1例体外膜氧合治疗患者美罗培南和伏立康唑血浆浓度偏低的病例分析

目的探讨体外膜氧合(ECMO)对抗菌药物药动学的影响,为ECMO患者使用抗菌药物剂量提供参考。方法分析1例ECMO治疗期间美罗培南和伏立康唑血浆浓度监测结果。结果 ECMO可能使伏立康唑血浆浓度降低,而对美罗培南药动学影响小。结论脂溶性药物或蛋白结合率高的药物更易被ECMO管路和膜氧合器吸附,导致血浆浓度降低。     

儿童患者伏立康唑治疗药物监测研究进展

伏立康唑在成人体内呈现非线性药动学特征，主要在肝脏中代谢，受基因多态性和药物相互作用的影响，个体间及个体内差异较大。因此，治疗药物监测在伏立康唑临床应用中发挥重要作用。相比成人，儿童患者的药动学更加复杂，目前针对儿童群体的研究数据相对较少，对于儿童目标浓度范围及剂量的调整策略尚存在争议，故该群体使用伏立康唑存在较大风险。本文分别从治疗药物监测必要性、监测策略、剂量调整策略共3个方面分析了儿童患者中伏立康唑治疗药物监测研究进展，以期为儿童患者临床抗真菌感染治疗提供参考。     

1例老年患者口服伏立康唑剂量调整的病例分析

伏立康唑是新一代三唑类抗真菌药物,具有抗菌谱广、抗菌作用强等特点,临床上常作为治疗侵袭性曲霉菌感染的首选药物。伏立康唑在体内的代谢呈非线性药代动力学特征,血药浓度易受基因多态性、药物相互作用和病生理状态等多种因素影响,个体间呈现明显差异。本文对1例肺部真菌感染患者应用伏立康唑血药浓度偏高的原因进行分析,为临床用药提供参考。     

新型抗真菌药伏立康唑

伏立康唑 (voriconazole)是第 2代三唑类抗真菌药 ,具有抗菌谱广、抗菌效力强的特点 ,尤其对于侵袭性曲霉菌侵润所致感染疗效好。本品口服吸收好 ,病人也有很好的耐受性。本文对其药效学、药动学、药物相互作用、临床应用、不良反应等研究作一综述。     

伏立康唑及其临床应用

伏立康唑是最新上市的第2代三唑类广谱抗真菌药物,能有效抑制真菌羊毛甾醇14α去甲基化酶,阻断麦角甾醇生物合成,从而影响细胞膜的流动性、通透性,在体内、外具有广泛的抗真菌活性临床研究结果表明,伏立康唑可用于念珠菌感染和其他药物治疗无效的克柔念珠菌及烟曲菌感染。本文综述了伏立康唑的药效学、药动学特性及临床应用等研究进展。     

抗真菌药伏立康唑的药理学性质及其临床应用

伏立康唑是第二代三唑类抗真菌药,它具有广谱、高效、安全的特点。本文通过检索相关文献资料,对其作用机制、抗菌谱、药动学、临床应用及不良反应等方面作一个综述。     

伏立康唑与血液病患者常用药的药物相互作用研究

目的探讨伏立康唑与血液病患者常用药间的药物相互作用,指导伏立康唑个体化用药。方法收集2015-2017年天津市第一中心医院应用伏立康唑预防或治疗侵袭性真菌感染的血液病患者的血药浓度资料,应用非线性混合效应模型法,考察血液病患者常用药物与伏立康唑联用时的相互作用。结果伏立康唑清除率和表观分布容积的群体典型值分别为8.24 L·h^-1和163 L。群体药动学模型显示碱性磷酸酶对伏立康唑的清除率有显著影响(P<0.005)。联用兰索拉唑或环孢素时,伏立康唑的清除率分别降低33.4%、32.8%,而联用地塞米松使伏立康唑的清除率增加41.0%。结论临床上伏立康唑与兰索拉唑、环孢素或地塞米松联用时,需注意相互作用的产生,并合理调整用药剂量。     

伏立康唑治疗移植后真菌感染研究进展

伏立康唑是第二代三唑类广谱抗真菌药,具有更广泛的抗菌谱,在移植后真菌感染的治疗中发挥着越来越广泛的作用.该文就近两年来伏立康唑在移植后真菌感染的应用和不良反应、药物相互作用及治疗药物监测等进行综述.     

伏立康唑个体化给药研究进展

伏立康唑是目前临床用于治疗一些真菌感染的首选药物,其药动学复杂多变且受多种因素的影响。本文阐述了影响伏立康唑代谢的重要因素,包括药物相互作用、CYP2C19的基因多态性、炎症状态;总结了各国指南中对伏立康唑TDM指征、有效浓度范围、剂量调整等方面的推荐;并对不同人群中伏立康唑应用的研究进行了探讨。本文旨在推进伏立康唑个体化给药。     

伏立康唑药动学主要影响因素及特殊人群药动学特征研究进展

伏立康唑（voriconazole）是一种新型的三唑类抗真菌药,主要用于治疗侵袭性曲霉菌和念珠菌引发的感染,特别是对耐氟康唑的白色念珠菌有极好疗效,目前已广泛应用于临床。掌握和了解其药动学特征及其影响因素对于临床给药方案的选择和调整具有重要的指导意义。从伏立康唑药动学主要影响因素以及特殊人群的药动学特征两个方面对其药动学行为进行比较和分析,为临床安全、合理用药提供理论依据。     

Therapeutic drug monitoring of voriconazole

Voriconazole is a triazole antifungal developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi, and opportunistic molds. Voriconazole has a nonlinear pharmacokinetic profile with a wide inter- and intraindividual variety. This variability is caused by many factors such as gender, age, genotypic variation, liver dysfunction, the presence of food, and so on. Another important factor influencing voriconazole's pharmacokinetic profile is drug-drug interactions with CYP450 inhibitors as well as inducers. Variability in plasma concentrations, as a result of the previously mentioned aspects, may lead to variability in efficacy or toxicity. Determination of plasma concentrations is indicated in situations to guide dosing and to individualize and improve the treatment options resulting in better therapeutic outcome or fewer side effects. In this article, we review factors influencing voriconazole pharmacokinetic profile, the data supporting exposure-effect and exposure-toxicity relationships, review the gaps in current knowledge, which make broad recommendations for therapeutic drug monitoring difficult for voriconazole, provide the indications in which therapeutic drug monitoring is reasonable based on currently available data (eg, children), and outline the ways in which this problem could be solved. We provide a summary of the problem so that further research can be conducted to address this are of clinical need.     

Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach

Voriconazole is a broad‐spectrum antifungal agent commonly used to treat invasive fungal infections. Voriconazole has significant intraindividual and interindividual pharmacokinetics variability in different patient populations. Pharmacokinetic data of voriconazole in patients with liver dysfunction were limited. The aims of this study were to evaluate the population pharmacokinetics of voriconazole in patients with liver dysfunction and to identify the factors that affect voriconazole pharmacokinetics. A total of 166 samples taken from 57 patients with liver dysfunction were included in the study. A one‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. Voriconazole clearance (CL) was 0.58 L/h, the volume of distribution (V_d) was 134 L, and oral bioavailability (F) was 80.8%. This study showed that platelet count was significantly associated with voriconazole pharmacokinetic parameters. CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Voriconazole CL was significantly decreased in patients with liver dysfunction. This study provides useful pharmacokinetics information for patients with liver dysfunction while highlighting the value of therapeutic drug monitoring in adjusting doses.     

Therapeutic drug monitoring of voriconazole and posaconazole

Despite the availability of newer antifungal agents, invasive fungal diseases remain a leading cause of morbidity and mortality in immunocompromised patients. Voriconazole and posaconazole are two extended-spectrum triazoles indicated for treatment and prophylaxis of invasive fungal diseases. Recently, there has been increased interest in the utility of therapeutic drug monitoring to optimize safety and efficacy of antifungals in an attempt to improve patient outcomes. We reviewed the pharmacokinetic and pharmacodynamic characteristics of voriconazole and posaconazole in the context of clinical indications for therapeutic drug monitoring. In addition, the most recent evidence examining the relationship between serum concentrations of voriconazole and posaconazole and their efficacy or toxicities was evaluated. This information was then integrated to formulate recommendations for use of therapeutic drug monitoring in clinical settings.     

Review of the safety,tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole

Managing invasive fungal infections often presents a challenge for clinicians in the treatment of immunocompromised patients. Two very different systemic antifungal agents, voriconazole and caspofungin, have recently been introduced into the market place. Voriconazole is a new triazole antifungal, while caspofungin is the first echinocandin antifungal. Voriconazole acts by inhibiting the synthesis of ergosterol in the fungal cell membrane. Caspofungin inhibits beta-1,3-D-glucan synthesis in the cell wall, a target present in fungal cells, but absent from mammalian cells. Both agents are broad-spectrum, with efficacy against invasive Aspergillus and Candida infections. The safety and tolerability profile of caspofungin presented with a low incidence of adverse events in clinical trials. Pending further data, coadministration of cyclosporine has been recommended only if the benefit outweighs the risk for patients. Voriconazole has three important side-effects that the clinician must consider: liver abnormalities, skin abnormalities and visual disturbances. Liver abnormalities in particular should be monitored very carefully. The drug interaction profile of voriconazole also warrants a careful evaluation of the concomitant medication, mainly due to cytochrome P450 metabolism. This article reviews the available data concerning the safety and tolerability profiles of each drug, as well as drug interactions and contraindications.     

Therapeutic drug monitoring of voriconazole in children

Voriconazole is an extended-spectrum triazole antifungal with activity against a wide variety of pathogens, including Aspergillus, Candida, Cryptococcus neoformans, Fusarium, and Scedosporium. It exerts its antifungal activity by blocking the synthesis of fungal cell membranes and is considered the first-line treatment for invasive aspergillosis. Because the pharmacokinetics of voriconazole can demonstrate considerable variability, it has been suggested that monitoring plasma levels of voriconazole may play an important role in optimizing the efficacy and safety of the drug in complex patients like those at risk of or who have invasive aspergillosis. In this article, we review the criteria for therapeutic drug monitoring and assess the evidence for using plasma voriconazole concentrations to individualize doses in children.     

Review of the safety,tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole

SUMMARY

Managing invasive fungal infections often presents a challenge for clinicians in the treatment of immunocompromised patients. Two very different systemic antifungal agents, voriconazole and caspofungin, have recently been introduced into the market place. Voriconazole is a new triazole antifungal, while caspofungin is the first echinocandin antifungal. Voriconazole acts by inhibiting the synthesis of ergosterol in the fungal cell membrane. Caspofungin inhibits β-1,3-D-glucan synthesis in the cell wall, a target present in fungal cells, but absent from mammalian cells. Both agents are broad-spectrum, with efficacy against invasive Aspergillus and Candida infections. The safety and tolerability profile of caspofungin presented with a low incidence of adverse events in clinical trials. Pending further data, coadministration of cyclosporine has been recommended only if the benefit outweighs the risk for patients. Voriconazole has three important side-effects that the clinician must consider: liver abnormalities, skin abnormalities and visual disturbances. Liver abnormalities in particular should be monitored very carefully. The drug interaction profile of voriconazole also warrants a careful evaluation of the concomitant medication, mainly due to cytochrome P450 metabolism. This article reviews the available data concerning the safety and tolerability profiles of each drug, as well as drug interactions and contraindications.     

Voriconazole: in the treatment of invasive aspergillosis

Voriconazole, a broad-spectrum triazole antifungal agent, inhibits the cytochrome P450-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the fungal membrane and stopping fungal growth. The drug shows excellent in vitro activity against Aspergillus spp., including itraconazole- and amphotericin B-resistant A. fumigatus isolates. At 12 weeks, 52.8% of voriconazole recipients achieved a successful outcome (complete or partial response) versus 31.6% of amphotericin B recipients in a randomised, nonblind trial in 392 patients (aged > or =12 years) with invasive aspergillosis. Patients received intravenous voriconazole (6 mg/kg once every 12 hours on day 1, then 4 mg/kg once every 12 hours for > or =7 days; patients could then be switched to oral voriconazole 200mg once every 12 hours) or intravenous amphotericin B (1 to 1.5 mg/kg/day for > or=14 days). At the investigators' discretion, those who failed to respond to or experienced toxicity with the initial randomised drug could be switched to other licensed antifungal therapy. Voriconazole was generally well tolerated. The most common treatment-related adverse events were transient visual disturbances (approximately 30% of patients) and skin rashes (6%). Voriconazole was generally better tolerated than amphotericin B; voriconazole recipients experienced significantly (p < 0.02 both comparisons) fewer treatment-related adverse events or serious adverse events. The incidence of visual disturbances was significantly (p < 0.001) higher with voriconazole than amphotericin B treatment.     

Review of the safety and efficacy of voriconazole

Voriconazole is a new triazole antifungal agent structurally related to fluconazole, but with improved potency and spectrum of activity. Voriconazole has good in vitro activity against Candida species, Cryptococcus neoformans, Aspergillus spp. and other mould spp. Initial clinical studies and case reports demonstrate efficacy with voriconazole against invasive aspergillosis and infections caused by C. neoformans, Scedosporium apiospermum, Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum. Voriconazole is available both as oral and iv. preparations and exhibits complex pharmacokinetics. This drug is metabolised by the cytochrome (CYP) P450 enzyme system and therefore, has potential drug interactions. This review evaluates the current literature regarding the safety and efficacy of voriconazole.     

Voriconazole: new preparation. Invasive aspergillosis: benefits to be confirmed

(1) Amphotericin B is the antifungal drug of choice for the treatment of invasive aspergillosis, severe candidiasis and Fusarium infection. Voriconazole is an antifungal azole sold in France for oral and intravenous treatment of these infections. (2) In 391 patients with established or probable invasive aspergillosis, combined analysis of two trials comparing voriconazole (intravenously then orally) with conventional amphotericin (intravenously) showed that the 12-week survival rate was significantly higher with voriconazole (70.8% versus 57.9%). Unfortunately, these results are undermined by methodological flaws such as the lack of blinding, the very different intravenous treatment periods in the two groups, and subsequent oral treatment with different antifungal drugs. Voriconazole has not been compared with liposomal amphotericin B. (3) In the treatment of severe candidiasis, and severe Scedosporium and Fusarium infections, we only have the (favourable) results of non comparative trials in small numbers of patients refractory to other antifungal drugs. (4) The main adverse effects were visual disturbances, elevated hepatic enzyme levels, acute renal failure, and sometimes serious cutaneous reactions. It lengthens the QT interval and can cause torsades de pointes. It inhibits the cytochrome P450 isoenzymes CY3A4, CYP2C9 and CYP2C19, hence a high risk of potentially serious drug interactions. (5) Voriconazole can be given by mouth or by IV infusion, whereas liposomal amphotericin B must be given intravenously. (6) In practice, another more rigorous trial is needed to confirm the favourable results obtained with voriconazole in invasive aspergillosis. Voriconazole is the first-line treatment for severe Scedosporium infections, despite limited experience. It is a last resort for severe candidiasis and severe Fusarium infection.