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.

Candidemia chronicles:Retrospective analysis of candidemia epidemiology,species distribution,and antifungal susceptibility patterns in Bahrain

BACKGROUND Invasive fungal infections,particularly candidemia,pose significant clinical challenges globally.Understanding local epidemiology,species distribution,and antifungal susceptibility patterns is crucial for effective management despite regional variations.AIM To investigate the epidemiology,species distribution,antifungal susceptibility patterns,and associated risk factors of candidemia among patients in Bahrain from 2021 to 2023.METHODS This retrospective study analyzed demographic data,Candida species distribution,antifungal susceptibility profiles,and risk factors among candidemia patients treated at a tertiary care hospital in Bahrain over three years.Data was collected from medical records and analyzed using descriptive statistics.RESULTS A total of 430 candidemia cases were identified.The mean age of patients was 65.7 years,with a mortality rate of 85.5%.Candida albicans(C.albicans)was the most common species,followed by Candida parapsilosis,Candida tropicalis(C.tropicalis),and emerging multidrug-resistant Candida auris(C.auris).Antifungal susceptibility varied across species,with declining susceptibility to azoles observed,particularly among C.albicans and C.tropicalis.Major risk factors included central venous catheters,broad-spectrum antibiotics,and surgical procedures.CONCLUSION This study highlights the substantial burden of candidemia among older adults in Bahrain,characterized by diverse Candida species.It also concerns levels of antifungal resistance,notably in C.auris.The findings underscore the importance of local epidemiological surveillance and tailored treatment strategies to improve outcomes and mitigate the spread of multidrug-resistant Candida species.Future research should focus on molecular resistance mechanisms and optimizing therapeutic approaches to address this growing public health concern.

Screening of Two Biocontrol Strains of Bacillus subtilis against Ginseng Soil-borne Disease and Their Antifungal Activities

[ Objective] The paper was to obtain biocontrol strains with good control effects against ginseng soil-borne disease through screening. [ Method] Dilu- tion plate method and plate confrontation culture method were used to isolate and screen biocontrol bacteria from the rhizosphere soil of diseased ginseng. The strains were identified through morphology, physiological and biochemical characteristics and 16S rDNA. [ Result ] With Rhizoctonia solani, Fusarium oxysporum and Fu- sarium solani as the indicator strains, two biocontrol strains B59 and X1 with strong antagonistic effects were screened from the rhizosphere soil of diseased ginseng in Tieli farm of Heilongjiang Province, and they were identified to be Bacillus subtilis. The inhibition rates of two biocontrol strains against eight different fungi were all greater than 90%. The primary study indicated that B59 and X1 strains could secrete antifungal active substances. [ Conclusion] Two biocontrol Bacillus subti- lis strains 1359 and X1 all had strong antagonistic effect against ginseng soil-borne disease, which had certain potential for development and utilization.

Antifungal Activity of Extracts from Clerodendrum Bungei Leaves against Two Species of Phytopathogens

The test was undertaken to reveal the antifungal activity of extracts from Clerodendrum bungei leaves against Pestalotia and Rhizoctonia solani, the results showed that optimal condition for best antifungal activity of extracts against pestalotia and Rhizoctonia solani are as follows： material-liquid ratio of 1：6,75% ethanol as extracting solvent, reflux at 90℃ for 1.5 h. The substances with good dissolubility in ethanol and water solution such as organic acid, bioflavonoid and alkaloid are main antifungal bioactive substances in Clerodendrun bungei.

Screening and Identification of Myxobacterias with Antifungal Activity

[ Objective] The paper was to screen myxobacteria with antifungal activity, and identify its species. [ Method] 237 myxobacteria were isolated and pu- rified from 200 copies of soil samples collected from 23 provinces in China. The strains were fermented in four different media, and the fermentation products were extracted by methanol to obtain metabolites. With Candida albicans as the model, the secondary metabolites were carried out high-throughput screening. [ Result ] A strain of myxohacteria numbered ZJ2 was obtained after secondary screening, its secondary metabolites had activities against G. albicans. 16S rDNA cloning and sequencing results showed that ZJ2 was Myxococcus fidvus. [ Conclusion ] The secondary metabolites of ZJ2 strain had bioactive substances with significant inhibi- tion effect against the growth of C. albicans, which had potential pharmaceutical research and development value.

Isolation and Identification of Antifungal Bacterial Strain KL-1 against Plant Wilt Disease

[Objective] The antifungal bacteria of plant wilt disease was screened and identified to provide foundation for the study on bio-control preparation of plant wilt disease.[Method] Confrontation culture method was adopted to screen the bio-control bacteria with good antifungal effect against plant wilt disease,Biolog bacteria automatic identification system and 16S rDNA sequence analysis method were selected to identify its taxonomic status,the biological safety of the strain towards cotton and mice was also determined.[Result] 12 bacterial strains were isolated from rhizosphere of cotton.Among those strains,5 isolates showed antifungal activity against F.decemcellulare Brick,F.oxysporum f.sp.Diathi,F.oxysporum f.sp.vasinfectum.The antifungal effect of KL-1 strain against three target strains of pathogen reached 69.09%,80.78% and 78.89% respectively.Identification results of Biolog bacteria automatic identification system and 16S rDNA sequence analysis method showed that KL-1strain was Bacillus amyloliquefaciens;primary determination results of biological safety also showed that the strain KL-1 was safe and non-toxic towards cotton and mice.[Conclusion] KL-1strain of B.amyloliquefaciens had antifungal effect against several pathogens of plant wilt diseases,which was safe and non-toxic towards cotton and mice,being the bio-control strain with research and development potential.

Synthesis of a New Series of Chalcone Derivatives and Their Antifungal Activities

To study the antifungal effect of chalcone derivatives. Methods Sixteenchalcone derivatives were synthesized and confirmed by ~1H NMR and IR spectra, and tested forantifungal activity against four common pathogenic fungi. Their structure-activity relationship isdiscussed. Results Among 16 title compounds, there were 5 new compounds, which have not beenreported before. The preliminary antifungal test showed that all title compounds exhibitedantifungal activities to a certain extent. The activity of compound 8 against Trichophyton rubrumhad a potency equal to that of fluconazole, with a MIC of 4 μg·mL^(-1) . Conclusion Sixteenchalcones were prepared and their antifungal activities against four common pathogenic fungi invitro were examined. Some of them exhibited antifungal activities to a certain extent.

A New Antifungal Flavonol Glycoside from Hypericum perforatum

In addition to six known flavonoids quercitrin, hyperoside, avicularin, rutin, quercetin and kaemferol, a new flavonol glycoside named 6″_O_acetyl quercetin 3_O_β_ D _alloside (1) was isolated from the aerial parts of Hypericum perforatum L. The structures were determined on the basis of spectroscopic methods (UV, IR, FAB_MS, 1H_NMR and 13 C NMR). Antifungal assay of all compounds showed that metabolite 1, quercitrin and quercetin were inhibitory to the growth of phytopathogenic fungus Helminthosporium sativum Pamel King et Bakke with minimum inhibitory concentrations (MICs) of 25, 50 and 50 μg/mL, respectively. Moreover, glycoside 1 and quercitrin were also shown to be able to inhibit the growth of Fusarium graminearum Schw. with MIC of 100 μg/mL. The MICs of ketoconazole used as control against the test fungi were 0.5 μg/mL in our assay.

Antifungal Effect of Streptomyces 702 Antifungal Monomer Component DZP8 on Rhizoctonia solani and Magnaporthe grisea

The aim of this study was to investigate the in vitro antifungal effects of antifungal monomer component DZP8 isolated from Streptomyces 702 on the mycelium growth, sclerotium formation and germination of Rhizoctonia solani and on the mycelium growth, conidial formation, germination, appressorium formation of Magnaporthe grisea. The results showed that the antifungal monomer component DZP8 has strong antifungal effect on both the R. solani and M. grisea. The EC50 and EC90 of DZP8 were 1.81 and 3.35 μg/ml on Ft. solani respectively, and 37.01 and 136.21 μg/ml on M. grisea respectively. Under the treatment of 48.01 μg/ml DZP8, the sclerotium formation rate of R. solani was just 39.21%, the formation time delayed by 216 h and the dry weight decreased by 81.37% in comparison the con- trol; and 33.51 μg/ml DZP8 significantly inhibited the sclerotium germination. In the presence of 160.08 μg/ml DZP8, the sporulation of M. grisea was just 9.29% of control sample; 20.14 μg/ml DZP8 inhibited the conidial germination suppression rate by 95.16%, and the appressorium formation by 100%.

Inhibitory Effect of Antifungal Substances from Chaetomium globosum ND35 on Pathogenic Fungi of Valsa canker

[Objective] Inhibition mechanism of the antifungal substances from Chaetomium globosum ND35 against pathogenic fungi of Valsa canker was investigated.[Method] The inhibitory effect of antifungal substances （AFS） produced by endophytic C. globosum ND35 on pathogenic fungi of Valsa canker was studied by means of dual culture,extraction,thin layer chromatography and bioassay of antifungal activity. [Result] The crude extracts of AFS could strongly inhibit Valsa sordida and V. mali. The suppression percentage of mycelial growth of two pathogenic fungi were 66.4% and 72.6%,respectively. The inhibition percentages of conidia germination of two pathogenic fungi were 92.2% and 80.4%,respectively. Separation of thin layer chromatography and bioassay of antifungal activity indicated that the fraction No.2 of AFS played an important role in the process of inhibition on pathogenic fungi,causal agents of Valsa canker. [Conclusion] The antifungal substances from C. globosum ND35 is potential for biological control on Valsa canker.

Study on the Antifungal Activities of Mikania micrantha Extracts

The stems and leaves of Mikania micrantha were successively extracted with petroleum ether, ethyl acetate and ethanol. In vitro and in vivo test method was adopted to deten＇nine the inhibition activity of three solvent extracts against three plant pathogens. Growth rate method showed that ethyl acetate extract could significantly inhibit the mycelial growth of Botrytis circrea, Gtomerclla ciugulata and Fusarium bulbigeuum under the given concentration of 0.09 g/ml in dry sam- ple, and the inhibition rates were all greater than 90%. Organization test showed that the curative effect of petroleum ether extract against B. cirerea was 63.55% under the given concentration of 0.18 g/ml in dry sample, and the curative effect of ethanol extract was 71.47%. In the potting test against Erysiphe gramiuis, the curative effect of petroleum ether extract was 81.26%, while the curative effect of ethyl acetate extract was 62.07%.

Bioinformatics Analysis of Antifungal Peptide 25a2 of Cotton Verticillium Wilt

Protein 25a2 is the antifungal peptide of cotton Verticillium wilt which was isolated from Bacillus amyloliquefaciens. The amino acid sequence of antifungal peptide 25a2 was analyzed using bioinformatics tools, and the characters of signal peptides, transmembrane topological structura, physicochemical signatures, protein domain, secondary and tertiary structure of protein were predicted. The results showed that 25a2 was a secreted protein, the sequence of which included a signal peptide in N end and a transmembrane domain in C end. The predicted secondary structure showed that the antibacterial peptide was mainly free random coils, belonging to mixed protein, three-dimensional model of 25a2 was a compact ball. These results showed that the most possible action mechanism of antifungal peptide 25a2 might be ＂carpet＂ model.

Antifungal Activity of Botanical Extracts against Botrytis cinerea and Alternaria solani

[Objective] The antifungal activity of the extracts from,Atractylodes macracephal Koidz and Pulsatilla chinensis Bunge Regel,against Botrytis cinerea and Alternaria solani were studied under the condition of laboratory,in order to develop and utilize these two plants.[Method] The mycelium growth rate test was applied to measure the antifungal activities of extracts against fungi.[Result] the extracts of all the two plants showed strong antifungal activity against the target pathogenic fungi,especially the antifungal activity of the extract from Pulsatilla chinensis Bunge Regel was stronger and more stable.The inhibition rate to the mycelium growth of Botrytis cinerea was 80.25%.At the same concentration,the extract from Atractylodes macracephal Koidz showed little inhibition to Botrytis cinerea and Alternaria solani.The petrolelum ether extract of Atractylodes macracephal Koidz showed stronger antifungal activities and the EC50 was 5.31 mg/ml,and the n-butanol extract of Pulsatilla chinensis Bunge Regel showed stronger antifungal activities and the EC50 was 2.93 mg/ml.[Conclusion] The extracts from Pulsatilla chinensis Bunge Regel showed the stronger antifungal activity against Botrytis cinerea and Alternaria solani.

Preliminary Studies on Antifungal Activity of Xanthium sibiricum and the Endophytic Fungi

[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.

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.

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 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.

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.