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International Journal of Antimicrobial... Aug 2022Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay.... (Meta-Analysis)
Meta-Analysis
AIM
Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay. The aim of this review was to evaluate and compare efficacy and safety of antifungal agents for the treatment of candidemia.
METHODS
A systematic review with network meta-analysis (NMA), surface under the cumulative ranking analysis (SUCRA) and stochastic multicriteria acceptability analyses (SMAA) was performed (PROSPERO-CRD42020149264). Searches were conducted in PubMed and Scopus (Nov-2021). Randomised controlled trials evaluating the effect of oral antifungals (any dose or regimen) on mycological cure, discontinuation rates and adverse events were included.
RESULTS
Overall, 13 trials (n=3632) were analysed. There were no significant differences between therapies for the efficacy outcomes; however, caspofungin (50-150 mg), rezafungin (200-400 mg) and micafungin (100-150 mg) had higher rates of clinical and mycological responses (SUCRA overall response >60%) and were considered the most promising therapies. Fluconazole (400 mg) rated worst for overall response (17%). Rezafungin (200-400 mg) and micafungin (100 mg) were associated with lower discontinuation rates (<40%). Conventional amphotericin B (0.6-0.7 mg/kg) was more likely to be discontinued (odds ratio [OR] 0.08; 95% credibility interval [CrI] 0.00-0.95 vs. caspofungin 150 mg) and may impair liver function (87%).
CONCLUSION
Echinocandins are recommended as first-line treatments for invasive candidiasis following a priority order of caspofungin then micafungin. Rezafungin, an echinocandin under development, represents a potential option that should be further investigated. Azoles and liposomal amphotericin B can be used as second-line treatments in cases of fungal resistance or hypersensitivity.
Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Echinocandins; Humans; Lipopeptides; Micafungin; Network Meta-Analysis
PubMed: 35691603
DOI: 10.1016/j.ijantimicag.2022.106614 -
The Journal of Pharmacy and Pharmacology Dec 2017Echinocandins are the newest addition of the last decade to the antifungal armamentarium, which, owing to their unique mechanism of action, selectively target the fungal... (Comparative Study)
Comparative Study Review
OBJECTIVES
Echinocandins are the newest addition of the last decade to the antifungal armamentarium, which, owing to their unique mechanism of action, selectively target the fungal cells without affecting mammalian cells. Since the time of their introduction, they have come to occupy an important niche in the antifungal pharmacotherapy, due to their efficacy, safety, tolerability and favourable pharmacokinetic profiles. This review deals with the varying facets of echinocandins such as their chemistry, in-vitro and in-vivo evaluations, clinical utility and indications, pharmacokinetic and pharmacodynamic profiles, and pharmacoeconomic considerations.
KEY FINDINGS
Clinical studies have demonstrated that the echinocandins - caspofungin, micafungin and anidulafungin - are equivalent, if not superior, to the mainstay antifungal therapies involving amphotericin B and fluconazole. Moreover, echinocandin regimen has been shown to be more cost-effective and economical. Hence, the echinocandins have found favour in the management of invasive systemic fungal infections.
CONCLUSIONS
The subtle differences in echinocandins with respect to their pharmacology, clinical therapy and the mechanisms of resistance are emerging at a rapid pace from the current pool of research which could potentially aid in extending their utility in the fungal infections of the eye, heart and nervous system.
Topics: Anidulafungin; Animals; Antifungal Agents; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Mycoses
PubMed: 28744860
DOI: 10.1111/jphp.12780 -
Clinical Pharmacokinetics Mar 2018Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-D-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion... (Review)
Review
Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-D-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0.15-8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol-O-methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40-80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4-10 mg/kg in premature neonates and 2-4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.
Topics: Adult; Antifungal Agents; Candidiasis; Candidiasis, Invasive; Child; Critical Illness; Dose-Response Relationship, Drug; Esophagitis; Humans; Infant; Infant, Newborn; Micafungin
PubMed: 28791666
DOI: 10.1007/s40262-017-0578-5 -
Peptides Mar 2019Lipopeptide antibiotics have linear or cyclic structures with one or more hydrocarbon tails linked to the N-terminus of a short oligopeptide that may be chemically... (Review)
Review
Lipopeptide antibiotics have linear or cyclic structures with one or more hydrocarbon tails linked to the N-terminus of a short oligopeptide that may be chemically modified and/or contain unusual amino acid residues in their structures. They possess huge potential as pharmaceutical drugs and biocontrol agents, and ˜30 representative genera of fungi are known to produce them. Some chemically synthesised derivatives have already been developed into commercial products or subjected to clinical trials, including cilofungin, caspofungin, micafungin, anidulafungin, rezafungin, emodepside, fusafungine and destruxins. This review summarizes 200 fungi-derived compounds reported since 2000, including 95 cyclic depsipeptides, 67 peptaibiotics (including 35 peptaibols, eight lipoaminopeptides, and five lipopeptaibols), and 38 non-depsipeptide and non-peptaibiotic lipopeptides. Their sources, structural sequences, antibiotic activities (e.g. antibacterial, antifungal, antiviral, antimycobacterial, antimycoplasmal, antimalarial, antileishmanial, insecticidal, antitrypanosomal and nematicidal), structure-activity relationships, mechanisms of action, and specific relevance are discussed. These compounds have attracted considerable interest within the pharmaceutical and agrochemical industries.
Topics: Anidulafungin; Anti-Infective Agents; Caspofungin; Depsipeptides; Echinocandins; Fungal Proteins; Fungi; Lipopeptides; Micafungin; Structure-Activity Relationship
PubMed: 30738838
DOI: 10.1016/j.peptides.2019.02.002 -
International Journal of Antimicrobial... Feb 2024The use of extracorporeal membrane oxygenation (ECMO) as a cardiocirculatory or respiratory support has tremendously increased in critically ill patients. In the setting...
BACKGROUND AND OBJECTIVE
The use of extracorporeal membrane oxygenation (ECMO) as a cardiocirculatory or respiratory support has tremendously increased in critically ill patients. In the setting of ECMO support, invasive fungal infections are a severe cause of morbidity and mortality. This vulnerable population is at risk of suboptimal antifungal exposure due to an increased volume of distribution (Vd), drug sequestration and decreased clearance. Here, we aimed to summarize ex-vivo and clinical studies on the potential impact of ECMO on the pharmacokinetics (PK) of antifungal agents and dosing requirements.
METHODS
A systematic search of the literature within electronic databases PubMed and EMBASE was conducted from database inception to 30 April 2023. Inclusion criteria were as follows: critically ill patients receiving ECMO regardless of age and reporting at least one PK parameter.
RESULTS
Thirty-six studies met inclusion criteria, including seven ex-vivo experiments and 29 clinical studies evaluating three classes of antifungals: polyenes, triazoles and echinocandins. Based on the available ex-vivo PK data, we found a significant sequestration of highly lipophilic and protein-bound antifungals within the ECMO circuit such as voriconazole, posaconazole and micafungin but the PK of several antifungals remains to be addressed such as amphotericin B, isavuconazole and anidulafungin. Most clinical studies have shown increased Vd of some antifungals like fluconazole and micafungin, particularly in the pediatric population. Conflicting data exist about caspofungin exposure.
CONCLUSIONS
The available literature on the antifungal PK changes in ECMO setting is scarce. Whenever possible, therapeutic drug monitoring is highly advised to personalize antifungal therapy.
Topics: Humans; Antifungal Agents; Caspofungin; Critical Illness; Extracorporeal Membrane Oxygenation; Micafungin
PubMed: 38161046
DOI: 10.1016/j.ijantimicag.2023.107078 -
Antimicrobial Agents and Chemotherapy Jun 2021Concentrations of anidulafungin and micafungin were determined in eight different tissues obtained during autopsy of four deceased individuals who had been treated with...
Concentrations of anidulafungin and micafungin were determined in eight different tissues obtained during autopsy of four deceased individuals who had been treated with anidulafungin and of seven who had received micafungin. The largest amounts were recovered from liver, with anidulafungin concentrations of 11.01 to 66.50 μg/g and micafungin levels of 0.36 to 5.53 μg/g (0.65 μg/g 30 days after the last administration). The lowest anidulafungin levels were measured in skeletal muscle, and the lowest micafungin concentrations were in kidneys.
Topics: Anidulafungin; Antifungal Agents; Echinocandins; Humans; Lipopeptides; Micafungin; Tissue Distribution
PubMed: 33875434
DOI: 10.1128/AAC.00169-21 -
Cellular Physiology and Biochemistry :... 2016The antifungal drug Micafungin is used for the treatment of diverse fungal infections including candidiasis and aspergillosis. Side effects of Micafungin treatment...
BACKGROUND/AIMS
The antifungal drug Micafungin is used for the treatment of diverse fungal infections including candidiasis and aspergillosis. Side effects of Micafungin treatment include microangiopathic hemolytic anemia and thrombocytopenia with microvascular thrombosis. The development of thrombosis may be fostered by stimulation of eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, activated protein kinase C (PKC), casein kinase 1α or p38 kinase and activated caspases. The present study explored, whether Micafungin induces eryptosis.
METHODS
Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Hemolysis was quantified by measuring haemoglobin concentration in the supernatant.
RESULTS
A 48 hours exposure of human erythrocytes to Micafungin (10 - 25 µg/ml) significantly increased hemolysis and the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Micafungin (25 µg/ml) did not significantly modify Fluo3-fluorescence, DCFDA fluorescence, or ceramide abundance. The effect of Micafungin on annexin-V-binding was not significantly modified by removal of extracellular Ca2+, by PKC inhibitor staurosporine (1 µM), p38 kinase inhibitor SB203580 (2 µM), casein kinase 1α inhibitor D4476 (10 µM) or pancaspase inhibitor zVAD (10 µM).
CONCLUSIONS
Micafungin triggers hemolysis and eryptosis with cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane.
Topics: Antifungal Agents; Benzamides; Calcium; Casein Kinase I; Cell Size; Ceramides; Echinocandins; Eryptosis; Erythrocyte Membrane; Erythrocytes; Flow Cytometry; Hemolysis; Humans; Imidazoles; Lipopeptides; Micafungin; Microscopy, Confocal; Phosphatidylserines; Protein Kinase C; Pyridines; Reactive Oxygen Species; Staurosporine; p38 Mitogen-Activated Protein Kinases
PubMed: 27394133
DOI: 10.1159/000445650 -
IDCases 2019A 37-year-old African American male with a past medical history significant for end stage renal disease on hemodialysis via a femoral arteriovenous graft, systemic lupus...
A 37-year-old African American male with a past medical history significant for end stage renal disease on hemodialysis via a femoral arteriovenous graft, systemic lupus erythematous, with a recent hospitalization for cavitary Candida pneumonia treated with micafungin, presented with a fever of 102° F for 3 days and worsening left groin pain. He also complained of chills, nausea, and malaise. On physical examination, the patient was hemodynamically stable with swelling and tenderness at the site of the graft. He was started on vancomycin, piperacillin/tazobactam and micafungin. Computed tomography scan and duplex scan of the left lower extremity showed diffuse swelling and attenuation of the graft material consistent with thrombosis of the graft. Excision of the graft and thrombectomy was performed and the graft thrombus was sent for culture. Examination of the sample showed fungal hyphae (Figure). Micafungin was switched to voriconazole; however, the patient did not show any improvement of his groin pain. On day 5 of hospitalization, culture showed , and hence amphotericin B was added resulting in subsequent clinical improvement. We are presenting an unusual site of infection which responded to combination therapy, a case which has not been reported.
PubMed: 30847281
DOI: 10.1016/j.idcr.2019.e00511 -
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