Pharmacologic therapy of mycotic keratitis

Mycotic keratitis continues to be an important cause of corneal blindness, especially in tropical and subtropical countries. The prognosis is poor compared with many other forms of keratitis because of the lack of effective antifungal drugs. The currently available antifungal drugs suffer from multiple drawbacks such as poor ocular penetration, unpredictable bioavailability, and adverse effects associated with systemic medications. Over the last decade, several new drugs and drug-delivery systems have been introduced in an attempt to improve the treatment outcomes. Thorough knowledge of the currently available antifungal drugs, their spectrum of action, and associated adverse effects is essential to deal with cases of mycotic keratitis. We discuss the pharmacologic properties and clinical use of the currently available antifungal drugs.     

Clinical hepatotoxicity associated with antifungal agents

Introduction: Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents.

Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure.

Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.     

伏立康唑在新西兰白兔眼组织中的浓度测定及眼组织分布研究

目的 建立新西兰白兔眼组织中伏立康唑浓度的测定方法,并应用于玻璃体腔注射伏立康唑的眼组织分布研究。方法 采用高效液相色谱-串联质谱（HPLC-MS/MS）法测定兔眼组织中伏立康唑浓度。以甲苯磺丁脲为内标,色谱柱为Waters X-Bridge BEH C₁₈（50 mm×2.1 mm,2.5 μm）,流动相A：0.2%甲酸-水溶液;流动相B：0.2%甲酸-乙腈溶液;梯度洗脱程序：0～0.30 min,30% B;0.30～1.81 min,30%→90% B;1.81～2.30 min,90% B;2.30～2.31 min,90%→30% B;2.31～2.60 min,30% B;体积流量为0.5 mL·min^-1,柱温30℃,进样量1 μL。使用电喷雾离子源,以多重反应监测方式进行正离子扫描,用于定量分析的离子对分别为m/z 350.1→281.1（伏立康唑）、m/z 271.1→155.0（内标）。新西兰白兔按照体质量、性别随机区间分成5组,每组6只,雌雄各半。无菌条件下,新西兰白兔眼部散瞳,im氯胺酮12 mg·kg^-1、赛拉嗪3 mg·kg^-1麻醉动物,玻璃体腔注入伏立康唑眼用注射剂,分别在行玻璃体腔注射术后的0.5、1.0、4.0、24.0、48.0 h,过量麻醉后放血处死试验兔。冰浴条件下分离兔眼组织（结膜、角膜、房水、虹膜、晶体、玻璃体、视网膜、脉络膜、巩膜）,采用建立的HPLC-MS/MS测定各组织中伏立康唑浓度。结果 伏立康唑质量浓度在0.5～500.0 ng·mL^-1,线性关系良好（R²＞0.98）,定量下限为0.5 ng·mL^-1。批内精密度（RSD）和准确度（RE）均小于15%,伏立康唑各眼组织的提取回收率均大于85%;新西兰白兔单眼单次给予伏立康唑后,其主要在眼后段分布,且视网膜浓度相对玻璃体、脉络膜更高。结论 建立的伏立康唑测定方法分析时间短,能够快速检测眼组织中的药物,准确度和灵敏度高,适用于伏立康唑在眼组织的分布研究。     

伏立康唑与埃索美拉唑联用致乙肝肝硬化并肺部侵袭性真菌感染患者横纹肌溶解症

伏立康唑目前被认为是治疗侵袭性真菌感染应用较多的抗真菌药物,但由于其具有潜在的较多的药物相互作用及药代动力学个体间差异较大,使其在临床使用过程中问题重重。1例54 a男性患者因乙肝肝硬化(活动期、失代偿期)并自发性腹膜炎入院治疗,常规性给予埃索美拉唑、拉米夫定、呋塞米、前列地尔、多烯磷脂酰胆碱、美罗培南、白蛋白等抑酸、抗病毒、利尿、改善肝功能、护肝、抗感染、补充白蛋白等治疗。住院第3日可疑肺部侵袭性真菌感染,首先给予氟康唑经验性抗真菌治疗,3 d后根据药敏实验结果及患者经济状况改为伏立康唑(针剂4 d,口服12 d)治疗。肝功能有好转迹象,但住院第21日患者开始出现全身不适、乏力,轻度胸闷、气促,呕吐症状,怀疑与使用伏立康唑或拉米夫定有关,次日停用。住院第23日相关检查结果示横纹肌溶解症伴肝功能衰竭。经小剂量补碱、丙种球蛋白封闭抗体及提高免疫力、甲强龙抗炎、血液透析等对症治疗1周,患者肌酶进行性下降,但之后出现血钾、肌酐、尿素氮进行性升高,尿量进行性减少,最终导致急性肾功能衰竭,肺部感染加重,自动出院。推测:原因为埃索美拉唑的肝药酶CYP2C19抑制作用引起伏立康唑血药浓度升高从而加重伏立康唑的肝药酶抑制作用...     

Characterization of Candida parapsilosis complex isolates

Candida parapsilosis former groups II and III have recently been established as independent species, named Candida orthopsilosis and Candida metapsilosis, respectively. We investigated the distribution of C. parapsilosis complex species in 122 isolates from blood and other sources in a southern Spain tertiary-care hospital, and we examined the relationship between species, site of isolation and biofilm positivity. We also evaluated the planktonic MICs and sessile MICs (SMICs) of voriconazole, amphotericin B and anidulafungin. One hundred and eleven isolates (91%) were categorized as C. parapsilosis sensu stricto, whereas ten isolates (8.2%) were categorized as C. orthopsilosis and one (0.8%) as C. metapsilosis. Biofilm positivity was observed in 58.5% (65 of 111) of C. parapsilosis sensu stricto isolates vs. 0% (0 of 11) of C. orthopsilosis and C. metapsilosis isolates (p <0.01). There was no difference in biofilm production among C. parapsilosis sensu stricto isolates from blood and other sources. MIC values showed that all isolates were susceptible to voriconazole and amphotericin B, whereas two isolates (1.8%) of C. parapsilosis sensu stricto were non-susceptible to anidulafungin. However, the MIC₉₀ value of voriconazole was higher (0.125 mg/L) for C. orthopsilosis than for C. parapsilosis sensu stricto (0.03 mg/L). In contrast to planktonic cells, the SMICs show that amphotericin B and anidulafungin are moderately effective against the biofilm of C. parapsilosis sensu stricto, whereas voriconazole is ineffective.     

Update on antifungal agents for paediatric patients

Paediatric age groups display important differences in host biology, predisposing conditions, epidemiology and presentation of fungal infections relative to the adult population. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the paediatric development of antifungal agents has moved forwards in an exemplary manner. Invasive fungal infections will remain important causes of morbidity and mortality in immunocompromised paediatric patients. Whereas the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex, and a thorough understanding of the available antifungal armamentarium is essential for the successful management of the individual patient. This article provides an update on the pharmacokinetics, safety and dosing of antifungal agents in paediatric patients, and their clinical indications.