Successful treatment of Aspergillus empyema using combined intrathoracic and intravenous administration of voriconazole: A case report

Aspergillus empyema is treated with either systemic administration of antifungal drugs or surgery, but the mortality rate is very high. Here, we report a case of Aspergillus empyema successfully treated using combined intrathoracic and intravenous administration of voriconazole (VRCZ). Treatment success was achieved by monitoring VRCZ plasma trough concentration. The patient was a 71-year-old Japanese woman diagnosed with Aspergillus empyema whom we started on intravenous administration of VRCZ. Although penetration of VRCZ into the pleural effusion was confirmed, the level was below 1 μg/mL, which is the minimum inhibitory concentration for Aspergillus fumigatus determined by antifungal susceptibility testing in pleural effusion culture. Therefore, we initiated combination therapy with intrathoracic and intravenous administration of VRCZ. VRCZ 200 mg was first dissolved in 50–100 mL of saline and administered into the thoracic cavity via a chest tube. The chest tube was clamped for 5–6 h, and then VRCZ solution was excreted though the chest tube. When a single dose of the VRCZ was administered into the intrathoracic space, the plasma concentration before intravenous administration increased from 1.45 μg/mL on day 27 to 1.53 μg/mL on day 28. Although intravenous administration was continued, the VRCZ plasma trough concentration decreased to 1.36 μg/mL on day 29. We therefore decided on an intrathoracic administration schedule of 2–3 times a week. Intrathoracic administration was performed 14 times in total until fenestration surgery on day 64. Our case suggests that combined intrathoracic and intravenous administration of VRCZ may be a valid treatment option for Aspergillus empyema.     

1例非HIV播散型马尔尼菲篮状菌病的护理体会

目的 探讨非HIV播散型马尔尼菲兰篮状菌感染患者的护理方法。方法 皮肤及口腔护理，两性霉素B和伏立康唑的用药指导，疼痛护理，心理护理，病情观察，出院指导。结果 经过76d的精心治疗和护理，患者病情稳定出院。结论 制定个体化的护理措施，做好相应的症状护理是患者康复出院的保证。     

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。     

Scedosporium Apiospermum Infection after Near-drowning

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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.     

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.     

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。     

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.     

播散性马尔尼菲青霉菌感染二例报道并文献复习

目的 探讨儿童播散性马尔尼菲青霉菌感染的实验室检查、临床表现和治疗策略.方法报道分析播散性马尔尼菲青霉菌感染患儿临床表现,病原学检查,影像学资料和治疗结果.结果病例1,男,1岁,发热、咳嗽1个月;骨髓、血培养:马尔尼菲青霉菌;伏立康唑治疗后好转.病例2,女,8岁,发热1个月,烦躁1d;血培养:马尔尼菲青霉菌.结论儿童播散性马尔尼菲青霉菌感染可累及中枢神经系统.伏立康唑可作为静脉-口服序贯治疗策略的选择.