Posaconazole responsive cerebral aspergillosis in an immunocompetent adult

Cerebral aspergillosis is a rare manifestation of invasive aspergillosis that usually affects immunocompromised patients. There are few treatment options for recurrent disease and experiences with immunocompetent patients are lacking. We report the clinical course of an immunocompetent patient with recurrent cerebral aspergillosis, following initial treatment with burr hole aspiration and voriconazole, who showed remarkable response to posaconazole. The patient remains clinically well with no evidence of recurrence on MRI 7 years following diagnosis. To our knowledge this is the first reported experience with posaconazole in an immunocompetent patient with cerebral aspergillosis.     

Voriconazole and the liver

Voriconazole is an azole useful for the prophylaxis and the treatment of aspergillosis and other fungal infections in immunosuppressed subjects, as those found in aplasia after aggressive polychemotherapy treatments, after hematopoietic stem cell, liver or lung transplantation. Its administration in therapeutic doses lead to extremely varied serum levels from patient to patient and even to the same patient. The explanations are varied: nonlinearpharmacokinetics, certain patient-related factors, including genetic polymorphisms in the cytochrome P450 2C19 gene, the kidney and liver function, simultaneous administration with other drugs metabolised by the same cytochrome. It is recommended to maintain the serum concentrations of voriconazole between 1.5 and 4 μg/m L. At lower values its efficacy decreases and at higher values the risk of neurological toxicity increases. Even at these concentrations it is not excluded the possible appearance of a variety of toxic effects, including on the liver, manifested by cholestasis, hepatocytolisis, or their combination. It is recommended to monitor the clinical and laboratory evolution of all patients treated with voriconazole, and of the serum levels of the drug of those who belong to risk groups, even if there is still no consensus on this issue, given the lack of correlation between the serum level and the occurrence of adverse effects in many patients.     

HPLC-MS/MS法同时测定人血浆中伏立康唑及其氮氧化代谢物浓度

目的：建立快速测定人血浆中伏立康唑及其主要代谢物伏立康唑-N-氮氧化物浓度的HPLC-MS/MS方法,用于人体药代动力学研究。方法：以伏立康唑和伏立康唑-N-氮氧化物的D3同位素为内标,血浆样品经蛋白沉淀后,用Agilent ZORBAX SB-Aq色谱柱（2.1 mm × 50 mm,1.8 μm）和API 4000质谱仪进行正离子模式电喷雾离子化分析。流速为0.6 mL·min-1,以甲醇为有机相,0.1%甲酸为水相,按一定程序进行梯度洗脱。结果：伏立康唑和伏立康唑-N-氮氧化物在10.00 ~ 8000 ng·mL-1范围内线性关系良好,该方法的特异性、批内/批间精密度、准确度、介质效应、提取回收率、稳定性和稀释可靠性符合相关要求。结论：建立了一种准确、简便、可靠的HPLC-MS/MS分析方法,成功应用于健康中国人静脉注射4 mg·kg-1伏立康唑后的药代动力学研究。     

Scedosporium Apiospermum Infection after Near-drowning

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伏立康唑雾化吸入对侵袭性肺曲霉病患者细胞因子及肺纤维化的影响

目的：探讨伏立康唑雾化吸入对侵袭性肺曲霉病(IPA)患者细胞因子及肺纤维化的影响。方法选择2010年1月至2013年12月期间我院收治的68例IPA患者为研究对象,将其随机分为观察组和对照组。观察组36例患者给予伏立康唑雾化吸入,对照组32例患者给予伏立康唑静脉滴注治疗。比较两组患者的治疗效果,血清IL-6、IL-8、TNF-α水平以及肺总量(TCL)、一氧化碳弥散量(DLco)和血氧饱和度(SaO2)。结果观察组有效率为86.11%,优于对照组的65.63%,差异有统计学意义(P<0.05)。治疗后两组TCL、DLco、SaO2均较治疗前明显改善(P<0.05),但观察组TCL、DLco、SaO2改善幅度大于对照组(P<0.05)。观察组治疗后血清TNF-α水平明显较治疗前降低(P<0.05),也明显低于同期对照组(P<0.05)。观察组治疗后血清IL-8、IL-6水平明显较治疗前降低(P<0.05),也明显低于同期对照组(P<0.05)。对照组治疗后血清TNF-α、IL-8、IL-6水平低于治疗前(P<0.05)。观察组和对照组不良反应发生率分别为8.33%和6.25%,差异无统计学意义(P>0.05)。结论伏立康唑雾化吸入用于IPA的治疗,可有效改善患者肺纤维化程度,抑制炎症反应,临床疗效佳,且不良反应轻。     

In vitro biofilm characterization and activity of antifungal agents alone and in combination against sessile and planktonic clinical Candida albicans isolates

Thirty clinical isolates of Candida albicans were collected from blood or other sterile site infections. Biofilm dry weight and metabolic activity were measured for each isolate. Planktonic and sessile antifungal susceptibilities of each isolate were determined for amphotericin B deoxycholate, caspofungin, and voriconazole. Sessile susceptibilities were determined for the combination of caspofungin/voriconazole. No significant differences in biofilm dry weight or metabolic activity were found between bloodstream and other invasive isolates. Planktonic MIC90 values and sessile MIC90 (SMIC90) values were 0.25 and 2, 0.06 and >256, and 0.5 and 2 microg/mL for amphotericin, voriconazole, and caspofungin, respectively. The SMIC90 of the combination of caspofungin/voriconazole against sessile isolates was 0.5/2 microg/mL. Therefore, the source of invasive C. albicans clinical isolates did not affect in vitro biofilm formation. Susceptibility to antifungal agents decreased when C. albicans was associated with biofilm, and the combination of caspofungin/voriconazole did not appear to provide enhanced activity compared with caspofungin alone.     

角膜基质内注射不同浓度伏立康唑治疗真菌性角膜炎

目的观察角膜基质内注射不同浓度伏立康唑治疗真菌性角膜炎的临床疗效。方法前瞻性病例对照研究。87例(87眼)真菌性角膜炎患者随机分为三组,均行KOH湿片检查和真菌培养,A组(28眼)给予5 g·L^-1氟康唑和50 g·L^-1那他霉素滴眼液滴眼,B组(30眼)和C组(29眼)在A组治疗的基础上再分别给予0.25 g·L^-1和0.50 g·L^-1的伏立康唑行角膜基质内注射。术后随访4个月,观察三组患者的疗效及并发症情况。结果KOH湿片检查阳性率为86.2%(75/87),真菌培养阳性率为93.1%(81/87);前三位的致病菌依次是镰刀菌40例(46.0%),曲霉菌19例(21.8%),链格孢霉菌13例(15.0%),三组患者致病菌分布差异无统计学意义(χ^2=0.932,P=0.988)。A组的治愈率为42.9%(12/28),明显低于B组的76.7%(23/30)和C组的86.2%(25/29),差异均有统计学意义(P=0.009、0.000);B组和C组治愈率比较差异无统计学意义(P=0.347)。A、B、C三组的治愈时间依次为(31.96±10.20)d、(26.17±7.23)d和(21.50±7.32)d,两两相比差异均有统计学意义(均为P<0.05)。A组治疗前后视力比较差异无统计学意义(P=0.905);B、C两组治疗前后视力比较差异均有统计学意义(P=0.027、0.022)。B、C两组的注射次数分别是(3.93±1.26)次和(3.41±1.12)次,差异无统计学意义(P=0.099)。未愈者A组16眼、B组7眼、C组4眼。结论对轻度、中度真菌性角膜炎患者可选择0.25 g·L^-1伏立康唑角膜基质内注射治疗,对于0.25 g·L^-1伏立康唑角膜基质内注射治疗效果不理想或病情较重者可考虑用0.50 g·L^-1伏立康唑行角膜基质内注射治疗。     

Impact of flavin-containing monooxygenase 3 and CYP2C19 genotypes on plasma disposition and adverse effects of voriconazole administered orally in immunocompromised patients

Flavin-containing monooxygenase (FMO) 3 together with cytochrome P450 (CYP) 2C19 play a significant role in voriconazole N-oxidation. This study aimed to evaluate the influence of FMO3 and CYP2C19 genotypes on the plasma disposition and adverse effects of voriconazole in immunocompromised patients. Sixty-five Japanese immunocompromised patients receiving oral voriconazole were enrolled. Predose plasma concentrations of voriconazole and N-oxide were determined at day 5 or later. The adverse effects of voriconazole and the FMO3 and CYP2C19 genotypes were investigated. The patients with FMO3 E158K/E308G had a lower plasma concentration of voriconazole. The metabolic ratio to N-oxide was significantly higher in the FMO3 E158K/E308G group than in the wild group. In contrast, FMO3 V257M was not associated with the plasma concentration of voriconazole. No significant difference was observed in the saturation index, defined as a correlation coefficient of the regression line between the absolute plasma concentration of voriconazole and the inverse value of the metabolic ratio to N-oxide, between the FMO3 genotypes. CYP2C19 phenotype did not affect the plasma concentration and metabolic ratio of voriconazole. The saturation index of voriconazole rose in the order of CYP2C19 extensive, intermediate, and then poor metabolizer groups. However, the FMO3 and CYP2C19 genotypes and their associated voriconazole pharmacokinetics did not have an effect on the incidence of adverse effects. In conclusion, FMO3 E158K/E308G decreased the plasma concentration of voriconazole through its higher metabolic activity. The FMO3 genotype altered the plasma exposure of voriconazole, while the CYP2C19 phenotype affected the metabolic capacity in immunocompromised patients.     

HPLC-MS/MS 法测定人血浆中伏立康唑浓度的不确定度评价

目的 评价高效液相色谱 - 串联质谱法 (HPLC-MS/MS) 测定人血浆中伏立康唑浓度的不确定度。方法 分析 HPLCMS/MS 法测定人血浆中伏立康唑浓度过程中的不确定度来源,计算其大小并合成。结果 HPLC-MS/MS 法测定伏立康唑浓度 的不确定度在低浓度时主要由标准曲线拟合、样品提取和重复性引入,在高浓度时主要由仪器允差,重复性和样品提取引入。 人血浆中伏立康唑在低浓度(0.025μg/mL)、中浓度(1.5μg/mL)和高浓度(8.0μg/mL)的扩展不确定度分别为0.0018、0.2057和0.8723 ( 置信概率 P=95.45%, k=2)。结论 为有效减小测量结果的不确定度,建议在今后工作中应尽量避免过宽的标准曲线范围,增加 测定点的个数和重复测定次数,同时提高向处理后的基质中添加内标或质控溶液的加样技巧。