氟康唑。结果 在临床药师参与下,2例患者感染逐渐被控制,病原菌得到清除。采用两性霉素B脂质体联合氟胞嘧啶诱导、氟康唑巩固的方案治疗隐球菌脑膜炎,采取氟康唑治疗来源于尿路的念珠菌血症,均取得较好疗效。结论 临床应充分重视临床药师在治疗方案制定中的作用。
近年来,随着免疫缺陷患者如恶性肿瘤、血液病、艾滋病和使用免疫抑制药的器官移植或自身免疫性疾病患者增多,侵袭性真菌感染(invasive fungal infections,IFI)发病率急剧上升,其病原体也发生了很大变化[1]。在机会性真菌致病菌中最重要的是白念珠菌、新型隐球菌和曲霉菌,上述真菌感染不但诊断困难,且病死率高,是临床治疗的难点和热点问题。自2003年起,我院临床药师参与临床用药,接受临床疑难感染病例会诊,提供用药方案,进行药学监护等,现将临床药师会诊中遇到的2个疑难病例报道如下。
患者,女,21岁,患系统性红斑狼疮、狼疮性肾炎6年余。2010年6月开始服用吗替麦考酚酯分散片,0.5 g,po,bid;泼尼松10 mg,po,qd。并行规律血液透析。2016年1月18日无明显诱因出现畏寒、发热,体温最高38.2 ℃。2016年1月26日开始头痛,伴有恶心、呕吐。2016年1月28日以“发热查因:支气管炎?系统性红斑狼疮,狼疮性肾炎,慢性肾脏病5期,维持血液透析治疗”收住肾内科。血常规:白细胞(WBC)8.5×109·L-1、中性粒细胞百分比(percentage of neutrophils,N%)95%、C反应蛋白(C-reaction protein,CRP)92.89 mg·L-1、降钙素原(procalcitionin,PCT)0.803 ng· mL-1;头部磁共振成像(magnetic resonance imagin,MRI)示:脑实质内未见异常信号影;尿常规:WBC 591个· μL-1。疑为呼吸道感染、尿路感染,先后给予头孢呋辛、头孢哌酮/他唑巴坦、头孢泊肟酯片治疗15 d,但仍间有发热,体温37.2~38.5 ℃,头痛逐渐加重,伴恶心,呕吐胃内容物(非喷射性)。
2016年2月13日,考虑患者可能存在中枢神经系统感染,行腰椎穿刺。脑脊液压力>2.94 kPa;脑脊液常规、生化:WBC 0.154×109·L-1、单个核细胞百分比 90%、多叶核细胞百分比 10%(
表1 脑脊液检查结果汇总
Tab.1 Results summary of cerebrospinal fluid test
2016年3月24日,患者退热已2周,头痛基本缓解,抗真菌治疗已足30 d,临床药师会诊认为:患者目前治疗有效,但诊断不明确,仍不能排除隐球菌性脑膜炎的可能。建议:①继续目前抗感染方案不变,复查脑脊液常规、生化,若脑脊液压力正常,可考虑给予氟康唑胶囊400 mg,po,qd,6~8个月序贯治疗;②请上级医院微生物专家协助行脑脊液沉渣真菌培养,脑脊液墨汁染色,寻找隐球菌依据;③监测肝、肾功能。2016年3月26日,患者脑脊液墨汁染色找到隐球菌,每个高倍镜视野8~10个隐球菌;脑脊液培养检出新型隐球菌,对两性霉素B、氟胞嘧啶、氟康唑、伏立康唑、伊曲康唑均敏感。临床药师会诊认为:患者隐球菌性脑膜炎诊断明确。建议调整治疗方案为:①诱导治疗,两性霉素B脂质体 3 mg·kg-1·d-1+5%葡萄糖注射液500 mL,静脉滴注,qd;氟胞嘧啶37.5 ng·kg-1·d-1,po,qd(透析后给药),至少8周;②巩固治疗,氟康唑400 mg,po,qd,至少12周;两性霉素B脂质体:起始剂量0.1 mg·kg-1·d-1,使用过程中注意避光,以注射用水溶解后加5%葡萄糖注射液500 mL缓慢静脉滴注(浓度<0.15 mg· mL-1,速度<30滴·min-1),剂量逐日增加0.25~0.5 mg·kg-1·d-1,直至3 mg·kg-1·d-1,静脉滴注过程中监测体温、脉搏、呼吸、血压。医师采纳建议。
2016年5月22日,两性霉素B脂质体联合氟胞嘧啶诱导治疗8周结束,患者无发热,透析时间轻微头痛。考虑患者病情明显好转,转换治疗方案为氟康唑400 mg,po,qd。2016年6月8日,患者无发热、头痛,病情稳定,办理出院,嘱继续每天口服氟康唑胶囊400 mg,完成共12周的巩固治疗。2016年8月15日,患者完成随访计划,未诉明显不适,脑脊液压力、常规、生化均正常,脑脊液墨汁染色未找到隐球菌。见
新型隐球菌(
《隐球菌感染诊治专家共识》[5]和美国《隐球菌病临床处理实践指南》[6]推荐两性霉素B联合氟胞嘧啶用于隐球菌性脑膜炎的诱导治疗,而氟康唑用于巩固和维持治疗。与氟康唑相比,两性霉素B具有在脑脊液内杀菌作用更快、死亡率更低的特点;而氟康唑易产生原发性或继发性耐药,仅在医疗资源贫乏地区推荐用于隐球菌性脑膜炎的全程治疗[6],或用于两性霉素B不能耐受或疗程延长者[7]。但与两性霉素B相比,氟康唑具有不良反应少、可透过血脑屏障、有吸收好的口服制剂等优点,同时其比两性霉素B脂质体更经济。临床药师初次(2016年2月21日)会诊时,考虑虽然哌拉西林/他唑巴坦剂量稍显不足,但患者在尿常规白细胞已有所下降的情况下(提示尿路感染好转)仍有发热,且头痛、呕吐进行性加重,脑脊液压力明显增高,故结合该患者的临床症状和脑脊液常规、生化检查,已高度怀疑其患隐球菌性脑膜炎。然而该患者多次脑脊液涂片和培养均未能找到隐球菌,无法确诊。鉴于家属对两性霉素B不良反应的担忧,权衡利弊,临床药师建议选用氟康唑。2016年3月26日,患者脑脊液墨汁染色、真菌培养均找到隐球菌,明确了隐球菌性脑膜炎的诊断。但患者此时使用氟康唑抗感染治疗已1个月,发热、头痛、呕吐已明显缓解,是继续维持治疗还是进行补救治疗,《指南》未明确推荐,笔者也未见相关文献报道。但临床药师第3次会诊时,仍建议给予患者两性霉素B联合氟胞嘧啶的补救诱导治疗,理由如下:①患者经过氟康唑治疗1个月,脑脊液压力仍高,涂片仍可找到隐球菌,提示氟康唑对脑脊液中隐球菌的杀灭效果不佳;②初始诱导治疗采用氟康唑,有发生原发及继发性耐药的风险[6];氟康唑对新生隐球菌耐药日趋增多[8-10];目前国内虽有大剂量氟康唑用于隐球菌脑膜炎治疗的报道[11],但其疗效并未获得认可。该患者按此方案规范完成治疗疗程,最终取得较好效果。
新型隐球菌外周有一层3~5 μm厚的胶质样荚膜,一般染色法不易着色,因而被称为“隐球菌”。直接涂片墨汁染色是一种快速检测隐球菌的方法,将脑脊液和印度墨汁混合到洁净载玻片上,盖上盖玻片,显微镜下即可看到圆形或卵圆形的透亮菌体。虽然是一种经典、简单的方法,但涂片不均匀、杂质污染以及检验人员对隐球菌镜下形态识别经验不足等均易造成阳性率低[12],有报道通过3~7次墨汁涂片或脑脊液培养才找到隐球菌[13],故涂片需找有经验的技术员检查,以免漏诊或误诊。该患者初始3次脑脊液墨汁染色均未找到隐球菌,第4次在上级医院微生物专家指导下检测到了隐球菌,提示我院实验室技术人员仍需加强隐球菌检测能力的培养。
两性霉素B脂质体具有极高的蛋白结合率(90%),表观分布容积约131 L·kg-1,其分布与普通两性霉素B不同,较多地分布在肝、脾、肺,在肾组织内浓度较低。经肾脏缓慢排泄,呈现非线性消除,消除半衰期约153 h,透析后无需补充剂量[14]。该患者根据说明书(药品商品名:锋克松),两性霉素B脂质体逐渐加量至3 mg·kg-1·d-1,临床未出现严重不良反应。治疗过程中临床药师还对患者进行了密切药学监护:①嘱医师应以5%葡萄糖注射液作为溶剂(若以氯化钠为溶剂,配伍后2 h内会出现沉淀,有效药物含量降至57%);嘱护士输液瓶用黑色胶袋包裹,以免药物效价降低;②嘱医师两性霉素B应从小剂量开始,起始剂量0.1 mg·kg-1·d-1,剂量逐日增加0.25~0.5 mg·kg-1·d-1,直至3 mg·kg-1·d-1,每次滴注时间不少于8 h。滴注前30 min给予异丙嗪注射液25 mg肌内注射,以减轻因输液引起的发热和寒战[15];③滴注过程中,临床药师还密切监护患者发热、寒战、恶心等症状,并监测心率、血压以及肝肾功能,根据患者的耐受情况决定次日的药品增加剂量。总之,整个治疗过程中临床药师实施了密切的药学监护,最大程度地减少了两性霉素B可能导致的不良反应。
患者,女,37岁,既往有1型糖尿病病史1年,未规律治疗;右肾结石病史1年余。2016年10月26日因“右侧腰痛,伴畏寒、发热”在外院治疗,体温最高40 ℃;WBC 23.0×109·L-1;血肌酐(Ccr)629 μmol·L-1;B超:右肾多发结石、右侧输尿管上端结石、伴右肾轻度积水。2016年10月28日考虑病情危重转至我院重症监护室(intensive care unit,ICU)。
入院后血常规:WBC 20.78×109·L-1、N% 91%;CRP 128.89 mg·L-1;PCT>100 ng· mL-1;尿常规:WBC 130个· μL-1;血气分析示代谢性酸中毒;脑利钠肽(brain natriuretic peptide,BNP)6 453 pg· mL-1;肾功能血尿素氮(BUN)17.35 mmol·L-1、Ccr 636.7 μmol·L-1;B超:①右侧输尿管上段扩张并右肾积水,右肾结石;②左肾体积缩小;床边胸片:肺部感染、肺水肿、肺淤血,提示急性左心功能不全。诊断为“①脓毒血症;②泌尿道感染;③肺部感染;④1型糖尿病;⑤心功能不全;⑥糖尿病肾病、肾功能不全、代谢性酸中毒;⑦右肾多发结石;⑧右侧输尿管结石”。给予亚胺培南/西司他丁钠1.0 g+0.9%氯化钠注射液100 mL,静脉滴注,q8h;万古霉素1.0 g+0.9%氯化钠注射液100 mL,静脉滴注,q24h;连续肾脏替代疗法(continuous renal replacement therapy,CRRT)清除炎症递质。
2016年11月1日,尿培养(2016年10月29日送检):检出白念珠菌,对两性霉素B、氟胞嘧啶、氟康唑、伏立康唑、伊曲康唑敏感。医师考虑定植菌,未予处理;血培养(2016年10月29日送检):无菌生长。患者仍持续发热,体温最高39.5 ℃,感染控制不佳。2016年11月1日行右侧输尿管内支架植入术,术中留置输尿管内支架管后有炎性尿液流出,考虑右肾积脓,予留置导尿,术中送脓性分泌物培养。2016年11月3日尿培养(2016年11月1日术中送检)、2016年11月5日双侧手臂静脉血培养(2016年11月2日送检)均检出白念珠菌,对两性霉素B、氟胞嘧啶、氟康唑、伏立康唑、伊曲康唑均敏感;(1,3)-
2016年11月11日双侧手臂静脉血培养(11月8日送检):再次检出白念珠菌,对两性霉素B、氟胞嘧啶、氟康唑、伏立康唑、伊曲康唑均敏感;复查G试验>1 000 pg· mL-1;复查泌尿系CT示:原右侧输尿管上段结石碎裂下移,右肾积水及肾周炎症减轻,仍伴明显积水。临床药师会诊建议:①换用氟康唑400 mg+0.9%氯化钠注射液250 mL,静脉滴注,qd(首剂800 mg)抗感染治疗;②请泌尿外科医师对右肾积水梗阻进行干预;③行眼底检查,及早发现可能发生的念珠菌眼内炎;④行心脏彩超检查,及早发现可能发生的感染性心内膜炎,必要时拔除中心静脉导管;⑤监测体温、血常规、CRP、PCT、G试验以及肾功能变化。医师换用氟康唑。同时再次请泌尿外科行更换输尿管内支架术,术中见输尿管口大块结石,予碎石及取石,见大量脓尿流出;请眼科会诊,未见明显异常;心脏彩色多普勒检查未见明显异常;拔除右侧中心静脉导管,停CRRT治疗。
2016年11月13日,患者体温逐渐下降,2016年11月18日体温正常,感染指标明显好转;胸部、盆腔CT示:①双肺病灶较前片明显吸收、好转,双侧胸腔积液较前吸收;②右肾积水及肾周炎症较前减轻。考虑患者感染症状好转,停万古霉素、亚胺培南/西司他丁,换用哌拉西林/他唑巴坦2.5 g+0.9%氯化钠注射液250 mL,静脉滴注,q8h降阶梯治疗;2016年11月21日,患者两次血培养均示无菌生长。医师再次请临床药师调整抗真菌治疗方案,临床药师建议:氟康唑400 mg,po,qd,序贯治疗,总疗程2周。医师采纳。2016年12月5日,患者神志清楚,未诉不适,复查血常规、尿常规、PCT、G试验均正常;肾功能BUN 14.3 mmol·L-1、Ccr100.9 μmol·L-1,明显好转,考虑患者病情恢复,给予办理出院。嘱内分泌科随诊控制血糖,泌尿外科随诊,及时拔除泌尿道内置支架。
念珠菌血症是侵袭性念珠菌病最常见的临床表现,其常源于消化道或皮肤定植的念珠菌,而尿路结石手术也是导致尿路定植念珠菌入血的常见原因[16]。该患者具有尿路梗阻、糖尿病等尿源性脓毒血症的高危因素[17],初始又存在尿路白念珠菌感染,2016年11月3日行“右侧输尿管内支架植入术”可能为白念珠菌入血直接原因。术后患者持续高热,多次双侧手臂静脉血培养均检出白念珠菌,且G试验>1 000 pg· mL-1,故认为白念珠菌血症诊断明确。
念珠菌血症病死率高达47%[18-19],而抗真菌治疗的时间点以及感染源的控制与死亡率密切相关[20]。2016年《美国念珠菌病治疗临床实践指南》[20]对于非中性粒细胞减少念珠菌血症患者,推荐初始治疗首选棘白菌素类药物。但对于棘白菌素能否控制导致血流感染的源头,指南并未给予说明和推荐。给予该患者卡泊芬净50 mg静脉滴注,qd(首剂70 mg)治疗4 d,剂量加倍3 d后,仍有反复发热、G试验>1 000 pg·μL-1,提示抗感染效果不佳。故临床药师初次会诊建议换用氟康唑,理由如下:①卡泊芬净在尿液中原形浓度约1.4%[21],不足以杀灭尿路白念珠菌,无法控制脓毒血症感染源,可能是治疗效果不佳的原因。氟康唑在尿液中原形的浓度达到80%,可加快尿中念珠菌清除,有助于控制感染源;②棘白菌类药物存在“矛盾现象”,即棘白菌素类药物质量浓度较低时,真菌对其表现为敏感,但随着治疗浓度升高,真菌对其敏感性下降,该现象常见于白念珠菌和热带念珠菌[22]。该患者在卡泊芬净加大剂量后抗感染效果仍不佳,提示病原菌可能对其敏感性下降;③患者无氟康唑暴露史,且多次血培养检出的病原菌均为白念珠菌,非对氟康唑敏感性低的光滑念珠菌和克柔念珠菌,体外药敏也显示对氟康唑其敏感,故建议换用氟康唑。当然,感染灶的清除在脓毒血症的控制中也具有重要地位[23],考虑该患者尿路梗阻解除不彻底,导致右肾持续积水,可能也是抗感染效果不佳的原因,故临床药师同时建议请泌尿外科会诊再次手术解除右肾梗阻。而氟康唑在CRRT时的剂量,临床药师根据相关文献[24]建议给予400 mg静脉滴注,q24h,抗感染疗程根据指南[21]建议至连续2次血培养阴性和感染症状缓解之后2周,医师采纳建议。
3种棘白菌素类药物(卡泊芬净、米卡芬净、阿尼芬净)对念珠菌属均具有较强杀菌活性,对唑类药物耐药率较高的光滑念珠菌和克柔念珠菌均有较低的MIC值[25]。其血浆峰浓度可达到6~16 μg· mL-1,对于念珠菌血症,无论是否有中性粒细胞减少,均是一线治疗药物。在临床试验中,卡泊芬净治疗念珠菌血症比使用两性霉素B具有更好的耐受性和更高的成功率[26]。而关于侵袭性念珠菌病治疗的随机试验的汇总分析,也表明初始棘白菌素治疗具有较好的生存优势[27]。同时棘白菌素主要通过非酶途径代谢,不影响细胞色素P450,药物相互作用以及不良事件更少,无需因肾功能不全或透析调整剂量。但由于棘白菌素对脑膜和玻璃体的穿透性差,在尿液中的浓度低于10%[21,28],因此其不宜用于中枢神经系统、玻璃体以及尿路念珠菌属感染。而唑类药物(氟康唑、伊曲康唑、伏立康唑)对光滑念珠菌和克柔念珠菌的抗菌活性均较低,氟康唑注射液作为棘白菌素治疗念珠菌血症的替代方案,可用于非氟康唑耐药的念珠菌属感染的患者;同时对氟康唑敏感的念珠菌(如白念珠菌)感染,初始抗真菌治疗有效血培养结果阴性后,可将棘白霉素类更换为氟康唑进行序贯治疗;而可加大氟康唑和伏立康唑的剂量用于光滑念珠菌感染的患者[20]。除了氟康唑在尿中浓度较高(原形80%),可用于尿道感染以外,其余唑类药物以原形从尿道排泄均不足30%,一般不用于尿道感染。但氟康唑治疗念珠菌血症具有比棘白霉素更经济的优点,伏立康唑则与棘白霉素相当。
念珠菌血症常见并发症为血流播散导致其他组织器官感染,如眼内炎、脑膜炎和骨髓炎。因此临床药师会诊时建议及时行眼底检查以排除眼内炎、心脏彩超检查以排除心内膜炎,结果显示患者并未出现上述并发症。同时在治疗过程中临床药师也多次回访患者,监护其视觉及转氨酶,以及有无恶心、呕吐等不良反应。
本文中2例侵袭性真菌感染病例,第1例为隐球菌脑膜炎,初始氟康唑抗感染治疗有效,但在明确诊断后,是继续维持治疗还是给予补救治疗,指南无明确指引,笔者也未见相关文献报道,临床药师分析两种治疗方案的优缺点,给予了两性霉素联合氟胞嘧啶的补救诱导治疗,取得了较好的效果;第2例为尿路来源的白念珠菌血症,初始给予卡泊芬净治疗,效果不佳。此时该如何调整治疗方案,是一个需要仔细思考的问题。临床药师根据所掌握的药动学知识,建议换用在尿液中有较高浓度的氟康唑,同时充分引流,有效控制了感染。治疗过程中,临床药师还根据患者个体情况,查阅大量相关文献制定给药剂量,并对患者进行了密切的药学监护,赢得了医生和患者的信任。
The authors have declared that no competing interests exist.
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Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et l. appearing elsewhere in this supplement).
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1简介 隐球菌属在真菌分类学上归人半知菌亚门、芽孢菌纲、隐球酵母目、隐球酵母科，引起人类感染的隐球菌主要是新生隐球菌和格特隐球菌。两种隐球菌的无性繁殖体均为无菌丝的单芽孢酵母样菌，在体外为无荚膜或仅有小荚膜，进入人体内后很快形成厚荚膜，有荚膜的隐球菌菌体直径明显增加，致病力明显增强。
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Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.
[本文引用:3]
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Abstract OBJECTIVES: Cryptococcal meningitis is the third-most-common opportunistic infection in HIV patients in Cambodia. Hospitalized patients were given amphotericin B for initial therapy followed by fluconazole for maintenance therapy. The antifungal drug susceptibility of Cryptococcus neoformans isolated from cerebrospinal fluid (CSF) was determined. METHODS: Isolates of C. neoformans were collected during active laboratory-based surveillance, the first batch from April 2000 to March 2001 (134 new cases), the second batch from April 2001 to March 2002 (268 new cases). Etest strips were used to determine the MICs of amphotericin B and fluconazole. The antigenic agglutination slide test was used for serotyping. RESULTS: The MIC(50)s and MIC(90)s of fluconazole changed significantly from year 2000 to 2002; the MIC(50)s increased from 4 to 12 mg/L, and the MIC(90)s from 12 to 96 mg/L. For amphotericin B, the MIC(50)s and MIC(90)s remained stable. Moreover, in the second batch, fluconazole MICs were >/=256 mg/L for 20 isolates. By serotyping, it was found that 98.5% of the isolates were serotype A. CONCLUSIONS: C. neoformans strains isolated from CSF of AIDS patients in Cambodia remain susceptible in vitro to amphotericin B. These strains are less susceptible in vitro to fluconazole, 2.5% being resistant in the first year and 14% in the second year of study. Nevertheless, in vitro resistance of C. neoformans to fluconazole appeared to be linked to extended maintenance treatments.
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Invasive candidiasis (IC) is a leading cause of mycosis-associated mortality in the United States. We examined data from the National Center for Health Statistics and reviewed recent literature in order to update the epidemiology of IC. IC-associated mortality has remained stable, at approximately 0.4 deaths per 100,000 population, since 1997, while mortality associated with invasive aspergillosis has continued to decline. Candida albicans remains the predominant cause of IC, accounting for over half of all cases, but Candida glabrata has emerged as the second most common cause of IC in the United States, and several less common Candida species may be emerging, some of which can exhibit resistance to triazoles and/or amphotericin B. Crude and attributable rates of mortality due to IC remain unacceptably high and unchanged for the past 2 decades. Nonpharmacologic preventive strategies should be emphasized, including hand hygiene; appropriate use, placement, and care of central venous catheters; and prudent use of antimicrobial therapy. Given that delays in appropriate antifungal therapy are associated with increased mortality, improved use of early empirical, preemptive, and prophylactic therapies should also help reduce IC-associated mortality. Several studies have now identified important variables that can be used to predict risk of IC and to help guide preventive strategies such as antifungal prophylaxis and early empirical therapy. However, improved non-culture-based diagnostics are needed to expand the potential for preemptive (or early directed) therapy. Further research to improve diagnostic, preventive, and therapeutic strategies is necessary to reduce the considerable morbidity and mortality associated with IC.
[本文引用:0]
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目的:评价1例氟康唑耐药隐球菌肺炎的治疗方案,考察药物治疗效果.方法:查阅大量国内外文献报道,参考 隐球菌病治疗指南,综述氟康唑耐药隐球菌肺炎的药物治疗方案.结果:临床药师参与药物治疗过程,根据循证医学证据选择合理用药.结论:采用伏立康唑、泊沙 康唑或者联合治疗方案应对氟康唑耐药隐球菌感染,可取得较好疗效.
[本文引用:1]
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新型隐球菌脑膜炎是由新型隐球菌感染引起的脑膜炎,是中枢神经系统最常见的真菌感染,其病情 重,病死率高,起病隐匿,临床症状、体征和脑脊液检查缺乏特异性,极易误诊。本文将1995-01/2008-12住我院经明确诊断为新型隐球菌脑膜炎的 35例作回顾性分析,汲取误诊教训,为临床早期确诊提供帮助。
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篇首： 新型隐球菌感染是一种中枢神经系统难治性疾病,临床误诊率极高,尤其在多次脑脊液检查末找到隐球菌的情况下.本文就我科1992-02～2002～11经 脑脊液涂片找新型隐球菌或经病理证实的分别误诊为结核性脑膜炎(结脑)、病毒性脑膜炎(病脑)、神经症、脊髓肿瘤、播散性脑脊髓炎及原发性淋巴瘤的16例 中枢神经系统新型隐球菌感染的病例,结合相关文献讨论其误诊原因.
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AbstractPurposeTo review the incidence of UTIs, post-operative fever, and risk factors for post-operative fever in PCNL patients.Materials and methodsBetween 2007 and 2009, consecutive PCNL patients were enrolled from 96 centers participating in the PCNL Global Study. Only data from patients with pre-operative urine samples and who received antibiotic prophylaxis were included. Pre-operative bladder urine culture and post-operative fever (>38.5 C) were assessed. Relationship between various patient and operative factors and occurrence of post-operative fever was assessed using logistic regression analyses.ResultsEight hundred and sixty-five (16.2%) patients had a positive urine culture; ConclusionsApproximately 10% of PCNL-treated patients developed fever in the post-operative period despite receiving antibiotic prophylaxis. Risk of post-operative fever increased in the presence of a positive urine bacterial culture, diabetes, staghorn calculi, and a pre-operative nephrostomy.
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Antifungal testing results from the SENTRY Antimicrobial Surveillance Program (2008 to 2009) were analyzed for regional variations of invasive Candida species infections. Among 2,085 cases from the Asian-Pacific (APAC) (51 cases), Latin American (LAM) (348 cases), European (EU) (750 cases), and North American (NAM) (936 cases) regions, Candida albicans predominated (48.4%), followed by C. glabrata (18.0%), C. parapsilosis (17.2%), C. tropicalis (10.5%), and C. krusei (1.9%). Resistance to echinocandins (anidulafungin [2.4%] and micafungin [1.9%]) and azoles (3.5 to 5.6%) was most prevalent among C. glabrata isolates, as determined using recently established CLSI breakpoint criteria. C. glabrata isolates were more common in NAM (23.5%), and C. albicans isolates were more common in APAC (56.9%), with C. parapsilosis (25.6%) and C. tropicalis (17.0%) being more prominent in LAM. Emerging resistance patterns among C. glabrata cases in NAM require focused surveillance.
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It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
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Traditionally, many invasive fungal infections were associated with a poor prognosis, because effective therapeutic options were limited. The recent development of new antifungal agents has significantly contributed to the successful treatment of fungal diseases. These drugs offer novel mechanisms of action and expanded spectrums of activity over traditional treatment options. However, with these new agents comes the need for increased awareness of the potential interactions and toxicities associated with these drugs. Therefore, an understanding of the pharmacokinetic and pharmacodynamic properties of the classes of antifungal compounds is vital for the effective management of invasive fungal infections. This review provides a summary of the pharmacologic principles involved in treatment of fungal diseases.
DOI:10.1086/504492
URL
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Abstract Continuous renal replacement therapy (CRRT) is now commonly used as a means of support for critically ill patients with renal failure. No recent comprehensive guidelines exist that provide antibiotic dosing recommendations for adult patients receiving CRRT. Doses used in intermittent hemodialysis cannot be directly applied to these patients, and antibiotic pharmacokinetics are different than those in patients with normal renal function. We reviewed the literature for studies involving the following antibiotics frequently used to treat critically ill adult patients receiving CRRT: vancomycin, linezolid, daptomycin, meropenem, imipenem-cilastatin, nafcillin, ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulanic acid, cefazolin, cefotaxime, ceftriaxone, ceftazidime, cefepime, aztreonam, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, colistin, amikacin, gentamicin, tobramycin, fluconazole, itraconazole, voriconazole, amphotericin B (deoxycholate and lipid formulations), and acyclovir. We used these data, as well as clinical experience, to make recommendations for antibiotic dosing in critically ill patients receiving CRRT.
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Caspofungin is an echinocandin agent with fungicidal activity against candida species. We performed a double-blind trial to compare caspofungin with amphotericin B deoxycholate for the primary treatment of invasive candidiasis.We enrolled patients who had clinical evidence of infection and a positive culture for candida species from blood or another site. Patients were stratified according to the severity of disease, as indicated by the Acute Physiology and Chronic Health Evaluation (APACHE II) score, and the presence or absence of neutropenia and were randomly assigned to receive either caspofungin or amphotericin B. The study was designed to compare the efficacy of caspofungin with that of amphotericin B in patients with invasive candidiasis and in a subgroup with candidemia.Of the 239 patients enrolled, 224 were included in the modified intention-to-treat analysis. Base-line characteristics, including the percentage of patients with neutropenia and the mean APACHE II score, were similar in the two treatment groups. A modified intention-to-treat analysis showed that the efficacy of caspofungin was similar to that of amphotericin B, with successful outcomes in 73.4 percent of the patients treated with caspofungin and in 61.7 percent of those treated with amphotericin B (difference after adjustment for APACHE II score and neutropenic status, 12.7 percentage points; 95.6 percent confidence interval, -0.7 to 26.0). An analysis of patients who met prespecified criteria for evaluation showed that caspofungin was superior, with a favorable response in 80.7 percent of patients, as compared with 64.9 percent of those who received amphotericin B (difference, 15.4 percentage points; 95.6 percent confidence interval, 1.1 to 29.7). Caspofungin was as effective as amphotericin B in patients who had candidemia, with a favorable response in 71.7 percent and 62.8 percent of patients, respectively (difference, 10.0 percentage points; 95.0 percent confidence interval, -4.5 to 24.5). There were significantly fewer drug-related adverse events in the caspofungin group than in the amphotericin B group.Caspofungin is at least as effective as amphotericin B for the treatment of invasive candidiasis and, more specifically, candidemia.
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BACKGROUND: Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy. METHODS: We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of >/=2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes. RESULTS: Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02; P = .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08-1.14; P = .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18-2.44; P = .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11-2.39; P = .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35-.72; P = .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45-.94; P = .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point. CONCLUSIONS: Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC.
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