Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.     

Newer triazole antifungal agents: pharmacology,spectrum, clinical efficacy and limitations

New triazole antifungals (voriconazole, posaconazole, ravuconazole and albaconazole) have been developed to meet the increasing need for new antifungals, and address the rising incidence of invasive fungal infections and the emergence of fungal resistance. This report describes the spectrum of activity of the newer-generation triazoles based on data from in vitro, animal and clinical studies. The authors discuss the use of these agents in combination with other antifungals, the extent of cross-resistance, their toxicity profile and pharmacokinetic properties. A total of two agents are currently available: voriconazole (which is becoming a primary treatment for the management of invasive aspergillosis) and posaconazole (which demonstrates a broad antifungal spectrum). A further two agents, albaconazole and ravuconazole, are undergoing early clinical evaluation and their future is uncertain. For all newer triazoles, concerns about emerging drug-resistant fungi and the incidence and management of breakthrough infections will dictate their role in antifungal prophylaxis and treatment.     

Fungal infections in solid organ transplantation

Renal, liver, heart and lung transplantation are now considered to be the standard therapeutic interventions in patients with end-stage organ failure. Infectious complications following transplantation are relatively common due to the transplant recipients overall immunosuppressed status. The incidence of invasive mycoses following solid organ transplant ranges from 5 to 42% depending on the organ transplanted. These mycoses are associated with high overall mortality rates. Candida and Aspergillus spp. produce most of these infections. This article will review the risk factors, clinical presentation and treatment of invasive fungal infections in solid organ transplant patients, and evaluate the role of prophylactic therapy in this group of patients.     

Clinical pharmacology of antifungal agents in pediatric patients

Invasive fungal infections have emerged as important causes of morbidity and mortality in profoundly immunocompromised children including cancer, transplant and intensive care unit patients. Present treatment strategies for these infections are limited by toxicity, drug interactions and expense. In order to overcome these limitations, new antifungal compounds are being developed, which may improve the therapeutic armamentarium for prevention and treatment of invasive mycoses in high-risk children. This article summarizes the clinical pharmacology of established and newly developed antifungal agents, including new triazoles and echinocandins in pediatric age groups.     

Epidemiology and management of cryptococcal meningitis: developments and challenges

The significance of cryptococcal infection as a cause of human disease has dramatically evolved in recent years. The objective of this study was to outline the worldwide significance of cryptococcosis and review developments in the management of cryptococcal meningitis. Cryptococcus neoformans var. grubii remains an important cause of disease, particularly in hosts with acquired immunosuppression. Cryptococcus gattii, on the other hand, infects hosts with seemingly normal immune systems and a recent dramatic outbreak in a new ecologic environment highlights the emerging clinical significance of this fungal pathogen. The introduction of new antifungal agents and the adoption of strategies for controlling elevated intracranial pressure in cryptococcal meningitis have added to our therapeutic options. However, the mortality from this infection remains unacceptably high and we are faced with the specific challenges in the management of this disease.     

Economic evaluation of the prevention and management of systemic fungal infections in neutropenic patients

Systemic fungal infections in neutropenic patients remain a clinical problem that is associated with morbidity and mortality. Continuing efforts are being made to develop improved (i.e., more effective or safe) drugs, and several new treatments have recently become available. These have increased the therapeutic options available to clinicians to address the problem of systemic fungal infections. Therapeutic choices are difficult when taking into account aspects of efficacy, safety and costs that are associated with the available alternatives. This review summarises the present status of health economic knowledge of the standard therapies that have been available for many years, and also reports on the most recent health economic evidence available for the newly developed treatment alternatives.     

Our 2014 approach to breakthrough invasive fungal infections

Evidence‐based clinical pathways to direct antifungal treatment options in patients with breakthrough fungal infections during current systemic antifungal therapy are not available. Nonetheless, for defined settings of such breakthrough infections approaches to management can be recommended based on clinical, epidemiological, pharmacological and in vitro susceptibility data.     

侵袭性真菌感染患者伏立康唑群体药动学研究及给药方案优化

 目的 本实验旨在评价伏立康唑在侵袭性真菌感染患者中的群体药动学特征, 寻找影响伏立康唑药动学参数变化的因素, 并对给药方案进行优化, 以指导临床用药。方法 为定量描述协变量与伏立康唑药动学参数之间的关系, 采用了群体药动学的研究方法对侵袭性真菌感染患者的临床稀疏血样进行分析。观察患者人口学资料、生化指标、合并用药、基因型等协变量对药动学参数的影响。使用内部验证Bootstrap法对最终模型进行验证。利用蒙特卡洛模拟法对给药方案进行优化。结果 通过NONMEM(monlinear mixed effect modoling)程序对151例住院患者的406个血样进行分析发现, 具有一级吸收和一级消除的一房室模型能够很好地拟合这些数据。其中, 表观分布容积为200 L, 清除率为6.95 L·h^-1。患者年龄、CYP2C19基因型和碱性磷酸酶值对清除率有显著的影响。内部验证结果表明最终模型稳定可靠。在患者人群中, 200 mg/q12 h, iv或200 mg/q 12 h, po的给药方案对曲霉菌感染是有效的。200 mg/q12 h, iv或300 mg/q12 h, po的给药方案对治疗念珠菌感染是有效的。结论 蒙特卡洛模拟法与群体药动学参数结合可以指导临床优化给药方案。     

新疆维吾尔族异基因造血干细胞移植高危患儿的伏立康唑血浆谷浓度的分布特征及对疗效和不良反应的影响

目的:评估伏立康唑血浆谷浓度测定在治疗和预防新疆维吾尔族异基因造血干细胞移植(hematopoietic stem cell,HSCT)高危患儿真菌感染的分布特征,并探讨影响伏立康唑血浆谷浓度的相关因素。方法:采用高效液相色谱法-质谱联用技术测定伏立康唑血浆谷浓度,采用Sanger测序技术检测患儿CYP2C19基因多态性,分析年龄、性别、体质量指数、给药途径、给药剂量和CYP2C19基因多态性对伏立康唑谷浓度的影响。 结果:9例患儿的伏立康唑血浆谷浓度＜0.5 μg·mL^-1,26 例伏立康唑谷浓度＞6 μg·mL^-1。伏立康唑血浆谷浓度与患儿的年龄存在显著相关性(F=2.671,P＜0.05)。静脉途径给药患儿的伏立康唑浓度剂量比结果显著高于口服途径给药的患儿(t=-2.330,P＜0.05)。伏立康唑在超快代谢型患儿中的血浆谷浓度显著低于慢代谢型、中间代谢型和正常代谢型患儿[(1.84±1.47),(4.21±12.26),(2.75±1.91),(3.60±2.13) μg·mL^-1;P＜0.05]。使用伏立康唑后,患儿谷丙转氨酶、谷草转氨酶、总胆红素、血肌酐及尿素氮水平均显著高于使用前水平(P＜0.05)。结论:通过监测伏立康唑血浆谷浓度并联合CYP2C19基因多态性来共同指导异基因HSCT高危患儿使用伏立康唑具有一定的临床意义。     

伏立康唑治疗儿童侵袭性真菌感染血药浓度与疗效相关性研究

目的 探索伏立康唑治疗儿童侵袭性真菌感染的剂量、血药浓度与疗效的相关性。方法 收集2019年1月至2019年12月,使用伏立康唑治疗的68例儿童侵袭性深部真菌感染病例,采用高效液相色谱法检测伏立康唑的血药谷浓度,统计分析伏立康唑的不同剂量与血药浓度和临床疗效的相关性。结果 检测显示不同给药剂量的血药谷浓度分别为：<4.0 mg/kg（6例）,谷浓度在0.4~3.31 μg/ml (r=0.613,P=0.195);4.0~7.0 mg/kg（44例）,谷浓度在0.35~7.02 μg/ml（r=0.325,P=0.018）;>7.0 mg/kg（18例）,谷浓度在1.46~12.45 μg/ml (r=0.584,P＜0.023),3组间差异有统计学意义(F=7.270, P=0.026)。68例患儿中总体有效58例（85.3%）,无效10例（14.7%）。上述不同谷浓度的疗效分别为：<1.0 μg/ml组14例,有效10例（71.4％）,无效4例;1.0~5.5 μg/ml组48例,有效44例（91.7％）,无效4例;>5.5 μg/ml组6例,有效4例（66.7%）,无效2例。3组间差异有统计学意义（χ^２=5.360, P=0.039）。10例出现不良反应（14.7%）,主要为轻度肝功能损伤,不影响治疗,保肝治疗后可恢复。结论 研究显示伏立康唑治疗儿童侵袭性真菌感染总体安全有效,且存在明显的剂量-血药浓度与疗效的相关性。因此,进一步开展药动学与疗效相关研究,有利于实现理想的个体化治疗。