-
Clinical Infectious Diseases : An... May 2019Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide... (Review)
Review
Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its clinical efficacy. Since then, numerous clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preclinical and clinical setting. Nevertheless, insights into the pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound's safety. In this article, we review the clinical pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further clinical research.
Topics: Amphotericin B; Animals; Antifungal Agents; Fungi; Humans; Invasive Fungal Infections; Treatment Outcome
PubMed: 31222253
DOI: 10.1093/cid/ciz076 -
Clinical Infectious Diseases : An... Aug 2016It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with...
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Azoles; Echinocandins; Humans; Infectious Disease Medicine; Societies, Medical; United States
PubMed: 27365388
DOI: 10.1093/cid/ciw326 -
Drugs Mar 2016Liposomal amphotericin B (AmBisome(®); LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important... (Review)
Review
Liposomal amphotericin B (AmBisome(®); LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.
Topics: Amphotericin B; Animals; Chemistry, Pharmaceutical; Clinical Trials as Topic; Deoxycholic Acid; Drug Combinations; Half-Life; Humans; Tissue Distribution
PubMed: 26818726
DOI: 10.1007/s40265-016-0538-7 -
Infectious Disease Clinics of North... Mar 2019Diagnostic advances in visceral leishmaniasis include the development of the rK39 and rK28 rapid diagnostic test. The direct agglutination test is also increasingly... (Review)
Review
Diagnostic advances in visceral leishmaniasis include the development of the rK39 and rK28 rapid diagnostic test. The direct agglutination test is also increasingly used, as well as conventional and real-time polymerase chain reaction, which also performs well on peripheral blood. The choice of treatment for visceral leishmaniasis depends on the geographic region where the infection is acquired. Liposomal amphotericin B is generally found to be safe and effective in most endemic regions of the world; antimonials still remain to be the most effective in eastern Africa despite its high toxicity. Combination therapy is increasingly explored. Immunosuppressed patients require adapted diagnostic and therapeutic strategies.
Topics: Amphotericin B; Antiprotozoal Agents; Clinical Trials as Topic; Humans; Leishmaniasis, Visceral; Molecular Diagnostic Techniques
PubMed: 30712769
DOI: 10.1016/j.idc.2018.10.005 -
Clinical Microbiology and Infection :... Nov 2020EUCAST has revised the definition of the susceptibility category I from 'Intermediate' to 'Susceptible, Increased exposure'. This implies that I can be used where the... (Review)
Review
BACKGROUND
EUCAST has revised the definition of the susceptibility category I from 'Intermediate' to 'Susceptible, Increased exposure'. This implies that I can be used where the drug concentration at the site of infection is high, either because of dose escalation or through other means to ensure efficacy. Consequently, I is no longer used as a buffer zone to prevent technical factors from causing misclassifications and discrepancies in interpretations. Instead, an Area of Technical Uncertainty (ATU) has been introduced for MICs that cannot be categorized without additional information as a warning to the laboratory that decision on how to act has to be made. To implement these changes, the EUCAST-AFST (Subcommittee on Antifungal Susceptibility Testing) reviewed all, and revised some, clinical antifungal breakpoints.
OBJECTIVES
The aim was to present an overview of the current antifungal breakpoints and supporting evidence behind the changes.
SOURCES
This document is based on the ten recently updated EUCAST rationale documents, clinical breakpoint and breakpoint ECOFF documents.
CONTENT
The following breakpoints (in mg/L) have been revised or established for Candida species: micafungin against C. albicans (ATU = 0.03); amphotericin B (S ≤/> R = 1/1), fluconazole (S ≤/> R = 2/4), itraconazole (S ≤/> R = 0.06/0.06), posaconazole (S ≤/> R = 0.06/0.06) and voriconazole (S ≤/> R = 0.06/0.25) against C. dubliniensis; fluconazole against C. glabrata (S ≤/> R = 0.001/16); and anidulafungin (S ≤/> R = 4/4) and micafungin (S ≤/> R = 2/2) against C. parapsilosis. For Aspergillus, new or revised breakpoints include itraconazole (ATU = 2) and isavuconazole against A. flavus (S ≤/> R = 1/2, ATU = 2); amphotericin B (S ≤/> R = 1/1), isavuconazole (S ≤ /> R = 1/2, ATU = 2), itraconazole (S ≤/> R = 1/1, ATU = 2), posaconazole (ATU = 0.25) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. fumigatus; itraconazole (S ≤/> R = 1/1, ATU = 2) and voriconazole (S ≤/> R = 1/1, ATU = 2) against A. nidulans; amphotericin B against A. niger (S ≤/> R = 1/1); and itraconazole (S ≤/> R = 1/1, ATU = 2) and posaconazole (ATU = 0.25) against A. terreus.
IMPLICATIONS
EUCAST-AFST has released ten new documents summarizing existing and new breakpoints and MIC ranges for control strains. A failure to adopt the breakpoint changes may lead to misclassifications and suboptimal or inappropriate therapy of patients with fungal infections.
Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Fluconazole; Itraconazole; Microbial Sensitivity Tests; Practice Guidelines as Topic; Triazoles; Voriconazole
PubMed: 32562861
DOI: 10.1016/j.cmi.2020.06.007 -
Nature Nov 2023Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model. Recently, the clinically vital...
Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids.
Topics: Animals; Humans; Mice; Amphotericin B; Antifungal Agents; Cells, Cultured; Cholesterol; Drug Resistance, Fungal; Ergosterol; Kidney; Kinetics; Microbial Sensitivity Tests; Mycoses; Polyenes; Serial Passage; Sterols; Time Factors
PubMed: 37938782
DOI: 10.1038/s41586-023-06710-4 -
The Journal of Antimicrobial... Nov 2022The discovery of amphotericin B, a polyene antifungal compound, in the 1950s, and the formulation of this compound in a liposomal drug delivery system, has resulted in...
The discovery of amphotericin B, a polyene antifungal compound, in the 1950s, and the formulation of this compound in a liposomal drug delivery system, has resulted in decades of use in systemic fungal infections. The use of liposomal amphotericin B formulation is referenced in many international guidelines for the treatment of fungal infections such as Aspergillus and cryptococcal disease and Candida infections, as well as other less common infections such as visceral leishmaniasis. With the development of liposomal amphotericin B, an improved therapeutic index could be achieved that allowed the attainment of higher drug concentrations in both the plasma and tissue while simultaneously lowering the toxicity compared with amphotericin B deoxycholate. In over 30 years of experience with this drug, a vast amount of information has been collected on preclinical and clinical efficacy against a wide variety of pathogens, as well as evidence on its toxicity. This article explores the history and nature of the liposomal formulation, the key clinical studies that developed the pharmacokinetic, safety and efficacy profile of the liposomal formulation, and the available microbiological data.
Topics: Humans; Amphotericin B; Antifungal Agents; Mycoses; Candidiasis; Liposomes
PubMed: 36426673
DOI: 10.1093/jac/dkac351 -
Clinical Microbiology Reviews Dec 2021Infections due to species are an acute threat to human health; members of the section are the most frequently occurring agents, but depending on the local... (Review)
Review
Infections due to species are an acute threat to human health; members of the section are the most frequently occurring agents, but depending on the local epidemiology, representatives of section or section are the second or third most important. species complex is of great interest, as it is usually amphotericin B resistant and displays notable differences in immune interactions in comparison to . The latest epidemiological surveys show an increased incidence of as well as an expanding clinical spectrum (chronic infections) and new groups of at-risk patients being affected. Hallmarks of these non- invasive mold infections are high potential for tissue invasion, dissemination, and possible morbidity due to mycotoxin production. We seek to review the microbiology, epidemiology, and pathogenesis of species complex, address clinical characteristics, and highlight the underlying mechanisms of amphotericin B resistance. Selected topics will contrast key elements of with . We provide a comprehensive resource for clinicians dealing with fungal infections and researchers working on pathogenesis, aiming to bridge the emerging translational knowledge and future therapeutic challenges on this opportunistic pathogen.
Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Humans; Microbial Sensitivity Tests
PubMed: 34190571
DOI: 10.1128/CMR.00311-20 -
The Journal of Antimicrobial... Nov 2022Most invasive fungal infections are opportunistic in nature but the epidemiology is constantly changing, with new risk groups being identified. Neutropenia is a...
Most invasive fungal infections are opportunistic in nature but the epidemiology is constantly changing, with new risk groups being identified. Neutropenia is a classical risk factor for fungal infections, while critically ill patients in the ICU are now increasingly at risk of yeast and mould infections. Factors to be considered when choosing antifungal treatment include the emergence of rarer fungal pathogens, the risk of resistance to azoles and echinocandins and the possibility of drug-drug interactions. Liposomal amphotericin B has retained its place in the therapeutic armamentarium based on its clinical profile: a broad spectrum of antifungal activity with a low risk of resistance, predictable pharmacokinetics with a rapid accumulation at the infection site (including biofilms), a low potential for drug-drug interactions and a low risk of acute and chronic treatment-limiting toxicities versus other formulations of amphotericin B. It is a suitable choice for the first-line empirical or pre-emptive treatment of suspected fungal infections in neutropenic haematology patients and is an excellent alternative for patients with documented fungal disease who can no longer tolerate or continue their first-line azole or echinocandin therapy, both in the haematology setting and in the ICU. Moreover, it is the first-line drug of choice for the treatment of invasive mucormycosis. Finally, liposomal amphotericin B is one of the few antifungal agents approved for use in children of all ages over 1 month and is included in paediatric-specific guidelines for the management of fungal disease.
Topics: Humans; Amphotericin B; Antifungal Agents; Azoles; Echinocandins; Neutropenia; Invasive Fungal Infections
PubMed: 36426672
DOI: 10.1093/jac/dkac352 -
Bioconjugate Chemistry Oct 2015A strategy is introduced for enhancing the cellular selectivity of Amphotericin B (AmB) and other classes of membrane-disrupting agents. This strategy involves attaching...
A strategy is introduced for enhancing the cellular selectivity of Amphotericin B (AmB) and other classes of membrane-disrupting agents. This strategy involves attaching the agent to a molecular umbrella to minimize the disruptive power of aggregated forms. Based on this approach, AmB has been coupled to a molecular umbrella derived from one spermidine and two cholic acid molecules and found to have antifungal activities approaching that of the native drug. However, in sharp contrast to AmB, the hemolytic activity and the cytotoxcity of this conjugate toward HEK293 T cells have been dramatically reduced.
Topics: Amphotericin B; Animals; Antifungal Agents; Cholic Acid; Drug Evaluation, Preclinical; Erythrocytes; HEK293 Cells; Hemolytic Agents; Humans; Spermidine; Structure-Activity Relationship
PubMed: 26340430
DOI: 10.1021/acs.bioconjchem.5b00463