侵袭性真菌感染中抗真菌药物的合理使用

侵袭性真菌感染(IFI)患者病情危重,治疗较为复杂,合理使用抗真菌药物是取得理想抗真菌疗效的关键。临床医生在选择抗真菌药物时应该全面考虑患者的自身情况和(可能)感染的病原菌类型,选择抗真菌活性高、疗效确切、安全性高、耐受良好的抗真菌药物治疗。棘白菌素类是新型抗真菌药物,作用机制独特,广谱覆盖常见念珠菌和曲霉菌,治疗侵袭性念珠菌病和肺曲霉病疗效确切,药物安全性高于多烯类和三唑类,被更多的临床医生选择用于各种IFI患者的治疗。     

氟康唑治疗老年人肺部白色念珠菌感染14例疗效分析

对我院收治的１４例老年肺部白色念珠菌感染患者应用氟康唑（大扶康）治疗，进行疗效分析，并与１６例老年患者应用其他抗真菌药物治疗疗效进行比较。氟康唑组１３例治愈，ｌ例死亡；其他抗真菌药物组９例治愈，７例死亡。氟康唑组病死率（７．１％）明显降低。氟康唑为三唑类第三代抗真菌药物，具有疗效好、副作用轻、使用安全的特点，值得临床上广泛应用。     

十全大补汤在抗真菌治疗中的辅助作用实验研究

通过实验性动物白念珠菌全身感染，研究在免疫功能低下状态，抗真菌经单纯治疗和与中药方剂十全大补汤伍用，其疗效的差异。实验结果证明：十全大补汤无直接抗真菌活性；抗真菌药对处于免疫功能低下状态的动物，其疗效也不十分理想。抗真菌药在治疗全身白念珠菌感染时，如用十全大补汤，通过后者ＢＲＭ样作用，可改善机体免疫状态，从而提高抗真菌药的疗效，与单纯使用抗真菌治疗有明显差异（Ｐ＜０．０５）。据此可以认为：处于免疫功能低下的机体，一旦感染真菌，在抗真菌治疗同时伍用十全大补汤有利于提高抗真菌药物的疗效。     

卡泊芬净治疗恶性血液病并发侵袭性真菌感染患者的疗效观察

恶性血液病患者因接受大剂量化疗,应用免疫抑制剂及广谱强效抗生素,造成中性粒细胞严重减少,免疫功能明显下降,极易发生侵袭性真菌感染(IFI)。抗真菌治疗疗程长,而多数并发真菌感染者的基础疾病重,对药物耐受性差,老年患者更为突出。我院采用卡泊芬净治疗恶性血液病并发IFI患者41例,观察其疗效和安全性,报告如下。     

肺孢子菌肺炎药物治疗策略及新药靶点研究进展

肺孢子菌肺炎（Pneumocystis pneumonia,PCP）是免疫功能低下患者严重的机会性感染疾病。目前临床治疗肺孢子菌肺炎常用的一线、二线药物因副作用及特定人群耐受力差等原因而应用受限,亟需开发新药并寻找新的治疗方法以改善PCP患者的预后。本文综述了近些年PCP的药物治疗策略及新的药物靶点研究进展,包括抗真菌药物、免疫调节剂的潜在应用等,以期为PCP的临床治疗提供新的参考。     

经纤维支气管镜介入气管内置管注药治疗肺隐球菌病2例

近年来，随着广谱抗生素、免疫抑制剂、糖皮质激素和抗癌药物等的广泛使用，肺隐球菌病的发病率有上升趋势，其治疗手段主要包括手术切除和抗真菌药物的应用。我们收治2例肺隐球菌病患者，确诊后在全身应用抗真菌药物的同时，辅以经纤维支气管镜(纤支镜)气管内置管局部注射抗真菌药物治疗，均痊愈，报道如下。     

抗真菌药物及其临床应用

随着广谱抗菌药物及免疫抑制剂的应用，器官移植、肿瘤等患者的增多，真菌感染在临床越来越多见。与细菌感染相比较，真菌感染预后更差，更难以在短期内治愈。但值得庆幸的是，近年来有几种疗效与安全性都比较理想的抗真菌制剂投入临床应用，为临床医生提供了新的选择，本文重点对这些药物加以介绍，以供临床抗真菌感染治疗时参考。     

重症监护病房肺部侵袭性真菌感染的早期经验性治疗1例报告

重症监护病房(ICU)内收治的重症患者由于病情危重、治疗过程中使用广谱抗生素、类固醇激素及免疫抑制剂的机会较多,加之各种侵入性操作频繁,使侵袭性真菌感染(IFI)的发病率较高,占院内感染的10%～15%[1].IFI确诊困难,等待确诊可能延误治疗,增加致残率和病死率.同时,由于抗真菌药物的广泛应用,白色念珠菌菌株日趋增多[2].早期对临床高危患者选择安全性良好的药物进行经验性抗真菌治疗,有可能抓住治疗机会,取得较好疗效[3-4].现将我科在"5·12"汶川特大地震中收治的1例老年重症伤员合并肺部IFI早期经验性抗真菌治疗病例报道如下.     

经纤维支气管镜介入气管内置管注药治疗肺隐球菌病2例

近年来 ,随着广谱抗生素、免疫抑制剂、糖皮质激素和抗癌药物等的广泛使用 ,肺隐球菌病的发病率有上升趋势 ,其治疗手段主要包括手术切除和抗真菌药物的应用。我们收治 2例肺隐球菌病患者 ,确诊后在全身应用抗真菌药物的同时 ,辅以经纤维支气管镜 (纤支镜 )气管内置管局部注射抗真菌药物治疗 ,均痊愈 ,报道如下。1　临床资料病例 1,患者男性 ,5 5岁。因咳嗽、咳痰一月余 ,于 2 0 0 0年 12月 30日入院。患者曾在当地医院胸部X线及CT检查提示“右上肺、右下肺及左下肺可见边缘不清的斑片状阴影 ,左下肺斑片状阴影内可见一大小约 5 .5cm× 5 …     

环孢素A治疗免疫相关性血细胞减少症血药浓度与疗效关系的研究

目的了解治疗免疫相关性血细胞减少症(IRP)过程中,环孢素A(CsA)血药浓度与疗效的关系。方法对2008年8月至2009年3月天津医科大学总医院血液科50例IRP患者CsA用药血药浓度及疗效进行分析。结果IRP患者空腹CsA血药浓度(C0)(141.3±97.0)μg/L;用药2 h后CsA血药浓度(C2)(437.2±241.9)μg/L。C2≥300μg/L的病例疗效、脱离血制品输注情况、髂骨骨髓增生情况均好于C2<300μg/L的病例。C0≥90μg/L患者的疗效、胸骨巨核数均好于C0<90μg/L的患者。应用CsA同时应用唑类抗真菌药物的病例血清尿素氮(BUN)升高的比例明显高于未用抗真菌药的患者。结论IRP患者CsA血药浓度与疗效相关,C2≥300μg/L及C0≥90μg/L疗效较好。CsA常规用量是安全的,并用唑类抗真菌药可引起肾损害。     

Evaluating prophylaxis of invasive fungal infections in patients with haematologic malignancies

OBJECTIVE: Patients with hematologic malignancies are at substantial risk of developing invasive fungal infections (IFI) that are associated with substantial morbidity and mortality. This article reviews the epidemiology, risk factors, and efficacy of antifungal prophylaxis in patients with hematologic malignancies. METHODS: A PubMed search was conducted to identify relevant studies with special emphasis on meta-analyses and direct comparisons between antifungal agents. RESULTS: The epidemiology of IFI has changed substantially in recent years with Candida albicans becoming less common owing to the widespread prophylactic use of azole antifungals. Invasive aspergillosis, fusariosis, and zygomycosis have increased in frequency. This change is at least partly related to the use of broad-spectrum antifungal agents, either as prophylaxis or as empirical treatment. Other risk factors for IFI include prior fungal exposure, immunosuppression, underlying disease, graft-vs.-host disease, and organ dysfunction. Inconsistent results have been reported in studies evaluating the efficacy of antifungal prophylaxis in patients at risk of IFI. Meta-analyses found that antifungals, such as fluconazole and itraconazole, are effective in decreasing IFI and IFI-related mortality, primarily owing to yeast infections in patients with more severe immunosuppression (i.e. patients undergoing bone marrow transplantation), but do not decrease the overall mortality. The European Conference on Infections in Leukemia (ECIL) guidelines currently recommend fluconazole (AI, ie. strongly recommended, based on at least 1 well-executed, randomized trial) and itraconazole (BI, ie. generally recommended, based on at least 1 well-executed, randomized trial) in allogeneic transplant recipients. Posaconazole, a triazole antifungal, has been recently shown to decrease IFI incidence and overall mortality in some high-risk patients compared with standard azoles. Based on preliminary data, a provisional AI ECIL recommendation has been given. CONCLUSIONS: Because of the substantial morbidity and mortality associated with IFI, there is a need to accurately define patient groups at greatest risk of IFI and, when appropriate, to initiate effective antifungal prophylaxis.     

Antifungal therapy in patients with hematological malignancies: how to avoid overtreatment?

Historically, treatment of invasive fungal infections (IFI) has consisted of amphotericin B. However, new therapeutic agents have recently been introduced. At the same time, the relatively low incidence of IFI and the progress in the diagnostic accuracy of IFI have made routine use of empirical antifungal therapy questionable. OBJECTIVES AND METHODS: With the aim to define the present trends in the use of antifungal agents for the treatment of IFI, we prospectively observed type, safety, and efficacy of given antifungal treatment in patients with hematological malignancies during a recent 18-month period. We also analyzed the impact of restricted use of empirical antifungal therapy on IFI-related mortality. RESULTS: A total of 279 episodes of neutropenia and fever following the chemotherapy were recorded. Treatment of IFI was given during the management of 41 (14%) episodes. Voriconazole (27 episodes) and caspofungin (14 episodes) were the only antifungal agents used as initial therapy. The rate of antifungal therapy success outcome was 78%. The overall 4-week mortality rate was 8%. Two patients died of invasive pulmonary aspergillosis. Empirical antifungal therapy was given in 13 episodes with persistent febrile neutropenia (PFN) and resulted in successful outcome in 92% of cases. In general, antifungal agents were well tolerated and only two patients had to discontinue treatment because of severe adverse event. In 127 episodes of PFN, antifungal therapy was deemed unnecessary and accordingly was not administered. In this subgroup of patients, no IFI-related mortality occurred. CONCLUSION: A better tolerability and efficacy of voriconazole and caspofungin together with the availability of an oral formulation of voriconazole most probably contributed to the observed shift in the use of antifungal agents. A restricted use of empirical antifungal therapy was, in this setting, not associated with an increased IFI-related mortality.     

Advances in antifungal prophylaxis and empiric therapy in patients with hematologic malignancies

Abstract: Invasive fungal infection (IFI) is associated with significant morbidity and mortality in patients with hematologic malignancies. There have been significant changes in the epidemiology and outcomes of IFI in this patient population, due in part to advances in transplant procedures, supportive care, and use of newer antifungal agents. A thorough knowledge of risk factors, potential causative organisms, and the safety and efficacy of appropriate antifungal agents is required to optimize treatment. Proper diagnosis of IFI is challenging and the correlation of delays in diagnosis and treatment with poor outcome suggest that earlier intervention may result in more effective management of high‐risk patients. Because all risks may not be equal, stratifying high‐risk patients may further help target patients most likely to benefit from prophylaxis. This review focuses on various risk factors specific to patients with hematologic malignancies and discusses the use of preemptive, empiric, and prophylactic strategies in the management of IFI in this patient population.     

Evaluating the role of prophylaxis in the management of invasive fungal infections in patients with hematologic malignancy

Invasive fungal infection (IFI) is a persistent problem among critically ill and immunocompromised patients, especially hematopoietic stem cell transplant or solid organ transplant recipients, or patients on intensive chemotherapy for acute leukemia. Although numerous antifungal agents are available, IFI remains a serious problem because of obstacles to timely diagnosis and high morbidity and mortality rates associated with such infection. Improvements in treatment of underlying diseases have rapidly expanded the patient populations at risk for IFI with increased use of immunosuppressants, aggressive chemotherapy, broad-spectrum antibiotics, and narrow-spectrum antifungal prophylaxis. There are various treatment strategies that can be used to manage IFI: prophylaxis, empiric, preemptive, and directed. As the infection progresses, the prospect of successfully treating an infection diminishes; conversely, the earlier the intervention, the greater the possibility of unnecessary treatment. This article discusses the epidemiology of the most important fungal pathogens, identifies high-risk patient groups and risk factors associated with IFI, and critically evaluates the advantages and disadvantages of available diagnostic tests and treatment strategies and the rationale for antifungal prophylaxis. For patients at high risk for IFI, antifungal prophylaxis is an attractive strategy, and numerous randomized, controlled clinical studies have documented the benefit of such prophylaxis as well as the most efficacious of currently available agents.     

A prospective, randomized study of empirical antifungal therapy for the treatment of chemotherapy-induced febrile neutropenia in children

Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) [88·0% in Arm B; 83·9% in Arm C (P = 0·72)], and 42/48 at low risk (87·5%) [87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41)]. None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8-15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.     

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.     

Caspofungin as second-line therapy for fever of unknown origin or invasive fungal infection following allogeneic stem cell transplantation

Caspofungin (CAS) is the first of a new class of antifungal agents, the echinocandins, that interfere with fungal cell wall synthesis by inhibition of glucan synthesis. Here, we report the results of 31 patients treated with CAS following allogeneic SCT. CAS was administered as a second-line agent to patients with invasive fungal infection (IFI) (n=15) or fever of unknown origin (n=16) who were recalcitrant to or intolerant of prior antifungal therapy. Unsuccessful first-line regimes included amphotericin B (n=17), liposomal amphotericin B (n=5), fluconazole (n=3), itraconazole (n=1), and voriconazole (n=2). All patients received concomitant immunosuppressive therapy for graft-versus-host disease. In 23 patients, cyclosporin A (CSA) and CAS were administered concurrently without any major side effects detected. Observed increases in GPT were not clinically significant. Normalization of serum creatinine and significant reductions in C-reactive protein were observed in response to CAS. Favorable outcome to CAS were documented in eight of 15 patients with IFI and in 15 of 16 patients with fever of unknown origin. CAS is a promising alternative in patients with IFI and fever of unknown origin in the setting of allogeneic SCT.     

A clinical cohort trial of antifungal combination therapy: efficacy and toxicity in haematological cancer patients

Summary  Invasive fungal infections (IFI) are a major cause of morbidity and mortality in patients with haematological malignancies. Antifungal combination therapy is a promising treatment option. However, available data on feasibility, toxicity and efficacy of this therapy are limited. Therefore, this study was conducted to evaluate the feasibility, toxicity and outcome of different antifungal combination therapies. Patients with haematological malignancies receiving antifungal combination therapy for IFI were retrospectively analysed. Toxicity and response were documented at the end of therapy. Survival was evaluated at the end of therapy and after 12 weeks. Fifty-six patients were treated with different antifungal combinations in the period between 2001 and 2007. The majority of patients (63%) received a combination of liposomal amphotericin B and caspofungin as antifungal combination treatment. Toxicity of all applied combinations was tolerable. At the end of combination therapy, favourable response was 65%, whereas unfavourable outcome occurred in 35% of the cases. Mortality at the end of treatment was 11% and 34% 3 months after initiation of combination therapy. Antifungal combination therapy is feasible and efficient in haematological cancer patients and allogeneic stem cell transplant recipients with IFI. Prospective studies to evaluate the optimal combinations are needed.     

What is the role of therapeutic drug monitoring in antifungal therapy?

Despite an expanding number of therapeutic options for treating invasive fungal infection (IFI), the mortality rate from these infections remains high. Many risk factors for poor outcome from IFI (eg, the compromised immune status of the host) are not modifiable by the treating clinician. Thus, elevated interest exists in any modifiable factor that might improve outcome. Many of the new antifungal agents have marked variability in drug concentration based on either inconsistent absorption or elimination, leading to very wide interpatient variability. Many agents also have a narrow therapeutic index, meaning a small range between drug levels too low to achieve the desired clinical benefit and high enough to produce unwanted or toxic effects. Therefore, therapeutic drug monitoring is useful to maximize efficacy while minimizing drug toxicity of some antifungal agents.     

Aspergillus PCR testing: results from a prospective PCR study within the AmBiLoad trial

Objectives: Invasive fungal infection (IFI) is a major cause of morbidity and mortality in severely immunocompromised patients and is difficult to diagnose. The significance of molecular methods for diagnosis of IFI is still controversial. In a subset of patients treated within the AmBiLoad Trial, samples were investigated prospectively by a nested Aspergillus PCR assay to re‐evaluate the significance of PCR in this setting. Patients and methods: In the randomized, prospective multicenter AmBiLoad trial, patients with proven or probable IFI were randomized to receive liposomal amphotericin B (L‐AMB) 3 or 10 mg/kg QD for 14 d followed by L‐AMB 3 mg/kg QD. From 91 patients, 459 serial samples (98% blood samples) were investigated by a nested PCR assay for Aspergillus DNA. All samples were investigated in our laboratory with a previously described nested and a quantitative PCR assay. As required by the study protocol, serial Aspergillus antigen galactomannan was performed. IFI was defined according to modified EORTC/MSG 2002 criteria as applied in the AmBiLoad trial. Results: Seven and 52 patients had proven and probable IFI according to modified EORTC/MSG criteria, respectively. The median number of samples investigated per patient was 4. Seventy percent of samples were obtained during treatment with antifungal study medication. Forty‐three samples gave positive PCR results. Patients with an unfavorable outcome had a significantly higher rate of positive PCR results (48% versus 21%). Conclusions: The sensitivity of Aspergillus PCR testing is limited during antifungal therapy. The tendency for persistently positive PCR results to indicate a poor prognosis has to be confirmed in further studies.