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.

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.

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.

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.

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.

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.

Antifungalmycin,an antifungal macrolide from Streptomyces padanus 702

Two polyene macrolide antibiotics:antifungalmycin(1)and fungichromin(2)were isolated from the culture mycelia of Streptomyces padanus 702 via bioactivity-guided fractionation using various chromatographic procedures.Their structures were elucidated on the basis of spectral analysis,and 1 is a new polyene macrolide.Compounds 1 and 2 showed significant inhibition against Gibberella zeae with EC_(50)values of 26.71 and 2.21μg/mL,Fusicoccum sp.(plantain head blight)with EC_(50)values of 23.4 and 3.17μg/mL,Mucor ssp.8894 with EC_(50)values of 28.80 and 2.11μg/mL,Ustilaginoidea virens with EC_(50)values of 26.72 and 0.21μg/mL,respectively.This shows that the microbial secondary metabolites 1 and 2 have the potential to be developed as agricultural fungicides for use against G.zeae,Fusicoccum sp.,Mucor ssp.8894,and U.virens.

<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.

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.

Design, synthesis and antifungal activity of novel triazole derivatives

Twenty-three 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-(N-cycloproyl-N-substituted-amino)-2-propanols were designed and synthesized on the basis of the active site of lanosterol 14α-demethylase. In vitro antifungal activities showed that some of the title compounds had higher antifungal activity and broader antifungal spectrum than fluconazole.

Antifungal,Insecticidal and Herbicidal Properties of Volatile Components from Paenibacillus polymyxa Strain BMP-11

The volatiles produced by Paenibacillus polymyxa strain BMP-11 which was isolated from the rhizosphere soil of cucumber in a greenhouse were analyzed by SPME-GC-MS.Based on the preliminary test,three kinds of purchased commercial products 1-octen-3-ol,benzothiazole and citronellol were chosen to give further assessment of their bioactivity.Antifungal bioassays in sealed dishes revealed that those three compounds strongly inhibited the mycelia growth of the eight pathogens at a low treatment dosage and induced the mycelial morphological abnormalities.During the experiment,we even found that citronellol completely prevented the pigment production of the tested fungus,Fusarium oxysporum,however,1-octen-3-ol and benzothiazole had slight effect.The germination was inhibited to different degrees when spores of Botrytis cinerea exposed to these compounds for 24 h in water agar plate.Furthermore,fumigation results showed that 1-octen-3-ol and benzothiazole had strong toxicity against Tribolium castaneum,LC50 was 16.76 and 3.50 mg L-1,respectively.The fumigation activity was also found similar to the positive control,1,3-dichloropropene （LC50 =10.13 mg L-1）.Results of herbicidal assays showed that tested compounds had inhibitory effects on the seed germination and seedling growth of Amaranthus retroflexus,Echinochloa crusgalli and Chenopodium album.Findings of the present study suggested that the antifungal,insecticidal and herbicidal properties of the components were contained in volatiles.These agents or even their derivatives may have a potential to be used as fungicide,insecticide as well as herbicide.

Medium Optimization for Antifungal Active Substance Production from Streptomyces Lydicus Using Response Surface Methodology

Response surface methodology was used to optimize the medium for antifungal active substance production from Streptomyces lydicus E12 in flask cultivation.Initially,the component factors,which influence antifungal substance production,were studied by varying one factor at a time.Starch,soybean cake powder,K_2HPO_4·3H_2O and MgSO_4·7H_2O were found to have a significant effect on the production of antifungal substances by the traditional design.Then,a Box-Behnken design was applied for further optimization.A quadratic model was found to fit antifungal active substance production.The analysis revealed that the optimum values of the tested variable were starch 84.96 g/L,soybean cake powder 4.13 g/L,glucose 5 g/L,MgSO_4·7H_2O 1.23 g/L,K_2HPO_4·3H_2O2.14 g/L and NaCl 0.5 g/L.The test result of 67.44%antifungal inhibition agreed with the prediction and increased by 14.28%in comparison with the basal medium.

C_(17)-fengycin B,produced by deep-sea-derived Bacillus subtilis,possessing a strong antifungal activity against Fusarium solani

Root rot disease caused by Fusarium solani is the most devastating disease of the tomato and legume crops in China.The metabolites of Bacillus species can inhibit many fungal diseases.In this study,the metabolites of deep-sea-derived bacterium Bacillus subtilis 2 H11 can significantly inhibit the growth of F.solani.The metabolite C_(17)-fengycin B,one of the cyclic lipopeptides,was identified by the combination of silica column chromatography,high-performance liquid chromatography(HPLC),high-energy collision induced dissociation mass spectrometry(HCD-MS)and tandem mass spectrometry(HCD-MS/MS).The results of scanning electron microscopy(SEM)and transmission electron microscopy(TEM)showed that C_(17)-fengycin B could destroy the structure of the hyphae and spores of F.solani.The antifungal activities of C_(17)-fengycin B against F.solani were tested at concentrations ranging from 0.05 mg/mL to 0.20 mg/mL.The results indicated that C_(17)-fengycin B inhibited the growth of F.solani with antifungal index of 89.80%at 0.20 mg/mL,and the antifungal activity of C_(17)-fengycin B was further verified by the pot experiment.In addition,the cytotoxicity experiment showed that C_(17)-fengycin B had good biocompatibility and was a potential candidate for the development of biocontrol pesticide in the future.

Antifungal activity of four honeys of different types from Algeria against pathogenic yeast:Candida albicans and Rhodotorula sp.

Objective:To evaluate the antifungal activity of four honeys of different types from Algeria against pathogenic yeast i.e.Candida albicans(C.albicans) and Rhoddtorula sp.Methods:Four Algeria honeys of different botanical origin were analvzed to test anlilungal effect against C.albicans,and Rhodotorula sp.Different concentrations(undiluted,10%,30%,50%and 70%w/v) of honey were studied in vitro for their antifugal aclivity using C.albicans and Rhodotorula sp.as fungal strains.Results:The range of the c liameter of zone of inhibition of various concentrations ol tested honeys was(7-23 mm) for Rhodotorula sp.,while C.albicans showed clearly resistance towards all concentrations used.The MICs of tested honey concentrations against C.albicans and Rhodotorula sp.were(70.09-93.48)%and(4.90-99.70)%v/v,respectively.Conclusions:This study demonstrales that,in vitro,these natural products have clearly an antifungal activity against Rhodotorula sp.and C.albicans.

Design and synthesis of novel triazole antifungal derivatives based on the active site of fungal lanosterol 14a-demethylase(CYP51)

A series of 1-（1H-1,2,4-triazole-1-yl）-2-（2,4-difluoropheny1）-3-（N-isoproy1-N-substituted-amino）-2-propanols have been designed and synthesized on the basis of the active site of lanosterol 14a-demethylase （CYP51）. Their structures were confirmed by MS and ^1H NMR. In vitro antifungal activities of these synthesized compounds were evaluated against eight human pathogenic fungi. The results showed that all title compounds exhibited activity against fungi tested to some extent. Compounds 3c, 3d, 7a, 7b and 7e exhibited more potent antifungal activities against nearly all fungi tested except AspergiUus fumigatus than fluconazole. ？2009 Qiu Ye Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All fights reserved.

Additive potential of ginger starch on antifungal potency of honey against Candida albicans

Objective:To evaluate the additive action of ginger starch on the antifungal activity of honey against Candida albicans(C.albicans).Methods:C.albicans was used to determine the minimum inhibitory concentration(MIC)of four varieties of Algerian honey.Lower concentrations of honey than the MIC were incubated with a set of concentrations of starch and then added to media to detennine the minimum additive inhibitory concentration(MAIC).Results:The MIC for the four varieties of honey without starch against C.albicans ranged between 38%and 42%(v/v).When starch was incubated with honey and then added to media,a MIC drop was noticed with each variety.MAIC of the four varieties ranged between 32%honey(v/v)with 4%starch and 36%honey(v/v) with 2%starch.Conclusions:The use of ginger starch allows honey benefit and will constitute an alternative way against the resistance to antifungal agents.

Antifungal activity of Ocimum sanctum Linn.(Lamiaceae) on clinically isolated dermatophytic fungi

Objective:To assess antifungal activity of Ocimum sanctum leaves against dermatophytic fungi. Methods:Antifungal activity of Ocimum sanctum leaves was measured by 38 A NCCLS method. Minimum inhibitory concentration(MIC) and minimum fungicidal concentration(MFC) of various extracts and fractions of Ocimum sanctum leaves were also determined.Results:Ocimum sanctum leaves possessed antifungal activity against clinically isolated dermatophytes at the concentration of 200μg/mL.MIC and MFC were high with water fraction(200μg/mL) against dermatophytic fungi used.Conclusions:Ocimum sanctum has antifungal activity,and the leaf extracts may be a useful source for dermatophytic infections.