棘白菌素类的新品种:米卡芬净

米卡芬净[1]于2005年通过美国FDA的审批,成为继卡泊芬净之后第2个应用于临床的棘白菌素类药物。一、体外抗菌作用米卡芬净是水溶性抗真菌药,它主要抑制真菌细胞壁的主要成分1,3-β-D-葡聚糖合成,从而破坏真菌细胞壁的合成,影响细胞形态和渗透压,导致细胞溶解死亡。米卡芬净还能     

棘白菌素对念珠菌体外药敏试验产生“矛盾现象”的分析

目的观察棘白菌素对念珠菌的"矛盾现象"。方法体外药敏试验中,采用微量稀释法分别观察卡泊芬净和米卡芬净对180株念珠菌的最低抑菌浓度(MIC)和"矛盾现象"。结果卡泊芬净对白色念珠菌、热带念珠菌、近平滑念珠菌和光滑念珠菌均产生"矛盾现象",发生率分别为66.0%、77.5%、55.0%和35.0%,各菌矛盾现象的起点/终点中位数浓度分别为8/32、16/32、8/32、4/16μg/mL;米卡芬净只对白色念珠菌和热带念珠菌产生"矛盾现象",发生率分别为45%和67.5%,各菌矛盾现象的起点/终点中位数浓度分别为4/16、8/32μg/mL。结论 "矛盾现象"的产生存在念珠菌种间差异性和棘白菌素类药物特异性。卡泊芬净出现"矛盾现象"的发生率高于米卡芬净。各菌株对卡泊芬净、米卡芬净产生"矛盾现象"的发生率与MIC的高低无明显相关性。     

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。     

新型抗真菌药卡泊芬净

Echinocandins是新一类抗真菌药 ,通过非竞争性抑制 1 ,3 β D肽聚糖合成酶而阻止真菌细胞壁合成。此类药物毒性低 ,对大多数分离的念珠菌属均有快速杀菌作用 ,且因其良好的药代动力学特性而可每日 1次给药 ,故具有较好的临床应用前景。卡泊芬净 (Caspofunginacetate ,亦称MK 0 991 ,L 74 3,872 )是第一个批准用于临床的棘白菌素 (echinocan din)。一、药理作用卡泊芬净是一种半合成脂肽 ,属 1 6环脂肽[1] 。通过非竞争性抑制 1 ,3 β D肽聚糖合成酶而抑制真菌细胞壁合成[2 ] 。 1 ,3 β D肽聚糖合成酶催化真菌细胞壁多聚葡聚糖的合成 ,…     

抗深部真菌感染药物——米卡芬净

由于病原的变迁,广谱抗生素的应用或滥用,器官移植导致免疫抑制剂的大量使用,化疗以及更具侵袭性的医疗方法的应用等各种原因引起的免疫低下患者增多,真菌感染发病率呈上升趋势,其病原菌的流行病学也发生了显著改变,特别是严重的深部真菌感染的发病率和病死率逐年增加[1].     

抗深部真菌感染药物——米卡芬净

由于病原的变迁,广谱抗生素的应用或滥用,器官移植导致免疫抑制剂的大量使用,化疗以及更具侵袭性的医疗方法的应用等各种原因引起的免疫低下患者增多,真菌感染发病率呈上升趋势,其病原菌的流行病学也发生了显著改变,特别是严重的深部真菌感染的发病率和病死率逐年增加。当前治疗深部真菌感染的药物主要有：氟康唑、两性霉素B、伏立康唑、伊曲康唑等。     

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.     

侵袭性肺烟曲霉病1例

患者男,55岁。2004年5月起咳嗽、低热,无咯血、胸痛,用抗生素无效,胸部X线检查疑为肺肿瘤伴阻塞性肺炎,于9月11日行微创肺癌切除术,术后证实为小细胞癌(混合型)。术后患者低热,咳嗽、白痰,先后用头孢呋辛、头孢唑肟、亚胺培南、氟康唑等治疗,无效。10月初出现高烧,咳巧克力色脓痰,于同年10月转入我院。     

卡泊芬净治疗急性白血病并发真菌感染10例临床分析

我们选择因心脏、肾脏功能有损害或年龄≥70岁或因其他抗真菌药物治疗失败的急性白血病患者合并真菌感染的使用卡泊芬净治疗观察临床疗效和不良反应。1资料与方法1.1病例选择按照中国侵袭性真菌感染工作组制定的血液病/恶性肿瘤患者侵袭性真菌感染的诊断标准[1],10例中确诊5例,     

卡泊芬净治疗危重患者肺部真菌感染的护理

危重患者由于严重的基础疾病、合并疾病、手术、导管留置以及广谱抗菌药、糖皮质激素的应用等,使肺部真菌感染患病率增加。卡泊芬净具有广谱抗真菌作用,对白色念珠菌、非白色念珠菌及曲霉菌均具有很好的抗菌活性,     

Echinocandins in invasive candidiasis]

Invasive fungal infections on the intensive care unit are predominantly caused by Candida spp., most frequently manifesting as candidemia. In spite of increasing treatment options during the last 2 decades, mortality of invasive candidiasis remains high with 20-50%. With the echinocandins, a new class of antifungal drugs with activity against clinically relevant Aspergillus and Candida spp. has become available since the beginning of the new millennium. The echinocandins have shown convincing efficacy in numerous multicenter, mostly double-blinded phase III clinical trials. These trials compared current standard treatment regimens with the echinocandins anidulafungin, caspofungin, and micafungin. All trials observed noninferiority of the new drugs against the standard treatment; in the case of anidulafungin, superiority against fluconazole was demonstrated. Especially in trials utilizing amphotericin B as comparator, significantly less treatment-related adverse events were observed when using an echinocandin. Echinocandins have a low drug-drug interaction profile and are only marginally affected by liver function. Especially in ICU (intensive care unit) patients frequently showing single- or multiorgan failure and receiving a multitude of drugs with complex interactions, echinocandins have become the treatment of first choice for invasive candidiasis.     

Cardiac Effects of Echinocandins in Endotoxemic Rats

Echinocandins are known as effective and safe agents for the prophylaxis and treatment of different cohorts of patients with fungal infections. Recent studies revealed that certain pharmacokinetics of echinocandin antifungals might impact clinical efficacy and safety in special patient populations. The aim of our study was to evaluate echinocandin-induced aggravation of cardiac impairment in septic shock. Using an in vivo endotoxemic shock model in rats, we assessed hemodynamic parameters and time to hemodynamic failure (THF) after additional central-venous application of anidulafungin (2.5 mg/kg of body weight [BW]), caspofungin (0.875 mg/kg BW), micafungin (3 mg/kg BW), and control (0.9% sodium chloride). In addition, echinocandin-induced cytotoxicity was evaluated in isolated rat cardiac myocytes. THF of the animals in the caspofungin group (n = 7) was significantly reduced compared to that in the control (n = 6) (136 min versus 180 min; P = 0.0209). The anidulafungin group (n = 7) also showed a trend of reduced THF (136 min versus 180 min; log-rank test P = 0.0578). Animals in the micafungin group (n = 7) did not show significant differences in THF compared to those in the control. Control group animals and also micafungin group animals did not show altered cardiac output (CO) during our experiments. In contrast, administration of anidulafungin or caspofungin induced a decrease in CO. We also revealed a dose-dependent increase of cytotoxicity in anidulafungin- and caspofungin-treated cardiac myocytes. Treatment with micafungin did not cause significantly increased cytotoxicity. Further studies are needed to explore the underlying mechanism.     

Bioassay for Determining Voriconazole Serum Levels in Patients Receiving Combination Therapy with Echinocandins

Voriconazole levels were determined with high-performance liquid chromatography (HPLC) and a microbiological agar diffusion assay using a Candida parapsilosis isolate in 103 serum samples from an HPLC-tested external quality control program (n = 39), 21 patients receiving voriconazole monotherapy (n = 39), and 7 patients receiving combination therapy (n = 25). The results of the bioassay were correlated with the results obtained from the external quality control program samples and with the HPLC results in sera from patients on voriconazole monotherapy and on combination therapy with an echinocandin (Spearman''s rank correlation coefficient [r_s], > 0.93; mean ± standard error of the mean [SEM] % difference, <12% ± 3.8%).     

Chitin Synthases with a Myosin Motor-Like Domain Control the Resistance of Aspergillus fumigatus to Echinocandins

Aspergillus fumigatus has two chitin synthases (CSMA and CSMB) with a myosin motor-like domain (MMD) arranged in a head-to-head configuration. To understand the function of these chitin synthases, single and double csm mutant strains were constructed and analyzed. Although there was a slight reduction in mycelial growth of the mutants, the total chitin synthase activity and the cell wall chitin content were similar in the mycelium of all of the mutants and the parental strain. In the conidia, chitin content in the ΔcsmA strain cell wall was less than half the amount found in the parental strain. In contrast, the ΔcsmB mutant strain and, unexpectedly, the ΔcsmA/ΔcsmB mutant strain did not show any modification of chitin content in their conidial cell walls. In contrast to the hydrophobic conidia of the parental strain, conidia of all of the csm mutants were hydrophilic due to the presence of an amorphous material covering the hydrophobic surface-rodlet layer. The deletion of CSM genes also resulted in an increased susceptibility of resting and germinating conidia to echinocandins. These results show that the deletion of the CSMA and CSMB genes induced a significant disorganization of the cell wall structure, even though they contribute only weakly to the overall cell wall chitin synthesis.     

Echinocandins versus non-echinocandins for the treatment of invasive candidiasis: A meta-analysis of randomized controlled trials

IntroductionEchinocandins are frequent use antifungals in the treatment of invasive candidiasis, and it is important to update information on their efficacy and safety for optimal antifungal drug treatment. The aim of this study is to clarify whether echinocandins are superior to non-echinocandins for the treatment of invasive candidiasis.MethodsWe conducted a meta-analysis of RCTs of echinocandins and non-echinocandins for adult invasive candidiasis. The MEDLINE, Web of Sciences, Cochrane Register of Controlled Trials, and ClinicalTrials.gov databases before June 2019 were used. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel method random-effects model.ResultsWe identified 14,846 articles and screened, and five studies were included meta-analysis. The treatment success ratio for echinocandins was significantly higher than that for non-echinocandins (RR = 1.14, 95% CI 1.06–1.22, p = 0.0003). In regard to adverse events, there was no significant difference between the two treatment groups. A subgroup analysis showed that the treatment success ratio for echinocandins was significantly higher than that for azoles (RR = 1.20, 1.08–1.34, p = 0.001), whereas no significant differences were observed between echinocandins and polyenes. In safety analysis, the incidence ratio of electrolyte disorder (RR = 0.50, 0.33–0.76, p = 0.001), renal disorder (RR = 0.19, 0.09–0.40, p < 0.0001), and fever (RR = 0.46, 0.23–0.93, p = 0.03) were significantly lower in patients receiving echinocandins than in those receiving polyenes.ConclusionsThis meta-analysis based on RCTs was first to show that use of echinocandins was associated with improved clinical success. Echinocandins may be useful as a first-line drug for invasive candidiasis.     

Biofilm Production and Antibiofilm Activity of Echinocandins and Liposomal Amphotericin B in Echinocandin-Resistant Yeast Species

The echinocandins and liposomal amphotericin B are active against biofilm produced by echinocandin-susceptible Candida strains. However, few data have been reported on the production of biofilm by echinocandin-resistant isolates and their antifungal susceptibility. We studied the production of biofilm by fks mutant Candida strains and intrinsically echinocandin-resistant non-Candida isolates and the susceptibility of both entities to liposomal amphotericin B and echinocandins. We analyzed the production of biofilm by isolates from patients with fungemia (fks mutant Candida, n = 5; intrinsically echinocandin-resistant non-Candida, n = 12; and Candida wild type, n = 10). Biofilm formation was measured to classify strains according to biomass (crystal violet assay) and metabolic activity (XTT reduction assay). Preformed biofilms were tested against liposomal amphotericin B, caspofungin, micafungin, and anidulafungin. The sessile MIC was defined as the antifungal concentration yielding a 50% or 80% reduction in the metabolic activity of the biofilm compared to that of the growth control (SMIC₅₀ and SMIC₈₀, respectively). fks mutant Candida isolates formed biofilms in a fashion similar to that of Candida wild-type strains. The echinocandins had the highest activity against biofilms formed by wild-type Candida isolates, followed by fks mutant Candida isolates and non-Candida isolates. Liposomal amphotericin B had the highest activity against fks mutant Candida biofilms. The formation of biofilm by echinocandin-resistant strains was similar to that of wild-type strains, although resistance to echinocandins remained high.