泊沙康唑预防性抗真菌治疗在血液系统恶性肿瘤患者中的应用

目的 研究血液系统恶性肿瘤患者中预防性使用泊沙康唑抗真菌治疗的有效性和安全性.方法 回顾性分析2014年2月至2017年4月上海瑞金医院102例血液系统恶性肿瘤患者化疗期间预防性使用泊沙康唑抗真菌治疗的效果,采用Spearman进行相关性分析.结果 102例血液系统恶性肿瘤患者化疗期间,给予泊沙康唑预防性治疗后,2例(1.96%)发生侵袭性真菌感染.2例患者治疗期间发生死亡,但与泊沙康唑治疗无关.11例患者因不良反应停用泊沙康唑,不良反应导致的停药率为10.8%;2例侵袭性真菌感染抗真菌治疗失败和1例未确诊侵袭性真菌病患者停用泊沙康唑,泊沙康唑整体停药率为13.7%(14/102).泊沙康唑使用时间与住院时间、中性粒细胞缺乏时间均无相关性(rs=-0.02,P=0.853;rs=0.167,P=0.113),住院时间与中性粒细胞缺乏时间呈正相关(rs=0.448,P=0.000).结论 泊沙康唑用于血液系统恶性肿瘤患者侵袭性真菌病的预防性治疗,有效性和安全性均较佳.     

血液系统肿瘤患者泊沙康唑口服悬液预防后突破性侵袭性真菌病的发生及防治策略

由于放/化疗、造血干细胞移植、免疫抑制剂等广泛应用于血液系统肿瘤（hematological malignancy，HM）患者的治疗,使得这些患者侵袭性真菌感染（invasive fungal infection，IFI）的发病率和致死率呈上升趋势。IFI通常起病隐匿、进展迅速、诊断困难,是威胁血液系统肿瘤患者的严重并发症之一，泊沙康唑属于第二代三唑类抗真菌药物，抗菌谱较广,被广泛用于血液系统肿瘤患者侵袭性真菌病（invasive fungal disease，IFD）的预防，极大地减少了患者IFD的发生。由于多种因素可影响泊沙康唑口服悬液的吸收、分布、和代谢和清除，导致泊沙康唑血药浓度不能达到预防目标浓度，故仍常有患者发生真菌突破感染。如何预防和治疗泊沙康唑口服悬液预防后突破性真菌感染，目前国内外尚缺乏统一共识，本文拟对泊沙康唑口服悬液预防后真菌突破的发生及防治策略做一综述。      

两种药物对儿童急性白血病合并真菌感染的临床疗效观察

目的探讨泊沙康唑和伊曲康唑预防及治疗儿童急性白血病合并侵袭性真菌感染的疗效。方法回顾性分析接受常规化疗的57例白血病患儿,分别应用口服伊曲康唑及泊沙康唑预防及治疗侵袭性真菌感染,分别对两组的不良反应及临床疗效进行比较。结果泊沙康唑组CR率和总有效率均高于伊曲康唑组,但差异无统计学意义(P>0.05);泊沙康唑组不良反应发生率较伊曲康唑组增高,差异无统计学意义(P>0.05),具体不良反应方面,泊沙康唑组肝功能损害发生率明显高于伊曲康唑组,差异有统计学意义(P<0.05),而在神经毒性、视觉障碍、肾功能损害及消化道反应方面,两组间差异无统计学意义(P>0.05)。结论泊沙康唑预防及治疗侵袭性真菌感染有效率高于伊曲康唑,其肝功能损害的不良反应同时也高于伊曲康唑。     

氟康唑预防恶性血液病患者侵袭性真菌感染疗效的Meta分析

目的:系统评价氟康唑预防恶性血液病并真菌感染的疗效。方法:计算机检索中国知网(CNKI)、万方、Pubmed、EmBase数据库,采取RevMan 5.3软件进行Meta分析。结果:共纳入研究14篇,共3 767例,氟康唑组预防真菌感染失败率高于伊曲康唑组（P＝0.001）、伏立康唑组（P＝0.009）、泊沙康唑组（P＜0.001）,较空白对照组低（P=0.006）,且差异均有统计学意义。其中氟康唑组同伊曲康唑组和泊沙康唑组进行亚组分析,分别比较了白色念珠菌、曲霉菌感染率,其中泊沙康唑组曲霉菌感染率较氟康唑组低（P＜0.000 1）,且差异有显著统计学意义。伊曲康唑组白色念珠菌感染率、曲霉菌感染率及泊沙康唑组白色念珠菌感染率差异均无显著统计学意义。结论:氟康唑能有效预防恶性血液病并真菌感染发生率,但疗效低于伊曲康唑、伏立康唑、泊沙康唑。     

伏立康唑一级预防急性白血病患者化疗期间并发真菌感染的临床疗效北大核心

目的:探讨初诊急性白血病患者化疗期间应用伏立康唑进行预防侵袭性真菌病(IFD)的临床疗效及安全性。方法:回顾性分析2016年02月至2018年03月期间我院血液科收治的初诊急性白血病行化疗的患者166例,按照是否使用抗真菌药进行预防性治疗分为观察组(应用伏立康唑进行预防治疗,n=103)和对照组(未应用抗真菌药物,n=63),比较两组患者IFD发生率差异,并分析抗真菌药物应用的不良反应。结果:观察组IFD发生率为10.7%,对照组为33.3%,两组患者的IFD发生率有明显差异(P<0.05);所有应用伏立康唑进行预防治疗的患者均未出现严重的不良反应。结论:伏立康唑可以有效减低急性白血病患者化疗期间IFD发生率,并且有着较好的安全性,值得在临床推广应用。     

米卡芬净联合伏立康唑治疗血液肿瘤侵袭性真菌病患者的临床分析

目的∶探讨米卡芬净联合伏立康唑治疗血液肿瘤侵袭性真菌病（invasive fungal disease,IFD）患者的临床疗效及安全性。方法∶回顾性分析 2019年6月至2020年6月中国医学科学院肿瘤医院深圳医院接受米卡芬净联合伏立康唑抗真菌治疗的30例 IFD患者的临床资料,设为观察组,并选择同期单药应用伏立康唑抗真菌治疗的30 例IFD患者设为对照组,两组患者基数水平相当具有可比性,评价观察组和对照组的疗效及不良反应。结果∶观察组治疗中位时间16.5天（7~52天）,治疗有效率86.7%,发生不良反应率16.7%,对照组治疗中位时间22天（7~56 天）,治疗有效率63.3%,发生不良反应率20% ,观察组治疗中位时间少于对照组,治疗有效率高于对照组.差异均有统计学意义（P<0.05）。不良反应发生率略小于对照组,差异无统计学意义（P>0.05）。结论∶米卡芬净联合伏立康唑治疗IFD安全有效,值得临床选择。     

卡泊芬净治疗47例恶性血液病患者侵袭性真菌感染

目的 评价卡泊芬净治疗恶性血液病合并侵袭性真菌感染(IFI)的疗效与安全性.方法 采用回顾性分析法统计山西医科大学第二医院2007年8月至2009年9月47例恶件血液病住院患者的临床资料,其中男28例,女19例,中位年龄42(17～76)岁.47例患者中急件髓细胞白血病(AML)28例、急性淋巴细胞白血病(ALL)11例、重型再生障碍性贫血(SAA)2例、骨髓增生异常综合征(MDS)3例、非霍奇金淋巴瘤(NHL)自体造血干细胞移植术后1例、慢性粒细胞白血病(CML)异基因造血干细胞移植术后2例,所有恶性血液病患者处于化疗后骨髓抑制期或造血干细胞移植术后,使用卡泊芬净的疗效和不良事件(卡泊芬净首日70mg/d,之后50mg/d静脉输注,输注时间不得少于1h,疗程依患者病情而定).结果 47例病例分析中显示卡泊芬净总有效例数为25例(58.1%),药物相关的不良反应发生率低且较轻.结论 卡泊芬净抗菌谱广,疗效确切,安全性好,是血液病患者抗真菌经验治疗的较为理想的药物.     

卡泊芬净治疗47例恶性血液病患者侵袭性真菌感染

目的 评价卡泊芬净治疗恶性血液病合并侵袭性真菌感染(IFI)的疗效与安全性.方法 采用回顾性分析法统计山西医科大学第二医院2007年8月至2009年9月47例恶件血液病住院患者的临床资料,其中男28例,女19例,中位年龄42(17～76)岁.47例患者中急件髓细胞白血病(AML)28例、急性淋巴细胞白血病(ALL)11例、重型再生障碍性贫血(SAA)2例、骨髓增生异常综合征(MDS)3例、非霍奇金淋巴瘤(NHL)自体造血干细胞移植术后1例、慢性粒细胞白血病(CML)异基因造血干细胞移植术后2例,所有恶性血液病患者处于化疗后骨髓抑制期或造血干细胞移植术后,使用卡泊芬净的疗效和不良事件(卡泊芬净首日70mg/d,之后50mg/d静脉输注,输注时间不得少于1h,疗程依患者病情而定).结果 47例病例分析中显示卡泊芬净总有效例数为25例(58.1%),药物相关的不良反应发生率低且较轻.结论 卡泊芬净抗菌谱广,疗效确切,安全性好,是血液病患者抗真菌经验治疗的较为理想的药物.     

卡泊芬净治疗血液肿瘤合并侵袭性真菌感染64例

 目的　分析、评价卡泊芬净治疗血液肿瘤并发侵袭性真菌感染（IFI）的疗效及安全性。方法　回顾性分析2007年1月至2009年2月应用卡泊芬净治疗的血液肿瘤并发IFI疗程≥7 d的64例患者,应用SPSS13.0软件包分析卡泊芬净的疗效、影响因素及安全性。结果　64例疗效可评价的病例中,总有效率为54.7 %（35／64）,确诊组、临床诊断组和拟诊组的有效率分别为66.7 %（2／3）、54.9 %（28／51）、60.0 %（6／10）,各组之间比较差异无统计学意义（P＞0.05）。发热病例中位生效时间为1（1～10）d。体温正常患者肺部阴影开始缩小的中位时间12.5（2～30）d。年龄、检出真菌、中性粒细胞（ANC）＜0.5×109／L持续时间、接受移植、移植物抗宿主病（GVHD）状态、使用免疫抑制剂、影像学表现、卡泊芬净负荷量及是否为挽救性治疗等各组间比较差异无统计学意义（P值均＞0.05）。不良反应发生率低且为可逆转性。结论　卡泊芬净经验性或挽救性治疗IFI的效果较好,不受免疫状态、ANC数量及有无影像学变化的影响,且不良反应小。     

皮下注射粒细胞-巨噬细胞集落刺激因子预防多发性骨髓瘤患者侵袭性真菌病效果分析

目的探讨皮下注射粒细胞-巨噬细胞集落刺激因子(GM-CSF)对多发性骨髓瘤(MM)患者侵袭性真菌病(IFD)的预防效果。方法回顾性分析2015年1月至2021年6月哈尔滨医科大学附属第二医院收治的接受诱导化疗的222例初治MM患者的临床资料。患者均于中性粒细胞(ANC)≤1.5×109/L时应用GM-CSF(3～5 μg·kg-1·d-1, GM-CSF组)或粒细胞集落刺激因子(G-CSF, 2～5 μg·kg-1·d-1, G-CSF组), 白细胞计数(WBC)≥10.0×109/L时停用。比较两组患者IFD(包括确诊、临床诊断和拟诊)及突破性侵袭性真菌感染发生情况。结果所有患者中IFD发生率为8.1%(18/222)。GM-CSF组和G-CSF组IFD发生率分别为3.5%(3/85)和10.9%(15/137), 两组差异有统计学意义(χ2=3.88, P=0.049)。GM-CSF组接受真菌感染预防的9例及G-CSF组接受真菌感染预防的15例患者中, 发生突破性侵袭性真菌感染分别为0、7例, 两组差异有统计学意义(P=0.022)。结论 MM患者应用GM-CSF可减少IFD和突破...     

Posaconazole prophylaxis – impact on incidence of invasive fungal disease and antifungal treatment in haematological patients

Since two large‐scale, randomised studies on posaconazole prophylaxis have demonstrated a clear benefit for patients at high risk for contracting invasive fungal disease (IFD), posaconazole prophylaxis has been adopted as standard of care for this patient collective. Several years on from implementation at our institution, we wanted to evaluate its impact on the incidence and use of empirical antifungal therapy in a real‐life setting. We analysed retrospectively incidence and severity of IFD in high‐risk patients with prophylaxis, using a historical cohort as comparator. A total of 200 patients had either received the extended spectrum triazole posaconazole in prophylactic dosage of 200 mg tid or empirical antifungal therapy. Disease events were analysed by application of the revised EORTC/MSG definitions for IFD. Before posaconazole prophylaxis, we recorded 57/100 cases of IFD which was reduced to 28/100 with prophylaxis. The empirical use of antifungal drugs was reduced to 41% from 91% in the non‐prophylaxis cohort. Furthermore, we observed a shift in the categorisation of IFD according to EORTC/MSG criteria. Our data suggest that posaconazole was effective in reducing the rate and probability of invasive fungal disease in high‐risk patients.     

血液系统恶性肿瘤患者侵袭性真菌感染的诊断与治疗进展

血液系统恶性肿瘤患者中侵袭性真菌病（invasive fungal disease,IFD）的发病率和死亡率均较高,早期诊断和治疗可以有效降低IFD的发生率。目前间接试验方法（包括放射方法）均无法明确诊断侵袭性真菌感染（invasive fungal infection,IFI）,需结合不同的诊断方法及患者的临床表现综合判断。但即使未得到明确的IFD诊断证据,对符合条件的患者仍需进行早期干预治疗。临床治疗方案的选择需综合考虑患者临床特征、实验室和放射学检查结果、药物药理学特性和患者经济负担等因素的影响。本文拟对血液系统恶性肿瘤患者IFI的诊断与治疗进展进行综述。      

Posaconazole prophylaxis in patients with acute myelogenous leukaemia--results from an observational study

Patients with acute myelogenous leukaemia (AML) and neutropenia after chemotherapy are at high risk for life-threatening invasive fungal disease (IFD), in particular, invasive aspergillosis (IA). The aim of the study was to evaluate data on characteristics, risk factors, complications and additional antifungal treatment of patients with AML receiving posaconazole prophylaxis (PP) after chemotherapy in an actual clinical setting. A retrospective single-centre observational study on 40 patients with AML, median age 66 years, was conducted. PP 200 mg three times daily was given routinely. After 76 cycles of remission induction chemotherapy followed by PP, median duration of 31 days (range 6-61 days), no fatal case occurred. The majority of patients had at least one additional risk factor for IFD and during 32 cycles (42.1%), three risk factors were present. During 40 therapy cycles (52.6%), fever of unknown origin occurred. Pneumonia was diagnosed after 23 cycles (30.3%), thereof one case of proven IA (1.3%). PP was interrupted in 25 cycles (32.9%) and was followed by systemic antifungal therapy with different agents, with a median duration 15 days (range: 6-32 days). PP appears to be an effective and well-tolerated protection against IFD for AML patients under natural clinical conditions.     

Voriconazole is effective as secondary antifungal prophylaxis in leukemia patients with prior pulmonary fungal disease: case series and review of literature

Although previous invasive fungal diseases (IFD) pose a significant risk of reactivation during successive chemotherapies in patients with acute leukemia, and secondary antifungal prophylaxis is regarded as mandatory, much remains unknown about the optimal strategy including the efficacy of voriconazole. During January 2006 and October 2008, a total of 15 patients with acute leukemia had pulmonary IFD (4 probable and 11 possible cases) before or during chemotherapy. After successful treatment of primary IFD with oral voriconazole, all of them received voriconazole during a total of 35 courses of successive chemotherapy. All but one patient successfully accomplished planned treatment without suspected IFD or significant toxicity despite profound neutropenia. We retrieved the previous reports of myelosuppressive therapies after IFD using various secondary prophylaxes, and showed that voriconazole is the most effective drug to suppress IFD relapses.     

Treatment cost development of patients undergoing remission induction chemotherapy: a pharmacoeconomic analysis before and after introduction of posaconazole prophylaxis

Prior clinical trials have demonstrated efficacy and effectiveness of posaconazole in the prophylaxis of invasive fungal diseases in high‐risk patients. Controversy exists about the cost‐effectiveness of this approach. We performed an analysis comparing the direct costs of posaconazole prophylaxis against polyene mouthwash (thrush) prophylaxis in patients with acute myelogenous leukaemia (AML). Data of AML patients receiving remission‐induction chemotherapy were extracted from the CoCoNut (Cologne Cohort of Neutropenic Patients) database to compare hospital costs of patients before (2003–2005) and after (2006–2008) introduction of posaconazole prophylaxis. Treatment on general ward, intensive care unit (ICU), mechanical ventilation, diagnostic procedures, and all anti‐infectives were calculated. Patient groups were well matched according to age, gender and duration of neutropenia. The mean costs per patient in the posaconazole group (n = 76) and the polyene mouthwash group (n = 81) were €21 040 (95% confidence interval (CI): €18 204–€23 876) and €23 169 (95% CI: €19 402–€26 937) per patient. Antifungal treatment costs were €4580 (95% CI: €3678–€5482) and €4019 (95% CI: €2825–€5214). Duration on the ICU was 2582 (95% CI: 984.1–4181.7) and 5517 (95% CI: 2206–8827.3) min. In our hospital, primary antifungal prophylaxis by posaconazole was cost‐effective. There was a trend towards cost savings, which was primarily caused by a shorter overall length of stay and the less frequent ICU treatment.     

Posaconazole: when and how? The clinician’s view

Posaconazole is the newest triazole antifungal agent available as an oral suspension with an extended spectrum of activity against Candida species, Aspergillus species, Cryptococcus neoformans, Zygomycetes and endemic fungi. Among posaconazole advantages are the relatively low potential of cross-resistance with other azoles, few drug interactions compared with other azoles and its activity against Zygomycetes. Randomised, double-blind trials have shown that posaconazole is effective for prophylaxis against invasive fungal infections (IFI), especially aspergillosis, in high-risk patients. Results of Phase III clinical trials and case/series reports indicate that posaconazole is effective in treating oesophageal candidiasis, including azole-refractory disease, and other IFI refractory to standard antifungal therapies. To date, posaconazole has appeared to be well tolerated even in long-term courses; it has an excellent safety profile with gastrointestinal disturbances being the most common adverse events reported. The dose of posaconazole is 200 mg three times daily for prophylaxis, 800 mg daily in two or four divided doses for the treatment of IFI and 100 mg daily (200 mg loading dose) for the treatment of oropharyngeal candidiasis. On the basis of early clinical experience, it appears that posaconazole will be a valuable aid in the management of life-threatening fungal infections.     

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations

Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty‐seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1‐7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8‐2.7) for prophylaxis and 1.76 mg/L (IQR 1.3‐2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.     

Invasive Fungal Disease in Patients with Chronic Lymphocytic Leukemia in Japan: A Retrospective Database Study

Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients with hematological malignancies. As chronic lymphocytic leukemia (CLL) is a rare hematological malignancy in Japan, IFD incidence in Japanese patients with CLL is unclear. This study aimed to investigate IFD incidence in Japanese patients with CLL. This retrospective cohort study used data of patients with CLL registered between April 2008 and December 2019 in the Medical Data Vision database (n = 3484). IFD incidence after CLL diagnosis in the watch-and-wait (WW) and drug therapy (DT) groups was 1.5% and 9.2%, respectively. The most common type of IFD was invasive aspergillosis (28.1%). Cox proportional hazards multivariate analysis revealed that DT (hazard ratio [HR]: 2.13) and steroid use (HR: 4.19) were significantly associated with IFD occurrence. IFD incidence was significantly higher in the DT group than in the WW group (log-rank p < 0.001); however, there was no significant between-group difference in the time to IFD onset or the type of IFD (p = 0.09). This study determined the incidence of IFD in patients with CLL during WW. Physicians should monitor for IFD, even among patients with CLL undergoing the WW protocol.