Amphotericin B lipid complex for the treatment of invasive fungal infections

Amphotericin B lipid complex (ABLC; Abelcet, Enzon Pharmaceuticals) has become the dominant marketed lipid amphotericin B compound to emerge since the approval of these agents from the mid-1990s onwards. This agent is a 1:1 combination of amphotericin B and a lipid moiety consisting of dimyristoyl phosphatidylcholine and dimyrisoyl phosphatidylcholine, which exists in a ribbon-like molecular structure. ABLC undergoes rapid reticuloendothelial uptake from the circulation and achieves significantly higher tissue concentrations in the liver, spleen and lung compared to comparably dosed conventional amphotericin B. ABLC is approved by the FDA for all mycoses in amphotericin B-intolerant or -refractory infection. Randomised, controlled trials of amphotericin B have shown comparable efficacy in candidiasis and an improved outcome in invasive aspergillosis versus historical controls. ABLC has demonstrated a reduced incidence of nephrotoxicity and infusion reactions versus amphotericin B. Comparative studies against other lipid formulations are quite limited and have shown variable differences in infusion toxicity, nephrotoxicity, hepatotoxicity and clinical efficacy. Postapproval experience has shown substantial efficacy for less common mycotic pathogens including zygomycosis. The precise position of ABLC versus both other lipid formulations and expanding formulary of new antifungal agents is in flux. Future studies which examine its clinical efficacy, role in combination therapy, toxicity and cost-effectiveness in these complex patients are needed.     

Recommendations for the treatment of fungal pneumonias

Incidences of fungal pneumonias have increased in immunocompromised patients with HIV infection or receiving bone marrow replacement or solid organ transplantation. Fungal pneumonias including aspergillosis, cryptococcosis, candidiasis, coccidioidomycosis, histoplasmosis and blastomycosis are one of the major causes of morbidity and mortality among the immunosuppressed hosts. Therefore, clinicians should consider the most appropriate and aggressive treatment of fungal pneumonias in this population. This report outlines the state of the art in the treatment of fungal pneumonias and discusses recent advances in antifungal therapy. Practice guidelines for the treatment with commonly used antifungal agents including amphotericin B, fluconazole, itraconazole, ketoconazole and flucytosine, are very useful for clinicians to manage the diseases appropriately. Echinocandins and second-generation triazoles will hopefully help clinicians to overcome the limitations of the current therapy.     

Best practice guidelines for the management of adverse events associated with amphotericin B lipid complex

Importance of the field: Amphotericin B lipid complex is a widely used lipid-based formulation of amphotericin B, which has a broad spectrum of activity against a variety of fungal pathogens. It has also been shown to be significantly less nephrotoxic than conventional amphotericin B. However, infusional drug reactions, similar to those seen when using conventional amphotericin B, have been reported in a significant number of patients, so it is important that these are prevented or managed effectively, particularly in light of the changing epidemiology of systemic fungal infections.

Areas covered in this review: This article reviews effective strategies that can be used to reduce the risk of drug delivery reactions associated with amphotericin B lipid complex. Preserving renal function and managing spikes in serum creatinine levels are also discussed.

What the reader will gain: The aim of this paper is to provide healthcare professionals with clear guidance on the management of adverse events associated with amphotericin B lipid complex. Recommendations are based upon the published evidence and clinical experience from a number of different centres.

Take home message: Amphotericin B lipid complex represents a valuable therapeutic option in the treatment of fungal infections but improved strategies for the management of infusion-related adverse events are required.     

New investigational antifungal agents for treating invasive fungal infections

Systemic fungal infections have been recognised as a major cause of morbidity and mortality during the last two decades. There are only a few therapeutic options for these infections. Severe toxicity, such as impairment of renal function, limits the use of amphotericin B. Flucytosine is associated with side effects and drug resistance. Fluconazole and itraconazole are safer, though emergence of resistance and innate resistance in some fungal pathogens is a concern in their use. Therefore, there is a need for developing novel drugs and/or treatment strategies to combat these infections. In recent years, increased efforts by the pharmaceutical industry and academia have led to the discovery of new re-engineered or reconsidered antifungal agents that are more efficacious, safer and have a broad spectrum of activity. Lipid formulations of polyene antifungal agents, amphotericin B and nystatin, have the advantage of improved therapeutic index. Activity against resistant fungi, high bioavailability, safety and longer half-life are the properties that encourage development of the newer triazoles (e.g., voriconazole, ravuconazole and posaconazole). Echinocandin-like lipopeptide antibiotics are among the antifungal agents with a novel mode of action. In addition to these lead investigational compounds, development of newer antifungal agents is underway.     

Diagnosis and treatment of fungal infections in allogeneic stem cell and solid organ transplant recipients

Importance of the field: Invasive fungal diseases (IFD) are severe complications in patients receiving immunosuppression after solid organ or allogeneic stem cell transplantation. Extensive study has been conducted on therapeutic strategies for IFD in neutropenic patients, mostly those with hematological malignancy. There is an ongoing discussion on whether these studies may be applied to transplant patients as well.

Areas covered in this review: We have reviewed relevant literature on transplantation and clinical mycology of the last 20 years and selected articles relevant for today's treatment decisions. This article reports on the epidemiology of IFD in transplant recipients and current antifungal drugs in the context of tansplantation medicine. For invasive aspergillosis and invasive candidiasis, we give a detailed report of current clinical evidence.

What the reader will gain: This review is intended as a quick-start for clinicians and other care providers new to transplant care and as an update for experienced transplant physicians. In a field in which evidence is scarce and conflicting, we provide evidence-based strategies for diagnosing and treating the most relevant IFD in transplant recipients.

Take home message: Physicians treating transplant patients should maintain a high level of awareness towards IFD. They should know the local epidemiology of IFD to make the optimal decision between current diagnostic and therapeutic strategies. Prophylaxis or early treatment should be considered given the high mortality of IFD.     

Recent advances in the treatment of life-threatening,invasive fungal infections

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative.

Areas covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole.

Expert opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.     

Amphotericin B lipid complex in the management of invasive fungal infections in immunocompromised patients

Invasive fungal infections are associated with a poor outcome and their incidence is rising. Amphotericin B has for a long time been the gold standard for treatment of these infections, but the conventional formulation is associated with a high incidence of adverse events. Lipid formulations of amphotericin, developed to overcome these drawbacks, are now routinely used in clinical practice for the treatment of invasive fungal infections in immunocompromised patients. Amphotericin B lipid complex (ABLC) is prepared from amphotericin complexed to two phospholipids, a process that confers a number of important pharmacodynamic and pharmacokinetic properties compared with conventional amphotericin B. The results of retrospective observational studies and the analysis of databases, including the large Collaborative Exchange of Antifungal Research (CLEAR) database, have shown ABLC to be associated with response rates of up to about 80% in patients with confirmed fungal infections and around 60% in those treated empirically. Intranasal administration of ABLC for prophylaxis of invasive fungal infection in immunocompromised patients is safe and appears to be a promising treatment strategy for the future. ABLC is associated with a substantially lower incidence of nephrotoxicity than conventional amphotericin. Infusion-related reactions also occur less frequently than with conventional amphotericin and can be managed using premedication protocols. When direct and indirect costs are measured, ABLC appears to be less expensive than conventional amphotericin. The number of approved antifungal agents that are effective treatments for invasive fungal infections is increasing. However, lipid formulations of amphotericin, such as ABLC, are effective and well tolerated and remain the standard of care in the treatment of invasive fungal infections. Treatment strategies such as intranasal administration for prophylaxis and combination therapy with newer agents are future directions for these agents.     

The reformulation of Amphotericin B for oral administration to treat systemic fungal infections and visceral leishmaniasis

Amphotericin B (AmB) is a parenterally administered broad-spectrum antifungal and leishmanicidal drug that has been on the market for over sixty years. Unfortunately, significant infusion-related side effects and renal toxicity often accompany treatment, limiting its clinical applications. Lipid-based formulations have somewhat ameliorated the associated toxicity, but the increased cost of formulations restricts widespread use. AmB is amphipathic and exhibits low solubility and permeability, resulting in negligible absorption when administered orally. Advances in drug delivery systems have overcome some of the solubility issues that prevent oral bioavailability and new formulations are currently in development. The existence of an effective, safe and inexpensive oral formulation of amphotericin B would have significant applications for the treatment of disseminated fungal infections and would dramatically expand access to treatment of visceral leishmaniasis by introducing a readily available highly tolerated oral formulation of a drug with known efficacy.     

两性霉素B脂质体治疗白血病合并霉菌性肺炎6例

目的：探讨白血病患儿霉菌性肺炎的临床特征及两性霉素B脂质体的临床疗效和不良反应。方法：回顾性分析我院2004～2006年确诊为白血病合并霉菌性肺炎6例的临床表现和诊疗过程。结果：6例白血病患儿病原菌培养均为霉菌,两性霉素B脂质体治疗真菌感染疗效满意,主要不良反应是低钾血症。结论：霉菌是引起白血病患儿化疗后院内感染重要病原菌之一,肺炎常规治疗临床改善不明显时,要重视霉菌检查并及时改用两性霉素B治疗。     

两性霉素 B脂质体治疗侵袭性真菌感染病人发生急性肾损伤危险因素分析

目的研究两性霉素 B脂质体(L-AMB)治疗侵袭性真菌感染病人发生急性肾损伤(AKI)的危险因素。方法回顾性分析南京医科大学附属淮安第一医院 2018年 1月至 2021年 12月 61例两性霉素 B脂质体治疗侵袭性真菌感染病人的临床资料,根据是否发生两性霉素 B脂质体相关 AKI分为 AKI组 23例( 37.7%)非 AKI组 38例( 62.3%)。采用单因素分析法比较两组临床资料, logistic回归分析两性霉素 B脂质体( L-AMB)治疗侵袭性真菌感,染病人发生 AKI的危险因素,应用受试者操作特征曲线( ROC曲线)评价 L-AMB使用累积剂量及治疗前血清钾水平在诊断 AKI方面的能力。结果有 23例病人在使用 L-AMB治疗过程中发生 AKI,AKI发生率为 37.7%。L-AMB疗程、累积剂量、日剂量, L-AMB治疗前血钾水平在 AKI及非 AKI两组病人比较中均差异有统计学意义(均 P<0.05);累积剂量是发生 L-AMB相关 AKI的独立危险因素［ OR=1.46,95%CI:(1.08,1.98),P=     

Unidirectional Inhibition of Lipid Transfer Protein I-Mediated Transfer of Cholesteryl Esters Between High-Density and Low-Density Lipoproteins by Amphotericin B Lipid Complex

No HeadingPurpose. The purpose of this study was to determine whether Fungizone or amphotericin B lipid complex (ABLC; ABELCET^®) affects the transfer of cholesteryl ester (CE) by lipid transfer protein I (LTP I; also known as cholesteryl ester transfer protein) between HDL and LDL (bidirectional transfer HDL to LDL and LDL to HDL).Methods. Increasing concentrations of either Fungizone or ABELCET^® (1.25–12.5 g AmpB/ml) were incubated with HDL and [3H]CE-LDL or [3H]CE-HDL and LDL (the amount of each fraction added was equivalent to 10 g of cholesterol) and LTP I in delipidated human plasma at 37C for 90 min. As a positive control, TP2, a monoclonal antibody directed against LTP-1, was added instead of drug. After incubation, manganese and phosphate reagents were then added to precipitate out all of the LDL. The supernatant, consisted of only HDL, was counted for radioactivity to determine the amount of CE transferred from LDL. Similarly, the precipitate consisted of only LDL, was counted for radioactivity to determine the amount of CE transferred from HDL.Results. For Fungizone, the transfer of cholesteryl ester (CE) between HDL and LDL were not significantly different compared to nontreated controls. For ABELCET^®, CE transfer from HDL to LDL was significantly decreased at 12.5 g AmpB/ml compared to control. However, transfer from LDL to HDL was not significantly different compared to non-treated controls. Similar results were observed with the major lipid component of ABELCET^®, dimyristoylphosphatidylcholine. CE transfer from HDL to LDL and LDL to HDL was significantly decreased when using the positive control (TP2).Conclusions. Fungizone does not affect LTP I–mediated transfer of CE between HDL and LDL. ABELCET^® inhibits transfer from HDL to LDL, but has no effect on CE transfer from LDL to HDL. This uni-directional inhibition may contribute to the high recovery of AmpB in HDL but the very low presence of drug in the LDL fraction following ABELCET^® incubation.     

Block Copolymer Micelles for the Encapsulation and Delivery of Amphotericin B

Purpose. To assess the effect of fatty acid substitution of a micelle-forming poly(ethylene oxide)-block-poly(N-hexyl stearate-L-aspartamide) (PEO-b-PHSA) on the encapsulation, hemolytic properties and antifungal activity of amphotericin B (AmB). Methods. PEO-b-PHSA with three levels of stearic acid substitution were synthesized and used to encapsulate AmB by a solvent evaporation method. Size exclusion chromatography and UV spectroscopy were used to confirm and measure levels of encapsulated AmB. The hemolytic activity of encapsulated AmB toward human red blood cells and its minimum inhibitory concentration against Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans were obtained and compared to AmB alone. Results. An increase in the level of stearic acid substitution on PEO-b-PHSA improved the encapsulation of AmB while reducing its hemolytic activity. PEO-b-PHSA micelles having 50% and 70% stearic acid substitution (mol fatty acid: mol reacted and unreacted hydroxyls) were completely non-hemolytic at 22 g/ml. At 11% stearic acid substitution, AmB caused 50% hemolysis at 1 g/ml. AmB in PEO-b-PHSA micelles was as effective as AmB alone against pathogenic fungi. Conclusions. PEO-b-PHSA micelles with a high level of stearic acid side chain substitution can effectively solubilize AmB, reduce its hemolytic activity yet retain its potent antifungal effects.     

国产两性霉素B脂质体治疗艾滋病合并侵袭性真菌病的病例报道

本文报道国产两性霉素B脂质体（锋克松）治疗11例艾滋病合并侵袭性真菌病（IFD）病例的临床疗效。结果显示,治愈6例,显效4例,1例中断治疗。其中1例合并侵袭性肺曲霉菌病患者治疗7d后因胸部CT提示病情加重而加大剂量至2mg／kg／d继续治疗1周,复查CT显示肺部病灶开始吸收。患者主要不良反应为贫血、低血钾和血肌酐升高。除1例因再度贫血中断治疗,其余患者经对症治疗后均好转。提示国产两性霉素B治疗艾滋病合并IFD疗效好,不良反应小。     

Emerging echinocandins for treatment of invasive fungal infections

The echinocandins are a new class of antifungals, developed in response to the need for safe and effective antifungals for the treatment of invasive fungal infections. These agents work by inhibiting 1,3-β-d-glucan synthase, an enzyme essential for production of cell walls in select fungi. Echinocandins appear to demonstrate favourable activity in vitro against a variety of yeasts (including both Candida albicans and non-albicans Candida) as well as select moulds (including Aspergillus spp.) In general, all echninocandins demonstrate a favourable safety profile and require once-daily parenteral administration. Caspofungin is the first of these agents to be available in the US, and is approved for empirical antifungal therapy in febrile neutropenic patients, candidaemia and select forms of invasive candidiasis, and for management of invasive aspergillosis in patients refractory to or intolerant of other therapies. Micafungin was recently approved by the FDA for treatment of oesophageal candidiasis, and for the prophylaxis of fungal infections in haematopoietic stem cell transplant recipients. Emerging data indicate micafungin may have an important role in the treatment of invasive forms of candidiasis. Anidulafungin is an echinocandin approved in the US for treatment of candidaemia and oesophageal candidiasis. Aminocandin (HMR-3702, IP-960) is an investigational agent, with published experience limited to in vitro studies and animal models of infection.     

The current role of amphotericin B lipid complex in managing systemic fungal infections

Abstract

Background:

An increase in the number of immunocompromised patients has led to a rising burden of systemic fungal infections. Historically, conventional amphotericin B has been used to treat these infections due to its broad spectrum of activity. The development of lipid-based amphotericin B agents, such as Abelcet^* (ABLC), has allowed clinicians to take advantage of the broad spectrum of activity of amphotericin B while reducing adverse events. As well as this, a number of new antifungal agents have been developed in recent years which have significantly added to the treating physician’s antifungal armamentarium.     

Retrospective analysis of the dosage of amphotericin B lipid complex for the treatment of invasive fungal infections.

STUDY OBJECTIVE: To understand the relationship between dosage and therapeutic response of amphotericin B lipid complex (ABLC) by analyzing underlying diseases, types of infections, and therapeutic outcomes with different dosages as second-line antifungal therapy. DESIGN: Retrospective analysis of low-dose (initial dose < or = 3 mg/kg) ABLC from three open-label, clinical, second-line treatment studies. SETTING: Centers in the United States (204), Canada (3), Australia (1), Mexico (1), and The Netherlands (1). PATIENTS: Five hundred fifty-one patients (5 enrolled twice) with invasive fungal infections, of whom 289 failed and 267 were intolerant to conventional antifungal therapy. INTERVENTIONS: Patients were to receive the recommended dosage of ABLC 5 mg/kg/day, with dosage reduction for markedly increased serum creatinine. The duration of treatment was 4 weeks; therapy could be extended if the investigator considered additional treatment necessary. MEASUREMENTS AND MAIN RESULTS: Seventy-three patients (13%) received ABLC 3 mg/kg/day (low dosage) instead of the protocol-recommended 5 mg/kg/day Response was 65% and 56%, respectively. Logistic regression analysis revealed that the following patients are most likely to start therapy at the lower dosage: those with candidiasis and other yeast infections, patients with nephrotoxicity due to prior amphotericin B, and those with underlying conditions other than hematologic malignancy. CONCLUSION: These results suggest that ABLC 3 mg/kg/day may be effective in treating patients with candidiasis who do not have hematologic malignancy.     

Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections

Background:

Voriconazole is a broad-spectrum, second-generation triazole antifungal agent with demonstrated efficacy in the treatment of invasive fungal infections caused by Aspergillus spp. and Candida spp. Given the characteristically poor prognosis of patients with invasive fungal infections and the protracted duration of treatment required, therapeutic monitoring of voriconazole is, in theory, an attractive method to optimize antifungal therapy.

Objective:

To determine the utility of therapeutic drug monitoring for voriconazole.

Methods:

A previously published decision-making algorithm was used to assess the currently available literature on therapeutic drug monitoring of voriconazole.

Results:

Several analytical methods can be used to quantify plasma or serum concentrations of voriconazole. Reasons for therapeutic monitoring of this drug include wide variability both within and between individuals secondary to drug properties, drug–drug interactions, and disease states. Furthermore, voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance. Another potential factor in favour of therapeutic drug monitoring for voriconazole is genetic polymorphism of CYP2C19, whereby patients who are homozygous for poor metabolism (about 19% of non-Indian Asians) can have 4-fold greater exposure to voriconazole. The concentrations of this drug are also greater in patients with hepatic impairment. Drug–drug interactions with other substrates of CYP2C9, CYP2C19, and CYP3A4 can also alter voriconazole concentrations. However, the correlations between plasma concentrations of voriconazole and its efficacy and toxicity are not well defined. Although lower and upper target thresholds of 0.25–2 mg/L and 4–6 mg/L, respectively, have been suggested, studies to date have not been appropriately designed or powered to reveal any definitive association.

Conclusions:

Routine therapeutic drug monitoring of voriconazole is not recommended except in certain circumstances, such as lack of response to therapy or evidence of toxicity, in which case selective monitoring of voriconazole concentrations may be of clinical utility.     

Recent advances and challenges in the treatment of invasive fungal infections

The frequency of invasive fungal infections (IFIs) has increased over the last decade with the rise in at-risk populations of patients. The morbidity and mortality of IFIs are high and management of these conditions is a great challenge. With the widespread adoption of antifungal prophylaxis, the epidemiology of invasive fungal pathogens has changed. Non-albicans Candida, non-fumigatus Aspergillus and moulds other than Aspergillus have become increasingly recognised causes of invasive diseases. These emerging fungi are characterised by resistance or lower susceptibility to standard antifungal agents. Invasive infections due to these previously rare fungi are therefore more difficult to treat. Recently developed antifungal agents provide the potential to improve management options and therapeutic outcomes of these infections. The availability of more potent and less toxic antifungal agents, such as second-generation triazoles and echinocandins, has led to considerable improvement in the treatment of IFIs. This article reviews the changing spectrum of invasive mycosis, the properties of recently developed antifungal agents and their role in the management of these infections.     

卡泊芬净在器官移植术后侵袭性真菌感染病人中的应用

目的对卡泊芬净治疗器官移植术后侵袭性真菌感染的疗效进行评价。方法采用病例对照研究方法,选择我院器官移植术后出现侵袭性真菌感染病人100例,分为3组。卡泊芬净组36例,氟康唑组36例,两性霉素B组28例,分别予卡泊芬净、氟康唑和两性霉素B治疗,观察抗真菌治疗疗效。结果卡泊芬净组、氟康唑组和两性霉素B组抗真菌治疗的有效率分别为76%、81%和67%,3组疗效无显著差异(P>0.05)。卡泊芬净组与氟康唑组、两性霉素B组用药过程中的不良反应发生率分别为6%、6%和14%。结论卡泊芬净对于器官移植术后病人侵袭性真菌感染有明显的治疗作用,疗效与两性霉素B和氟康唑相当。     

泊沙康唑预防侵袭性真菌感染疗效及安全性的Meta分析

目的 系统评价泊沙康唑预防侵袭性真菌感染的疗效及安全性.方法 检索PubMed、Web of Science、Embase、Cochrane Library、Clinicaltrials.gov、中国知网期刊全文数据库、维普中文科技期刊数据库、万方数据库及中国生物医学文献数据库,截止时间2019年9月20日,收集所有关...