Lipid-based Formulations Of Amphotericin Research Articles

Sixtyyears of AmphotericinB: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections.

Introduced in the late 1950s, polyenes represent the oldest family of antifungal drugs. The discovery of amphotericin B and its therapeutic uses is considered one of the most important scientific milestones of the twentieth century . Despite its toxic potential, it remains useful in the treatment of invasive fungal diseases owing to its broad spectrum of activity, low resistance rate, and excellent clinical and pharmacological action. The well-reported and defined toxicity of the conventional drug has meant that much attention has been paid to the development of new products that could minimize this effect. As a result, lipid-based formulations of amphotericin B have emerged and, even keeping the active principle in common, present distinct characteristics that may influence therapeutic results. This study presents an overview of the pharmacological properties of the different formulations for systemic use of amphotericin B available for the treatment of invasive fungal infections, highlighting the characteristics related to their chemical, pharmacokinetic structures, drug–target interactions, stability, and others, and points out the most relevant aspects for clinical practice.

Comparative Efficacy of Amphotericin B Lipid Complex and Liposomal Amphotericin B for the Treatment of Invasive Fungal Infections in HSCT Recipients and other Immunocompromised Patient Populations with Hematologic Malignancies: A Critical Review

Amphotericin B is an important agent for the treatment of invasive fungal infections in immunocompromised patients because of its broad spectrum. However, its toxicities and the availability of alternative agents limit its application. Lipid-based formulations of amphotericin B, such as amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB), are less nephrotoxic and as effective as conventional amphotericin B. However, because of their similarities, choosing between the two formulations remains a challenge. The majority of prospective and retrospective comparative studies have shown equivalence in terms of efficacy although some subset analyses favor ABLC over L-AMB. While both drugs penetrate well in the reticuloendothelial system, ABLC gets concentrated in the lungs to a much greater extent. This may have clinical implications because the lungs are the commonest site of invasive fungal infections. L-AMB is associated with less infusion-related adverse effects and less nephrotoxicity than ABLC. ABLC has been shown to be more cost-effective than L-AMB, although this is affected by variable institutional contracts and pricing. The choice between the two drugs should be based upon due consideration of all these factors.

Overview of treatment options for invasive fungal infections

The introduction of several new antifungals has significantly expanded both prophylaxis and treatment options for invasive fungal infections (IFIs). Relative to amphotericin B deoxycholate, lipid-based formulations of amphotericin B have significantly reduced the incidence of nephrotoxicity, but at a significant increase in drug acquisition cost. Newer, broad-spectrum triazoles (notably voriconazole and posaconazole) have added significantly to both the prevention and treatment of IFIs, most notably Aspergillus spp. (with voriconazole) and the treatment of some emerging fungal pathogens. Finally, a new class of parenteral antifungals, the echinocandins, is employed most frequently against invasive candidal infections. While the role of these newer agents continues to evolve, this review summarizes the activity, safety and clinical applications of agents most commonly employed in the treatment of IFIs.

Antifungal Treatment of Small Animal Veterinary Patients

Antifungal therapy has progressed significantly with the development of new drugs directed at various processes in fungal cell metabolism. Within veterinary medicine, treatment options for systemic mycoses remain limited to amphotericin B, ketoconazole, fluconazole, and itraconazole. However, newer triazoles, echinocandins, and lipid-based formulations of amphotericin B are now approved for use in humans. This article provides a comprehensive review of the antifungal medications available for veterinary patients, and includes a brief discussion of the newer, presently cost-prohibitive, antifungal therapies used for systemic mycoses in humans.

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 therapies for fungal pneumonia

This review summarizes recent developments in the diagnosis and treatment of fungal pneumonia, with an emphasis on invasive pulmonary aspergillosis. Improvements in nonculture-based fungal diagnostics, early implementation of pulmonary high resolution, or spiral computed tomography scanning and a recent expansion of the antifungal armamentarium have greatly improved the outcome of immunocompromised patients with invasive aspergillosis. However, the field is changing: new pathogens (such as Zygomycetes) are emerging, and novel risk groups (ICU patients in particular) are being identified. Galactomannan antigen detection is a valuable tool for evaluating patients at risk for invasive aspergillosis (as a screening assay on serum samples from neutropenic patients or as a confirmatory assay on bronchoalveolar lavage fluid samples, in general), but should be used in conjunction with modern imaging techniques. beta-D-Glucan and PCR assays are still investigational. Voriconazole is the drug of choice for invasive aspergillosis, whereas liposomal amphotericin B at 3 mg/kg per day is the preferred alternative in case of contraindication, drug-related side-effects, or intolerance. Whenever possible, optimal antifungal therapy should be complemented by surgical debridement of necrotic tissue. The added value of combination therapy is still unproven. Therapeutic drug monitoring of mold-active azoles should be implemented in order to minimize toxicity and maximize efficacy. Lipid-based formulations of amphotericin B, and to a lesser extent voriconazole, are the drugs of choice for non-Aspergillus related fungal pneumonia. Although active in prophylaxis, the efficacy of posaconazole in confirmed infections remains controversial.

Antifungal Therapy for Invasive Fungal Diseases in Allogeneic Stem Cell Transplant Recipients: An Update

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug-drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.

Efficiency and Safety of Inhaled Amphotericin B Lipid Complex (Abelcet) in the Prophylaxis of Invasive Fungal Infections Following Lung Transplantation

Background Invasive fungal infections (IFIs) in patients undergoing lung transplantation (LT) are associated with significant mortality. Previous studies have shown the efficacy of aerosolized amphotericin B deoxycholate and oral fluconazole for antifungal prophylaxis. Evolving data show a potential advantage of prophylaxis with lipid-based formulations of amphotericin B in the prevention of IFIs. We reviewed the incidence of IFIs among patients receiving aerosolized amphotericin B lipid complex (ABLC) in LT. Methods We undertook a retrospective review of the results of our antifungal protocol in a cohort of 60 LT patients. We analyzed the efficiency, safety, and tolerability of 50 mg of aerosolized ABLC administered postoperatively for IFI prophylaxis once every 2 days for 2 weeks and then once per week for at least 13 weeks. In addition, these transplanted patients received fluconazole (200 mg/d) during the first 21 days posttransplant. The prophylaxis-related efficiency and safety were quantified for IFIs and adverse events (AEs) for 6 months after study drug initiation. Results Prophylaxis was efficient in 59 (98.3%) patients. Only one patient developed a possible IFI, due to Aspergillus fumigatus. Four patients presented nausea and vomiting as an AE, although aerosolized amphotericin B was ongoing. Conclusions Nebulized ABLC was effective, safe, and well tolerated for the prophylaxis of aspergillosis in lung transplant patients during the early posttransplant period.

Retrospective Analysis of the Use of Lipid-Based Formulations of Amphotericin B in a Pediatric Hospital

ABSTRACT Background: The use of antifungal agents has been increasing in the growing population of immunocompromised patients. To address the problem of renal and infusion-related toxic effects of conventional amphotericin B, several lipid-based formulations of this drug have been developed. At the authors’ pediatric institution, recommendations for the use of these products were established in 2001. Objective: To evaluate the use of lipid-based formulations of amphotericin B and to make any necessary changes to the current recommendations. Methods: The charts of patients who received amphotericin B lipid complex or liposomal amphotericin B between April 2003 and July 2004 were reviewed. Practices in the use of lipid-based formulations of amphotericin B were compared with the recommendations. Results: Eighteen patients were identified for the chart review. The major reasons for prescribing lipid-based formulations of amphotericin B were current documented renal dysfunction or history of such dysfunction with conventional amphotericin B (9 patients) and serious infusion reactions (3 patients) with conventional amphotericin B. Liposomal amphotericin B was the most commonly prescribed initial therapy (13 patients), and all but one of the patients were eventually switched to this form of therapy. For 7 patients (39%), the reason for using either liposomal amphotericin B or amphotericin B lipid complex was consistent with the recommendations. In 8 cases (44%), amphotericin B lipid complex should have been used first, and in 3 cases there was no apparent reason for giving a lipid-based formulation of amphotericin B. Conclusions: Institutional recommendations for the use of lipid-based formulations of amphotericin B should be clearer and better enforced. They should specify that if amphotericin B is selected to treat a documented or suspected fungal infection, conventional amphotericin B should be given; that in patients with pre-existing impairment of renal function, a history of serious infusion reactions or renal impairment with conventional amphotericin B, and for those receiving concomitant nephrotoxic drugs or undergoing bone marrow transplantation, amphotericin B lipid complex should be the formulation of choice; and that liposomal amphotericin B should be restricted to patients whose clinical condition has deteriorated while receiving amphotericin B lipid complex and those in whom previous therapy with amphotericin B lipid complex has failed. RESUME Historique : On a de plus en plus recours aux antifongiques dans la population grandissante de patients immunodeprimes. Pour resoudre le probleme de toxicite renale et de toxicite associee a la perfusion avec l’amphotericine B classique, plusieurs preparations lipidiques de cet antifongique ont ete mises au point. L’etablissement auquel est rattache l’auteur de cet article a etabli en 2001 des recommandations concernant l’emploi de tels produits. Objectif : Evaluer l’emploi des preparations lipidiques d’amphotericine B et apporter les changements necessaires aux recommandations courantes. Methodes : Les dossiers medicaux de patients qui ont recu une preparation d’amphotericine B en complexe lipidique ou d’amphotericine B liposomique entre avril 2003 et juillet 2004 ont ete examines. Les habitudes de prescription des preparations lipidiques d’amphotericine B ont ete comparees aux recommandations. Resultats : On a passe en revue 18 dossiers-patients. Ils revelent que les preparations lipidiques d’amphotericine B ont ete prescrites principalement a cause d’un dysfonctionnement renal actuel documente ou d’antecedents d’un tel dysfonctionnement du a l’amphotericine B classique (9 patients sur 18) et de reactions graves liees a la perfusion d’amphotericine B classique (3 patients sur 18). L’amphotericine B liposomique etait la preparation la plus prescrite comme traitement initial (13 patients), et tous les patients, sauf un, sont passes a un moment ou a un autre a ce type de preparation. Chez 7 patients (39 %), la raison expliquant le recours a l’amphotericine B liposomique ou a l’amphotericine B en complexe lipidique etait conforme aux recommandations. Chez 8 patients (44 %), on aurait du employer d’abord l’amphotericine B en complexe lipidique, et chez 3 patients on n’a observe aucune raison apparente justifiant l’emploi d’une preparation lipidique d’amphotericine B. Conclusions : Les recommandations de l’etablissement sur l’emploi des preparations lipidiques d’amphotericine B doivent etre plus claires et mieux appliquees. Elles devraient notamment preciser que si l’on a recours a l’amphotericine B pour traiter une infection fongique confirmee ou soupconnee, on devrait d’abord utiliser l’amphotericine B classique; que chez les patients ayant une insuffisance renale preexistante, des antecedents de reactions graves liees a la perfusion ou d’insuffisance renale secondaires a l’amphotericine B classique, ainsi que chez ceux qui recoivent simultanement des medicaments nephrotoxiques ou qui subissent un greffe de moelle osseuse, l’amphotericine B en complexe lipidique devrait etre la preparation de choix; et que l’amphotericine B liposomique devrait etre reservee aux patients dont l’etat clinique s’est deteriore avec l’administration de preparations d’amphotericine B en complexe lipidique et aux patients dont un traitement anterieur par une preparation d’amphotericine B en complexe lipidique a echoue.

The experience is CLEAR ®

Conventional amphotericin B has been the ‘gold standard’ for antifungal efficacy, but nephrotoxicity problems limit its clinical utility. In the late 1990s, three lipid-based formulations of amphotericin B were introduced, all of which offered comparable efficacy and reduced renal complications. However, to date, robust safety and comparative efficacy data have been sparse. This paper briefly reviews the available clinical data on amphotericin B lipid complex (ABLC). Also, in detail, it reviews the findings of Collaborative Exchange of Antifungal Research (CLEAR ®), the most extensive dataset on systemic antifungal treatment with the lipid-based agent ABLC.

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.

Infrequent occurrence of amphotericin B lipid complex-associated nephrotoxicity in various clinical settings at a university hospital: A retrospective study

Background: Lipid-based formulations of amphotericin B (AMB) have been shown to significantly lessen the occurrence of nephrotoxicity associated with the conventional form of AMB. A MEDLINE search of literature published from 1983 to 2002, using the search terms amphotericin B and nephrotoxicity, identified only 1 large, randomized, prospective trial that has tried to compare the nephrotoxicity rates among lipid-based AMB formulations. Using the nephrotoxicity surrogate marker of doubling of serum creatinine (SCr) level, the investigators reported a high rate of AMB lipid complex (ABLC)-associated nephrotoxicity (42.3%). However, enrollment in that study was limited to only febrile neutropenic patients. Objective: This retrospective study estimated the rate of ABLC-associated nephrotoxicity in various clinical settings at a university hospital and compared that rate with previously reported rates of nephrotoxicity. Methods: Data from adult neutropenic and nonneutropenic patients receiving ABLC were collected and the degree of nephrotoxicity was determined using 2 definitions: (1) doubling of baseline SCr level using the peak value within the first 7 days, and (2) end-of-therapy doubling of baseline SCr level using the end-of-therapy value. Results: Data from 33 patients (20 men, 13 women; mean age, 48.6 years) were collected. Using these definitions of ABLC-associated nephrotoxicity, only 2 cases (6.1%) were observed. This rate was significantly below the 42.3% rate reported in the only large published study (95% CI, 1.7–19.6; P < 0.001). The median change in SCr level was 0.1 mg/dL (range, −1.1 to 4.3 mg/dL). Rates of change were higher in patients who died during hospitalization, but the difference was not significant. Use of concomitant nephrotoxic agents did not account for significant changes in SCr level. Conclusions: Data from this study suggest that ABLC infrequently causes clinically significant nephrotoxicity. Therefore, when formulary decisions are made in the selection of a drug for use in various clinical settings, earlier data derived from a single study in febrile neutropenic patients that suggested a significantly higher rate of nephrotoxicity should be interpreted cautiously. Larger trials with more diverse patient populations are needed to better characterize institutional rates of ABLC-associated nephrotoxicity and to aid formulary decision makers.

Management of systemic candidal infections in the intensive care unit.

Risk factors and treatment strategies for systemic candidal infections in the intensive care unit (ICU) are discussed. The past two decades have seen a dramatic increase in the frequency of infections caused by Candida species. Risk factors associated with candidemia include treatment with multiple antimicrobials for extended periods, presence of central venous catheters, total parenteral nutrition, colonization by Candida species, abdominal surgery, prolonged stay in the ICU, and compromised immune status. Since the 1960s, conventional amphotericin B has been the primary treatment option for fungal infections. Although effective, amphotericin B has extensive toxicity. Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease nephrotoxicity and improve drug delivery. Practitioners have also been offered alternatives by the introduction of less toxic azole antifungals, such as ketoconazole, fluconazole, and itraconazole; however, their widespread use has resulted in other problems, such as the selection of resistant isolates. There is controversy concerning fluconazole's effectiveness. In the treatment of systemic candidal infections, especially in critically ill patients. Clinical trials do not support the prophylactic or empirical use of fluconazole in the ICU. Treating patients who have no microbiological evidence of infection provides no therapeutic benefit and shifts the fungal flora to noncandidal strains that are more resistant to fluconazole. Patients in ICUs are often susceptible to systemic candidal infection. Preemptive therapy with fluconazole may reduce mortality in high-risk patients. Fluconazole and amphotericin B appear equally effective in treating established systemic candidal infections.

Quantitation of free and total amphotericin B in human biologic matrices by a liquid chromatography tandem mass spectrometric method.

Amphotericin B remains the standard of care for the treatment of invasive and disseminated fungal infections. Various lipid-based formulations of amphotericin B have been developed to improve its therapeutic index by decreasing toxicity. Previous bioanalytic methods using microbial inhibition or high-pressure liquid chromatography quantified total amphotericin B (free, plasma protein-bound, and lipid-complexed). Sensitivity of this method with a low limit of quantitation of 0.05 microg/mL was inadequate to determine free (unbound) amphotericin B. A sensitive LC/MS/MS method was developed to determine the total amphotericin B value in human plasma and other biologic matrices and the free amphotericin B concentration in plasma. For determination of total plasma amphotericin B concentrations, the sample was diluted and injected onto the LC/MS/MS. For total amphotericin B in other matrices and free amphotericin B in plasma, solid-phase extraction was used. Natamycin served as an internal standard. A PE Sciex API 3000 (Sciex; Concord, Ontario, Canada) was used to assess free amphotericin B in plasma ultrafiltrate determination and an API 3+ for the other matrices, with electrospray interfaced to a C18 analytic column. The low limit of quantitation was 1 ng/mL for ultrafiltrate. For total amphotericin B, the low limits were 2 microg/mL for plasma, 0.05 microg/mL for urine, and 0.4 microg/mL for fecal homogenate. The methods were validated to show the standard range linearity, sensitivity, selectivity, accuracy, precision, and stability of amphotericin B in the matrices tested.

Lipid-based formulations of amphotericin B

Lipid-based formulations of amphotericin B

Lipid-based formulations of antisense oligonucleotides for systemic delivery applications

Increasing the specificity of therapeutic drugs and improving their delivery to sites of disease are primary goals of today's pharmaceutical industry. One of the most exciting advances in recent years has been the development of antisense technologies, which are capable of modulating protein expression with exquisite specificity. Unfortunately, this class of drugs is particularly sensitive to nuclease degradation, is eliminated rapidly from the circulation after intravenous administration, and is severely limited in its ability to penetrate through cellular membranes unaided. Attempts to address these problems through medicinal chemistry have produced several key advances. However, chemical alterations to improve one property of the molecule often affect other properties, potentially in a negative manner. The past decade has seen extensive use of liposomes and lipid-based delivery systems to improve the pharmacological properties of a variety of drugs. The principal benefits afforded therapeutic agents by liposomal encapsulation are enhanced plasma-circulation lifetimes, increased delivery to sites of disease, and changes in tissue distribution, which can result in reduced toxic side effects. Liposomal preparations of doxorubicin (DOXIL) and daunorubicin (DaunoXome) have been approved for the treatment of HIV-associated Kaposi's sarcoma, whereas lipid-based formulations of amphotericin B (AmBisome, ABELCET, AMPHOTEC) are successful clinical products employed in the treatment of fungal infections. It is not surprising, therefore, that considerable interest has been on developing lipid-based delivery systems to overcome the problems associated with the systemic administration of DNA- and RNA-based therapeutics. The intent of this chapter is to introduce the reader to the various lipid-based formulations applied to polynucleic acid drugs, with emphasis on the generation and characterization of delivery vehicles for intravenous applications. The majority of examples apply to antisense oligodeoxynucleotides (ASODN) as they represent the most widely available class of DNA-based drugs.

Systemic Fungal Infections in Patients with Hematologic Malignancies: Indications and Limitations of the Antifungal Armamentarium

The rates of fungal infections have increased substantially in Europe as well as in North America. Most frequently Aspergillus spp. and Candida spp. are isolated. Despite the recent introduction of new azoles and lipid-based formulations of amphotericin B, there are relatively few randomized, controlled studies on the use of antifungal drugs in patients with hematological malignancies and invasive fungal infections. Conventional amphotericin B is considered the gold standard for the treatment of invasive fungal infections; however, adverse events limit conventional amphotericin B treatment. The newer azoles, fluconazole and itraconazole, are well tolerated; however, fluconazole has no activity against Aspergillus spp. An additional serious problem is the emerging resistance of nonalbicans Candida spp. to fluconazole. In this situation, lipid formulations of amphotericin B seem to be attractive, since the use of these drugs has been shown to be safe and effective. Considerably higher medical costs limit broader application of lipid formulations of amphotericin B. Because of the rapidly increasing incidence of serious fungal infections, we have reviewed current strategies and the role of newer antifungal drugs for the treatment of deep-organ infections.

Lipid-based formulations of amphotericin B

Lipid-based formulations of amphotericin B

Successful treatment of disseminated coccidioidomycosis with amphotericin B lipid complex

Coccidioidomycosis is endemic in regions of the Americas, but this infection may be encountered in travellers who return from an endemic region. A case is reported of a disseminated infection in a Hong Kong Chinese man, who was successfully treated with amphotericin B lipid complex (ABLC) after intolerance and toxicity precluded the use of other antifungal agents. Lipid-based formulations of amphotericin B merit further evaluation in the treatment of coccidioidomycosis and other systemic mycoses.

Lipid-based formulations of amphotericin B

Lipid-based formulations of amphotericin B