卡泊芬净联合其他抗真菌药物治疗血液病嗜中性粒细胞缺乏合并侵袭性真菌感染疗效观察

目的 分析评价卡泊芬净联合其他抗真菌药物治疗恶性血液病患者中性粒细胞缺乏时合并侵袭性真菌感染的有效性和安全性.方法 选择2005年6月至2007年6月应用卡泊芬净联合其他抗真菌药物治疗恶性血液病患者嗜中性粒细胞缺乏时合并侵袭性真菌感染16例(20例次)患者.16例患者急性淋巴细胞白血病3例,多发性骨髓瘤3例,急性非淋巴细胞白血病5例,淋巴瘤5例.其中确诊侵袭性真菌感染3例,临床诊断8例,拟诊5例.患者第1天用负荷剂量卡泊芬净70 mg静脉滴注,第2天开始用50mg,每日1次,直至血象上升或症状好转后改口服其他抗真菌药,在用卡泊芬净同时联合应用其他抗真菌药(两性霉素B,或伏立康唑,或伊曲康唑),连用7～10 d停用其他抗真菌药,卡泊芬净至少应用7 d,最长应用57 d.平均应用14 d.所有患者在发热时均行真菌抗原检测及其血培养、痰培养,均行胸部CT检查,治疗结束进行疗效评估.治疗成功包括完全反应和部分反应.结果 16例(20例次)患者有17次出现血氧饱和度下降.经联合用药后1～6 d血氧饱和度恢复正常,3次为临床诊断患者大剂量化疗或造血干细胞移植期间治疗用药.16例患者抢救治疗成功率100%,应用卡泊芬净治疗期间未见明显不良反应.结论 对于危重血液病患者粒细胞缺乏期卡泊芬净联合其他抗真菌药物治疗重度侵袭性真菌感染,疗效可靠,副作用小,具有临床应用价值.     

抗真菌新药卡泊芬净在血液病患者经验性抗真菌治疗中的疗效观察

目的 探讨卡泊芬净在血液病患者经验性抗真菌治疗中的疗效.方法 将2008年10月至2010年10月收治的40例抗生素治疗无效且怀疑真菌感染的血液病患者随机分为两组,各20例,A组给予卡泊芬净治疗,第1天70 mg静脉滴注,第2天起50 mg静脉滴注;B组患者给予脂质体两性霉素B治疗,3 mg/(kg·d)静脉滴注.两组均治疗10 d,观察两组患者的疗效和不良反应.结果两组总有效率比较(66.7% vs.61.1%),差异无统计学意义(χ2=1.17,P>0.05),但A组肾毒性、输液反应发生率明显低于B组(χ2=4.37,4.37,P<0.05).结论 卡泊芬净用于血液病患者经验性抗真菌治疗,效果较好,患者耐受性较好,是侵袭性真菌感染的一个较好选择.     

两性霉素B治疗白血病化疗后肺部侵袭性真菌感染患儿的临床疗效

目的探讨两性霉素B治疗白血病化疗后肺部侵袭性真菌感染患儿的临床疗效,分析对炎症因子及预后的影响。方法选取2018年1月～2019年3月我院收治的白血病化疗后肺部侵袭性真菌感染患儿56例,随机分为观察组和对照组各28例。两组患者均在化疗后根据粒细胞缺乏情况进行抗真菌药物治疗,其中对照组使用米卡芬净,观察组采用两性霉素B。对比两组患儿临床疗效,观察比较化疗前后的中性粒细胞数、白介素-6(IL-6)、超敏C-反应蛋白(hs-CRP)及不良反应发生率。结果对照组临床总有效率64.29%,低于观察组的89.29%,差异有统计学意义(P<0.05)。治疗前,两组hs-CRP、IL-6水平、中性粒细胞数比较差异无统计学意义(P>0.05);治疗后,两组hs-CRP、IL-6水平均提高,中性粒细胞数均减少,且对照组变化幅度大于观察组,差异有统计学意义(P<0.05);对照组不良反应总发生率高于观察组,但数据比较,差异无统计学意义(P>0.05)。结论静脉滴注两性霉素B治疗白血病化疗后肺部侵袭性真菌感染患儿可有效抗感染、抑菌,提高免疫力,降低炎症因子,且安全性高。     

卡泊芬净治疗中性粒细胞减少症伴发热患者9例分析

目的观察卡泊芬净治疗白血病患儿中性粒细胞减少症伴发热的疗效和安全性。方法9例白血病合并中性粒细胞减少症，伴发热，疑为侵袭性真菌感染，使用卡泊芬净首次剂量70mg·m^-2·d^-1，维持剂量50mg·m^-2·d^-1。其中4例合用脂质体两性霉素B2mg·m^-1·d^-1；持续治疗15～40d；观察用药前后不同时间患儿临床症状、体征，肝。肾功能、电解质和胸部CT的变化。结果卡泊芬净治疗I临床总有效率为88．8％，各种不良反应的发生率为11．1％，联合用药的起效快，疗程短。结论卡泊芬净治疗9例患儿有效率高，未发现明显不良反应，是治疗白血病患儿发热伴中性粒细胞减少症的的一种选择。     

卡泊芬净在中性粒细胞缺乏伴持续发热患者经验性抗真菌治疗中的疗效观察

卡泊芬净(caspofungin acetate.亦称MK20991,L2743872)是第一个批准用于临床的棘白菌素。此类药物毒性低,对大多数临床分离的念珠菌属和曲霉属均有快速杀菌作用。在血液科恶性肿瘤接受化疗或进行造血干细胞移植、再生障碍性贫血等发生中性粒细胞缺乏的患者中,侵袭性真菌感染是其重要的死亡原因。本研究报道6例中性粒细胞缺乏患者经验性应用卡泊芬净的疗效与不良反应。     

恶性血液病患者中侵袭性真菌病的二级预防

侵袭性真菌病在恶性血液病患者中发病率及死亡率均很高,有真菌感染病史的患者在进一步的化疗或造血干细胞移植中真菌感染复燃率高、预后差。真菌的二级预防可有效地预防真菌感染复燃。给予有效的二级预防,既往侵袭性真菌感染病史不影响化疗继续进行,也不再是异基因造血干细胞移植的绝对禁忌症。已经证明广谱抗真菌药物如伏立康唑、伊曲康唑、两性霉素B、卡泊芬净作为二级预防药物取得了很好的疗效,但在粒细胞缺乏和免疫抑制状态下预防真菌感染复燃仍然面临巨大的挑战。本文就恶性血液病患者中二级抗真菌预防的现状作一综述。     

经验治疗、抢先治疗和针对性治疗侵袭性霉菌病随机对照临床试验结果混合比较的系统回顾

<正>侵袭性霉菌病是恶性血液病患者发病和死亡的主要原因之一。在20年前,治疗侵袭性霉菌病药物只有两性霉素B和伊曲康唑。目前,已开发出脂质体两性霉素B、卡泊芬净、伏立康唑、泊沙康唑等新型抗真菌药。这些新药大大提高侵袭性霉菌病的治疗疗效并增加经验积累。多种治疗方案和新的诊断方法使治疗策略发生了变化。虽然嗜中性粒细胞缺乏伴持续发热患者的抗真菌经验治疗仍被广泛应用,但只证明新型唑类药物的预防应用对侵袭性曲霉病有效,并     

卡泊芬净与氟康唑治疗慢阻肺急性加重期合并肺部真菌感染疗效对比

目的：分析卡泊芬净与氟康唑治疗慢阻肺（COPD）急性加重期合并肺部真菌感染的临床疗效。方法：选取2018年2月~2020年4月收治的COPD急性加重期合并肺部真菌感染患者60例,采用随机数字表法分为卡泊芬净组和氟康唑组,各30例。在常规治疗基础上,卡泊芬净组采用注射用醋酸卡泊芬净治疗,氟康唑组采用氟康唑注射液治疗,两组连续治疗2周。比较两组患者体温恢复正常时间、肺部真菌涂片检查转阴时间、白细胞恢复正常时间、真菌清除率以及不良反应发生情况。结果：卡泊芬净组患者体温恢复正常时间、肺部真菌涂片检查转阴时间以及白细胞恢复正常时间均短于氟康唑组,差异有统计学意义（P＜0.05）;治疗2周后,卡泊芬净组光滑念珠菌清除率及总清除率高于氟康唑组,差异有统计学意义（P＜0.05）。治疗期间,两组均未发生明显不良反应。结论：卡泊芬净治疗COPD急性加重期合并肺部真菌感染患者疗效要优于氟康唑,可以加速肺部真菌转阴和白细胞恢复正常,能更有效地清除真菌,且不良反应少,耐受性较好。     

卡泊芬净与米卡芬净治疗重症侵袭性真菌感染的临床疗效与药物利用评价

目的探讨卡泊芬净和米卡芬净治疗重症侵袭性真菌感染（invasive fungal infections,IFI）患者的临床疗效,评价药物利用。方法随机抽取四川省人民医院2009年1月至2011年12月分别经卡泊芬净和米卡芬净治疗的IFI病例各40例,分析评价卡泊芬净和米卡芬净治疗IFI的疗效、不良反应及药物利用情况。结果治疗总有效率卡泊芬净组为57.5%,米卡芬净组为55.0%,差异无统计学意义（P〉0.05）;两组首选治疗有效率均远高于三唑类（如氟康唑、伊曲康唑）、多烯类（如两性霉素B及其脂质体）治疗无效或不能耐受而进行的挽救治疗有效率,差异有统计学意义（P〈0.05）;不良反应发生率卡泊芬净组高于米卡芬净组,但差异无统计学意义（P〉0.05）;药物利用指数（DUI）卡泊芬净为0.985,米卡芬净为1.000,使用基本合理;日用药金额卡泊芬净为1942.04元/天,米卡芬净为1260.00元/天。结论卡泊芬净和米卡芬净治疗重症IFI的疗效相当,首选二者治疗的有效率均高于挽救治疗;二者不良反应发生率相近;DUI≤1.0,为合理用药。二者在疗效和不良反应相当的情况下,从经济学角度考虑米卡芬净更具优势。     

卡泊芬净治疗儿童血液病侵袭性真菌感染的疗效及安全性评价

目的探讨卡泊芬净治疗儿童血液病侵袭性真菌感染的临床疗效及安全性。方法回顾性分析35例真菌感染的血液病患儿,给予静脉滴注卡泊芬净,第1天单次70mg/m2负荷剂量(日实际剂量不超过70mg),之后给予每天50mg/m2(日实际剂量不超过70mg),疗程4～36d,根据患儿临床表现和肺影像学变化判断疗效。结果确诊3例为血源感染,临床诊断25例、拟诊7例均为肺部感染,治疗总有效率71.43%;有效组疗程为(17.80±6.97)d,无效组疗程(10.40±5.54)d,差异有统计学意义(P<0.05);抢先/经验治疗组有效率为84%,高于目标/挽救治疗组的40%,差异有统计学意义(P<0.05);未见明显不良反应。粒细胞缺乏≥10d是治疗失败的危险因素。结论卡泊芬净治疗儿童血液病侵袭性真菌感染是安全有效的治疗选择;抢先治疗能提高疗效。     

Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B

Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 x 10(9) neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%]; P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.     

FLAG和MEA方案治疗难治复发性急性髓系白血病疗效分析

目的探讨氟达拉滨联合大剂量阿糖胞苷、重组人粒细胞集落刺激因子（FLAG）方案及米托蒽醌、足叶乙甙及阿糖胞苷（MEA）方案治疗难治复发性急性髓系白血病的临床疗效及不良反应。方法难治复发性急性髓系白血病患者63例,按不同化疗方案分为使用FLAG方案者33例（FLAG组）与使用MEA方案化疗者30例（MAE组）,比较2组完全缓解率、部分缓解率,粒细胞缺乏持续时间、侵袭性真菌感染发生率及非血液学不良反应发生率。结果FLAG组完全缓解率与侵袭性真菌感染发生率明显高于MEA组（P〈0．05）,部分缓解率与粒细胞缺乏持续时间均稍高于MEA组,但差异均无统计学意义（P〉0．05）;2组非血液学不良反应发生率均为100％,差异无统计学意义（P〉0．05）。结论FLAG方案治疗难治复发性急性髓系白血病疗效优于MEA方案,其不良反应可被患者接受。     

伏立康唑治疗老年白血病合并侵袭性肺部真菌感染的临床效果

目的探讨伏立康唑治疗老年白血病合并侵袭性肺部真菌感染的临床效果。方法选择2014年3月至2018年12月在我院住院治疗的68例老年白血病合并侵袭性肺部真菌感染患者作为研究对象,按照入院顺序将其分为对照组和观察组,各34例。对照组给予两性霉素B治疗,观察组给予伏立康唑治疗。比较两组临床疗效、不良反应发生情况、血清炎症因子水平及真菌感染清除率。结果观察组治疗总有效率为94.12%,高于对照组的76.47%,差异具有统计学意义(P<0.05)。治疗后,两组TNF-α、IL-12水平均较治疗前降低,IL-10水平较治疗前升高,且观察组优于对照组,差异具有统计学意义(P<0.05)。观察组的不良反应总发生率为11.76%,低于对照组的32.35%,差异具有统计学意义(P<0.05)。观察组真菌感染清除率为82.35%,高于对照组的67.65%,差异具有统计学意义(P<0.05)。结论伏立康唑和两性霉素B治疗老年白血病合并侵袭性肺部真菌感染患者均有效,且均可改善患者的血清炎症因子水平,但伏立康唑治疗效果更佳,使用更为安全。     

Caspofungin: antifungal activity in vitro, pharmacokinetics, and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis

OBJECTIVES: Evaluation of the potential of caspofungin, in relation to pharmacokinetics, in order to optimize its use in the treatment of filamentous fungal infections. METHODS: The in vitro antifungal activity, pharmacokinetics and therapeutic efficacy of caspofungin versus amphotericin B was investigated in vitro as well as in a model of aerogenic Aspergillus fumigatus infection in neutropenic rats, using rat survival and decrease in fungal burden as parameters for therapeutic efficacy. RESULTS: In contrast to amphotericin B, caspofungin shows a concentration-dependent gradual decrease in fungal growth in vitro, which makes it difficult to perform visual readings of antifungal activity (CLSI guidelines). The quantitative XTT [2,3-bis(2-methoxy-4-nitro-5-[(sulphenylamino) carbonyl]-2H-tetrazolium-hydroxide] assay measuring a decrease in fungal metabolic activity seems more appropriate for caspofungin susceptibility testing. Using this assay, in vitro caspofungin was 4-fold less active than amphotericin B. In the infection model, therapy was started 16 h after fungal inoculation, and continued once daily for 10 days. Caspofungin was administered intraperitoneally at 1, 2, 3 or 4 mg/kg/day (CAS 1, 2, 3 or 4), amphotericin B at 1 mg/kg/day (AMB 1). Treatment with CAS 1 or AMB 1 provided modest prolongation of animal survival. The combination of caspofungin and amphotericin B did not show additive effects. Increasing the dosage of caspofungin to 2, 3 or 4 mg/kg/day resulted in a dose-dependent significant increase in efficacy. There was 100% survival among rats in the CAS 4 group, which was correlated with a significant decrease in fungal burden, based on the concentration of A. fumigatus galactomannan in serum and lung tissue and quantification of A. fumigatus DNA in lung tissue. Pharmacokinetic analysis suggested that the CAS 4 dose in rats produced drug exposure comparable to the human situation, visualized by similar 24 h AUC and trough concentrations. CONCLUSIONS: The therapeutic efficacy of caspofungin is superior to amphotericin B, which seemed to be discrepant with their in vitro antifungal activity.     

吡柔比星与阿霉素为主的方案治疗非霍奇金淋巴瘤30例疗效比较

【目的】分析比较吡柔比星（吡喃阿霉素,THP）与盐酸阿霉素（ADM）治疗非霍奇金淋巴瘤（NHL）的疗效与不良反应。【方法】将58例NHL患者随机分成两组,A组30例,选用THP联合化疗;B组28例,选用ADM联合化疗,4个疗程后比较两组疗效及不良反应。【结果】A组与B组比较,总有效率分别为76．66％和71．43％,A组高于B组,但差异无显著性（P〉0．05）。两组心脏毒性发生率分别为6．25％和17．66％,胃肠道反应分别为50％和67．66％,两者比较有显著性差异（P〈0．05）,脱发分别为37．5％和82．14％,两者比较有非常显著性差异（P〈0．01）,骨髓抑制两者比较无明显差异。【结论】THP相对于ADM联合化疗患者不良反应发生率低,尤其消化道反应、脱发率及心脏毒性较低,且程度上也较轻,故THP较适合用于NHL患者。     

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.     

不同方案沙利度胺治疗多发性骨髓瘤的临床效果及其与TNF-α水平的关系

本研究探讨不同方案沙利度胺（thalidomide）治疗多发性骨髓瘤（multiple myeloma，MM）的临床疗效和不良反应，寻求沙利度胺一线治疗多发性骨髓瘤的最佳方案，并分析临床疗效与血清TNF-α水平的关系。分别应用高剂量沙利度胺（HD—T）、沙利度胺＋VAD化疗（T—VAD）、沙利度胺＋MP化疗（T—MP）、沙利度胺＋地塞米松（TD）及低剂量沙利度胺（LD—T）等方案治疗85例多发性骨髓瘤，以常规VAD化疗组为对照，观察临床疗效、不良反应、治疗相关死亡率；同时应用双抗体夹心酶联免疫吸附法（ELISA）检测30例沙利度胺治疗的多发性骨髓瘤（15例有效，15例无效）患者治疗前后血清TNF-α水平并与临床疗效比较。结果表明：HD—T、T—VAD、T—MP、TD、LD-T5个组的治疗有效率分别为25．0％、80．0％、71．4％、33．3％、27．3％，其中T-VAD、T-MP组治疗有效率较其他组及常规VAD化疗组显著增高（P〈0．05）。显著不良反应（外周神经病变、乏力、腹胀、便秘、皮疹、水肿、白细胞和血小板减少）5个组的发生率为75．0％、30．0％、28．6％、14．3％、9．1％。没有出现Ⅳ级毒性，没有患者出现深静脉血栓，治疗相关死亡率为0％。同时发现，沙利度胺治疗无效组治疗前后血清TNF-α水平分别是（44．7±5．7）pg／ml和（46．3±5．7）pg／ml，两者无显著差异（P〉0．05）；沙利度胺治疗有效组的治疗后血清TNF-α水平（27．3±6．4）pg／ml，较治疗前（49．2±7．3）pg／ml显著降低（P〈0．05）。结论：与常规化疗比较，沙利度胺是治疗多发性骨髓瘤的有效药物，其联合化疗（T—VAD，T—MP）效率高，副作用小，可认为是优选方案。患者血清TNF-α水平是判断沙利度胺治疗多发性骨髓瘤疗效的指标之一，它在多发性骨髓瘤发病中可能具有一定作用。     

Itraconazole versus amphotericin B plus nystatin in the prophylaxis of fungal infections in neutropenic cancer patients.

The efficacy and safety of itraconazole oral solution and a combination of amphotericin B capsules plus nystatin oral suspension were compared in the prophylaxis of fungal infections in neutropenic patients. In an open, randomized, multicentre trial, 144 patients received itraconazole oral solution 100 mg bd, and 133 patients received amphotericin B 500 mg tds plus nystatin 2 MU qds. Overall, 65% of itraconazole-treated patients were considered to have had successful prophylaxis, compared with 53% in the polyene group. Proven deep fungal infections occurred in 5% of patients in each group. Fewer patients receiving itraconazole than amphotericin plus nystatin had superficial infections (3 versus 8%; P = 0.066). This trend in favour of itraconazole was seen in patients with profound neutropenia (neutrophil count <0.1 x 10(9) cells/L at least once) or prolonged neutropenia (neutrophil count <1.0 x 10(9) cells/L for >14 days). The median time to prophylactic failure was longer in the itraconazole group (37 days) than in the polyene group (34 days). The number of patients with fungal colonization (nose, sputum, stool) changed more favourably from baseline to endpoint in the itraconazole group than in the polyene group. Both treatments were safe and well tolerated; however, patients receiving amphotericin plus nystatin had a higher incidence of nausea and rash. In conclusion, itraconazole oral solution at doses of 100 mg bd and oral amphotericin B plus nystatin have similar prophylactic efficacy against fungal infections in neutropenic patients. On the basis of reduced incidence of superficial fungal infections, fungal colonization and specific adverse events, itraconazole may be the preferred treatment.