-
Journal of Ocular Pharmacology and... Jun 2017Fungal infections of the eye, especially fungal keratitis and endophthalmitis, are major causes of concern and if left untreated could lead to vision loss. Currently,... (Review)
Review
Fungal infections of the eye, especially fungal keratitis and endophthalmitis, are major causes of concern and if left untreated could lead to vision loss. Currently, natamycin (polyene antifungal) is the only commercially available topical agent used for the treatment of ocular fungal infections. The other antifungals, belonging to the polyene and azole classes, are used off-label in treating ocular infections and are administered topically, orally, intraocularly, or systemically. Even though their use through the different routes of administration has shown favorable outcomes, challenges such as poor ocular penetration, low bioavailability, ocular toxicity, and systemic side effects limit their utility. Hence, in search of alternative strategies, the echinocandin class of antifungals are currently being assessed for their use in ocular infections. Their evaluation in the ophthalmic arena has been propelled by their efficacy, safety, and tolerability reports in the treatment of systemic invasive fungal infections. This review compiles the reports on the ocular investigations of the 3 commercially available echinocandins-caspofungin, micafungin, and anidulafungin-to understand their potential as ocular antifungal agents.
Topics: Animals; Antifungal Agents; Echinocandins; Eye Diseases; Humans; Mycoses
PubMed: 28437176
DOI: 10.1089/jop.2016.0186 -
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 -
Revista Iberoamericana de Micologia 2019Fungal infections should be suspected in severe wounds that have been contaminated with organic material or soil, even when the patient is immunocompetent. The aim of...
BACKGROUND
Fungal infections should be suspected in severe wounds that have been contaminated with organic material or soil, even when the patient is immunocompetent. The aim of this article is to contribute to a better understanding and knowledge of the antifungal sensitivity and epidemiology of some rare pathogens that may trigger severe infections.
CASE REPORT
Four different moulds were isolated from the wounds of an immunocompetent woman who was involved in a road accident: Lichtheimia corymbifera, Scedosporium boydii, Fusarium solani and Purpureocillium lilacinum. Some of them were isolated from different sites. A profile of in vitro resistance was performed with an Epsilometer (Etest™) using five antifungal agents: voriconazole, posaconazole, itraconazole, anidulafungin an amphotericin B. The results obtained were consistent with those from other cases reported in the literature.
CONCLUSIONS
Early aggressive surgery, antifungal therapy and, above all, frequent debridement of necrotic tissue, are the tools against filamentous fungi infections. Antifungal sensitivity of any mould involved in an infection has to be determined, in order to a better understanding of these rare pathogens whose incidence is increasing.
Topics: Antifungal Agents; Female; Fungi; Humans; Microbial Sensitivity Tests; Middle Aged; Mycoses; Soft Tissue Injuries
PubMed: 30686746
DOI: 10.1016/j.riam.2018.07.006 -
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 -
Antibiotics (Basel, Switzerland) Nov 2020Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs...
Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A () gene promoter region and a leucine-to-histidine substitution at codon 98 of . Altogether, the emerging resistance of pathogens to currently available antifungal drugs and insufficiency in the discovery of new therapeutics engender the urgent need for the development of new antifungals and/or alternative therapies for effective control of fungal pathogens. We discuss the current needs for the discovery of new clinical antifungal drugs and the recent drug repurposing endeavors as alternative methods for fungal pathogen control.
PubMed: 33203147
DOI: 10.3390/antibiotics9110812 -
The Journal of Antimicrobial... Jan 2018First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe... (Review)
Review
First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe treatment-emergent adverse events or frequent drug interactions. Among antifungals, echinocandins present a unique value proposition given their lower rates of toxic events as compared with azoles and polyenes. However, with the emergence of echinocandin-resistant Candida species and the fact that a pharmacometric approach to the development of anti-infective agents was not a mainstream practice at the time these agents were developed, we question whether echinocandins are being dosed optimally. This review presents pharmacokinetic/pharmacodynamic (PK/PD) evaluations for approved echinocandins (anidulafungin, caspofungin and micafungin) and rezafungin (previously CD101), an investigational agent. PK/PD-optimized regimens were evaluated to extend the utility of approved echinocandins when treating patients with resistant isolates. Although the benefits of these regimens were apparent, it was also clear that anidulafungin and micafungin, regardless of dosing adjustments, are unlikely to provide therapeutic exposures sufficient to treat highly resistant isolates. Day 1 probabilities of PK/PD target attainment of 5.2% and 85.1%, respectively, were achieved at the C. glabrata MIC90 (0.12 mg/L) and MIC97 (0.06 mg/L) values, respectively, for these agents. However, evaluations of rezafungin demonstrated high probabilities of target attainment over 4 weeks of therapy (100%) after administration of a single-dose regimen at the MIC90 of 0.06 mg/L. This signals that although existing therapies are not optimal to treat resistant organisms, more potent new echinocandins (relative to achievable drug exposures) may be on the horizon.
Topics: Antifungal Agents; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Humans
PubMed: 29304211
DOI: 10.1093/jac/dkx448 -
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 -
Revista Iberoamericana de Micologia 2016The echinocandins share pharmacodynamic properties, although there are some interesting differences in their pharmacokinetic behaviour in the clinical practice. They are... (Review)
Review
The echinocandins share pharmacodynamic properties, although there are some interesting differences in their pharmacokinetic behaviour in the clinical practice. They are not absorbed by the oral route. They have a somewhat special distribution in the organism, as some of them can reach high intracellular concentrations while, with some others, the concentration is reduced. They are highly bound to plasma proteins, thus it is recommended to administer a loading dose for anidulafungin and caspofungin, although this procedure is not yet clear with micafungin. Echinocandins are excreted via a non-microsomal metabolism, so the urinary concentration is very low. Some carrier proteins that take part in the biliary clearance process are probably involved in the interactions described with caspofungin and micafungin. These two drugs must be used with caution in patients with severely impaired hepatic function, while all of them can be used without special precautions when there is renal impairment or the patient requires renal replacement therapy.
Topics: Antifungal Agents; Echinocandins; Humans
PubMed: 27395024
DOI: 10.1016/j.riam.2016.02.004 -
The Journal of Antimicrobial... May 2022Increased fluconazole and echinocandin resistance in Candida glabrata requires prompt detection in routine settings. A phenotypic test based on the EUCAST E.DEF 7.3.2...
BACKGROUND
Increased fluconazole and echinocandin resistance in Candida glabrata requires prompt detection in routine settings. A phenotypic test based on the EUCAST E.DEF 7.3.2 protocol was developed for the detection of fluconazole- and anidulafungin-resistant isolates utilizing the colorimetric dye XTT.
METHODS
Thirty-one clinical C. glabrata isolates, 11 anidulafungin resistant and 14 fluconazole resistant, were tested. After optimization studies, 0.5-2.5 × 105 cfu/mL of each isolate in RPMI 1640 + 2% d-glucose medium containing 100 mg/L XTT + 0.78 μΜ menadione and 0.06 mg/L anidulafungin (S breakpoint) or 16 mg/L fluconazole (I breakpoint) in 96-well flat-bottom microtitration plates were incubated at 37°C for 18 h; we also included drug-free wells. XTT absorbance was measured at 450 nm every 15 min. Differences between the drug-free and the drug-treated wells were assessed using Student's t-test at different timepoints. ROC curves were used in order to identify the best timepoint and cut-off.
RESULTS
The XTT absorbance differences between fluconazole-containing and drug-free wells were significantly lower for the resistant isolates compared with susceptible increased exposure isolates (0.08 ± 0.05 versus 0.25 ± 0.06, respectively, P = 0.005) at 7.5 h, with a difference of <0.157 corresponding to 100% sensitivity and 94% specificity for detection of resistance. The XTT absorbance differences between anidulafungin-containing and drug-free wells were significantly lower for the resistant isolates compared with susceptible isolates (0.08 ± 0.07 versus 0.200 ± 0.03, respectively, P < 0.001) at 5 h, with a difference of <0.145 corresponding to 91% sensitivity and 100% specificity, irrespective of underlying mutations.
CONCLUSIONS
A simple, cheap and fast phenotypic test was developed for detection of fluconazole- and anidulafungin-resistant C. glabrata isolates.
Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Microbial Sensitivity Tests
PubMed: 35323941
DOI: 10.1093/jac/dkac075