深部真菌感染诊断治疗进展

近20余年来深部真菌感染呈持续增多趋势,1980—1990年,美国医院获得性深部真菌感染率由2‰增加至3.8‰,念珠菌血流感染增加5倍。据欧洲一份报道在教学医院的尸检病例中,真菌感染由1978—1982年的1.6%增加至1988—1992年的4.1%。美国医院感染监测资料(NNIS)显示:1995—2002年期间念珠菌菌血症占医院获得血流感染中的第4位,但病死率居首位。美国疾病预防与控制中心(CDC)于1992—1993年进行的大系列流行病学研究显示,深部真菌感染的年发病率为178.3/百万。其中,念珠菌病年发病率为72.8/百万,隐球菌病为65.5/百万,曲霉病为12.4/百万,球孢子菌病为15.3/百万,组织胞浆菌病为7.1/百万[1]。CDC同期进行的另一项大系列流行病学研究显示念珠菌血症的年发病率为8~10/10万,病死率29%~40%,1岁以下婴幼儿年发病率高达75/10万,65岁以上老年人年发病率达45/10万[2]。深部真菌感染预后差,病死率高,例如侵袭性念珠菌病的病死率为10%~49%,侵袭性曲霉病可高达62%~85%,粒细胞缺乏患者曲霉感染病死率超过90%,镰刀菌属感染病死率更可高达79%~...     

Strategies for managing systemic fungal infection and the place of itraconazole

Systemic fungal infections are an increasing cause of mortality and morbidity in patients with haematological malignancies and certain other conditions associated with profound immunosuppression. The majority of such infections are caused by Aspergillus and Candida species. In recent years, the number of available drugs effective in the therapy of these difficult infections has expanded. Large clinical trials have been performed in different settings such as prophylaxis, empirical and first-line therapy. For prophylaxis, the azoles fluconazole and itraconazole have been most widely studied. These azoles are available in both oral and intravenous formulations. Itraconazole has a wide spectrum of activity including Aspergillus, Candida albicans and non-albicans species. Two large studies comparing the use of itraconazole with fluconazole for primary prophylaxis in high-risk patients who were recipients of allogeneic stem cell transplants have recently been reported. These have confirmed that itraconazole is effective in this setting in reducing the rate of systemic fungal infections. However, there are concerns with regard to increased toxicity and the potential for drug interactions with itraconazole compared with fluconazole. In the empirical setting, large randomized studies support the use of caspofungin and liposomal amphotericin B. Voriconazole and lipid-associated amphotericin B have been shown to be effective in first-line therapy and caspofungin for salvage. New approaches to management include efforts at improving diagnosis, combination antifungal therapy and treatment strategies for emerging moulds.     

伊曲康唑治疗血液系统恶性肿瘤伴发真菌感染临床观察

目的观察伊曲康唑治疗血液系统恶性肿瘤患者伴发真菌感染的效果。方法选择我院2004年2月至2009年6月收治的恶性血液病合并侵袭性真菌感染患者(IFI)31例并分为两组,A组17例,予伊曲康唑注射液静脉注射2 d后改口服液续贯治疗,B组14例,予伊曲康唑注射液静脉注射14 d后改口服液续贯治疗。结果A组与B组IFI患者有效率分别为64.7%和64.3%。结论恶性血液病合并侵袭性真菌感染者应用改良伊曲康唑方案治疗有效,节约了医疗费用,其抗感染疗效与免疫力恢复速度密切相关。     

重视与加强深部真菌感染的临床研究

近20年来深部真菌感染呈持续增多趋势，据报道1980年至1990年，美国真菌医院感染由2‰增至4‰，念珠菌败血症增加5倍。1995-2002年美国49所医院连续7年的监测资料显示：念珠菌败血症在医院感染败血症中居第4位，仅次于凝固酶阴性葡萄球菌、金葡菌和肠球菌，病死率则居首位。念珠菌败血症的发生率在住院患为4．6‰，在社区人群中年发病率为8～10／10万，病死率29%～47．1％。     

Changing patterns and trends in systemic fungal infections

Invasive mycoses are a significant and growing public health problem. Although bloodstream infections with Candida albicans may be decreasing in frequency, the number of persons at risk for them continues to grow. Moreover, infections with other Candida species, such as Candida glabrata, are increasing in incidence. Invasive mould infections in general, and Aspergillus infections in particular, are becoming more frequent. Fungal opportunistic infections in persons with AIDS are no longer a major problem in developed countries, but are resulting in significant morbidity and mortality in developing countries with AIDS epidemics. Further studies are needed to define populations at very high risk for fungal opportunistic infections who might benefit from targeted antifungal chemoprophylaxis, which remains the most promising of the potential prevention strategies. This review highlights the changing patterns in risk factors, changes in epidemiology, the impact of changes in medical practice in intensive care and organ transplantation on the incidence of systemic fungal infections, and gives an overview of fungal infections in paediatric patients, patients with haematological malignancy, and the emergence of antifungal resistance.     

伊曲康唑序贯治疗25例深部真菌感染的临床研究

目的评价伊曲康唑序贯治疗深部真菌感染的疗效和安全性。方法采用开放、随机、非对照试验。注射用伊曲康唑的起始剂量为200 mg,静脉滴注,每12小时1次,第3天开始剂量为200mg,静脉滴注,每天1次,静脉制剂总疗程为2周,继之伊曲康唑胶囊口服,200 mg/次,每12小时1次,疗程2～4周。结果共入选呼吸道感染、血流感染等深部真菌感染患者25例,其中包括确诊(proven)病例12例,拟诊(probable)病例11例,疑似(possible)病例2例。可进行疗效评价的22例患者中,痊愈11例,显效4例,进步2例,无效5例,有效率68.2%(15/22),痊愈率50.0%(11/22)。共获病原真菌24株,其中念珠菌属22株,曲霉及组织胞浆菌各1株。治疗后清除18株,真菌清除率为75.0%(18/24)。应用伊曲康唑治疗25例患者中,发生临床不良事件与药物可能有关者3例,主要包括药物热、胸闷、心悸,食欲下降等。实验室异常与药物可能有关者4例,主要为丙氨酸转移酶及天冬氨酸转移酶的轻度升高,1例患者出现血肌酐、尿素氮值升高及溶血。除1例外,不良反应多数属轻度,患者可耐受。结论伊曲康唑序贯治疗深部真菌感染获良好疗效,多数患者耐受性良好。     

New perspectives in the diagnosis of systemic fungal infections

Profound and prolonged neutropenia following chemotherapy is a major risk factor for systemic fungal infections. Mortality associated with disseminated fungal infection is high, and treatment with conventional amphotericin B is complicated by renal toxicity. Candida and Aspergillus are among the major pathogens in these patients. Many patients remaining neutropenic over a prolonged period of time will receive empirical antifungal therapy. The clinical and laboratory diagnoses of these infections are neither sensitive nor specific and are generally limited in the early detection of invasive fungal infection. However, several new approaches to diagnosis are being developed, which should be translated into routine practice, based on a greater understanding of the pathogenesis of systemic fungal infection and virulence determinants of fungal pathogens. These include antigen detection and polymerase chain reaction. Patients with presumed fungal infection require more intense and accurate monitoring for signs of disseminated infection. Early diagnosis may guide appropriate treatment and prevent mortality. Continued development of commercial tests should help achieve the objective of definitive diagnostic tests for systemic fungal infections.     

Management of systemic fungal infections in the presence of a cardiac implantable electronic device: A systematic review

Evidence to inform the management of systemic fungal infections in the setting of a cardiac implantable electronic devices (CIED), such as a permanent pacemaker or implantable cardioverter‐defibrillator, is scant and limited to case reports and series. The available literature suggests high morbidity and mortality. To better characterize the shared experience of these cases and their outcomes, we performed a systematic review. We investigated all published reports of systemic fungal infections—fungemia and fungal vegetative disease—in the context of CIED, drawing from PubMed, EMBASE, and the Cochrane database of systematic reviews, inclusive of patients who received treatment between January 2000 and May 2020. Exclusion criteria included presence of ventricular assist device and concurrent bacteremia, bacterial endocarditis, bacterial vegetative infection, or viremia. Among 6261 screened articles, 48 cases from 41 individual studies were identified. Candida and Aspergillus species were the most commonly isolated fungi. There was significant heterogeneity in antifungal medication selection and duration. CIED extraction—either transvenous or surgical—was associated with increased survival to hospital discharge (92%) and clinical recovery at latest follow‐up (81%), compared to cases where CIED extraction was deferred (56% and 40%, respectively). Importantly, there were no prospective data, and the data were limited to individual case reports and one small case series. In summary, CIED extraction is associated with improved fungal clearance and patient survival. Reported antifungal regimens are heterogeneous and nonuniform. Prospective studies are needed to verify these results and define optimal antifungal regimens.     

Progress in fighting systemic fungal infections in haematological neoplasia

 Considering the limited data available, there is clearly a need for thorough, well-designed clinical research on the epidemiology, diagnosis, treatment and prevention of invasive fungal infection in patients who are treated for cancer. Our knowledge has increased, but the information obtained so far is patchy and not generally applicable, as it is influenced by local problems and circumstances. New diagnostic tools have become available, but they are still insufficient in many cases. Until the value of the presently available chemoprophylaxis has been established beyond doubt, the strategy should be one of wait-and-see for patients with a low or moderate risk of developing infection. In bone marrow transplant recipients fluconazole has shown favourable results in eliminating yeast infections, but in patients at high risk of mould infections early initiation of intravenous treatment with amphotericin B at a therapeutic dose remains the best approach. The question of the optimal time point to start empirical antifungal treatment remains and has even been extended by the dispute about what antifungal drugs should be used for this purpose. Amphotericin B is still the drug of choice for the treatment of disseminated fungal infection, but its lipid formulations seem to offer a safer, though far more expensive, alternative. Head-to-head comparisons between the different formulations are required before a final conclusion on their respective efficacies and toxicities can be drawn, and it is questionable whether a higher dose will produce better results. Fluconazole appears very useful against the majority of Candida infections, whereas itraconazole is effective against both yeast and moulds, providing that adequate resorption can be ensured. The results of the first clinical trial of voriconazole in pulmonary aspergillosis have proved very promising.     

Management of invasive fungal infections: a role for polyenes

The spectrum of invasive fungal infections (IFIs) continues to evolve with the emergence of rare and resistant fungal pathogens. Clinicians are faced with difficult diagnostic and treatment challenges in the management of immunocompromised patients at high risk of developing IFIs. Early and appropriate antifungal therapy is essential for a successful outcome when treating invasive mycoses. The armamentarium of antifungal drugs continues to grow; the three main classes of commonly administered drugs are the polyenes, azoles and echinocandins. The newer triazoles and the echinocandins have changed primary treatment options for some fungal infections, such as aspergillosis and candidiasis. However, despite their toxic potential, the oldest antifungal drugs, polyenes, remain useful in the treatment of IFIs because of their broad-spectrum activity, low rates of resistance and established clinical record, particularly in immunocompromised patients with breakthrough fungal infections. This review highlights important issues in the treatment of IFIs for consideration by clinicians.     

Itraconazole (Sporanox) in superficial and systemic fungal infections

Itraconazole (Sporanox) is a triazole antifungal agent with a broad activity spectrum and favorable pharmacokinetic and safety profiles. Numerous clinical trials have established the efficacy and safety of itraconazole in the treatment of superficial fungal infections. In this field, full exploitation of its pharmacokinetics in keratinized tissues has led to the development of intermittent (pulse) treatment regimens that allow similar efficacy with lower overall drug exposure as well as a reduction in treatment costs. The additional anti-inflammatory action of itraconazole also makes it suitable for application in difficult-to-treat inflammatory skin disorders, such as seborrheic dermatitis. Recently, a new oral liquid formulation and an intravenous formulation have been developed, extending the therapeutic application of itraconazole to systemic fungal infections. Due to its broad activity spectrum and excellent tolerability, itraconazole is a valuable addition to the antifungal armamentarium used for prophylactic and empiric treatment in immunocompromised hosts.     

Nosocomial infections: new therapeutic alternatives

This symposium on nosocomial infections, antimicrobial resistance and the benefits of doripenem in this setting was held in Madrid, Spain, on 7 October 2009, and was supported by Janssen-Cilag. The topic was presented under an interdisciplinary approach by different international experts in the field.     

Nosocomial infections: new therapeutic alternatives

This symposium on nosocomial infections, antimicrobial resistance and the benefits of doripenem in this setting was held in Madrid, Spain, on 7 October 2009, and was supported by Janssen-Cilag. The topic was presented under an interdisciplinary approach by different international experts in the field.     

Management of fungal infections following allogeneic stem cell transplantation

Fungal infection remains an important complication in allogeneic stem cell transplantation (allo-SCT). Since the prognosis of fungal infection is poor, prophylaxis is critical for its management; owing to recent progression in allo-SCT management and widespread use of reduced-intensity regimens, the strategy of infectious prophylaxis has also changed. Various antifungals have recently been developed and applied to clinical use. A major change in antifungal management will probably occur in the next few years.     

Management of fungal infections following allogeneic stem cell transplantation

Fungal infection remains an important complication in allogeneic stem cell transplantation (allo-SCT). Since the prognosis of fungal infection is poor, prophylaxis is critical for its management; owing to recent progression in allo-SCT management and widespread use of reduced-intensity regimens, the strategy of infectious prophylaxis has also changed. Various antifungals have recently been developed and applied to clinical use. A major change in antifungal management will probably occur in the next few years.     

Endocrine and metabolic manifestations of invasive fungal infections and systemic antifungal treatment

Systemic fungal infections are increasingly reported in immunocompromised patients with hematological malignancies, recipients of bone marrow and solid organ allografts, and patients with AIDS. Mycoses may infiltrate endocrine organs and adversely affect their function or produce metabolic complications, such as hypopituitarism, hyperthyroidism or hypothyroidism, pancreatitis, hypoadrenalism, hypogonadism, hypernatremia or hyponatremia, and hypercalcemia. Antifungal agents used for prophylaxis and/or treatment of mycoses also have adverse endocrine and metabolic effects, including hypoadrenalism, hypogonadism, hypoglycemia, dyslipidemia, hypernatremia, hypocalcemia, hyperphosphatemia, hyperkalemia or hypokalemia, and hypomagnesemia. Herein, we review how mycoses and conventional systemic antifungal treatment can affect the endocrine system and cause metabolic abnormalities. If clinicians are equipped with better knowledge of the endocrine and metabolic complications of fungal infections and antifungal therapy, they can more readily recognize them and favorably affect outcome.     

系统性红斑狼疮合并深部真菌感染102例临床分析

目的:探讨SLE合并深部真菌感染的病原学特征、易感因素、治疗和转归.方法:对住院治疗的102例SLE合并深部真菌感染患者的临床资料进行回顾性分析.结果:102例真菌感染患者占同期住院1 350例SLE患者的7.6%,其中39例(38.2%)为医院内感染.感染部位最常见为肺(37.5%),其次为胃肠道和泌尿生殖道.20例发生2个或2个以上部位的感染.病原菌以白假丝酵母菌为主(40.6%),其次为热带假丝酵母菌、光滑假丝酵母菌和新生隐球菌.易感因素前3位为长期接受肾上腺皮质激素(激素)治疗者、联合应用免疫抑制剂者、低蛋白血症者.根据病原菌选择抗真菌药物,氟康唑、两性霉素B、伊曲康唑和伏立康唑为主要治疗药物.治愈48例,好转28例,未愈5例,死亡21例,病死率为20.6%.结论:SLE患者合并深部真菌感染率高,且病死率高.多部位感染常见,以肺部为感染的高发部位,病原菌以白假丝酵母菌为主,长期接受激素、免疫抑制剂、广谱抗生素治疗和侵入性操作等是其常见易感因素.建议在治疗原发病的同时做好真菌感染的防治工作,有助于改善SLE的预后.     

Pulmonary fungal ball due to Trichophyton successfully managed with oral itraconazole: a case report

Pulmonary fungal balls are caused by long-term fungal infection of the lung. They are sometimes a complication of previous cavitary pulmonary tuberculosis. Pulmonary fungal balls caused by Trichophyton are extremely rare. A 65-year-old man who worked in a leather recycling factory was admitted because of a productive cough and shortness of breath. He had a history of tuberculosis with lung destruction. A chest radiograph showed an opacity surrounding an air lucency over the left lung field, and chest computed tomography showed a mass within a cavity, producing a ball-in-hole appearance, over the left upper lung lobe. Bronchoalveolar lavage was performed, and fungal culture of the lavage fluid yielded Trichophyton. After 6 months of treatment with oral itraconazole, the patient’s general condition improved. This case emphasizes the importance of awareness of fungal infection within cavitary lesions of the lung and shows that Trichophyton may be the etiologic organism in such cases. Itraconazole is a recommended treatment of pulmonary fungal balls.