Cardiac Toxicity of Azole Antifungals

Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.

Antifungal pipeline:Is there light at the end of the tunnel?

The misuse and overuse of classic antifungals have accelerated the development of resistance mechanisms,diminishing the efficacy of established therapeutic pathways and necessitating a shift towards alternative targets.Despite this pressing need for new treatments,the antifungal drug pipeline has been largely stagnant for the past three decades,primarily due to the high risks and costs associated with antifungal drug development,compounded by uncertain market returns.Extensive research durations,special patient populations and rigorous regulatory demands pose significant barriers to bringing novel antifungal agents to market.In response,the“push-pull”incentive model has emerged as a vital strategy to invigorate the pipeline and encourage innovation.This editorial critically examines the current clinical landscape and spotlights emerging antifungal agents,such as Fosmanogepix,Ibrexafungerp,and Olorofim,while also unraveling the multifaceted challenges faced in new antifungal drug development.The generation of novel antifungals offers a beacon of hope in the battle against antimicrobial resistance,but it is premature to declare them as definitive solutions.Their future role hinges on thorough clinical validation,costeffectiveness assessments,and continuous post-marketing surveillance.Only through strategic implementation and integration with market strategies we can transform the landscape of antifungal development,addressing both the resistance crisis and the treatment challenges.

Global Burden of Fungal Infections and Antifungal Resistance from 1961 to 2024: Findings and Future Implications

Background: Antifungal resistance (AFR) is a global public health problem with devastating effects, especially among immunocompromised individuals. Addressing AFR requires a One Health approach including Antifungal Stewardship (AFS). This study aimed to comprehensively review global studies published on fungal infections and AFR and to recommend solutions to address this growing problem. Materials and Methods: This was a narrative review that was conducted using published papers on fungal infections, AFR, and AFS between January 1961 and March 2024. The literature was searched using PubMed, Google Scholar, Web of Science, and EMBASE. Results: This found that there has been an increase in fungal infections globally, especially among immunocompromised patients. Due to this increase in fungal infections, there has been a proportionate increase in the use of antifungal agents to prevent and treat fungal infections. This increased use of antifungal agents has worsened the problem of AFR contributing to increased morbidity and mortality. Globally, fungal infections have contributed to 150 million infections annually and 1.7 million deaths per year. By the year 2023, over 3.8 million people died from fungal infections. Addressing AFR remains a challenge because the treatment of antifungal-resistant infections is difficult. Finally, the treatment of fungal infections is a global challenge exacerbated by the limited number of antifungal agents to treat invasive fungal infections. Conclusion: The results of this study indicated that fungal infections and AFR are prevalent across humans, animals, agriculture, and the environment. Addressing this problem requires the provision of solutions such as improving the awareness of AFR, conducting further research on the discovery of new antifungal agents, and implementing AFS programs. If this global problem is not addressed, the morbidity and mortality associated with AFR will continue to rise in the future.

Epidemiology, Clinical Features and Antifungal Resistance Profile of Candida auris in Africa: Systematic Review

Candida auris since it discovery in 2009 is becoming a severe threat to human health due to its very quickly spread, its worldwide high resistance to systemic antifungal drugs. In resource-constrained settings where several conditions are met for its emergence and spread, this worrisome fungus could cause large hospital and/or community-based outbreaks. This review aimed to summarize the available data on C. auris in Africa focusing on its epidemiology and antifungal resistance profile. Major databases were searched for articles on the epidemiology and antifungal resistance profile of C. auris in Africa. Out of 2,521 articles identified 22 met the inclusion criteria. In Africa, nearly 89% of African countries have no published data on C. auris. The prevalence of C. auris in Africa was 8.74%. The case fatality rate of C. auris infection in Africa was 39.46%. The main C. auris risk factors reported in Africa were cardiovascular disease, renal failure, diabetes, HIV, recent intake of antimicrobial drugs, ICU admissions, surgery, hemodialysis, parenteral nutrition and indwelling devices. Four phylogenetic clades were reported in Africa, namely clades I, II, III and IV. Candida auris showed a pan-African very high resistance rate to fluconazole, moderate resistance to amphotericin B, and high susceptibility to echinocandins. Finally, C. auris clade-specific mutations were observed within the ERG2, ERG3, ERG9, ERG11, FKS1, TAC1b and MRR1 genes in Africa. This systematic review showed the presence of C. auris in the African continent and a worrying unavailability of data on this resilient fungus in most African countries.

A Bronchopulmonary Onset of Candidemia Revealing a Granulomatosis with Polyangiitis

Candidemia is defined as being a yeast infection confirmed by the presence of at least one positive Candida blood culture. It is a life threatening infection causing high mortality. The clinical signs are generally compatible with the causative agent (whether there is a deep venous catheter or not). On the other hand and according to the 2012 Revised Chapel Hill Classification, granulomatosis with polyangiitis GPA is classified as a vasculitis associated with antineutrophil cytoplasmic antibodies ANCA. It is a systemic disease characterized by the anatomopathological aspect of granuloma. We report the case of a patient who presented an atypical and a very rare revealing mode of GPA which was a bronchopulmonary candidiasis complicated by candidemia. Despite its controversy, the combination in the acute phase of antifungal treatment based on intravenous voriconazole and glucocorticoid therapy has made it possible to control candidemia and calm vasculitis.

Fusarium wilt of banana:Current update and sustainable disease control using classical and essential oils approaches

Fusarium species were reported to produce biofilms.Biofilms are superficial societies of microbes bounded and endangered by being situated or taking place outside a cell or cells.The most destructive fungal diseases caused by phytopathogens are as a result of biofilms formation.Fusarium wilt of banana(Panama disease)is caused by a soil-borne pathogen called Fusarium oxysporum f.sp.cubense.Fusarium oxysporum occurs in a form of a species complex(FOSC)which encompasses a crowd of strains.Horizontal genetic factor transfer may donate to the observed assortment in pathogenic strains,while sexual reproduction is unknown in the FOSC.Fusarium wilt is a notorious disease on several crops worldwide.Yield loss caused by this pathogen is huge,and significant to destroy crop yields annually,thereby affecting the producer countries in various continents of the world.The disease is also resistant to various synthetic chemical fungicides.However,excessive use of synthetic fungicides during disease control could be lethal to humans,animals,and plants.This calls for alternative eco-friendly management of this disease by targeting the biofilms formation and finally suppressing this devastating phytopathogen.In this review,we,therefore,described the damage caused by Fusarium wilt disease,the concept of filamentous fungal biofilms,classical control strategies,sustainable disease control strategies using essential oils,and prevention and control of vegetables Fusarium wilt diseases.

In Vitro Antifungal Activity of Dihydrochelerythrine and Proteomic Analysis in Ustilaginoidea virens

Dihydrochelerythrine(DHCHE)is an isoquinoline compound,which has distinct antifungal activity and can induce apoptosis.The antifungal activity of DHCHE against five rice pathogenic fungi was studied in vitro.At the concentration of 7.5 mg/L,DHCHE exhibited the highest efficacy among tested compounds in inhibiting mycelium growth,with an inhibition rate of 68.8%in Ustilaginoidea virens,which was approximately 2.4 times of that of validamycin(28.7%).After exposure to DHCHE,transmission electron micrographs revealed spores showed incomplete organelles,malformed cell walls and nuclear membranes,as well as irregular lipid spheres.Reactive oxygen species accumulation in treated spores was markedly higher than that in control spores.DHCHE induced cell damage increased in a dose-dependent manner,as indicated by the decrease in mitochondrial membrane potential and initiation of apoptosis.The differences of expression levels of Fip1,ACP1,PMS2 and COX13 that are important for oxidative phosphorylation and mismatch repair pathway were significant,which may be some of the reasons for the induction of apoptosis in DHCHE-treated U.virens.The protein levels of Fip1,ACP1,PMS2 and COX13 agreed with protein fold change ratio from parallel reaction monitoring Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway of differentially expressed proteins were further analyzed.These findings will help to elucidate the mechanisms associated with antifungal and pro-apoptotic effects of DHCHE on U.virens,thereby aiding the potential development of novel pesticides.

Antimicrobial activities of Acacia genus:A review

More than 1 300 species of the vast genus Acacia are found in tropical habitats. They are crucial economic plants since they produce traditional medicines, timber, and gum. The pharmacological uses of the Acacia genus include anti-diarrheal, anti-malarial, chronic pain relief, wound healing, anti-cancer, anti-rheumatism, and antidiabetes activities. It is also used for treating various illnesses such as gastroenteritis, allergies, Alzheimer’s disease, cough, and cardiovascular disease. The present review aims to summarize the antimicrobial activities including the antibacterial and antifungal activity of the Acacia genus. The literature was searched in books and online databases including SciFinder, Google Scholar, Scopus, Pub Med, and scientific journals using the most relevant keywords: Acacia+antimicrobial, Acacia+antibacterial, and Acacia+antifungal.

Development of Molecular Marker Linked with Cercospora Leaf Spot (CLS) Disease Resistance in Vigna radiata, Cloning, and Expression for Evaluating Antifungal Activity against Cercospora canescens

We developed a molecular marker for MAS of mungbean resistant varieties against CLS from the consensus sequence(MB-CLsRG)of identified RGAs(MB-ClsRCaG1 and MB-ClsRCaG2).The MB-CLsRG sequence-specific primer pair was used to screen Cercospora leaf spot(CLS)resistant varieties of mungbean in genomic analysis that showed congruency with phenotypic screening.Validation of molecular marker linkage with CLS resistance was performed using rtPCR in transcriptomic analysis.The sequenced PCR products showed 100%homology with MB-CLsRG sequence and putative disease resistance proteins that confirmed the linkage of molecular marker with CLS resistance in mungbean.The antifungal potential of MB-CLsRG gene encoding protein was assessed.The MB-CLsRG gene sequence was cloned in the E.coli expression vector for recombinant protein production.The recombinant protein was then investigated for its in vitro antifungal potential against Cercospora canescens.The in vitro investigation showed strong antifungal activity of recombinant protein as it restricted the growth of fungal mycelial mass.The results validated the linkage of developed marker with CLS-resistant mungbean varieties;therefore,it can be used to screen resistant varieties from a large population in MAS.Moreover,the recombinant protein of the MB-CLsRG gene sequence revealed antifungal potential,which proved the gene sequence could be suitable to use in transgenic plants technology to develop fungal-resistant transgenic crops.

Profiling of Antifungal Activities from the Leaf Extract of Selected Apiaceae Family Plants against Aspergillus fumigates

Many ethnic plants are used as a source of traditional medicine to cure a variety of illnesses in both humans and animals. Developing secondary metabolites in plants with antifungal characteristics, offer alternative medications for reasonably priced and safe treatments. In the present study, methanolic, ethanolic, hexane and ethyl acetate leaves extracts of fifteen Apiaceae family plants were taken on the premise of their ethno botanical uses. The antifungal activity was assessed against significant fungal strain;Aspergillus fumigates by measuring minimum inhibitory concentration (MIC) and Zone of inhibition compared with standard drug fluconazole. Ethanol and methanol extracts of the plants were more effective than the hexane and ethyl acetate extracts against A. fumigates. Extracts of Cuminum cyminum, Pastinca sativa, Carum carvi, Dacus carota, Centella asiatica, Anthriscus cerefolium, Trachyspermum ammi, Pimpenella anisum and Apium graveolens showed relatively low inhibition effects between 3.5 to 8.5 mm. The MIC value of extracts was determined ranging between 0.8 to 0.43 μg/ml. The extract of Petroselinum crispum, Foeniculum vulgare, Ferula assaefoetida, Bunium persicum, Anethum graveolens and Coriander sativum could be considered as potential source of antifungal compounds for treating diseases in humans. Conclude remarks that these six extracts show astonishing fungicidal properties that can be used to discover drugs of very high potential.

Anticandidal Activity of Moroccan Medicinal Plants

The prevalence of oral candidiasis has increased over recent years in patients with the compromised general condition. There are a large number of plant species that have been traditionally used for oral diseases by the Moroccan population. These species could provide a source for discovering new active principles of natural origin against Candida albicans involved in the appearance of candidiasis infections. Information was acquired using the electronic databases Web of Science, Scopus and PubMed. In the first part, this review presents the medicinal plants used by the Moroccan population for the treatment of oral disorders (Toothaches, gingivitis, ulcers, stomatitis, abscesses, ...). The second part describes different studies regarding the antifungal activity of essential oils and organic extracts of some Moroccan species against Candida albicans. Inhibition zone diameter (IZD), Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of essential oils and plant’s extracts were noted. The third part concerns Moroccan plants with the antifungal activity that can be used in medical and agricultural fields. Several species of Moroccan plant proved their effectiveness against Candida albicans and can be used for the treatment of oral candidiasis. Further research should be undertaken in the future to investigate the toxicity of essential oils and plant extracts with antifungal properties for clinical use. This review provided an update on Moroccan plants presenting antifungal activity and especially those active against Candida albicans.

Efficacy and Safety Assessment of Antifungal Sequential Therapy from Micafungin to Liposomal Amphotericin B for Antibiotics-Refractory Febrile Neutropenia in Patients with Hematologic Malignancies

Invasive fungal infections are a major challenging problem in the management of febrile neutropenia (FN) in patients with hematologic malignancies. Liposomal amphotericin B (L-AmB) or micafungin (MCFG) has been widely used as a first-line empirical antifungal therapy for suspected fungal infection in such patients. However, there are several issues in patients receiving these agents: drug related toxicities for L-AmB and breakthrough fungal infections for MCFG. In order to make the best use of these 2 agents, we conducted a prospective study of sequential therapy from MCFG to L-AmB, and evaluated the efficacy and safety of this strategy in FN patients with hematologic malignancies. A total of 18 patients were enrolled, and 11 patients who fulfilled the protocol defined criteria were evaluated. Underlying diseases consisted of acute leukemia (n = 9), non-Hodgkin lymphoma (n = 1), and myelodysplastic syndrome (n = 1). Treatment success was achieved in 8 patients (72.7%). Drug-related adverse events occurred in 8 patients (72.7%). All of those adverse events except one case were below grade 2. Three patients required discontinuation of L-AmB. Although our empirical antifungal sequential therapy seems to be encouraging for antibiotics-refractory FN in patients with hematologic malignancies, further investigation in large-scale studies is warranted.

In Vitro Evaluation of the Antifungal Activity of Essential Oils of Thymus vulgaris and Cymbopogon citratus on Some Strains of Sclerotinia sclerotiorum, Agent Responsible for White Rot of Beans

The present work was aimed to the study of the antifungal activity of essential oils of two aromatic plants against three strains of Sclerotinia sclerotiorum responsible for white rot of bean. The two essential oils (EO) of the studied plants: Thymus vulgaris (HET) and Cymbopogon citratrus (HEC), used at different concentrations: C1 (0.75 ml/ml), C2 (1.5 ml/ml) and C3 (3 ml/ml) presented significant inhibitory activities on the three tested fungal strains namely Bia 1, Bia 2, and Njo 2. Two control treatments (T-: containing no antifungal substance and T+: synthetic fungicide) were also used. The antifungal activity here is related to the inhibition of mycelial growth especially with high concentrations of essential oils. Thus, against S. sclerotiorum, HET showed the highest activity comparable to that of T+ (100% inhibition) at all concentrations on the Bia 1 and Bia 2 strains and at concentration C3 on the Njo 2 strain compared to that of HEC, which certainly inhibited the mycelial growth of the different strains considerably (with a maximum of 78.15% on the Njo 2 strain) but not completely. According to their sensitivity, the Bia 2 strain showed a higher sensitivity to essential oils than the others while the Njo 2 strain was more aggressive. On the basis of MIC50 and MIC90 obtained on the Njo 2 strain, the HET turns out to be the most efficient with respective lower values of (1.73 and 23.34 ml/ml) against (4.76 and 26.03 ml/ml) for the HEC. These EO could thus be exploited as biodegradable antifungal substances, likely to control white rot of bean.

Bismuth-Complex-Incorporated Nanocellulose Sheet for Biomedical Application:A Review on New Nanocellulose Composites

Antibiotic resistance is one of the major issues in the medical field and a potential threat to human health.However,newly emerging antimicrobial compounds failed to combat antimicrobial resistance developed by bacterial pathogens.Recently,a bismuth-based complex has been developed to eradicate antimicrobial-resistant microorganism infections.The complex is known as organobismuth(III)phosphinate,which is said to be a potential broad-spectrum antimicrobial agent.This complex has been incorporated into the nanocellulose suspension to fabricate a biomedical composite for various applications.The composite can be fabricated by two methods namely vacuum filtration and spray coating.In this paper,the surface and topography of the composite are investigated and discussed in terms of SEM micrographs and their antimicrobial potential.This review focuses on the organo-bismuth nanocellulose composite and its biomedical application in the future.

New Formulation Strategies in Topical Antifungal Therapy

Fungal infections of the skin are one of the often faced with dermatological diseases in worldwide. Topical therapy is an attractive choice for the treatment of the cutaneous infections due to its advantageous such as targeting of drugs to the site of infection and reduction of the risk of systemic side effects. Currently, antifungal drugs are generally used as conventional cream and gel preparations in topical treatment. The efficiency of that treatment depends on the penetration of drugs through the target layers of the skin at the effective concentrations. However, stratum corneum, the outermost layer of the skin, is an effective barrier for penetration of drugs into deeper layers of the skin. The physicochemical characteristics of drug molecules and the types of the formulations are effective factors in topical drug delivery. Therefore, a number of formulation strategies have been investigated for delivering antifungal compounds through targeted site of the skin. This review article focuses on the new alternative formulation approaches to improve skin penetration of antifungal drugs.

苍耳提取液与植物内生真菌抗菌活性研究(英文)

[Objective] The study was aimed to provide theoretical foundation for developing a new fungicide with high activity,low toxicity and low residua.[Method] Based on the plant growth rate and inhibition zone methods,the antifungal activity of extracts of every organ of Xanthium sibiricum,the fermentation liquid of endophytic fungi MC4-23,and the extract of mycelium were tested with six kinds of pathogenic fungi and three kinds of pathogenic bacteria respectively.[Result] The extract of every organ of Xanthium sibiricum,the fermentation liquid of endophyic fungi MC4-23,and the extract of mycelium all had antifungal activities.The acetone extracts of Xanthium sibiricum had stronger antifungal activities than the ethanol extracts of Xanthium sibiricum.The extracts of leaf have the strongest antifungal activities against fungi and bacteria.The inhibition rates of the six pathogenic fungi were all above 47.8%,and the inhibition diameters of the three pathogenic bacteria were all above 0.5 centimeter.The fermentation liquid of endophytic fungi also had strong activities against the fungi and bacteria.The inhibition rates of the six pathogenic fungi were all above 68.1%.The extracts of root of Xanthium sibiricum and the mycelium of endophytic fungi were all had antifungal activities.[Conclusion] Xanthium sibiricum and endophyic fungi MC4-23 had great value of development and utilization.

<i>In-Vitro</i>Comparison of Antifungal Activity of Herbs (Darehald and Pomegranate) with Azoles

Aim: Candida, an opportunistic organism is one of the commonest causes of hospital acquired infections among fungi. Currently available antifungal drugs have numerous adverse effects and drug-drug interactions (DDIs) along with increase in resistance over the time. Therefore, it is highly emergent to consider alternative treatments for candidal infections, having fewer adverse effects and is cost-effective. The current in-vitro study is undertaken to assess and compare the antifungal effects of the herbs, Berberis aristata (B. aristata, Darehald/Darhald) and Punica granatum (P. granatum, Pomegranate) with fluconazole and voriconazole, based on culture and sensitivity of candidal isolates. Materials and Methods: Ethanolic extracts of herbs (Berberis aristata and Punica granatum) and concentrations were formulated as per standard procedure. 130 samples were obtained for the study from in and out patients reported in clinical subsets of Ziauddin Hospital, Karachi from March to May, 2018. Samples were collected and grown according to the standard procedures like, wet mount test and gram’s staining. Species were identified by CHROM agar candida and API 20 C AUX methods. Sensitivity tests were performed by Kirby Bauer’s disc diffusion method according to CLSI guide lines M-44 A2, 2009. Data analysis was done by one-way ANOVA to compare the antifungal activities of drugs and herbs. Results: Mean inhibitory zones of herbs, B. aristata and P. granatum were highly significant against clinical candidal isolates with respective p-values of 0.00 and 0.02. Both of the herbs, B. aristata and P. granatum were found to be more sensitive, 98.5% and 97.7% respectively in comparison to fluconazole showing 42.3% and voriconazole showing 29.2% sensitivity against candidal isolates. The most resistant candidal specie was C. tropicalis that showed resistance against both fluconazole and voriconazole, contrary to that, this specie was highly sensitive to both of the herbs, showing sensitivity of 100% respective for Darehald and Pomegranate. Conclusion: In comparison to azoles: Culture sensitivity of both herbs (B. aristata and P. granatum) displayed more sensitivity against candidal isolates of patients having non-invasive and invasive candidiasis. These herbs can be considered as substitute or alternative antifungal agents to the conventional antifungal therapy, particularly in cases of treating candidemia patients, which is a life threating condition.

How could we reduce antifungal use in the intensive care unit?

Fungal infection is common in critically ill patients. However, this infection is difficult to diagnose, and alarge proportion of patients receive empirical antifungal treatment without further confirmation of invasive fungal disease. Whilst prompt appropriate antifungal treatment is associated with better outcome in patients with confirmed infections, this treatment has several drawbacks. In addition, no clear beneficial effect of empirical antifungal treatment was found in patients without confirmed infection. Reducing antifungal treatment in the intensive care unit(ICU) is feasible, and would allow avoiding drawbacks of this treatment without negative impact on outcome. Antifungal stewardship, preemptive antifungal treatment, based on colonization index and fungal biomarkers; and deescalation of antifungal treatment based on microbiology results and fungal biomarkers could be suggested to reduce antifungal use in the ICU, and are currently under investigation.

Two Novel Antifungal Saponins from Tibetan Herbal Medicine Clematis tangutica

Antifungal assay-guided isolation of the ethanol extract of the aerial parts of Clematis tangutica yielded two novel triterpene saponins. Their structures were determined to be 3-O-a-L-arabinopyranosyl hederagenin 28-O-a-L-rhamnopyranosyl ester (1) and 3-O-b-D- glucopyranosyl(14)-a-L-arabinopyranosyl hederagenin 28-O-a-L-rhamnopyranosyl ester (2) on the basis of spectral data and chemical reactions.

Antifungal activity of Aegle marmelos(L.) Correa(Rutaceae) leaf extract on dermatophytes

Objective:To evaluate the in vitro antifungal activity of Aegle marmelos leaf extracts and fractions on the clinical isolates of dermatophytic fungi like Trichophyton mentagrophytes,Trichophyton rubrum,Microsporum canis,Microsporum gypseum and Epidermophyton floccosum.Methods:The minimum inhibitory concentration(MIC) and minimum fungicidal concentration(MFC) of various extracts and fractions of the leaves of Aegle marmelos were measured using method of National Committee for Clinical Laboratory Standards(NCCLS).Results:Aegle marmelos leaf extracts and fractions were found to have fungicidal activity against various clinical isolates of dermatophytic fungi.The MIC and MFC was found to be high in water and ethyl alcohol extracts and methanol fractions(200μg/mL) against dermatophytic fungi studied.Conclusions:Aegle marmelos leaf extracts significantly inhibites the growth of all dermatophytic fungi studied.If this activity is confirmed by in vivo studies and if the compound is isolated and identified,it could be a remedy for dermatophytosis.