scholarly journals Pre-Existing Liver Disease and Toxicity of Antifungals

2018 ◽  
Vol 4 (4) ◽  
pp. 133 ◽  
Author(s):  
Nikolaos Spernovasilis ◽  
Diamantis Kofteridis
Keyword(s):  
Decision Making ◽  
Liver Disease ◽  
Antifungal Agents ◽  
Dosage Adjustment ◽  
Fungal Infections ◽  
Drug Efficacy ◽  
Antifungal Drugs ◽  
Current Evidence ◽  
Comprehensive Review

Pre-existing liver disease in patients with invasive fungal infections further complicates their management. Altered pharmacokinetics and tolerance issues of antifungal drugs are important concerns. Adjustment of the dosage of antifungal agents in these cases can be challenging given that current evidence to guide decision-making is limited. This comprehensive review aims to evaluate the existing evidence related to antifungal treatment in individuals with liver dysfunction. This article also provides suggestions for dosage adjustment of antifungal drugs in patients with varying degrees of hepatic impairment, after accounting for established or emerging pharmacokinetic–pharmacodynamic relationships with regard to antifungal drug efficacy in vivo.

Potential of Nanoparticles in Combating Candida Infections

2019 ◽  
Vol 16 (5) ◽  
pp. 478-491 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohd Sajjad Ahmad Khan ◽  
Iqbal Ahmad ◽  
Abdullah Safar Althubiani
Keyword(s):  
Targeted Delivery ◽  
Recent Progress ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Fold Increase ◽  
Antifungal Drugs ◽  
Low Toxicity ◽  
Candida Infections ◽  
Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

scholarly journals Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

scholarly journals Marine Bioactive Compounds against Aspergillus fumigatus: Challenges and Future Prospects

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 813
Author(s):  
Chukwuemeka Samson Ahamefule ◽  
Blessing C. Ezeuduji ◽  
James C. Ogbonna ◽  
Anene N. Moneke ◽  
Anthony C. Ike ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Bioactive Compounds ◽  
Antifungal Agents ◽  
Antifungal Drugs ◽  
Marine Resources ◽  
Future Prospects ◽  
Speed Up

With the mortality rate of invasive aspergillosis caused by Aspergillus fumigatus reaching almost 100% among some groups of patients, and with the rapidly increasing resistance of A. fumigatus to available antifungal drugs, new antifungal agents have never been more desirable than now. Numerous bioactive compounds were isolated and characterized from marine resources. However, only a few exhibited a potent activity against A. fumigatus when compared to the multitude that did against some other pathogens. Here, we review the marine bioactive compounds that display a bioactivity against A. fumigatus. The challenges hampering the discovery of antifungal agents from this rich habitat are also critically analyzed. Further, we propose strategies that could speed up an efficient discovery and broaden the dimensions of screening in order to obtain promising in vivo antifungal agents with new modes of action.

Antibiofilm activity of antifungal drugs, including the novel drug olorofim, against Lomentospora prolificans

2020 ◽  
Author(s):  
Lisa Kirchhoff ◽  
Silke Dittmer ◽  
Ann-Kathrin Weisner ◽  
Jan Buer ◽  
Peter-Michael Rath ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Biofilm Formation ◽  
Laser Scanning ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Pathogenic Fungus ◽  
Antifungal Drugs ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Antibiofilm Activity

Abstract Objectives Patients with immunodeficiency or cystic fibrosis frequently suffer from respiratory fungal infections. In particular, biofilm-associated fungi cause refractory infection manifestations, linked to increased resistance to anti-infective agents. One emerging filamentous fungus is Lomentospora prolificans. Here, the biofilm-formation capabilities of L. prolificans isolates were investigated and the susceptibility of biofilms to various antifungal agents was analysed. Methods Biofilm formation of L. prolificans (n = 11) was estimated by crystal violet stain and antibiofilm activity was additionally determined via detection of metabolically active biofilm using an XTT assay. Amphotericin B, micafungin, voriconazole and olorofim were compared with regard to their antibiofilm effects when added prior to adhesion, after adhesion and on mature and preformed fungal biofilms. Imaging via confocal laser scanning microscopy was carried out to demonstrate the effect of drug treatment on the fungal biofilm. Results Antibiofilm activities of the tested antifungal agents were shown to be most effective on adherent cells whilst mature biofilm was the most resistant. The most promising antibiofilm effects were detected with voriconazole and olorofim. Olorofim showed an average minimum biofilm eradication concentration (MBEC) of 0.06 mg/L, when added prior to and after adhesion. The MBECs of voriconazole were ≤4 mg/L. On mature biofilm the MBECs of olorofim and voriconazole were higher than the previously determined MICs against planktonic cultures. In contrast, amphotericin B and especially micafungin did not exhibit sufficient antibiofilm activity against L. prolificans. Conclusions To our knowledge, this is the first study demonstrating the antibiofilm potential of olorofim against the human pathogenic fungus L. prolificans.

scholarly journals Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Juliana Alves Parente-Rocha ◽  
Alexandre Melo Bailão ◽  
André Correa Amaral ◽  
Carlos Pelleschi Taborda ◽  
Juliano Domiraci Paccez ◽  
...  
Keyword(s):  
Drug Targets ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Public Health Problem ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Immunocompromised Patients ◽  
Dimorphic Fungi ◽  
Novel Drug ◽  
Novel Drug Targets

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

scholarly journals CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Claudia Spampinato ◽  
Darío Leonardi
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Diagnostic Methods ◽  
Opportunistic Pathogens ◽  
Yeast Infection ◽  
Life Threatening ◽  
Therapeutic Alternatives

The genusCandidaincludes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised.Candidainfections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genusCandidaand yeast infection causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the treatment ofCandidainfections is also provided.

scholarly journals Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Visesato Mor ◽  
Antonella Rella ◽  
Amir M. Farnoud ◽  
Ashutosh Singh ◽  
Mansa Munshi ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Sequencing Analysis ◽  
Fungal Cell ◽  
New Class ◽  
Narrow Spectrum

ABSTRACT Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.

scholarly journals Non-toxic Cobalt(III) Schiff Base Complexes with Broad Spectrum Antifungal Activity

2020 ◽  
Author(s):  
Angelo Frei ◽  
A. Paden King ◽  
Gabrielle J. Lowe ◽  
Amy K. Cain ◽  
Francesca L. Short ◽  
...  
Keyword(s):  
Schiff Base ◽  
Antifungal Activity ◽  
Broad Spectrum ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Schiff Base Complexes ◽  
In Vivo Studies

Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it stands to reason to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad spectrum antifungal activity. Some of these complexes (1-3) show minimum inhibitory concentrations (MIC) in the low micro- to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg/kg are tolerated without adverse effects, paving the way for further in vivo studies of these complexes. <br>

scholarly journals Caenorhabditis elegans as an Infection Model for Pathogenic Mold and Dimorphic Fungi: Applications and Challenges

2021 ◽  
Vol 11 ◽  
Author(s):  
Chukwuemeka Samson Ahamefule ◽  
Blessing C. Ezeuduji ◽  
James C. Ogbonna ◽  
Anene N. Moneke ◽  
Anthony C. Ike ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Filamentous Fungi ◽  
Virulence Factors ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Infection Model ◽  
Dimorphic Fungi ◽  
C Elegans

The threat burden from pathogenic fungi is universal and increasing with alarming high mortality and morbidity rates from invasive fungal infections. Understanding the virulence factors of these fungi, screening effective antifungal agents and exploring appropriate treatment approaches in in vivo modeling organisms are vital research projects for controlling mycoses. Caenorhabditis elegans has been proven to be a valuable tool in studies of most clinically relevant dimorphic fungi, helping to identify a number of virulence factors and immune-regulators and screen effective antifungal agents without cytotoxic effects. However, little has been achieved and reported with regard to pathogenic filamentous fungi (molds) in the nematode model. In this review, we have summarized the enormous breakthrough of applying a C. elegans infection model for dimorphic fungi studies and the very few reports for filamentous fungi. We have also identified and discussed the challenges in C. elegans-mold modeling applications as well as the possible approaches to conquer these challenges from our practical knowledge in C. elegans-Aspergillus fumigatus model.

scholarly journals Antifungal effect of all-trans retinoic acid against Aspergillus fumigatus in vitro and in a pulmonary aspergillosis in vivo model

2020 ◽  
Author(s):  
Elena Campione ◽  
Roberta Gaziano ◽  
Elena Doldo ◽  
Daniele Marino ◽  
Mattia Falconi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Aspergillus Fumigatus ◽  
Rat Model ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Antifungal Drugs ◽  
Pulmonary Aspergillosis ◽  
Fungistatic Activity

AIM: Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. Fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. MATERIALS AND METHODS: A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. RESULTS: ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of sub-inhibitory concentration of Amphotericin B (AmB) and Posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to Posaconazole. CONCLUSION: Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal Hsp90 expression and Hsp90-related genes. ATRA reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as suitable fungistatic agent, also to reduce dosage and adverse reaction of classical antifungal drugs, and new therapeutic strategies against IPA and systemic fungal infections.

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