Lipid-based formulations of amphotericin B

Amphotericin B remains the drug of choice for the treatment of invasive fungal infections and visceral leishmaniasis. However, both the dose-dependent nephrotoxicity and the low response rates (10-80%) associated with amphotericin B limit its clinical use. The first marketed formulation of amphotericin B with deoxycholate, Fungizone, remains the "gold standard" in spite of its renal toxicity. Several investigations have been made to reduce the nephrotoxicity of amphotericin B by formulation strategies. Lipid-based formulations of amphotericin B were found to reduce toxicity and to increase tolerance and therapeutic efficacy. Three lipid formulations are now available in most countries: liposomal amphotericin B (AmBisome), amphotericin B lipid complex and amphotericin B colloidal dispersion. Amphotericin B colloidal dispersion was less nephrotoxic, but immediate reactions to this formulation were as frequent and severe as those to amphotericin B. Amphotericin B lipid complex appeared to be as effective as amphotericin B, with improved general and renal tolerability. Several comparative studies have confirmed that AmBisome has similar or superior efficacy relative to amphotericin B in various fungal infections, in visceral leishmaniasis and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. A significant drawback to the newer, less toxic, commercial lipid-based formulations is their cost. There is a need to develop more affordable lipid-based formulations of amphotericin B.     

Pharmacoeconomic analysis of amphotericin B lipid complex versus liposomal amphotericin B in the treatment of fungal infections

BACKGROUND: Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. DESIGN: A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. RESULTS: No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53% vs 60%, p = 0.68), thus justifying the use of a cost-minimisation analysis. Among patients with baseline elevations in serum creatinine, 47% receiving ABLC and 10% receiving L-AMB experienced further increases in serum creatinine (p = 0.025). No differences in total treatment costs (level I, II, or III) were evident between patients receiving ABLC or L-AMB. When adjusted for duration of therapy, however, costs were significantly lower for ABLC than for L-AMB (level I: ABLC $US340 versus L-AMB $US435, p = 0.002; level II: ABLC $US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. CONCLUSION: In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.     

Delivery strategies of amphotericin B for invasive fungal infections

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.     

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.     

Lipid-based amphotericin B formulations: from animals to man

Amphotericin B has been the mainstay of systemic antifungal therapy for over 30 years, despite its serious side-effects, and, although numerous alternative antifungal agents have been developed, none to date has matched the efficacy of amphotericin B. However, modern drug delivery technology has improved the safety of amphotericin B by incorporating it into lipid-based delivery systems, including liposomes. Three such formulations, based on the natural affinity of amphotericin B for lipids, are currently marketed. All increase the therapeutic index of amphotericin B, thereby allowing more aggressive treatment than is possible with the conventional product. However, they differ in structure, side-effect profiles and evidence of proven efficacy as discussed in this review.     

两性霉素B治疗真菌感染的疗效及不良反应评价

目的：回顾性评价两性霉素B治疗真菌感染的疗效及药物不良反应（ADR）。方法：收集2011年1月～2014年6月我院应用两性霉素B治疗真菌感染的病例,以痊愈、显效、进步、无效4种评价标准对其疗效进行评价,并对不良反应进行分析研究。结果：共纳入患者131例,痊愈24例,显效77例,好转9例,无效21例,总体有效率为77.10%;110例患者出现不同程度的不良反应,其中6例（4.58%）因反应严重需要更换用药,其余患者对症处理后不影响治疗。结论：两性霉素B治疗真菌感染的疗效显著,药物不良反应在可控制范围内。     

Potential role of aerosolized amphotericin B formulations in the prevention and adjunctive treatment of invasive fungal infections

The incidence of invasive fungal infections (IFIs) continues to increase, largely due to the steady rise in the number of at-risk patients and the increased use of aggressive immunosuppressant agents. Many available treatments are often limited by concerns about efficacy, safety, drug interactions, and/or cost. Owing to the poor treatment outcomes of immunosuppressed patients with IFIs, new preventative and treatment strategies are being investigated. Among these are the aerosolized formulations of amphotericin B. Published experience with the use of aerosolized amphotericin B deoxycholate (AmBd) in the prevention of IFIs has raised concerns regarding challenges in drug administration and tolerability. However, evolving data regarding administration of lipid-based formulations of amphotericin B indicate potential advantages over AmBd in the prevention and adjunctive treatment of IFIs.     

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。     

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.     

Lipid-based amphotericin B: a review of the last 10 years of use

The last decade has been remarkable for the dramatic increase in the prevalence of serious fungal infections in patients with haematological disorders and neutropenic cancer patients. The mortality rate of deep-seated infection has been in excess of 90% and there is no doubt that this is one of the greatest challenges currently facing haematologists and oncologists. The development of the lipid-based drugs - liposomal amphotericin (AmBisome(R)), amphotericin B lipid complex, ABLC (Abelcet(R)), amphotericin B colloidal dispersion, Amphocil (ABCD(R)), has meant that doses of amphotericin B can be safely escalated for the first time whilst the problems of nephrotoxicity, infusion related reactions (including chills, rigors, fevers and hypoxia) can be reduced. These toxicities are variably reduced with AmBisome more than Abelcet and more than Amphocil and there is little information from randomised trials other than for AmBisome. AmBisome used in the setting of persistent fever and neutropenia not responding after 3-4 days of intravenous antibiotics, is associated with less breakthrough systemic fungal infections. There is also much less need for premedication, including steroids, compared with amphotericin B and Abelcet. The use of intermittent doses of Ambisome given prophylactically is now being explored. A new and exciting era of antifungal therapy is opening up with new compounds, such as itraconazole voriconazole, posaconazole and echinocandins, being investigated and for the first time, we also have options for combination therapy and prophylaxis.     

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.     

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.     

Development of novel lyophilized mixed micelle amphotericin B formulation for treatment of systemic fungal infection

The purpose of the study was to develop a stable, controlled release Amphotericin B (Amph B) lyophilized mixed micelle (MM) formulation using hydrogenated soya phosphatidylcholine (HSPC) and bile salts in monomeric form and evaluate it for therapeutic performance and side effects. The MM formulations of Amph B were prepared using sodium deoxycholate (NDC)/sodium taurocholate (NTC)/sodium cholate (NC), and HSPC. The optimization of bile salt: HSPC ratio in the MM formulation was done using 2(4) factorial designs. MM formulations were lyophilized using sucrose as a cryoprotectant and analyzed for per cent micelle yield, per cent drug loading and per cent entrapment efficiency. Comparative in vitro diffusion studies, hemolytic activity, and minimum inhibitory concentration (MIC) of developed MM formulations and marketed formulation (Fungizone) were evaluated using cellophane membrane, human red blood cells and Candida albicans respectively. In vivo studies of MM formulations were also carried out on Candida albicans infected white albino rats and compared with Fungizone. The optimized molar ratio of bile salt: HSPC was found to be 8:11. Among all MM formulations prepared, NDC/ HSPC formulation found to have maximum per cent drug loading (4.96+/-0.8%), per cent entrapment efficiency (93.2+/-1.5%) and per cent micelle yield (96.4+/-1.4%). The in vitro drug diffusion studies of developed MM formulations show close to zero-order diffusion kinetics. All MM formulations show improved therapeutic index and reduced side effects compared to reference formulation Fungizone. The NDC/HSPC MM formulation was found to have least hemolytic activity, MIC and mortality rate at all dosage levels. Improved antifungal activity and reduced toxicity of Amph B solubilized in MM may be due to higher cellular uptake of the drug by fungal cells of infected tissues from MM formulations. Hence, Amph B MM formulation could be a safe and effective viable alternative in the treatment of systemic fungal infections.     

国产伏立康唑与两性霉素B治疗急性白血病合并侵袭性真菌感染的临床分析

目的:比较国产伏立康唑与两性霉素B治疗急性白血病合并侵袭性真菌感染的疗效及不良反应.方法:回顾性分析急性白血病合并侵袭性真菌感染患者27例临床资料,分为治疗组14例和对照组13例,治疗组静脉滴注伏立康唑4mg/kg,1次/12h,对照组静脉滴注两性霉素B从5mg开始逐渐增加剂量为1mg/kg,1次/d,两组均于用药2周后评价疗效及不良反应.结果:治疗组及对照组有效率分别为78.57%和46.15%,差异有统计学意义(P<0.05),不良反应发生率分别为28.57%、69.23%,治疗组明显低于对照组,差异有统计学意义(P<0.05).结论:国产伏立康唑治疗急性白血病合并侵袭性真菌感染较两性霉素B疗效好,不良反应少.     

两性霉素B联合过氧化氢治疗真菌性外耳道炎的临床研究

目的 探讨两性霉素B溶液联合过氧化氢溶液治疗真菌性外耳道炎的临床疗效。方法 选取2021年9月—2023年9月青岛市城阳区人民医院收治的真菌性外耳道炎患者82例,随机分为对照组（41例）和治疗组（41例）。对照组给予过氧化氢溶液,3%溶液冲洗外耳道,3次/d。在对照组基础上,治疗组患者滴耳注射用两性霉素B,25 mg溶于注射用水5 mL,药液耳浴10 min,3次/d。两组治疗14 d。观察两组患者临床疗效,比较治疗前后两组患者症状缓解时间,气导（AC）和耳骨导（BC）听阈值,血清降钙素原（PCT）、肿瘤坏死因子-α(TNF-α)、转化生长因子-β1(TGF-β1)和白细胞介素-6(IL-6)水平。结果 治疗后,治疗组总有效率为92.68%,明显高于对照组（78.05%,P<0.05）。治疗后,治疗组症状缓解时间均明显短于对照组（P<0.05）。治疗后,两组患耳AC听阈值、BC听阈值比治疗前明显降低（P<0.05）,且治疗组患耳的AC听阈值、BC听阈值低于对照组（P<0.05）。治疗后,两组患者血清TNF-α、PCT、TGF-β1、IL-6水平低于治疗前（P&l...     

伏立康唑的临床合理应用

新型高效低毒抗真菌药物的出现和应用,优化了临床抗真菌治疗方案,提高了抗真菌治疗的疗效.伏立康唑作为新一代三唑类抗真菌药物,具有抗菌谱广、安全且组织分布广等特点,在临床抗真菌治疗中发挥重要作用,但其也存在明显的不良反应,并与较多的药物具有相瓦作用.临床应根据真菌感染类型、感染部位、机体免疫状况、真菌药敏以及药物间相互作用等合理选用伏立康唑.伏立康唑在真菌感染防治中的疗效和安全性需通过大规模前瞻性随机对照临床研究进一步观察和研究.     

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.     

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-beta-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.     

Heat shock protein inhibitors for the treatment of fungal infections

Invasive fungal infections are a leading cause of mortality, especially in immunocompromised patients. Therapy is made difficult by the limited number of antifungal agents currently available which mostly target ergosterol in fungal cell membranes. The paucity of targets allows the development of cross resistance to all drugs with a common target. This highlights the need to develop new therapeutic strategies for fungal disease including agents with novel mechanisms of action. Heat shock protein 90 stabilizes calcineurin which regulates response to stress, allowing for calcineurin dependent stress responses required to survive exposure to antifungal drugs. Heat shock protein 90 inhibition abrogates calcineurin dependent stress responses, changing fungistatic drugs to fungicidal. Targeting a highly conserved protein that has a vital role in many cellular signaling pathways, reduces the potential for emergence of resistance to heat shock proteins inhibitors. This article will review recent patents in novel heat shock protein inhibitor therapy, such as efungumab, which diminish the emergence of antifungal drug resistance and enable greater efficacy of existing antifungals.