两性霉素B治疗侵袭性肺部真菌感染的临床分析

目的 分析两性霉素B治疗ICU内侵袭性真菌感染的疗效与不良反应.方法 回顾性分析98例合并侵袭性肺部真菌感染的重症患者接受两性霉素B微泵静脉给药的临床资料.结果 两性霉素B的临床有效率77.55％,真菌清除率75.51％.不良反应包括寒战发热（9.18％）、皮疹（4.08％）、静脉炎（1.02％）、恶心呕吐（6.12％）、低钾血症（16.32％）、肝损害（1.02％）和肾损害（4.08％）.结论 国产两性霉素B对于重症患者侵袭性真菌感染疗效确定,采用持续微泵静脉给药不良反应发生率低.     

Therapeutic granulocyte transfusions for the treatment of febrile neutropenia in patients with hematologic diseases: a 10-year experience at a single institute

Background aimsThis single-center 10-year retrospective study assessed clinical efficacies and adverse events and determined prognostic factors in patients with hematologic disease and febrile neutropenia treated with granulocyte transfusions (GT) from unrelated healthy donors stimulated with recombinant human granulocyte–colony-stimulating factor (rhG-CSF) and dexamethasone.MethodsBetween September 1999 and June 2009, 1027 therapeutic GT were performed for the treatment of 170 episodes of febrile neutropenia in 157 patients. Efficacy analysis included 979 GT for 138 episodes in 128 patients who received at least three GT per episode. Adverse event analysis included all patients who received at least one GT.ResultsThe median granulocyte dose was 0.96 × 10⁹/kg/transfusion (range 0.47–1.80 × 10⁹/kg/transfusion). Infection was controlled in 73 episodes (52.9%). The 28-day infection-related survival rate was 64.7 ± 4.1%. The dose of granulocytes transfused did not correlate with clinical outcome. Multivariate analysis revealed that septic shock and pneumonia/multiple primary infection sites were related to infection control failure. Furthermore, refractory underlying disease and septic shock were associated with shorter infection-related survival. Massive hemoptysis (3.5%) and respiratory failure (5.9%) occurred in a few patients. Prior pneumonic infiltration, azotemia and a larger volume of daily GT were associated with serious respiratory complications.ConclusionsGT therapy is a viable adjunctive treatment option for febrile neutropenia as a bridge to autologous hematopoietic recovery in patients with hematologic disease with tolerable toxicity. GT therapy requires close monitoring in patients with prior pneumonic infiltration and azotemia. It is recommended that transfusion with higher volumes is avoided.     

In?vitro and in?vivo study on the effect of antifungal agents on hematopoietic cells in mice

Liposomal amphotericin B, voriconazole, and caspofungin are currently used for systemic and severe fungal infections. Patients with malignant diseases are treated with granulocyte-colony stimulating factor (G-CSF) for the recovery of granulocytes after chemotherapy or hematopoietic cell (HC) transplantation. Since they have a high incidence of fungal infections, they inevitably receive antifungal drugs for treatment and prophylaxis. Despite their proven less toxicity for various cell types comparatively with amphotericin B and the decrease in the number of leukocytes that has been reported as a possible complication in clinical studies, the effect of liposomal amphotericin B, voriconazole, and caspofungin on HCs has not been clarified. The present study aimed to examine the in vitro and in vivo effect of these three modern antifungals on HCs. Colony-forming unit (CFU) assays of murine bone marrow cells were performed in methylcellulose medium with or without cytokines and in the presence or absence of various concentrations of liposomal amphotericin B, voriconazole, and caspofungin. In the in vivo experiments, the absolute number of granulocytes was determined during leukocyte recovery in sublethally irradiated mice receiving each antifungal agent separately, with or without G-CSF. In vitro, all three antifungal drugs were nontoxic and, interestingly, they significantly increased the number of CFU-granulocyte-macrophage colonies in the presence of cytokines, at all concentrations tested. This was contrary to the concentration-dependent toxicity and the significant decrease caused by conventional amphotericin B. In vivo, the number of granulocytes was significantly higher with caspofungin plus G-CSF treatment, higher and to a lesser extent higher, but not statistically significantly, with voriconazole plus G-CSF and liposomal amphotericin B plus G-CSF treatments, respectively, as compared with G-CSF alone. These data indicate a potential synergistic effect of these antifungals with the cytokines, in vitro and in vivo, with subsequent positive effect on hematopoiesis.     

Aerosolized Delivery of Antifungal Agents

Pulmonary infections caused by Aspergillus species are associated with significant morbidity and mortality in immunocompromised patients. Although the treatment of pulmonary fungal infections requires the use of systemic agents, aerosolized delivery is an attractive option in prevention because the drug can concentrate locally at the site of infection with minimal systemic exposure. Current clinical evidence for the use of aerosolized delivery in preventing fungal infections is limited to amphotericin B products, although itraconazole, voriconazole, and caspofungin are under investigation. Based on conflicting results from clinical trials that evaluated various amphotericin B formulations, the routine use of aerosolized delivery cannot be recommended. Further research with well-designed clinical trials is necessary to elucidate the therapeutic role and risks associated with aerosolized delivery of antifungal agents. This article provides an overview of aerosolized delivery systems, the intrapulmonary pharmacokinetic properties of aerosolized antifungal agents, and key findings from clinical studies.     

Meta-analysis of prophylactic or empirical antifungal treatment versus placebo or no treatment in patients with cancer complicated by neutropenia.

OBJECTIVE: To determine whether antifungal agents given prophylactically or empirically decrease morbidity and mortality in patients with cancer complicated by neutropenia. DESIGN: Meta-analysis of randomised trials of amphotericin B, various lipid soluble formulations of amphotericin B (for example, AmBisome), fluconazole, ketoconazole, miconazole, or itraconazole compared with placebo or no treatment. SETTING: Trials conducted anywhere in the world. SUBJECTS: Patients with cancer complicated by neutropenia. MAIN OUTCOME MEASURES: Mortality, invasive fungal infection (defined as positive blood culture, oesophageal candidiasis, or lung or deep tissue infection), and colonisation. RESULTS: 24 trials with 2758 randomised patients were reviewed; the total number of deaths was 434. Prophylactic or empirical treatment with antifungals as a group bad no effect on mortality (odds ratio 0.92; 95% confidence interval 0.74 to 1.14). Amphotericin B decreased mortality significantly (0.58; 0.37 to 0.93) but the studies were small and the difference in number of deaths was only 15. Antifungal treatment decreased the incidence of invasive fungal infection (0.47; 0.35 to 0.64) and fungal colonisation (0.45; 0.30 to 0.69). For every 73 patients treated (95% confidence interval to 48 to 158) one case of fungal invasion was prevented in surviving patients. CONCLUSIONS: There seems to be no survival benefit of antifungal agents given prophylactically or empirically to patients with cancer complicated by neutropenia. These agents should be restricted to patients with proved infection and those in randomised trials. A large, definitive placebo controlled trial of amphotericin B is needed.     

国产两性霉素B抢先治疗血液病患者肺部侵袭性真菌感染的疗效与安全性分析

目的观察国产两性霉素B抢先治疗血液病患者侵袭性肺部真菌感染(以下简称IFI)的疗效与不良反应。方法回顾性分析我院2004年12月～2008年12月间,45例免疫功能低下IFI患者接受国产两性霉素B治疗的临床资料。结果 45例患者均应用两性霉素B治疗两周以上,最长应用时间为14周,中位数6周。总有效率为86.7%,不良反应主要有低钾血症、发热、转氨酶升高、肾功损害、胃肠道反应,根据WHO药物毒性分级标准均为I～II级毒性。结论国产两性霉素B对于血液病患者IFI临床诊断的抢先治疗疗效肯定,不良反应可耐受。     

急性淋巴细胞白血病患者侵袭性头状地霉感染1例及文献回顾

目的:通过报道1例急性淋巴细胞白血病患者侵袭性头状地霉感染的临床资料,并结合文献探讨头状地霉感染的临床特点、有效的诊断及治疗方法。方法:报道国内首例急性淋巴细胞白血病患者化疗后骨髓抑制期感染头状地霉病例,并对该病的诊断及治疗等进行系统文献回顾。结果:该白血病患者经血培养证实为头状地霉感染,并累及肺脏、肝脏和皮肤,治疗过程中先后采用卡泊芬净、脂质体两性霉素B和脂质体两性霉素B联合伏立康唑等治疗,虽然脂质体两性霉素B联合伏立康唑治疗患者体温正常,临床症状稍有改善,但是患者在化疗后40天放弃治疗并死于心肺功能衰竭。结论:头状地霉感染的发病率低,临床症状不够典型,诊断困难,预后差。根据患者的临床表现,结合血培养、GM实验、G实验和CT扫描等检查,可有助于诊断。头状地霉感染尚无非常有效的治疗方式,采用脂质体两性霉素B或两性霉素B联合伏立康唑或其他新的抗真菌药物可能获得一定的疗效,早期诊断、早期联合治疗和患者早期脱离粒缺状态是治疗成功的关键。     

非HIV感染的马尔尼菲青霉病2例报道并文献复习

目的 探讨非HIV感染的马尔尼菲青霉病的临床特征,提高对本病的早期诊断与治疗水平.方法 分析广州医科大学附属第一医院广州呼吸疾病研究所收治的2例非HIV感染的马尔尼菲青霉病患者的临床、影像、微生物和病理资料,并复习相关文献.结果 例1,男,37岁,反复咳嗽、发热1个月,双肩关节疼痛伴消瘦,广谱抗生素治疗无效,左锁骨上及左腹股沟淋巴结肿大,头颅MR发现颅内及咽后脓肿,经纤维支气管镜肺活检及脓液培养确诊马尔尼菲青霉病,继发性癫痫.予两性霉素B脂质体静滴治疗后好转出院,继续予伊曲康唑口服液治疗3个月症状消失,复查胸部CT及头颅MRI病灶吸收,患者自行停药后复发,再次予两性霉素B脂质体治疗仍有效.例2,男,32岁,咳嗽、咳痰5月余,皮下肿块伴发热3月余,胸部CT示纵膈脓肿伴胸骨骨髓炎形成,抽吸脓液培养有马尔尼菲青霉生长.予两性霉素B脂质体抗真菌治疗过程中,患者继发感染性休克,弥漫性血管内凝血.结论 马尔尼菲青霉病属于少见病,侵犯颅内的是国内首例报道,经纤维支气管镜肺活检和脓液培养可确诊.复发病例予两性霉素B脂质体治疗仍有效.早期诊断是提高治愈率的关键.     

Pulmonary mucormycosis diagnosed by fine needle aspiration cytology. A case report

BACKGROUND: The usefulness of fine needle aspiration cytology (FNAC) in the diagnosis of lung lesions is well documented. Fungal lesions are among nonneoplastic lesions of the lung in which FNAC has proven a useful technique in both immunocompromised and immunocompetent patients. These include cryptococcosis, aspergillosis, histoplasmosis and coccidiodomycosis. Pulmonary mucormycosis, an aggressive fungal infection, is rarely diagnosed on FNAC. We report a case of isolated pulmonary mucormycosis diagnosed on FNAC. CASE: A 62-year-old renal transplant recipient with diabetes mellitus and hypertension, asymptomatic for four months, presented with tachypnea, generalized malaise and weakness. Radiologic studies showed an enlarging, cavitating lesion in the right lung. Computed tomography-guided fine needle aspiration performed on the lung lesion showed fungal profiles with broad, ribbonlike, aseptate hyphae with right-angled branching consistent with the Zygomycetes class of fungi, which includes Rhizopus and Mucor species. Fungal cultures confirmed the presence of Rhizopus. The patient underwent right pneumonectomy, was placed on liposomal amphotericin B therapy and discharged with good pulmonary status and stable kidney function. CONCLUSION: FNAC is a useful technique in the diagnosis of pulmonary mucormycosis.     

Candidosis of the central nervous system in children of the first year--one of the problems in nosocomial fungal infections]

CNS candidosis is a severe disease, one of the nosocomial fungal infections, with often lethal issue or invalidation of the patient. Specific signs are absent and early diagnosis is very difficult. Risk factors are the following: prematurity, candidal carriage, prolonged hospitalization, treatment with broad spectrum antibiotics and immunosupressors, artificial pulmonary ventilation. No single effective antifungal agent exists. In the case of acute fungal CNS infection the drug of choice is fluconazole (diflucan) characterized by high efficacy and CSF sanitation rate, the drug is used intravenously with possible switching off to oral form. If the pathogen is not susceptible to the drug (C. crusel, C. glabrata and C. tropicalis) amphotericin B is recommended (C. lusitaniae is not susceptible). In the case of renal or hepatic failure AmBisome may be used as less toxic form. If the case of prolonged disease antifungal drugs are used in a long-term regime, drugs combinations are also recommended. Complex therapy with granulocyte colony stimulating factor may be used if the previous regime was not effective.     

Changes in endogenous microflora among febrile granulocytopenic patients receiving empiric antibiotic therapy: implications for fungal superinfection.

The ecologic effect of empiric systemic antibiotic therapy on the endogenous microflora was evaluated in 83 febrile granulocytopenic patients with cancer who were randomly allocated to receive moxalactam plus ticarcillin (45 patients) or tobramycin plus ticarcillin (38 patients) for suspected infection. Serial surveillance cultures of the nasal passages, oropharynx and feces performed twice a week showed that patients who received the former regimen had higher elimination rates and significantly lower acquisition rates (p = 0.027) for aerobic gram-negative bacilli than did patients who received the latter regimen. However, therapy with moxalactam plus ticarcillin also resulted in significantly higher acquisition rates for yeasts (p = 0.004). This was associated with a significantly higher fungal superinfection rate among these patients than among those who received tobramycin plus ticarcillin (40% v. 16%) (p less than 0.05). Moxalactam plus ticarcillin therapy created a greater microbial ecologic vacuum by the elimination of intestinal anaerobes, which, in turn, permitted fungal colonization and an increased risk of superinfection. Our results support the recommendation that an antipseudomonal penicillin plus an aminoglycoside be selected as empiric therapy for suspected infection in febrile granulocytopenic patients with cancer. Such a regimen would spare the anaerobic intestinal microflora, thereby reducing the risk of fungal colonization and infection.     

Pulmonary Toxocariasis Mimicking Invasive Aspergillosis in a Patient with Ulcerative Colitis

A 45-year-old-male who had underlying ulcerative colitis and presented with fever and dry cough. Initially, the patient was considered to have invasive aspergillosis due to a positive galactomannan assay. He was treated with amphotericin B followed by voriconazole. Nevertheless, the patient deteriorated clinically and radiographically. The lung biopsy revealed eosinophilic pneumonia, and ELISA for Toxocara antigen was positive, leading to a diagnosis of pulmonary toxocariasis. After a 10-day treatment course with albendazole and adjunctive steroids, the patient recovered completely without any sequelae. Pulmonary toxocariasis may be considered in patients with subacute or chronic pneumonia unresponsive to antibiotic agents, particularly in cases with eosinophilia.     

Asthma is a risk factor for acute chest syndrome and cerebral vascular accidents in children with sickle cell disease

BACKGROUND: Asthma and sickle cell disease are common conditions that both may result in pulmonary complications. We hypothesized that children with sickle cell disease with concomitant asthma have an increased incidence of vaso-occlusive crises that are complicated by episodes of acute chest syndrome. METHODS: A 5-year retrospective chart analysis was performed investigating 48 children ages 3-18 years with asthma and sickle cell disease and 48 children with sickle cell disease alone. Children were matched for age, gender, and type of sickle cell defect. Hospital admissions were recorded for acute chest syndrome, cerebral vascular accident, vaso-occlusive pain crises, and blood transfusions (total, exchange and chronic). Mann-Whitney test and Chi square analysis were used to assess differences between the groups. RESULTS: Children with sickle cell disease and asthma had significantly more episodes of acute chest syndrome (p = 0.03) and cerebral vascular accidents (p = 0.05) compared to children with sickle cell disease without asthma. As expected, these children received more total blood transfusions (p = 0.01) and chronic transfusions (p = 0.04). Admissions for vasoocclusive pain crises and exchange transfusions were not statistically different between cases and controls. SS disease is more severe than SC disease. CONCLUSIONS: Children with concomitant asthma and sickle cell disease have increased episodes of acute chest syndrome, cerebral vascular accidents and the need for blood transfusions. Whether aggressive asthma therapy can reduce these complications in this subset of children is unknown and requires further studies.     

Invasive aspergillosis: clinical manifestations and treatment

During the last decade the incidence of invasive aspergillosis has substantially grown due to the increasing use of powerful immunosupressive drugs in more patients. Unfortunately, the associated mortality with this infection is still very high and has not decreased in recent years. Pulmonary aspergillosis is by far the most frequent clinical picture of this infection, followed by sinus, tracheo-bronchial and central nervous system disease. The degree of immunosupression is the main factor influencing the evolution and dissemination of aspergillosis. Conventional amphotericin B has been the first-line therapy of invasive aspergillosis for the last 30 years, and most authors have long considered amphotericin B related toxicity as one of the main causes for the poor results obtained in the outcome of patients who developed this infection. Fortunately, in the last few years new safer and more effective drugs have been developed for the treatment of this entity. However, if we are really trying to substantially decrease invasive aspergillosis associated-mortality we should use these drugs earlier in the development of the infection, using new more sensitive diagnostic tests and/or a riskbase strategy which could identify patients at the highest risk to develop this infection.     

Role of circulating platelets and granulocytes in PAF-induced pulmonary dysfunction in awake sheep

The effects of a single intravascular bolus injection of platelet-activating factor (PAF) on pulmonary hemodynamics, lung mechanics, and lung fluid and solute exchange were studied in 13 chronically instrumented unanesthetized sheep. Since PAF has profound effects on both platelets and granulocytes, we investigated the effects of platelet and granulocyte depletion on the sheep's response to exogenous PAF. Sheep received PAF when granulocyte and platelets counts were normal and after platelet depletion with rabbit antisheep platelet antibodies (n = 5) or granulocyte depletion with hydroxyurea (n = 5). Sheep served as their own controls, and the order of experimentation was varied. Bolus injections of PAF had reproducible effects on pulmonary hemodynamics (pulmonary arterial pressure increased acutely to 85 +/- 3.7 cmH2O) and lung mechanics (dynamic compliance of the lungs decreased to 24.5 +/- 3.8% of base line and resistance to airflow across the lungs increased greater than 10-fold) and caused marked increases in lung lymph concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha. The single bolus injection of PAF also caused marked prolonged elevations in lung lymph flow and increases in the lymph-to-plasma protein concentration ratio for 3 h after PAF. PAF had profound effects despite platelet and granulocyte depletion. Platelet depletion slightly attenuated the pulmonary hypertension observed after PAF injection. Platelet depletion also attenuated the increases in thromboxane B2 concentrations in lung lymph, and lung mechanics normalized more rapidly in platelet-depleted sheep. There were no statistically significant effects of granulocyte depletion to less than 200 granulocytes/mm3 on any of the measured variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative efficacy of fluconazole and amphotericin B in the parenteral treatment of experimental paracoccidioidomycosis in the rat

Patients with severe and complicated paracoccidioidomycosis are treated with amphotericin B by the intravenous route. Fluconazole is active in vitro against Paracoccidioides brasiliensis and can also be administered intravenously, but few clinical or experimental data are available about its action against the infection caused by this fungus. In the present study, the efficacy of fluconazole andamphotericin B was assessed comparatively in rats inoculated parenterally with P. brasiliensis. The treatment was performed 3 times a week for 4 weeks starting one week after infection. Fluconazole administered intraperitoneally (14 mg/kg bodyweight/dose) was more effective (P > 0.001)than amphotericin B (2 mg/kg body weight/dose) in reducing the number of colony forming units in the lungs and spleen. When administered intravenously at the dose of 3 mg/kg body weight, fluconazole was as effective as amphotericin B (0.8 mg/kg body weight) in reducing the pulmonary fungal burden. Under these conditions, the rats treated with fluconazole had a smaller number of colony forming units than untreated animals (P > 0.001), but amphotericin B was more effective than fluconazole in reducing spleen infection (P > 0.005). Except for this result obtained with a low dose, fluconazole showed an antifungal action equal to or higher than that of amphotericin B. The activity of fluconazole at doses equivalent to those used for human treatment suggests that this antifungal agent may be an alternative to amphotericin B for the early intravenous treatment of patients with paracoccidioidomycosis. This revised version was published online in June 2006 with corrections to the Cover Date.     

Production of Tumor Necrosis Factor-α in Granulocytopenic Mice with Pulmonary Candidiasis and Its Modification with Granulocyte Colony-Stimulating Factor

In the present study, a lethal model of pulmonary candidiasis was established using granulocytopenic mice with cyclophosphamide. These mice started to die 1 day after infection and had all died within the next 48 hr. The counts of live C. albicans in the lung gradually increased with time, while the organisms were quickly eliminated in the normal mice. From the histology and measurements on bronchoalveolar lavage fluid (BALF), polymorphonuclear cells (PMN) response was almost zero up to 24 hr, and then a weak but significant response was observed at 48 hr, while a marked accumulation of PMN was detected from as early as 6 hr in normal mice. In contrast, macrophages had accumulated in BALF by 48 hr in granulocytopenic mice, but not in normal mice. Both in serum and BALF, a considerable level of tumor necrosis factor-α (TNF-α) was detected from 6 hr, peaking at 24 to 48 hr, while in normal mice the quantity was under the detection limit in serum and very low in BALF. The effects of administering granulocyte colony-stimulating factor (G-CSF) on these parameters were next examined. G-CSF significantly prolonged the survival time of granulocytopenic mice, promoted the clearance of organisms through increasing the counts of PMN in the lung, and strongly inhibited the production of TNF-α both in BALF and serum. These results suggest that this cytokine does not protect them, but plays some role in their death due to candidial infection in granulocytopenic mice.     

两性霉素B联合伊曲康唑或卡泊芬净治疗恶性血液病并发侵袭性真菌感染

目的观察两性霉素B联合伊曲康唑或卡泊芬净治疗恶性血液病患者并发侵袭性真菌感染(IFI)的临床疗效及安全性。方法收集我院联合治疗患者9例,对其疗效及毒副反应进行分析研究。结果9例患者7例有效,1例无效,1例停药。低钾是最常见的副反应,其他副反应包括畏寒、发热及肝、肾功能受损。结论两性霉素B联合伊曲康唑或卡泊芬净治疗IFI,经济、有效,患者依从性较好。     

老年肺结核并存糖尿病合并下呼吸道真菌感染的临床分析

目的探讨老年肺结核并存糖尿病患者合并下呼吸道真菌感染的病原学特征和耐药情况,为今后真菌感染的预防和治疗提供病原学依据。方法对浙江大学西溪校区校医院2009年1月至2013年12月共计127例老年肺结核并存糖尿病患者合并下呼吸道真菌感染的病例进行回顾性分析,研究其病原菌分布及耐药特征;采用ATB自动细菌鉴定仪及配套鉴定药敏条进行试验,按CLSI标准判定药敏结果,用WHONET 5.6软件分析数据。结果 127株真菌主要为白假丝酵母菌,占59.8%,其次为热带假丝酵母菌,占13.4%,药敏结果显示5种主要酵母样真菌对伊曲康唑的耐药率最高,对5-氟胞嘧啶和两性霉素B全敏感。结论从老年肺结核并存糖尿病患者下呼吸道中分离出的真菌对常用抗真菌药物已具有一定的耐药性,临床应加强监测与控制,并根据药敏试验结果合理用药。     

尖端赛多孢和多育赛多孢所致的深部真菌感染2例并文献复习

目的分别报道国内少见的由尖端赛多孢导致的化脓性关节感染伴骨髓炎和多育赛多孢的血行播散感染。方法取患者1的关节冲洗液和患者2的外周血标本直接涂片和真菌培养,根据真菌培养的菌落特点和镜下形态,鉴定致病菌种,并对分离的致病菌进行体外药敏试验。结果两个病例分别培养出尖端赛多孢和多育赛多孢。体外药敏试验显示两种菌对伏立康唑有较低的MIC值,而都对两性霉素B高耐。结论赛多孢菌的感染少见,且难治疗。应加深对少见真菌病的认识,提高诊治水平。