伊曲康唑静脉注射液/口服液序贯治疗血液系统疾病患者侵袭性真菌感染

目的 观察伊曲康唑静脉注射液/口服液序贯治疗血液系统疾病患者侵袭性真菌感染(IFI)的疗效及安全性.方法 所有血液系统疾病住院患者,符合IFI的诊断标准,后者类型包括确诊IFI、临床诊断IFI、拟诊IFI.本研究为开放研究,疗程为4～6周,分静脉给药阶段和口服给药阶段.静脉给药共14d,最初2d剂量为400mg/d,分两次给药,给药间隔12h;其后12d,剂量为200ms/d,1次/d.静脉用药结束后,继续给受试者序贯伊曲康唑口服液维持治疗,推荐剂量400mg/d,分两次给药(200 mg,2次/d),共用2～4周.根据受试者的病情决定每1～2周进行疗效与安伞性评价.结果 227例入组患者治疗结束后有效率为75.33%,其巾痊愈率达47.14%;227例患者治疗后205例退热(90.3%),中位退热时间5 d(2～20 d);可评价的186例患者,真菌学清除率为69.89%.发生与药物相关的不良事件11例,无与药物相关的严重不良事件发生.结论 伊曲康唑静脉注射液/口服液序贯治疗血液系统疾病患者IFI的疗效可靠,应用安全.     

伊曲康唑治疗血液病患者侵袭性真菌感染的多中心回顾性分析

目的 观察伊曲康唑在治疗血液病及造血干细胞移植(HSCT)后患者侵袭性真菌感染(IFI)的疗效和安全性.方法 采取开放、多中心回顾性研究的方法 ,选择2007年1-7月确诊、临床诊断和拟诊IFI的血液病或HSCT患者666例,给予静脉伊曲康唑,按前2天200ms/次、12h静脉滴注1次,第3天起200 ms/次,每天静脉滴注1次的方案治疗,并根据病情序贯伊曲康哗口服液或胶囊.根据临床和微生物学疗效标准,综合评价该药物的疗效,并观察其安全性.结果 全部患者抗真菌治疗的退热有效率为70.1%,治疗有效率为69.5%,其中确诊、临床诊断和拟诊IFI患者的有效率分别为73.7%、68.1%、68.2%,其问差异无统计学意义(P=0.380).全部患者中有58例(8.7%)出现与伊曲康唑相关的不良事件,主要表现为轻中度的肝胆系统和胃肠系统功能受损.结论 伊曲康唑是治疗血液病及HSCT患者IFI有效且安全的药物,适用于抗真菌的经验治疗.     

异基因造血干细胞移植治疗有侵袭性真菌感染史的急性白血病3例并文献复习

目的：探讨有侵袭性真菌感染史的急性白血病患者进行异基因造血干细胞移植（allo—HSCT）的可行性。方法：3例急性白血病患者移植前均有真菌感染病史,2例肺部真菌感染,1例肺部及肝脾真菌感染,经抗真菌治疗病情好转后行异基因HSCT。所选供者均为HLAA、B、DR位点全相合的同胞兄弟姐妹,使用改良BU／CY预处理方案,用MTX加CsA预防急性移植物抗宿主病,移植0d开始使用抗真菌药预防真菌感染。结果：随访1年半,3例患者无白血病复发,1例出现肺部真菌感染,抗真菌治疗后好转。余2例真菌感染病灶均稳定。结论：通过控制真菌感染的易感因素及再次预防,有真菌感染史的急性白血病进行HSCT是可行的。     

泊沙康唑预防造血干细胞移植患者侵袭性真菌病临床观察

目的 观察泊沙康唑预防恶性血液病患者造血干细胞移植(HSCT)后侵袭性真菌病的临床效果和安全性。方法 收集我院血液科2015年3月-2016年2月HSCT 19例,2例移植前有肺部真菌病史,从预处理开始口服泊沙康唑600mg/天,至中性粒细胞恢复,之后异基因造血干细胞移植患者改为伊曲康唑或伏立康唑口服至 75天。结果 19例患者未发生突破性真菌感染,在泊沙康唑使用过程中未观察到严重毒副反应发生,到随访结束时,17例存活。结论 泊沙康唑对预防恶性血液病患者造血干细胞移植后侵袭性真菌病是安全、有效的。     

伊曲康唑注射液治疗ICU侵袭性真菌感染的疗效与安全性

目的 评价伊曲康唑注射液治疗ICU侵袭性真菌感染(IFI)的疗效与安全性.方法 采用多中心、开放前瞻性研究,选1CU内IFI患者,应用伊曲康唑静脉注射液治疗,观察用药第7天及用药结束后的临床有效性、真菌清除率及安全性.结果 共33家医院495例患者纳入本研究.临床诊断289例(62.02%,289/466),拟诊143例(30.69%,143/466),确诊34例(7.29%,34/466).最常见的感染部位为肺(86.51%),其次为泌尿系和血液(各占4.07%).真菌种类以念珠菌最多见(82.66%),其次为曲霉菌(14.63%).与真菌感染相关因素中,最多见的是广谱抗生素应用(70.47%),其次分别为病情危重(69.45%)和长期住院(62.12%)等.临床疗效分析显示,治疗第7天临床有效率为53.91%,治疗结束后升至78.53%.治疗第7天真菌清除率为58.62%,治疗结束后升至86.27%.不良事件发生率为8.48%,其中与药物相关的不良事件发生率为6.87%.不良事件中最多见的是消化道症状(17/495,3.53%).结论 伊曲康唑注射液治疗ICU内IFI具有较好的临床疗效及安全性.     

造血干细胞移植后患者侵袭性真菌感染发生及危险因素分析

目的 了解造血干细胞移植（HSCT）后患者侵袭性真菌感染（ZVI）的发病率及危险因素。方法 选择2003年6月至2004年9月于我所进行HSCT的患者148例,按照我国IFI的诊断标准及临床疗效进行回顾性分析。结果 诊断IFI的患者共52例,其中确诊者35例,拟诊者17例。其发生时间为移植后2—400d,中位时间为62d。确诊IFI在移植后3、6个月及1年的累积发病率分别为15．6％、42．5％、48．9％。根据多因素分析,早期IFI的危险因素为：Ⅲ～Ⅳ度的急性移植物抗宿主病（GVHD）、广谱抗生素的长期应用及巨细胞病毒感染;晚期IFI的危险因素为：广泛型慢性GVHD和激素的长期应用。结论 具有较多危险因素的HSCT受者更易发生IFI,而避免或减少上述危险因素是预防IFI的有效方法。     

更昔洛韦胶囊在造血干细胞移植患者巨细胞病毒血症中的应用

目的 探讨更昔洛韦(ganciclovir,DHPG)胶囊治疗造血干细胞移植(HSCT)后患者巨细胞病毒(CMV)血症的疗效和安全性.方法 选择2006年2月至5月在北京大学血液病研究所行HSCT的30例移植后CMV血症患者进行前瞻性研究.CMV感染预防采用更昔洛韦10 mg/(kg·d),分2次静脉滴注,移植前第9天至移植前第2天,连续8 d.移植后应用定量多聚酶链反应(PCR)定期进行病毒DNA检测,CMV-DNA定量＞6.0×102拷贝/mL或＜1×105拷贝/mL的患者应用更昔洛韦胶囊1 g每日3次治疗.结果 HSCT后发生CMV血症的中位时间为移植后42 d,诊断时CMV-DNA中位数4.626×103拷贝/mL.更昔洛韦胶囊治疗的总有效率为90%,14 d转阴率66.67%,转阴中位时间10 d.4例(13.3%)出现不良事件,程度为轻至中度,表现为血细胞计数减少3例,转氨酶升高1例.结论 更昔洛韦胶囊用于治疗HSCT后CMV血症患者安全有效.     

伊曲康唑治疗恶性血液病患者侵袭性真菌感染

目的分析伊曲康唑治疗恶性血液病患者侵袭性真菌感染(IFI)的疗效和安全性。方法选择四川省人民医院血液科2006-02/2009-06住院的72例恶性血液病并发IFI患者,其中,男46例、女26例,中位年龄42岁。确诊或拟诊真菌感染或经验性治疗者使用伊曲康唑,剂量为:每次200mg,静脉滴注,1次/12h;用2d后,每次200mg,1次/d,完成疗程7d以上评价疗效。完成者共53例,疗程为732d,中位数14d。结果 53例完成疗程患者中:痊愈15例,显效19例,进步5例,无效14例,有效率为64.15%(34/53);不良反应发生率19.44%(14/72),主要表现为心血管系统、消化系统、皮肤的症状,均为一过性。结论伊曲康唑治疗恶性血液病患者IFI具有广谱抗真菌功效,其引发的不良事件较少,安全性高。     

伊曲康唑预防血液肿瘤患者粒细胞减少期并发真菌感染的疗效观察

目的:探究应用伊曲康唑口服液预防血液肿瘤患者化疗后粒细胞减少期并发真菌感染的效果.方法:将62例化疗后中性粒细胞减少的血液肿瘤患者随机分为真菌感染预防用药组和对照组,其中预防用药组患者预防性地服用伊曲康唑口服液,而对照组患者未接受任何预防性抗真菌药物治疗.观察并比较2组患者真菌感染的发生率和严重程度.结果:31例服用伊曲康唑口服液患者中,仅2例发生真菌感染,真菌感染率仅为6.5%,而对照组31例中,8例并发真菌感染,包括3例深部真菌感染,真菌感染率为25.8%,明显高于预防用药组(P<0.01),而且2组患者并发真菌感染的病原菌存在明显差异.结论:预防性应用伊曲康唑口服液能有效降低血液肿瘤患者化疗后粒细胞减少期真菌感染的概率.     

造血干细胞移植患者侵袭性真菌感染的预防和治疗进展

侵袭性真菌感染（IFI）是引起异基因造血干细胞移植（ALLO—HSCT）死亡的重要原因之一。ALL0-HSCT后发生IFI具有如下特点：临床上无特异性症状和体征,组织病理学需要侵袭性操作,很难培养出真菌。ALLO-HSCT后IFI的诊断常被延误,且病死率较高。因此,针对移植患者采取有效预防真菌感染的措施并进行积极治疗具有十分重要的意义。     

Secondary Antifungal Prophylaxis in Hematopoietic Stem Cell Transplantation (HSCT)/Acute Leukemia Patients

In this review, the role of secondary antifungal prophylaxis (SAP) in prevention of invasive fungal infections (IFIs) in patients with leukemia and in those receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) is discussed. A history of IFI is not an absolute contraindication for allo-HSCT or continuation of cytotoxic chemotherapy, provided that SAP is administered. We suggest that the last antifungal drug successfully used for treatment of the previous IFI is also used for SAP; during SAP, we propose an algorithm of thorough clinical, radiological and microbiological monitoring with monthly CT scan and twice weekly galactomannan assays. However, the optimal preventive strategy for patients with a prior IFI has not been defined and concerted efforts are warranted to optimize the management of affected patients.     

A prospective randomized trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients

Fluconazole antifungal prophylaxis is standard care in allogeneic hematopoietic stem cell transplant (HSCT) recipients, but this drug lacks anti-Aspergillus activity, the primary cause of invasive fungal infection (IFI) in many transplantation centers. We performed a randomized trial to compare itraconazole vs fluconazole, for prevention of IFIs in patients with acute leukemia (AL) and HSCT recipients. One hundred and ninety-five patients were randomly assigned to either fluconazole or itraconazole antifungal prophylaxis, after stratification into high-risk and low-risk groups. Antifungal prophylaxis was started at the beginning of chemotherapy and continued until resolution of neutropenia, or until amphotericin B treatment was started. IFI occurred in 11 (11%) of itraconazole, and in 12 (12%) fluconazole recipients. Invasive candidiasis (IC) developed in two (2%) itraconazole and one (1%) fluconazole recipients, while invasive aspergillosis (IA) developed in nine (9%) itraconazole and 11(11%) fluconazole recipients. There was no difference in the incidence of total IFI, IC and IA between the two study arms. However, there was a nonsignificant trend towards reduced mortality among patients who developed IA while receiving itraconazole prophylaxis (3/9=33% vs 8/11=73%, P=0.095).     

Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at increased risk for invasive fungal infections (IFIs) over prolonged periods of time. Aerosolized amphotericin B lipid complex (ABLC) has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways avoiding systemic toxicities. The safety and tolerability of aerosolized ABLC in 40 subjects undergoing allogeneic HSCT was prospectively investigated in an open-labeled, non-comparative study. Subjects received aerosolized ABLC treatment once daily for 4 days, then once weekly for 13 weeks; fluconazole was administered daily as standard of care through post-transplant day 100. Pulmonary mechanics were measured before and after each dose of inhaled ABLC; adverse events (AEs) and the development of IFI were also monitored. Cough, nausea, taste disturbance, or vomiting followed 2.2% of 458 total inhaled ABLC administrations; 5.2% of inhaled ABLC administrations were associated with >or=20% decrease in pulmonary function measurements (forced expiratory volume in 1 second or forced vital capacity) and none required treatment with bronchodilators or withdrawal from study. Four mild AEs were considered possibly or probably related to study treatment; no deaths or withdrawals from treatment were attributed to study drug. Of 3 proven IFIs occurring during the study period, only 1, a catheter-related case of disseminated fusariosis, occurred while the subject was receiving study medication. Aerosolized ABLC was well tolerated in allogeneic HSCT recipients. With only 1 of 40 subjects developing IFI while receiving treatment, the combination of fluconazole and inhaled ABLC warrants further study as antifungal prophylaxis following allogeneic HSCT.     

Haemopoietic cell transplantation of patients with a history of deep or invasive fungal infection during prophylaxis with liposomal amphotericin B

Relapse of a preceding fungal infection is a considerable risk during haemopoietic stem cell transplantation. The optimal secondary prophylaxis has not been found so far since the application of standard drugs is hampered by potential ineffectiveness or intolerable side effects. This investigation describes haemopoietic cell transplantation of patients with a history of invasive or systemic fungal infection (IFI). The strategy was either administration of liposomal amphotericin B as secondary prophylaxis or an early switch to liposomal amphotericin B after administration of azoles. The 43 patients had a history of proven (n = 14), probable (n = 14) and possible (n = 15) IFI. Twenty-eight patients (65%) could be discharged from the BMT ward without signs of mycosis. Transplant-related mortality was 35%. Overall, 12 fungus-related (IFI) deaths (28%) occurred. The percentage of fungus-related deaths was highest in the 'proven' group with 43% compared to 20 and 21% in the two other groups. Side effects of liposomal amphotericin B were low. A discontinuation of the drug was not necessary in any patient. Serum creatinine showed a slight increase to 128% (median) of the baseline allowing continuous administration of concomitant nephrotoxic drugs such as cyclosporin A. In conclusion, secondary prophylaxis with or early switch to liposomal amphotericin B facilitates allogeneic stem cell transplantation of patients with a history of IFI with minor side effects. However, fungal infections and transplant-related mortality remain major problems in this often heavily pretreated subgroup of patients.     

Risk-based antifungal prophylaxis in hematologic malignancy and stem cell transplantation

Invasive fungal infection (IFI) is an important cause of morbidity and mortality in patients with hematologic malignancy, prolonged neutropenia, or after hematopoietic stem cell transplant. Antifungal prophylaxis prevents IFI in high-risk hematology patients. This article discusses recent developments in antifungal prophylaxis, focusing on those expected to affect patient management. Significant advances have occurred in understanding risk stratification and assessment of individual patient risk for drug-drug interactions, toxicity, or variations in pharmacokinetics; choice of antifungal prophylaxis strategy, drug, dose, route, and regimen; therapeutic drug monitoring; cost effectiveness of prophylaxis; and the significance of breakthrough IFI. Research over the coming decade is likely to fundamentally alter antifungal prophylaxis by allowing clinicians to make individualized decisions for their patients informed by rapid, detailed, and personalized risk-benefit analyses.     

Prospective evaluation of procalcitonin in adults with non-neutropenic fever after allogeneic hematopoietic stem cell transplantation

The aim of this study was to analyze whether procalcitonin (PCT) is a diagnostic marker of infectious diseases during the non-neutropenic period in patients who have received an allogeneic hematopoietic stem cell transplant (HSCT). We included 65 patients in whom an allogeneic HSCT was performed in a 2-year period (April 2002-July 2004). PCT levels were monitored in every febrile episode by an immunoluminometric assay. Febrile episodes were classified according to the final diagnosis in: fever of unknown origin, microbiologically or clinically documented infection and non-infectious fever. Fifty-two febrile episodes in the non-neutropenic period were included in the study. Out of these 52, 26 had an infectious etiology: 11 fulfilled criteria for probable or proven invasive aspergillosis (IA), three were classified as possible invasive fungal infection (IFI) and 12 episodes were caused by other infections. Mean values of PCT on the first day of admission were: 8.0 (+/- 4.9) in probable-proven IA (P = 0.013, Kruskall-Wallis), 4.5 (+/- 3.4) in possible IFI and 1.5 (+/- 0.9) in infections other than IFI. Therefore, we could conclude that during the non-neutropenic phases of allogeneic HSCT, a high PCT value is associated significantly with IA.     

Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study

Acute graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT). It has been proposed that tumor necrosis factor alpha (TNF-alpha) blockade with infliximab may be an effective treatment for severe (grades III-IV) GVHD. We determined if infliximab use in this high-risk population was associated with an additional increased risk of non-Candida invasive fungal infections (IFIs). Records of the 2000-2001 HSCT cohort at our institution were reviewed. Fifty-three (20%) of 264 evaluable patients developed severe GVHD and 11 of these 53 (21%) received infliximab for treatment. Proven or probable IFI was documented in 10 (19%) of 53 patients with severe GVHD (incidence rate of 0.99 cases/1000 GVHD patient-days). When stratified by infliximab use, 5 of 11 infliximab recipients developed an IFI (6.78 cases/1000 GVHD patient-days), compared with 5 of 42 IFI cases among nonrecipients (0.53 cases/1000 GVHD patient-days). In a time-dependent Cox regression model among patients with severe GVHD, the adjusted IFI hazard ratio of infliximab exposure was 13.6 (P =.004; 95% CI, 2.29-80.2). We conclude that infliximab administration is associated with a significantly increased risk of non-Candida IFI in HSCT recipients with severe GVHD disease. Pre-emptive systemic antifungal therapy against molds should be considered in patients who develop severe GVHD after HSCT if infliximab is used.     

Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation

A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, −5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.     

Epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies

Invasive fungal infection (IFI) causes morbidity and mortality among patients with hematological malignancies who receive cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). We evaluated the incidence and treatment outcomes of proven and probable IFI in 22 institutions between 2006 and 2008 following the recent European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) consensus criteria. We analyzed 2,821 patients with hematological malignancies, including 597 who had undergone HSCT; these included patients with acute leukemia (n = 697), myelodysplastic syndrome (n = 284), lymphoma (n = 1465), or multiple myeloma (n = 375). IFIs were diagnosed in 38 (1.3%) patients (18 proven and 20 probable), including 20 patients who underwent HSCT and 18 who received chemotherapy alone; these included patients with aspergillosis (n = 23), candidiasis (n = 6), mucormycosis (n = 6), trichosporonosis (n = 2), and geotrichosis (n = 1). The incidence of IFI was 5.4 % in allogeneic HSCT patients, 0.4 % in autologous HSCT patients, and 0.8 % in patients receiving chemotherapy alone. Eighteen patients with aspergillosis were diagnosed with probable pulmonary IFI as determined by computed tomography scan and positive galactomannan assay. Overall, antifungal targeted therapies resulted in successful outcomes in 60.0 % of patients. IFI-attributable mortality rate was higher in HSCT patients than in those receiving chemotherapy alone, but the difference was not statistically significant.     

Absence of VOD in paediatric thalassaemic HSCT recipients using defibrotide prophylaxis and intravenous Busulphan

Hepatic veno-occlusive disease (VOD) is a common complication of haematopoietic stem cell transplantation (HSCT), with reported incidences of 5–40% in children. Recently, defibrotide (DF) has been successfully used as prophylaxis and treatment of VOD. This study reports data on 63 human leucocyte antigen-matched HSCT performed in 57 children affected by beta thalassemia at very high risk for developing VOD (liver fibrosis, iron overload, hepatitis C virus infections, busulphan-based conditioning, methotraexate + ciclosporine). All patients received a busulphan-based conditioning regimen, either orally (four HSCT) or intravenously (59 HSCT). All patients received oral DF (40 mg/kg per day, final dose) as VOD prophylaxis from median day −9 to median day +29. In order to overcome the lack of oral paediatric formulations, a galenic formulation was administered. DF was well tolerated. Only one patient fulfilled Seattle Criteria for VOD diagnosis. This patient had discontinued DF 6 d prior to VOD onset, due to high risk of haemorrhage. We concluded that oral defibrotide prophylaxis and i.v. busulphan safely abated VOD incidence in high-risk patients who had undergone HSCT. A galenic preparation of oral DF also permits this treatment in low-weight patients. Costs of DF prophylaxis are acceptable considering the reduced incidence of VOD.