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Expert Review of Anti-infective Therapy Jun 2015Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections:... (Review)
Review
Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.
Topics: Adolescent; Adult; Anidulafungin; Antifungal Agents; Candida; Caspofungin; Child; Critical Illness; Drug Interactions; Echinocandins; Hematologic Diseases; Humans; Infant, Newborn; Kidney; Lipopeptides; Liver; Micafungin; Microbial Sensitivity Tests; Obesity
PubMed: 25947367
DOI: 10.1586/14787210.2015.1028366 -
Applied Microbiology and Biotechnology Jan 2021Echinocandins are a clinically important class of non-ribosomal antifungal lipopeptides produced by filamentous fungi. Due to their complex structure, which is... (Review)
Review
Echinocandins are a clinically important class of non-ribosomal antifungal lipopeptides produced by filamentous fungi. Due to their complex structure, which is characterized by numerous hydroxylated non-proteinogenic amino acids, echinocandin antifungal agents are manufactured semisynthetically. The development of optimized echinocandin structures is therefore closely connected to their biosynthesis. Enormous efforts in industrial research and development including fermentation, classical mutagenesis, isotope labeling, and chemical synthesis eventually led to the development of the active ingredients caspofungin, micafungin, and anidulafungin, which are now used as first-line treatments against invasive mycosis. In the last years, echinocandin biosynthetic gene clusters have been identified, which allowed for the elucidation but also engineering of echinocandin biosynthesis on the molecular level. After a short description of the history of echinocandin research, this review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus of the diverse structural elements, their biosynthetic background, and structure-activity relationships. KEY POINTS: • Complex and highly oxidized lipopeptides produced by fungi. • Crucial in the design of drugs: side chain, solubility, and hydrolytic stability. • Genetic methods for engineering biosynthesis have recently become available.
Topics: Antifungal Agents; Echinocandins; Fungi; Lipopeptides; Microbial Sensitivity Tests; Multigene Family
PubMed: 33270153
DOI: 10.1007/s00253-020-11022-y -
Archives of Toxicology Apr 2017The echinocandins-caspofungin, anidulafungin and micafungin-are semi-synthetic cyclic hexapeptide antimicrobial agents with modified N-linked acyl lipid side chains... (Review)
Review
The echinocandins-caspofungin, anidulafungin and micafungin-are semi-synthetic cyclic hexapeptide antimicrobial agents with modified N-linked acyl lipid side chains which anchor the compounds to the phospholipid bilayer of the fungal cell membrane, thereby inhibiting synthesis of fungal cell wall glucan. Over the last 10 years, echinocandins have become the first-line antifungal treatment of candidaemia and other forms of invasive candidiasis (IC). Echinocandins are generally well tolerated, but their use is limited by their requirement for daily intravenous dosing, lack of oral formulation and limited spectrum. In critically ill patients, it is also recognised that achievement of their pharmacokinetic/pharmacodynamic targets shows large inter-individual variability. As a drug class, they are safe to use and are associated with few adverse reactions and few drug-drug interactions of significance. Recent discovery of their ability to prevent and treat Candida biofilm formation particularly in the presence of invasive medical devices and also their ability to penetrate into mucosal surfaces such as vulvovaginal candidiasis has opened up new opportunities for research into their drug delivery. New dosing intervals are being explored to allow less frequent intravenous dosing in the ambulatory setting, and a new long-acting echinocandin, CD101, is being developed for weekly and topical administration.
Topics: Administration, Intravenous; Anidulafungin; Animals; Antifungal Agents; Biofilms; Candidiasis; Caspofungin; Drug Administration Schedule; Drug Interactions; Echinocandins; Humans; Lipopeptides; Micafungin
PubMed: 28180946
DOI: 10.1007/s00204-016-1916-3 -
Antimicrobial Agents and Chemotherapy Jun 2020Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin...
Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01 to 0.66 μg/ml) and micafungin levels (<0.01 to 0.16 μg/ml) were lower than those in plasma concentrations (0.77 to 5.07 and 1.21 to 8.70 μg/ml, respectively) drawn simultaneously. In cerebral cortex, anidulafungin and micafungin levels were 0.21 to 2.34 and 0.18 to 2.88 μg/g, respectively. Thus, MIC values of several pathogenic strains exceed concentrations in CSF and in brain.
Topics: Adult; Anidulafungin; Antifungal Agents; Cerebral Cortex; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests
PubMed: 32340985
DOI: 10.1128/AAC.00275-20 -
BMC Medicine Oct 2022The severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV), was listed among the top 10 priority infectious...
BACKGROUND
The severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV), was listed among the top 10 priority infectious disease by World Health Organization due to the high fatality rate of 5-30% and the lack of effective antiviral drugs and vaccines and therefore raised the urgent need to develop effective anti-SFTSV drugs to improve disease treatment.
METHODS
The antiviral drugs to inhibit SFTSV infection were identified by screening the library containing 1340 FDA-approved drugs using the SFTSV infection assays in vitro. The inhibitory effect on virus entry and the process of clathrin-mediated endocytosis under different drug doses was evaluated based on infection assays by qRT-PCR to determine intracellular viral copies, by Western blot to characterize viral protein expression in cells, and by immunofluorescence assays (IFAs) to determine virus infection efficiencies. The therapeutic effect was investigated in type I interferon receptor defective A129 mice in vivo with SFTSV infection, from which lesions and infection in tissues caused by SFTSV infection were assessed by H&E staining and immunohistochemical analysis.
RESULTS
Six drugs were identified as exerting inhibitory effects against SFTSV infection, of which anidulafungin, an antifungal drug of the echinocandin family, has a strong inhibitory effect on SFTSV entry. It suppresses SFTSV internalization by impairing the late endosome maturation and decreasing virus fusion with the membrane. SFTSV-infected A129 mice had relieving symptoms, reduced tissue lesions, and improved disease outcomes following anidulafungin treatment. Moreover, anidulafungin exerts an antiviral effect in inhibiting the entry of other viruses including SARS-CoV-2, SFTSV-related Guertu virus and Heartland virus, Crimean-Congo hemorrhagic fever virus, Zika virus, and Herpes simplex virus 1.
CONCLUSIONS
The results demonstrated that the antifungal drug, anidulafungin, could effectively inhibit virus infection by interfering with virus entry, suggesting it may be utilized for the clinical treatment of infectious viral diseases, in addition to its FDA-approved use as an antifungal. The findings also suggested to further evaluate the anti-viral effects of echinocandins and their clinical importance for patients with infection of viruses, which may promote therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases.
Topics: Animals; Mice; Anidulafungin; Antifungal Agents; Antiviral Agents; Bunyaviridae Infections; Clathrin; Receptor, Interferon alpha-beta; SARS-CoV-2; Viral Proteins; Virus Diseases
PubMed: 36266654
DOI: 10.1186/s12916-022-02558-z -
Indian Journal of Medical Microbiology 2018The importance of antifungal agents and their clinical implications has received little attention in comparison to antibiotics, particularly in the health-care setting.... (Review)
Review
The importance of antifungal agents and their clinical implications has received little attention in comparison to antibiotics, particularly in the health-care setting. However, apart from bacterial infections rising in hospitals, the incidences of fungal infections are growing with the development of resistance to conventional antifungal agents. Newer antifungal agents such as echinocandins (ECs) have been extensively studied over the past decade and are recognised as a superior treatment compared with prior antifungals as a first line of therapy in tertiary institutions. Caspofungin (CAS), micafungin (MICA) and anidulafungin (ANID) are the three most widely used EC antifungal agents. The treatment of biofilm-associated fungal infections affecting patients in tertiary health-care facilities has been identified as a challenge, particularly in Indian Intensive Care Unit (ICU) settings. With the rising number of critically ill patients requiring invasive devices such as central venous catheters for treatment, especially in ICUs, these devices serve as a potential source of nosocomial infections. Candida spp. colonisation is a major precursor of these infections and further complicates and prolongs treatment procedures, adding to increasing costs both for hospitals and the patient. Analysing studies involving the use of these agents can help in making critical decisions for antifungal therapy in the event of a fungal infection in the ICU. In addition, the development of resistance to antifungal agents is a crucial factor for assessing the appropriate antifungals that can be used for treatment. This review provides an overview of ANID in biofilms, along with CAS and MICA, in terms of clinical efficacy, resistance development and potency, primarily against Candida spp.
Topics: Anidulafungin; Antifungal Agents; Biofilms; Candida; Candidiasis; Caspofungin; Critical Illness; Cross Infection; Drug Resistance, Fungal; Echinocandins; Humans; Intensive Care Units; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Tertiary Healthcare
PubMed: 29735833
DOI: 10.4103/ijmm.IJMM_17_400 -
Clinical Infectious Diseases : An... Dec 2015The etiology of cardiomyopathies are classified into 4 main groupings (dilated, hypertrophic, restrictive, and idiopathic) and can be mechanistically caused by... (Review)
Review
The etiology of cardiomyopathies are classified into 4 main groupings (dilated, hypertrophic, restrictive, and idiopathic) and can be mechanistically caused by myocarditis, conduction abnormalities, focal direct injury, or nutritional deficiency. Based on our review of this topic, evidence suggests that echinocandin-related cardiac dysfunction is a mitochondrial drug-induced disease caused by focal direct myocyte injury. With caspofungin or anidulafungin administration into the heart via central line, exposure is likely extreme enough to induce the acute toxicity. Chronic or low-dose exposure may lead to hypertrophic cardiomyopathy; however, only acute exposures have been explored to date.
Topics: Anidulafungin; Animals; Antifungal Agents; Cardiac Output; Cardiomyopathies; Cardiomyopathy, Dilated; Cardiotoxicity; Caspofungin; Echinocandins; Echocardiography; Humans; Lipopeptides; Mitochondria, Heart
PubMed: 26567285
DOI: 10.1093/cid/civ739 -
American Journal of Health-system... Apr 2023Echinocandins are favored drugs for the treatment of fungal infections. There is growing evidence that obese patients treated with echinocandins have lower exposures due... (Review)
Review
PURPOSE
Echinocandins are favored drugs for the treatment of fungal infections. There is growing evidence that obese patients treated with echinocandins have lower exposures due to pharmacokinetic (PK) alterations. We conducted a scoping review to characterize, evaluate, and summarize the available evidence on echinocandins exposures in obese patients.
SUMMARY
A comprehensive search of PubMed, Embase, and Cochrane Library for studies on echinocandins published from database inception to October 28, 2022, was conducted using PRISMA-ScR methodology. A total of 25 studies comprising more than 3,174 subjects (8 micafungin studies, 7 caspofungin studies, 9 anidulafungin studies, and 1 rezafungin study) were included in this review. Seventeen studies reported lower echinocandins exposures in overweight and obese individuals compared with normal-weight individuals; the authors of these studies recommended dose adjustments. Conversely, 8 studies did not find significant differences in echinocandin exposure among subjects in varying body weight categories. Clinicians may consider dose adjustments of echinocandins in obese patients; however, there is limited evidence on the ideal dose adjustment strategy to overcome the low echinocandins exposures in obese patients.
CONCLUSION
This scoping review shed light on a growing body of evidence indicating that obese patients have lower echinocandin exposures relative to targeted PK indices, which may lead to negative therapeutic implications. Currently, a lack of high-quality evidence impedes reaching consensus on recommendations for echinocandin dosing adjustment in obese patients. Future research evaluating the optimal echinocandin dosing strategy for obese patients is needed.
Topics: Humans; Antifungal Agents; Body Weight; Echinocandins; Lipopeptides; Microbial Sensitivity Tests; Obesity; Overweight
PubMed: 36680786
DOI: 10.1093/ajhp/zxad021 -
Antimicrobial Agents and Chemotherapy Jun 2023Candida auris is an emerging, multidrug-resistant fungal pathogen that causes refractory colonization and life-threatening, invasive nosocomial infections. The high...
Candida auris is an emerging, multidrug-resistant fungal pathogen that causes refractory colonization and life-threatening, invasive nosocomial infections. The high proportion of C. auris isolates that display antifungal resistance severely limits treatment options. Combination therapies provide a possible strategy by which to enhance antifungal efficacy and prevent the emergence of further resistance. Therefore, we examined drug combinations using antifungals that are already in clinical use or are undergoing clinical trials. Using checkerboard assays, we screened combinations of 5-flucytosine and manogepix (the active form of the novel antifungal drug fosmanogepix) with anidulafungin, amphotericin B, or voriconazole against drug resistant and susceptible C. auris isolates from clades I and III. Fractional inhibitory concentration indices (FICI values) of 0.28 to 0.75 and 0.36 to 1.02 were observed for combinations of anidulafungin with manogepix or 5-flucytosine, respectively, indicating synergistic activity. The high potency of these anidulafungin combinations was confirmed using live-cell microfluidics-assisted imaging of the fungal growth. In summary, combinations of anidulafungin with manogepix or 5-flucytosine show great potential against both resistant and susceptible C. auris isolates.
Topics: Antifungal Agents; Anidulafungin; Flucytosine; Candida auris; Candida; Microbial Sensitivity Tests
PubMed: 37162367
DOI: 10.1128/aac.01645-22 -
Journal de Mycologie Medicale Nov 2023Invasive fungal infection (IFI) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed...
INTRODUCTION
Invasive fungal infection (IFI) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole is not widely available. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction.
METHODS
This is a retrospective cohort encompassing newly diagnosed AML adult patients. All subjects received intensive chemotherapy and were divided into three groups: patients who did not receive any AP and patients who received fluconazole (150-400 mg/day) or anidulafungin (100 mg/day).
RESULTS
During AML induction, 82 patients did not receive AP, 108 and 14 patients received anidulafungin and fluconazole, respectively. IFI incidence was 27%, classified as possible, probable, and proven in 65, 2 and 33%, respectively. Multivariable analysis showed that lower neutrophil counts are associated with IFI (OR = 2.8), whereas age, genetic classification, and lymphocyte counts were not. To examine the impact of anidulafungin in comparison with 'no AP', a propensity score matching analysis was performed. Use of anidulafungin was not related to less IFI during induction, while neutrophil counts remained significant. Patients under prophylactic anidulafungin received less amphotericin B (p < 0.001) but not voriconazole (p = 0.49).
DISCUSSION
To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the incidence of mold infections did not decrease with AP, suggesting that in a setting with a high incidence of IFI, broad spectrum AP might be more suitable.
Topics: Adult; Humans; Antifungal Agents; Fluconazole; Anidulafungin; Retrospective Studies; Propensity Score; Remission Induction; Leukemia, Myeloid, Acute
PubMed: 37683564
DOI: 10.1016/j.mycmed.2023.101434