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.

Update on the Fungal Biofilm Drug Resistance and Its Alternative Treatment

Candida albicans (C. albicans) and Aspergillus fumigatus (A. fumigatus) are the two main pathogens in the clinical setting to cause serious, sometimes, lethal fungal infections. Immunocompromised patients fall victims to these fungi, with a mortality rate rising drastically over the past decades. This is in correlation with the fact that conventional antifungals are no longer capable of completely eradicating the disease, or if so, high doses are usually required to do so, leading to eventual resistance to those drugs and severe side effects. High drug resistance is in association with the discovery that these opportunistic pathogens have the ability to develop a multicellular complex, known as biofilm. Biofilms prevent drugs from reaching the fungal cells by sequestering them in their extracellular matrix. Other factors such as extracellular DNA, persister cells or heat shock protein 90 (Hsp90) also play a role in biofilm and contribute to drug recalcitrance. With the discovery of new antifungals lagging behind, scientists focused on other more profitable ways to counteract this phenomenon. Combination of two or more antifungals was found effective but came with serious drawbacks. Natural plant extracts, such as traditional Chinese medicine have also been demonstrated in vitro to possess antimicrobial actions. Great interest was directed towards their use with conventional antifungal agents with a possibility of lowering the necessary concentration required to inhibit the growth of fungi. This review aims in understanding the different factors contributing to clinical drug resistance and evaluating the effect of combination therapy and natural products on those cases difficult to treat.

A Ten-year Retrospective Study of Invasive Candidiasis in a Tertiary Hospital in Beijing

Objective This study aimed to evaluate the epidemiological,clinical and mycological characteristics of invasive candidiasis(IC)in China.Methods A ten-year retrospective study including 183 IC episodes was conducted in a tertiary hospital in Beijing,China.Results The overall incidence of IC from 2010–2019 was 0.261 episodes per 1,000 discharges.Candidemia(71.0%)was the major infective pattern;70.3%of the patients tested positive for Candida spp.colonization before IC and the median time to develop an invasive infection after colonization was13.5 days(interquartile range:4.5–37.0 days).Candida albicans(45.8%)was the most prevalent species,followed by Candida parapsilosis(19.5%),Candida glabrata(14.2%)and Candida tropicalis(13.7%).C.non-albicans IC was more common in patients with severe anemia(P=0.018),long-term hospitalization(P=0.015),hematologic malignancies(P=0.002),continuous administration of broad-spectrum antibiotics(P<0.001)and mechanical ventilation(P=0.012).In vitro resistance testing showed that11.0%of the Candida isolates were resistant/non-wild type(non-WT)to fluconazole,followed by voriconazole(9.6%),micafungin(3.8%),and caspofungin(2.9%).Fluconazole was the most commonly used drug to initiate antifungal therapy both before and after the proven diagnosis(52.6%and 54.6%,respectively).The 30-day and 90-day all-cause mortality rates were 24.5%and 32.7%,respectively.Conclusion The incidence of IC has declined in the recent five years.C.non-albicans contributed to more than half of the IC cases.Fluconazole can be used as first-line therapy if resistant strains are not prevalent.Prospective,multi-center surveillance of the clinical and mycological characteristics of IC is required.

Prevalence and virulence factors of Candida spp. associated with blow flies

Objective:To investigate the prevalence of Candida spp.and the virulence factors of Candida albicans(C.albicans) isolated from external surfaces of blow flies collected from Mae Sot,Tak Province,Thailand.Methods:The blow flies were collected by sterile sweep nets from three areas in Mae Sot.Yeast isolation was first performed on Sabouraud dextrose agar(SDA) supplemented with chloramphenicol and cycloheximide.The yeast isolates were then identified by using chromogenic agar,a yeast identification test kit,a germ tube formation test and a carbohydrate utilization test.The β-hemolysis was determined on 7% sheep blood agar,while phospholipase activity was measured on SDA agar supplemented with 10% egg yolk suspension.Antifungal susceptibility testing was determined by broth micro-dilution testing against ketoconazole and amphotericin B.Results:The prevalence rate of Candida spp.on the external surfaces of the blow flies was 78.1%.All C.albicans isolated from the blow fly demonstrated b-hemolysin and potent phospholipase activities and 47.1% of C.albicans were resistant to ketoconazole with MIC values 128 mg/m L.Conclusions:The results indicate that blow flies could play an essential role in the transmission of potentially pathogenic and antifungal resistant C.albicans into the environment.Further investigation on other virulence factors and genetic relatedness among isolates from the blow flies,the environment and clinical specimens is required to confirm this role.

Effects of Farnesol on Drug-Resistant and Non-Resistant <i>Candida albicans</i>: Implications for Cosmetic and Pharmaceutical Applications

Background: Farnesol is added to numerous consumer products that intentionally, or inadvertently come in contact with tissues that may harbor the opportunistic yeast, Candida albicans. Objective: This study explores biological consequences of the exposure of Candida albicans from community infections or from a panel of antifungal drug resistant organisms on growth and survival of these organisms when exposed to farnesol. Methods: ATCC supplied Candida albicans from the MP8 drug resistance panel and an additional 12 strains of community-acquired Candida albicans were cultured in the presence of farnesol. With standard micobiologic techniques and flow cytometry evaluation, a series of experiments considered growth, morphology, viability and entrance into the quiescent persister phenotype of Candida with emphasis on differences between drug resistant and community organisms. Results: Differences growth yield, relative cell size and heat susceptibility distinguished the community organisms from the drug-resistant organisms. Using a subset of these organisms, exposure to farnesol resulted in diminished growth, inhibited hyphal growth, diminished cell membrane integrity and increased heat stress susceptibility. Data provided suggest that exposure to farnesol pushes cultures of Candida albicans toward the quiescent persister phenotype. Conclusion: Exposure of drug resistant and community strains of Candida albicans are modestly affected by farnesol in ways that may lessen their pathogenic potential. In contrast, the tendency of farnesol to engender greater numbers of quiescent organisms could support persistence of Candida.

Cryptococcus neoformans,a global threat to human health

Background Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL,Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance. The purpose of this review is to drive research efforts to improve future diagnoses, therapies, and interventions associated with fungal infections.Methods We first reviewed trends in the global burden of HIV-associated cryptococcal infection, mainly based on a series of systematic studies. We next conducted scoping reviews in accordance with the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews using PubMed and ScienceDirect with the keywordCryptococcus neoformans to identify case reports of cryptococcal infections published since 2000. We then reviewed recent updates on the diagnosis and antifungal treatment of cryptococcal infections. Finally, we summarized knowledge regarding the resistance and tolerance ofC. neoformans to approved antifungal drugs.Results There has been a general reduction in the estimated global burden of HIV-associated cryptococcal meningitis since 2009, probably due to improvements in highly active antiretroviral therapies. However, cryptococcal meningitis still accounts for 19% of AIDS-related deaths annually. The incidences of CM in Europe and North America and the Latin America region have increased by approximately two-fold since 2009, while other regions showed either reduced or stable numbers of cases. Unfortunately, diagnostic and treatment options for cryptococcal infections are limited, and emerging antifungal resistance exacerbates the public health burden.Conclusions The rising threat ofC. neoformans is compounded by accumulating evidence for its ability to infect immunocompetent individuals and the emergence of antifungal-resistant variants. Emphasis should be placed on further understanding the mechanisms of pathogenicity and of antifungal resistance and tolerance. The development of novel management strategies through the identification of new drug targets and the discovery and optimization of new and existing diagnostics and therapeutics are key to reducing the health burden.

热带念珠菌临床分离株对氟康唑耐药分子机制的研究(英文)

Objective This study aimed to investigate the molecular mechanisms responsible for fluconazole resistance in clinical isolates of this pathogenic yeast.Methods A total of 41 Candida tropicalis strains were collected from the clinical laboratory of Taiyuan City Central Hospital.Antifungal susceptibility testing was performed by ATB FUNGU 3 method.The 14 α-demethylase (ERG11) gene in all clinical isolates of Candida tropicalis were amplified by PCR,and their nucleotide sequences were determined in order to detect point mutations.Likewise,efflux transporters (CDR1 and MDR1) and ERG11 genes were tested by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) for their expression in Candida tropicalis cells at the mRNA level.Results The fluconazole-resistant rate of 41 Candida tropicalis was 12.2%.The amino acid substitutions in ERG11p of R245K,Y221F and V362I were found in fluconazole-resistant isolates.And no amino acid substitution was detected in fluconazole-susceptible ones.The mRNA level of CDR1,MDR1 and ERG11 genes in fluconazole-resistant isolates all showed overexpression compared with fluconazole-susceptible ones.Conclusions Missense mutations in ERG11 gene associated with overexpression of CDR1,MDR1 and ERG11 gene seemed to be responsible for the acquired fluconazole resistance of these clinical isolates.