成人伏立康唑个体化用药监测分析

目的 基于《伏立康唑个体化用药指南》中伏立康唑的谷浓度与抗感染的疗效、肝脏毒性相关性仅以一个中等质量的证据来评判,不能很好满足临床需求。本论文将建立动态监测成人住院患者的伏立康唑谷浓度变化,力求探究谷浓度与疗效、不良反应的相关性。方法 收集使用伏立康唑治疗的成人患者63例,共107份血液标本,采用酶免方法动态监测伏立康唑的药物谷浓度,观察患者的用药疗效、有无不良反应,剖析伏立康唑谷浓度与临床指标的相关性。结果 ①使用常规剂量伏立康唑治疗后,62/107（57.9%）血液标本的伏立康唑谷浓度在0.5~5.0 μg/mL,均数为2.7 μg/mL;4/107（3.7%）血液标本的谷浓度<0.5 μg/mL,均数为0.3 μg/mL;41/107（38.4%）血液标本的谷浓度>5.0 μg/mL,中位数为8.7 μg/mL。②谷浓度<0.5 μg/mL组、谷浓度≥0.5 μg/mL组治疗有效的比率分别为50.0%、74.5%,但2组差异无统计学意义（P=0.624）。提高1例谷浓度<0.5 μg/mL且治疗无效的患者剂量,使谷浓度达到有效浓度,感染症状获得改善。③10例（15.8%）发生不良反应,谷浓度>5.0 μg/mL的患者与谷浓度≤5.0 μg/mL的患者不良反应发生率分别为18.2%、14.6%,主要体现为肝功能异常。④伏立康唑谷浓度≤5.0 μg/mL的患者组与谷浓度>5.0 μg/mL的患者组碱性磷酸酶（alkaline phosphatase,ALP）、谷氨酰转肽酶（glutamyl transpeptidase,GGT）差异有统计学意义（P<0.05）,当谷浓度>5.0 μg/mL时,抗感染治疗后,降钙素原（procalcitonin,PCT）明显降低（P<0.05）。结论 伏立康唑血药浓度个体间差异较大,必须规律监测谷浓度。伏立康唑谷浓度与肝功能、感染指标相关,可能要加大人群数或者在CYP2C19基因检测支持下来观察谷浓度与疗效、不良反应的相关性。     

Determination of surgical outcomes with a novel formulation of intrastromal natamycin in recalcitrant fungal keratitis: A pilot study

Purpose:To evaluate the outcomes of water-soluble intrastromal natamycin (IS-NTM) as an adjunct therapy for recalcitrant fungal keratitis.Methods:This was a prospective interventional pilot study in the setting of a tertiary eye-care center. Twenty eyes of 20 consecutive patients with microbiologically proven recalcitrant fungal keratitis (ulcer size >2 mm, depth >50%, and not responding to topical NTM for 2 weeks) were recruited. The selected patients were injected with a novel composition of IS-NTM (10 ug/0.1 mL, soluble natamycin) prepared aseptically in the ocular pharmacology department. All the patients continued using topical NTM suspension 5% 4-hourly until the ulcer healed. Repeat injections were undertaken after 72 h depending on the clinical response and all the patients were followed till 6 months.Results:The mean age of the patients was 40.42 ± 10.09 years. The mean duration of the presentation was 20.8 ± 5.1 days. The most commonly isolated organisms were Aspergillus sp. (12/20, 60%) and Fusarium sp. (8/20, 40%). No patient had iatrogenic perforation or precipitate formation after IS-NTM injection. The overall cure rate with IS-NTM was 95% (19/20 patients). The number of patients who healed with the 1^st, 2^nd, and 3^rd injection was 13, 5, and 1, respectively. One (5%) had no response to treatment and was subjected to penetrating keratoplasty. The average time taken for the resolution of the epithelial defect, stromal infiltrates, and hypopyon was 34 ± 5.2 days, 35.3 ± 6.4 days, and 15 ± 2.5 days. Healing with deep vascularization and cataract was noted in 6/19 eyes (31%) and 13/19 eyes (68.42%), respectively.Conclusion:Intrastromal injection of a novel formulation of NTM holds a promising role as adjunctive therapy to topical NTM in the management of recalcitrant filamentous fungal keratitis. The preliminary results are encouraging and further studies are required to validate the results.     

Voriconazole in an infant with cryptococcal meningitis

Cryptococcus neoformans （C. neoformans） is the most common cause of fungal meningitis worldwide.1 Cryptococcal meningitis is an opportunistic infection commonly found in immunocompromised hosts, especially HIV-infected adults. It also occurs in apparently immunocompetent individuals. Rarely has it been reported in children, and it is almost nonexistent in infants. Voriconazole is a member of a second generation of antifungal triazoles with broad spectrum antifungal activity, oral and parenteral bioavailability and a favorable safety profile in adults.3 This patient shows improved in vitro activity against C. neoformans when compared to fluconazole and it has been used successfully in about half the patients with refractory cryptococcosis.4 However, the efficacy and safety of voriconazole as a antifungal agent in children with cryptococcal meningitis have not been well assessed, This report described cryptococcal meningitis in a 13-day-old premature neonate who recovered without overt toxicity after voriconazole was added to an antifungal regimen that included amphotericin B and flucytosine. We focused on the response of this child with cryptococcal meningitis to voriconazole.     

Therapeutic drug monitoring and safety of intravenous voriconazole formulated with sulfobutylether β‐cyclodextrin in haematological patients with renal impairment

Because of concerns about accumulation of cyclodextrin, oral voriconazole is recommended for patients with renal impairment. However, intravenous voriconazole may occasionally be imperative in critically ill patients with life‐threatening invasive aspergillosis. We investigated the clinical effects of intravenous voriconazole formulated with sulfobutylether β‐cyclodextrin (SBECD) in patients with renal impairment. A prospective observational study was conducted on 25 adult patients with haematological malignancies who were treated with intravenous voriconazole for invasive aspergillosis. Among them, seven patients had a baseline creatinine clearance (CrCl) <50 ml min^?1 (case). Although voriconazole trough concentrations were significantly higher in cases (5.84 mg l^?1) than controls (2.28 mg l^?1), the proportion of concentrations within the target range did not differ between two groups (4/7 and 12/18, respectively; P = 0.658). The frequency of severe adverse events in cases (3/7) was comparable to that of controls (4/18; P = 0.355). No patients showed significant deterioration in renal function after the voriconazole therapy even in patients with renal impairment. Although CrCl <50 ml min^?1 was associated with higher voriconazole concentrations, its clinical impact remains unclear. SBECD‐formulated intravenous voriconazole did not lead to a higher incidence of severe adverse events including nephrotoxicity in haematological patients with CrCl <50 ml min^?1.     

UPLC-MS/MS法同时测定人血浆中泊沙康唑、氟康唑、伏立康唑的血药浓度

目的:建立UPLC-MS/MS法同时测定血浆中3个三唑类抗真菌药物（泊沙康唑、氟康唑、伏立康唑）的浓度。方法:采用WatersBEHC18（2.1 mm×50 mm,1.7 μm）色谱柱,流速0.5 mL/min,流动相为甲醇（含2 mmol/L乙酸铵和0.1%甲酸）和2 mmol/L乙酸铵水溶液（含0.1%甲酸）,梯度洗脱,柱温40°C。质谱条件采用电喷雾离子源,正离子多反应监测模式进行扫描分析。结果:泊沙康唑、氟康唑、伏立康唑的专属性良好,线性范围分别为0.083~20.680、0.328~82.075、0.080~20.085 μg/mL,范围内线性关系良好,r均大于0.99。批内、批间精密度（RSD）均小于7.60%,提取回收率和基质效应RSD值均小于14.2%,不同储存条件下稳定性良好,RSD值均小于10.69%。结论:该方法准确度高,重复性好,简便快捷,可同时测定3种血浆中三唑类抗真菌药的浓度,适用于临床对氟康唑、泊沙康唑及伏立康唑的治疗药物监测。     

Prophylactic administration of voriconazole with two different doses for invasive fungal infection in children and adolescents with acute myeloid leukemia

Background

Pediatric patients under treatment for acute myeloid leukemia (AML) are at high risk for invasive fungal infection (IFI). We evaluated the efficacy of prophylactic administration of voriconazole (VRCZ) with two different doses.