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Drugs Oct 2021The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased... (Review)
Review
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.
Topics: Animals; Antifungal Agents; Drug Development; Drug Interactions; Drug Resistance, Fungal; Fungi; Humans; Invasive Fungal Infections
PubMed: 34626339
DOI: 10.1007/s40265-021-01611-0 -
Drugs in R&D Mar 2022On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as... (Review)
Review
On 2 June, 2021, the US Food and Drug Administration approved ibrexafungerp (formerly MK-3118 and SCY-078) for the treatment of vulvovaginal candidiasis, also known as vaginal yeast infection. Ibrexafungerp is the first drug approved in a novel antifungal class in more than two decades, and the Food and Drug Administration's decision was based on positive results from two pivotal phase III studies in which oral ibrexafungerp proved both safe and effective in patients with vulvovaginal candidiasis. The decision was also based on substantial preclinical and clinical work in both the pharmacokinetics and pharmacodynamics of ibrexafungerp. This paper reviews that research and looks ahead to explore how this novel antifungal agent may be used in the future to address the expanding problem of drug-resistant mycotic infections.
Topics: Antifungal Agents; Candidiasis, Vulvovaginal; Female; Glycosides; Humans; Triterpenes; United States
PubMed: 34961907
DOI: 10.1007/s40268-021-00376-x -
Virulence Aug 2017Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve the best clinical outcomes... (Review)
Review
Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve the best clinical outcomes and minimize selective pressure and adverse events. Antifungal utilization has steadily risen over time in concert with the increase in number of immunocompromised adults and children at risk for invasive fungal infections (IFI). Challenges in diagnosing IFI often lead to delays in treatment and poorer outcomes. There are also emerging data linking prior antifungal exposure and suboptimal dosing to the emergence of antifungal resistance, particularly for Candida. Antimicrobial stewardship programs can take a multi-pronged bundle approach to ensure suitable prescribing of antifungals via post-prescription review and feedback and/or prior authorization. Institutional guidelines can also be developed to guide diagnostic testing in at-risk populations; appropriate choice, dose, and duration of antifungal agent; therapeutic drug monitoring; and opportunities for de-escalation and intravenous-to-oral conversion.
Topics: Adult; Antifungal Agents; Antimicrobial Stewardship; Candida; Candidiasis; Child; Drug Monitoring; Drug Resistance, Fungal; Humans; Immunocompromised Host; Invasive Fungal Infections; Microbial Sensitivity Tests; Pediatrics
PubMed: 27588344
DOI: 10.1080/21505594.2016.1226721 -
Virulence Feb 2017With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be... (Review)
Review
With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.
Topics: Animals; Antifungal Agents; Drug Discovery; Enzyme Inhibitors; Fluconazole; Fungi; Glucosyltransferases; Humans; Metabolic Networks and Pathways; Mycoses; Trehalose
PubMed: 27248439
DOI: 10.1080/21505594.2016.1195529 -
International Journal of Molecular... Dec 2022This study investigated whether sphingosine is effective as prophylaxis against spp. and spp. In vitro experiments showed that sphingosine is very efficacious against...
This study investigated whether sphingosine is effective as prophylaxis against spp. and spp. In vitro experiments showed that sphingosine is very efficacious against and (formerly named ). A mouse model of invasive aspergillosis showed that sphingosine exerts a prophylactic effect and that sphingosine-treated animals exhibit a strong survival advantage after infection. Furthermore, mechanistic studies showed that treatment with sphingosine leads to the early depolarization of the mitochondrial membrane potential (Δψm) and the generation of mitochondrial reactive oxygen species and to a release of cytochrome C within minutes, thereby presumably initiating apoptosis. Because of its very good tolerability and ease of application, inhaled sphingosine should be further developed as a possible prophylactic agent against pulmonary aspergillosis among severely immunocompromised patients.
Topics: Animals; Mice; Antifungal Agents; Candida; Sphingosine; Microbial Sensitivity Tests; Aspergillus
PubMed: 36555152
DOI: 10.3390/ijms232415510 -
International Journal of Molecular... Jan 2018Undecylenic acid (UA), known as antifungal agent, still cannot be used to efficiently modify commercial dental materials in such a way that this affects . Actually,...
Undecylenic acid (UA), known as antifungal agent, still cannot be used to efficiently modify commercial dental materials in such a way that this affects . Actually, issues with infections and fungal resistance compromise the use of Poly(methyl-methacrylate) (PMMA) as dental material. The challenge remains to turn PMMA into an antifugal material, which can ideally affect both sessile (attached) and planktonic (free-floating) cells. We aimed to tackle this challenge by designing PMMA-UA composites with different UA concentrations (3-12%). We studied their physico-chemical properties, the antifungal effect on and the cytotoxicity toward human cells. We found that UA changes the PMMA surface into a more hydrophilic one. Mainly, as-preparation composites with ≥6% UA reduced sessile for >90%. After six days, the composites were still efficiently reducing the sessile cells (for ~70% for composites with ≥6% UA). Similar results were recorded for planktonic . Moreover, the inhibition zone increased along with the UA concentration. The antifungal effect of UA was also examined at the surface of an UA-loaded agar and the minimal inhibitory concentration (MIC90) was below the lowest-studied 0.0125% UA. Furthermore, the embedded filamentation test after 24 h and 48 h showed complete inhibition of the growth at 0.4% UA.
Topics: Antifungal Agents; Candida albicans; Cell Line, Tumor; Cell Survival; Humans; Polymethyl Methacrylate; Undecylenic Acids
PubMed: 29316713
DOI: 10.3390/ijms19010184 -
Antimicrobial Agents and Chemotherapy Aug 2020The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due...
The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, ()-'-(5-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide and D13, we performed a structure-activity relationship study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified to be the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive activity of 2,4-dibromo-'-(5-bromo-2-hydroxybenzylidene)benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis, and aspergillosis. Specifically, animals treated with SB-AF-1002 not only survived the infection but also showed a clearing of fungal cells from key organs. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to those of the parent compound, D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents which warrant further development for the treatment of invasive fungal infections.
Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Invasive Fungal Infections; Mice; Mycoses
PubMed: 32601165
DOI: 10.1128/AAC.00946-20 -
Frontiers in Cellular and Infection... 2022Invasive fungal diseases (IFD) are a major global public health concern. The incidence of IFD has increased the demand for antifungal agents. Isavuconazole (ISA) is a... (Review)
Review
PURPOSE
Invasive fungal diseases (IFD) are a major global public health concern. The incidence of IFD has increased the demand for antifungal agents. Isavuconazole (ISA) is a new triazole antifungal agent that has shown promising efficacy in the prophylaxis and treatment of invasive fungal diseases. The aim of this review is to summarize the recent real-world experiences of using ISA for the treatment and prevention of IFD.
METHODS
We performed a comprehensive literature search of the MEDLINE, PubMed, Embase, and Cochrane databases for clinical applications of ISA in the real world. Tables and reference lists are presented for this systematic review.
RESULTS
IFD poses a major threat to public health and causes high mortality rates. ISA may provide a good treatment. For example, the efficacy of ISA in the treatment of invasive aspergillosis (IA) is comparable to that of voriconazole, and its efficacy in the treatment of invasive mucormycosis (IM) is similar to that of liposomal amphotericin B (L-AmB); therefore, ISA is recommended as the first-line treatment for IA and IM. ISA can also achieve good efficacy in the treatment of invasive candidiasis (IC) and can be used as an alternative to de-escalation therapy after first-line drug therapy. In addition, most studies have shown the efficacy and safety of ISA for the prophylaxis of IFD.
CONCLUSION
Taken together, ISA are expected to become a new choice for the treatment and prevention of IFD because of their good tolerability, high bioavailability, and few drug interactions.
Topics: Humans; Triazoles; Invasive Fungal Infections; Nitriles; Antifungal Agents; Aspergillosis; Mucormycosis; Candidiasis, Invasive
PubMed: 36530445
DOI: 10.3389/fcimb.2022.1049959 -
Drug Delivery Dec 2021We examined formulating a new antifungal agent, posaconazole (POS) and its derivatives, with different molecular vehicles. Several combinations of drug and carrier...
We examined formulating a new antifungal agent, posaconazole (POS) and its derivatives, with different molecular vehicles. Several combinations of drug and carrier molecules were synthesized, and their antifungal activities were evaluated against . Posaconazole and four of its derivatives were conjugated to either generation 5 (G5) dendrimers or partially modified G5 dendrimers. The antifungal activities of these compounds suggest that conjugates with specific chemical linkages showed better fungistatic activity than direct conjugates to POS. In particular, a polyethylene glycol (PEG)-imidazole modified G5 dendrimer demonstrated improved antifungal efficacy relative to the parent G5 molecule. Further studies were then conducted with POS derived molecules coupled to PEG-imidazole modified G5 dendrimers to achieve a highly soluble and active conjugate of POS. This conjugated macromolecule averaged 23 POS molecules per G5 and had a high solubility with 50 mg/mL, which improved the molar solubility of POS from less than 0.03 mg/mL to as high as 16 mg/mL in water. The primary release profile of the drug in human plasma was extended to over 72 h, which is reflected in the inhibition of growth of over 96 h. These POS-polymer conjugates appear to be novel and efficient antifungal agents.
Topics: Antifungal Agents; Aspergillus fumigatus; Chemistry, Pharmaceutical; Dendrimers; Dose-Response Relationship, Drug; Drug Carriers; Drug Liberation; Imidazoles; Nanoparticles; Polyethylene Glycols; Triazoles
PubMed: 34617850
DOI: 10.1080/10717544.2021.1986605 -
ChemMedChem Jan 2021Fluorinated aryl- and heteroaryl-substituted monohydrazones displayed excellent broad-spectrum activity against various fungal strains, including a panel of clinically...
Fluorinated aryl- and heteroaryl-substituted monohydrazones displayed excellent broad-spectrum activity against various fungal strains, including a panel of clinically relevant Candida auris strains relative to a control antifungal agent, voriconazole (VRC). These monohydrazones displayed less hemolysis of murine red blood cells than that of VRC at the same concentrations, possessed fungicidal activity in a time-kill study, and exhibited no mammalian cell cytotoxicity. In addition, these monohydrazones prevented the formation of biofilms that otherwise block antibiotic effectiveness and did not trigger the development of resistance when exposed to C. auris AR Bank # 0390 over 15 passages.
Topics: Animals; Antifungal Agents; Biofilms; Candida; Cell Line; Cell Survival; Drug Resistance, Microbial; Halogenation; Hemolysis; Humans; Hydrazones; Mice; Microbial Sensitivity Tests; Structure-Activity Relationship; Voriconazole
PubMed: 33063957
DOI: 10.1002/cmdc.202000626