两性霉素B脂质体联合氟康唑治疗早产儿真菌性中枢感染研究

目的 探讨两性霉素B脂质体联合氟康唑治疗早产儿真菌感染的疗效及安全性.方法 收集2009.10 - 2011.5收治的中枢神经系统真菌感染早产儿7例,均应用两性霉素B脂质体联合氟康唑治疗,总疗程8 ～ 12周,监测治疗过程中患儿临床症状、体征及相关的血清学、脑脊液及影像学检查指标.结果 两性霉素B脂质体联合氟康唑足量长疗程治疗使早产儿真菌感染得到良好控制,除1例放弃治疗外,余6例症状明显改善,血培养均转阴,中枢神经系统病灶较前明显改善.治疗过程中未发现较严重的药物不良反应.结论 两性霉素B脂质体联合氟康唑治疗早产儿真菌性中枢感染有效且相对安全.     

Use of amphotericin B colloidal dispersion in children

PURPOSE: To describe the experience with a new lipid-based amphotericin product (amphotericin B colloidal dispersion or ABCD) in children with fever and neutropenia who are at high risk for fungal infection. PATIENTS AND METHODS: Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with amphotericin B. An additional 70 children with presumed or proven fungal infection were treated with 5 different open-label studies of ABCD. Patients were registered into these studies for reasons of: 1) failure to respond to amphotericin B; 2) development of nephrotoxicity or preexisting renal impairment; or 3) willingness to participate in a dose-escalation study. Extensive data detailing response and toxicity were collected from each patient. RESULTS: In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4% [P = 0.003]). Other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12% of these patients. CONCLUSIONS: ABCD was well-tolerated at doses up to 5 times greater then those usually tolerated with amphotericin B. Renal toxicity was markedly less than expected, and there were no other unexpected severe toxicities. Further randomized studies are needed to further define the role of this and other liposomal products in children.     

Liposomal amphotericin B associated with severe hyperphosphatemia

We report 4 patients who developed hyperphosphatemia while receiving liposomal amphotericin B to treat an invasive fungal infection. Resolution of the hyperphosphatemia occurred after transition to amphotericin B lipid complex. This phenomenon may occur more commonly in patients with mild to moderate renal insufficiency.     

儿童白血病化疗后合并全身性真菌感染诊断及治疗体会

目的 积累和交流白血病化疗病人合并深部真菌感染时临床经验.方法 总结2年中明确诊断深部霉菌感染病人的诊断过程、方法、临床特征、治疗反应和转归.结果确诊深部真菌感染者共5例,均为白血病患儿,感染前或感染中白血病达完全缓解,特征性表现为发热,抗菌素治疗＞5天无效,轻中度压痛的多发性硬性皮下小结（2/5例）和肝脾肾散布性低密度病灶（3/5例）,需四周以上二性霉素治疗,有明显但可以处理的毒性反应.结论 发热、抗菌素治疗无效、硬性皮下小结和肝脾肾散布性低密度病灶时应考虑深部真菌感染,并给予4周以上二性霉素治疗.     

儿童白血病化疗后合并全身性真菌感染诊断及治疗体会

目的积累和交流白血病化疗病人合并深部真菌感染时临床经验。方法总结2年中明确诊断深部霉菌感染病人的诊断过程、方法、临床特征、治疗反应和转归。结果确诊深部真菌感染者共5例,均为白血病患儿,感染前或感染中白血病达完全缓解,特征性表现为发热,抗菌素治疗>5天无效,轻中度压痛的多发性硬性皮下小结(2/5例)和肝脾肾散布性低密度病灶(3/5例),需四周以上二性霉素治疗,有明显但可以处理的毒性反应。结论发热、抗菌素治疗无效、硬性皮下小结和肝脾肾散布性低密度病灶时应考虑深部真菌感染,并给予4周以上二性霉素治疗。     

Successful treatment of bilateral renal fungal balls with liposomal amphotericin B and fluconazole in an extremely low birth weight infant

At the age of 8 weeks, an extremely low birth weight infant (gestational age 26 0/7 weeks, birth weight 740 g) had non-obstructing bilateral renal fungal balls. Urine cultures had repeatedly grown Candida albicans. Combination therapy with liposomal amphotericin B intravenously and fluconazole orally was administered for 6 weeks. Monotherapy with fluconazole was then continued until complete resolution of the renal fungal balls. Conclusion Combination therapy with liposomal amphotericin B and fluconazole was successful in eliminating non-obstructing bilateral renal fungal balls and obviated the need for surgical intervention. Received: 10 December 1999 and in revised form: 18 February and 12 March 2000 Accepted: 24 March 2000     

两性霉素B脂质体治疗早产儿侵袭性真菌感染的疗效

目的分析早产儿侵袭性真菌感染的高危因素、临床特征,观察两性霉素B脂质体治疗的有效性和安全性。方法回顾性分析21例侵袭性真菌感染早产儿的临床资料,根据临床特点、实验室检查确诊病例10例,临床诊断11例。应用两性霉素B脂质体治疗,剂量由0.1mg.kg-1.d-1开始,后每天或隔天加0.1mg.kg-1,每周复查1,3-β-D葡聚糖,结合临床继续增加至1～3mg.kg-1.d-1。同时每周监测肝肾功能及血常规。结果早产儿侵袭性真菌感染的高危因素是低胎龄儿、极低出生体质量儿、使用中心静脉导管、胃肠外营养、气管插管及长期应用抗生素。临床特征非特异性,各种体液培养以白色念珠菌为主;血1,3-β-D葡聚糖检测均>1500pg.L-1。本组治愈17例,有效2例,放弃、死亡各1例;未见明显不良反应。结论NICU中侵袭性真菌感染发病率日益增高,应重视其发病高危因素,血1,3-β-D葡聚糖监测非常必要,两性霉素B脂质体治疗早产儿侵袭性真菌感染安全、有效。     

Scedosporium infection in immunocompromised patients: successful use of liposomal amphotericin B and itraconazole

BACKGROUND: Invasive fungal disease is a major cause of death in immunocompromised patients. The filamentous fungus Scedosporium consists of two species, S. prolificans and S. apiospermum, which can cause infections in immunocompromised patients that are often fatal. A significant feature of this pathogen is its broad resistance to many antifungal agents, including amphotericin B. PROCEDURE AND RESULTS: Five cases of infection with Scedosporium spp. occurred in patients with haematologic malignancies over a 10-month period. Three patients with S. prolificans were severely immunosuppressed and neutropenic; two were in relapse and another was early post-matched unrelated bone marrow transplant. All three died despite treatment with various combinations of amphotericin B and itraconazole. Two patients who were less immunosuppressed and had a normal neutrophil count developed S. apiospermum infection. Both were successfully treated with liposomal amphotericin B and itraconazole. CONCLUSIONS: Disseminated infection in immunocompromised hosts with Scedosporium spp. is often fatal. However, in patients with a lesser degree of immunocompromise and particularly in those infected with the less virulent S. apiospermum, intensive antifungal therapy with liposomal amphotericin B and itraconazole may be associated with complete eradication of infection. Med Pediatr Oncol 2001;37:122-125.     

Invasive esophageal aspergillosis associated with acute myelogenous leukemia: successful therapy with combination caspofungin and liposomal amphotericin B

Aspergillosis is one of the most common invasive fungal infections in patients with leukemia. In this patient group, this form of Aspergillus infection is a life-threatening condition with a mortality of 50-100%. The lungs are most often affected, but the esophagus can also be involved.The authors report the case of a child with leukemia who developed invasive esophageal aspergillosis. The condition was diagnosed by microscopic examination of endoscopic biopsy specimens. The patient was already receiving empirical liposomal amphotericin B when the diagnosis was made, so a second antifungal (caspofungin) was added to the regimen. This combination was successful. This case to demonstrates a case of successful treatment of invasive esophageal aspergillosis using combination therapy of liposomal amphotericin B and caspofungin.     

INVASIVE ESOPHAGEAL ASPERGILLOSIS ASSOCIATED WITH ACUTE MYELOGENOUS LEUKEMIA: Successful Therapy with Combination Caspofungin and Liposomal Amphotericin B

Aspergillosis is one of the most common invasive fungal infections in patients with leukemia. In this patient group, this form of Aspergillus infection is a life-threatening condition with a mortality of 50–100%. The lungs are most often affected, but the esophagus can also be involved.The authors report the case of a child with leukemia who developed invasive esophageal aspergillosis. The condition was diagnosed by microscopic examination of endoscopic biopsy specimens. The patient was already receiving empirical liposomal amphotericin B when the diagnosis was made, so a second antifungal (caspofungin) was added to the regimen. This combination was successful. This case to demonstrates a case of successful treatment of invasive esophageal aspergillosis using combination therapy of liposomal amphotericin B and caspofungin.     

Double invasive fungal infection and typhlitis in children with acute lymphoblastic leukemia

Invasive fungal infection is one of the major causes of morbidity and mortality in immunocompromised patients. The occurrence of two invasive fungal infections in one patient at the same time is quite rare. Here the authors report on two adolescent patients with acute lymphoblastic leukemia who developed combined invasive pulmonary aspergillosis and hepatosplenic candidiasis during chemotherapy. They were treated with liposomal amphotericin B, but one of them died due to massive pulmonary hemorrhage during recovery from neutropenia.     

Combination therapy with caspofungin and liposomal amphotericin B for invasive aspergillosis

Ina 24-month-old girl with acute lymphoblastic leukemia and invasive aspergillosis, only combination therapy with liposomal amphotericin B and caspofungin achieved a good response. Combination therapy could be a useful treatment option in children with invasive fungal disease, but before it can be routinely recommended, carefully controlled in vivo studies and well-designed randomized clinical trials are needed.     

DOUBLE INVASIVE FUNGAL INFECTION AND TYPHLITIS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Invasive fungal infection is one of the major causes of morbidity and mortality in immunocompromised patients. The occurrence of two invasive fungal infections in one patient at the same time is quite rare. Here the authors report on two adolescent patients with acute lymphoblastic leukemia who developed combined invasive pulmonary aspergillosis and hepatosplenic candidiasis during chemotherapy. They were treated with liposomal amphotericin B, but one of them died due to massive pulmonary hemorrhage during recovery from neutropenia.     

Conventional vs. Liposomal Amphotericin B in Immunosuppressed Children

Invasive fungal infections, mostly caused by Candida and Aspergillus species, are a major cause of early morbidity and mortality in immunocompromised children. 1,2 The treatment of choice for systemic fungal infections is still the early intravenous administration of amphotericin B. 3 However, conventional AMB therapy is often limited by severe side effects such as fever, chills, bronchospasm, and nephrotoxicity. 2 In recent reports liposomal AMB (AmBisome) was shown to be effective in the treatment of severe systemic fungal infections. 4,5 So far, clinical experience with AmBisome in children is still anecdotal and no comparative study is yet available. In the following we report on 11 immunosuppressed children who were treated with conventional or liposomal AMB for longer than 3 weeks.     

MEDICAL MANAGEMENT OF ASPERGILLUS FLAVUS ENDOCARDITIS

An 11-year-old boy underwent a matched unrelated bone marrow transplant for refractory acute myeloid leukemia. He developed invasive aspergillus pneumonia and endocarditis post-transplant. The fungal endocarditis was successfully eradicated with liposomal amphotericin at the dose of 10 mg/kg/day. Surgical intervention was not required and no serious side effects of liposomal amphotericin were observed at this dose.     

Medical management of Aspergillus flavus endocarditis

An 11-year-old boy underwent a matched unrelated bone marrow transplant for refractory acute myeloid leukemia. He developed invasive aspergillus pneumonia and endocarditis post-transplant. The fungal endocarditis was successfully eradicated with liposomal amphotericin at the dose of 10 mg/kg/day. Surgical intervention was not required and no serious side effects of liposomal amphotericin were observed at this dose.     

Amphotericin B nephrotoxicity in children

Amphotericin B is the treatment of choice for severe systemic fungal infections. Nephrotoxicity is the most clinically significant adverse effect, but studies examining nephrotoxicity in children are scarce. Nephrotoxicity includes decreased glomerular filtration rate and distal tubulopathy with urinary loss of potassium and magnesium, renal tubular acidosis, loss of urine concentrating ability, and sometimes Fanconi's syndrome. The mechanisms involved in nephrotoxicity include the use of deoxycholate, the vehicle for amphotericin, reduction in renal blood flow and glomerular filtration rate, increased salt concentrations at the macula densa, interaction of amphotericin with ergosterol in the cell membrane, and apoptosis in proximal tubular cells and medullary interstitial cells. Some risk factors for amphotericin nephrotoxicity have been determined over the years. Cumulative dosage, treatment duration, and dosing schedule as well as the combination of amphotericin with other nephrotoxic drugs, such as diuretics and cyclosporine, are important risk factors. Mechanisms to prevent nephrotoxicity include the use of lipid formulations such as amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B and the concurrent use of volume repletion. Amiloride can be considered in serious potassium loss.     

实体瘤患儿行自体外周血干细胞移植治疗中真菌感染情况

目的通过对31例实体瘤患儿行自体外周血干细胞移植(auto-PBSCT)治疗中真菌感染的情况进行分析,总结其临床特点、诊断与治疗经验。方法回顾性分析2006年5月-2009年12月本院儿科收治的31例实体瘤患儿行auto-PBSCT治疗过程中防治真菌感染的过程。结果 1.Ⅳ期进展期神经母细胞瘤患儿2例行自体外周血干细胞移植过程中经微生物学检查明确并肺部真菌感染,其中1例并脑、肝真菌感染;2例患儿血培养均为近平滑假丝酵母菌;4例患儿行肺部CT检查,表现为密度增高、渗出炎症阴影;1例进展期神经母细胞瘤患儿明确真菌感染后应用氟康唑、两性霉素B脂质体、伏立康唑静脉滴注抗真菌治疗有效,体温正常,度过骨髓抑制期,原发病获得部分缓解;1例进展期神经母细胞瘤患儿因存在颅内、骨骼、脊髓、肺、肝多发转移肿瘤,于自体外周血造血干细胞移植9 d后骨髓抑制期死亡。2.部分缓解期Ⅳ期神经母细胞瘤1例及进展期肝母细胞瘤1例患儿表现为发热、咳嗽、抽搐,怀疑侵袭性真菌感染,给予氟康唑、两性霉素B、伏立康唑治疗后好转度过骨髓抑制期,原发病获得部分缓解。3.余27例实体瘤患儿auto-PBSCT治疗中应用氟康唑预防真菌感染,临床未发生侵袭性真菌感染,1例进展期Ⅳ期神经母细胞瘤患儿因有多脏器转移,且有原发心脏损害,大剂量化疗后骨髓抑制期免疫耐受差,导致多脏器衰竭死亡。余26例实体瘤患儿顺利度过骨髓抑制期,病情获得缓解。结论实体瘤患儿auto-PBSCT治疗中易并真菌感染,需结合病史、血培养、G试验及CT、MRI等影像学检查做出诊断,经验性应用氟康唑、伏立康唑、两性霉素B等可防治真菌感染,原发病严重未缓解者预后差。     

Combination antifungal therapy with voriconazole for persistent candidemia in very low birth weight neonates

The purpose of this article is to report our experience with intravenous voriconazole therapy in the treatment of persistent Candida septicemia in very low birth weight (VLBW) neonates. Candidiasis was defined if an infant had a positive blood culture. Ten VLBW newborns developed Candida sepsis, and candidemia persisted in 6 of them despite 3 to 21 days of antifungal therapy with amphotericin B, either conventional or liposomal, and fluconazole. After the addition of voriconazole, clearance of Candida was achieved within 3-7 days of treatment. Antifungal therapy combination with liposomal amphotericin B and voriconazole was continued for at least two weeks after two negative cultures 48 hours apart. We conclude that considering the hazardous effects of Candida infections in preterm newborns, voriconazole can be added to the treatment of fungal sepsis in newborns who still have persistent candidemia despite conventional antifungal management. More clinical information is needed before voriconazole can be used as a first-line drug in antifungal therapy in newborns.     

Intracardiac fungal masses in high-risk neonates: clinical observations

Four cases of intracardiac fungal masses occurred over 2 y amongst 7 cases of systemic candidiasis in a neonatal referral unit. The gestations and birthweights were 25, 23, 24 and 30 wk and 805, 605, 640 and 1395 g, respectively. The pedunculated, solitary right atrial masses were detected 2-17 d after diagnosing candidemia in 3 cases, whereas it was the presenting feature in the 4th. All had indwelling right atrial catheters and received multiple courses of broad-spectrum antibiotics. The masses were removed successfully in two cases fit for surgery. None survived despite antifungal therapy, including liposomal amphotericin B at 6 mg/kg/d. Early introduction of enteral feeds, minimization of prolonged exposure to broad-spectrum antibiotics and judicious use of central catheters may reduce the incidence of systemic candidiasis in high-risk neonates. Surveillance echocardiography and timely surgical intervention may reduce the mortality and/or morbidity related to intracardiac fungal masses.