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.

Pulmonary fungal infection in a neonate with methylmalonic acidemia:A case report

BACKGROUND Methylmalonic acidemia(MMA)is characterized by non-specific symptoms such as vomiting,and feeding difficulties,along with delayed mental and physical development.However,no case of MMA combined with pulmonary fungal infection has been reported yet.CASE SUMMARY We report the case of a neonate who presented pulmonary fungal infection along with the non-specific features of MMA.Exome sequencing revealed a c.331C>T variant in exon 3 of MMACHC from the father,and a c.658-c.660delAAG variant in exon 4 from the mother,which confirmed the diagnosis of cblC type MMA combined with hyperhomocysteinemia.CONCLUSION Invasive fungal infection might occur in some infants with MMA.Therefore,early diagnosis is recommended for unexplained pulmonary infection.

Invasive fungal infection before and after liver transplantation

Invasive infections are a major complication before liver transplantation(LT)and in the early phase after surgery.There has been an increasing prevalence of invasive fungal disease(IFD),especially among the sickest patients with decompensated cirrhosis and acute-on-chronic liver failure,who suffer from a profound state of immune dysfunction and receive intensive care management.In such patients,who are listed for LT,development of an IFD often worsens hepatic and extra-hepatic organ dysfunction,requiring a careful evaluation before surgery.In the post-transplant setting,the burden of IFD has been reduced after the clinical advent of antifungal prophylaxis,even if several major issues still remain,such as duration,target population and drug type(s).Nevertheless,the development of IFD in the early phase after surgery significantly impairs graft and patient survival.This review outlines presentation,prophylactic and therapeutic strategies,and outcomes of IFD in LT candidates and recipients,providing specific considerations for clinical practice.

Fungal infections following liver transplantation

With increasing morbidity and mortality from chronic liver disease and acute liver failure,the need for liver transplantation is on the rise.Most of these patients are extremely vulnerable to infections as they are immune-compromised and have other chronic co-morbid conditions.Despite the recent advances in practice and improvement in diagnostic surveillance and treatment modalities,a major portion of these patients continue to be affected by post-transplant infections.Of these,fungal infections are particularly notorious given their vague and insidious onset and are very challenging to diagnose.This mini-review aims to discuss the incidence of fungal infections following liver transplantation,the different fungi involved,the risk factors,which predispose these patients to such infections,associated diagnostic challenges,and the role of prophylaxis.The population at risk is increasingly old and frail,suffering from various other co-morbid conditions,and needs special attention.To improve care and to decrease the burden of such infections,we need to identify the at-risk population with more robust clinical and diagnostic parameters.A more robust global consensus and stringent guidelines are needed to fight against resistant microbes and maintain the longevity of current antimicrobial therapies.

Modified ulcer debridement in the treatment of the superficial fungal infection of the cornea

AIM： To evaluate the efficacy of modified corneal ulcer debridement in superficial fungal keratitis unresponsive to medications.METHODS： A total of 209 patients（209 eyes） with fungal keratitis, involving no more than 50% of the stromal depth and not responding to antifungal agents for 2 wk, were recruited in this retrospective, noncomparative study. The patients were treated with modified corneal ulcer debridement. All visible corneal infiltrates were removed under an operating microscope to obtain a clean stromal bed and smooth incised edges. Antifungal drugs were used immediately after surgery. Healing time of the ulcers was recorded. Fungal recurrence, visual acuity, corneal thickness and risk factors for treatment failure were monitored.RESULTS： The follow-up was 13.6±5.8m o. The corneal ulcers healed in 195 of 209 eyes（93.3%）, with a mean healing time of 8.4±6.8 d. The other 14 eyes were further treated by penetrating keratoplasty（PK）（1 eye）, anterior lamellar keratoplasty（LK）（7 eyes）, conjunctival flap covering（4 eyes） or amniotic membrane transplantation（2 eyes）. The best corrected visual acuity（BCVA） was ≥20/70 in 80.3% of the eyes, ≥20/40 in 56.9% of the eyes, and ≥20/25 in 27.3% of the eyes. The corneas at the lesions became thinner, but all in the safe range. No fungal recurrence or corneal ectasis developed during the follow-up. The risk of treatment failure was higher in patients with preoperative hypopyon（P=0.036） and ever using steroid（P=0.025）.CONCLUSION： Modified surgical debridement is a simple and effective method for the treatment of superficial fungal infection of the cornea, with improved visual acuity and no recurrence. Such an intervention in time can rapidly control fungal infection and largely shorten corneal ulcer healing time.

Invasive Fungal Infections in People Living with HIV/AIDS

The increased incidence of invasive and opportunistic mycoses is probably related to the growth of the immunocompromised population, such as people living with HIV. This study is a literature review that aims to analyze the frequency of invasive fungal infections in people living with HIV. In most studies evaluated, Pneumocystis pneumonia was the most frequent invasive fungal infection among people living with HIV, and cryptococcosis was the second most frequent. Invasive fungal infections are associated with greater morbidity and mortality in people living with HIV. The most important highlighted information is that the lack of epidemiological data on fungal infections in the studied populations was reported by most studies. Therefore, there is a need for further studies to assess the frequency of invasive fungal infection in people living with HIV, which may serve as subsidies for the implementation of strategies for the prevention and management, with a consequent increase in the quality of life and reduction of morbidity/mortality in this population.

Dysregulated STAT1 gain-of-function:Pathogen-free autoimmunity and fungal infection

Inborn errors of the signal transducer and activator of transcription 1(STAT1)result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function:autosomal recessive(AR)complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant(AD)STAT1 deficiency,and AD STAT1 gain-of-function(STAT1-GOF).Of which,the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections,especially chronic mucocutaneous candidiasis(CMC)and Talaromyces marneffei infection and predisposition to humoral autoimmunity.STAT1-GOF mutations lead to enhanced phosphorylation of STAT1(pSTAT1),delayed dephosphorylation,and impaired nuclear dephosphorylation.As a result,the development of T helper(Th)17 cells is impaired,limiting the production of interleukin(IL)-17,which plays an important role in antifungal immunity.Additionally,mutations can also cause a decrease in the proportion of CD4^(+),CD8^(+),and natural killer(NK)cells.Recent research demonstrated that in the absence of overt infection,STAT-GOF mice can disrupt naïve CD4^(+)T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like(Tfh/Th1-like)T cells and germinal center-like(GC-like)B cells,and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection,which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies.In addition,sex and location of mutation were also associated with the clinical phenotype.Individuals with DNA binding domain(DBD)mutations had a higher prevalence of autoimmunity and aberrant B cell activation.Disrupted CD4^(+)T cell homeostasis occurred sooner and more robustly in females,highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome.Herein,we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and humoral immune deficiency in patients with fungal infection with or without autoimmunity.

Single-cell transcriptomics reveals T-cell heterogeneity and immunomodulatory role of CD4^(+) T native cells in Candida albicans infection

Objective:Candida albicans is a common fungal pathogen that triggers complex host defense mechanisms,including coordinated innate and adaptive immune responses,to neutralize invading fungi effectively.Exploring the immune microenvironment has the potential to inform the development of therapeutic strategies for fungal infections.Methods:The study analyzed individual immune cell profiles in peripheral blood mononuclear cells from Candida albicans-infected mice and healthy control mice using single-cell transcriptomics,fluorescence quantitative PCR,and Western blotting.We investigated intergroup differences in the dynamics of immune cell subpopulation infiltration,pathway enrichment,and differentiation during Candida albicans infection.Results:Our findings indicate that infiltration of CD4^(+)naive cells,regulatory T(Treg)cells,and Microtubules(MT)-associated cells increased after infection,along with impaired T cell activity.Notably,CD4^(+) T cells and plasma cells were enhanced after infection,suggesting that antibody production is dependent on T cells.In addition,we screened 6 hub genes,transcription factor forkhead box protein 3(Foxp3),cytotoxic T-lymphocyte associated protein 4(CTLA4),Interleukin 2 Receptor Subunit Beta(Il2rb),Cd28,C-C Motif Chemokine Ligand 5(Ccl5),and Cd27 for alterations associated with CD4^(+) T cell differentiation.Conclusions:These results provide a comprehensive immunological landscape of the mechanisms of Candida albicans infection and greatly advance our understanding of adaptive immunity in fungal infections.

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.

Prevalence of Bacterial and Fungal Infected Chronic Leg Ulcers at a Teaching Hospital in Ghana

Background: Chronic ulcers are responsible for considerable morbidity and significantly contribute to the escalation in the cost of health care. Chronic leg ulcers (CLUs) are susceptible to microbial infections and serious complications such as tissue necrosis and osteomyelitis, can result without the timely control of infections. Recent studies have also reported an increase in the association of fungal infections with chronic non-healing ulcers. Aim: To determine the prevalence of bacterial and fungal infections among patients reporting with chronic leg ulcers in participants without co-morbidities. Methods: A prospective cross-sectional study was conducted among patients with chronic leg ulcers at the National Reconstructive Plastic Surgery and Burns Centre, Korle-Bu Teaching Hospital (NRPS/BC-KBTH) and those who consented were enrolled. Characteristics of the wound as well as micro-organisms cultured from wound swabs were recorded. Results: A total of 50 participants were enrolled for the study with the mean (SD) age of 40.7 (10.7) years. Eighty percent of the participants presented with post traumatic leg ulcers with 80% being artisans and traders in the age group 31 - 50 years. There was no statistically significant association between sex and the organism cultured for post traumatic and cellulitis (p-value > 0.05). The prevalence of bacterial and fungal infection was 79.3% and 20.7% respectively. Pseudomonas species was the most isolated bacteria (61.5%) while Aspergillus niger was the most isolated fungi (41%). Conclusion: From this study, fungal infections should be included in managing chronic leg ulcers, especially among artisans, famers and gardeners even though there was a significantly higher burden of bacterial infections.

Clinical efficacy and safety of intravenous itraconazole in patients with invasive fungal infections in emergency intensive care unit

This study aimed to analyze the clinical efficacy and safety of itraconazole. We investigated 68 patients with invasive fungal infections（IFI） in emergency intensive care unit（EICU）. A retrospective analysis was performed in patients with IFI who were treated in the authors＇ institution, a grade III first class hospital in Beijing, China, between Feb. 2013 and Feb. 2015. The age of patients ranged from 35 to 90 years old with the mean age of（75.1±11.1） years old. The study population comprised 36 male and 32 female patients. Total response rate was 60.3%. The response rates in definitive diagnosis, clinical diagnosis and presumed diagnosis were 33.3%, 59.5% and 65.2%, respectively（P〈0.05）. The empirical treatment should be provided for patients with presumed diagnosis as earlier as possible. Eleven（16.2%） cases had adverse drug event（ADE） during treatment. The main signs were hepatic functional impairment and hypokalemia of ADE. The clinical efficacy and safety of intravenous itraconazole were precisely assessed. To reduce the adverse drug reaction（ADR）, hepatic and renal function and other biochemical criterion should be closely monitored.

Epidemiology of opportunistic invasive fungal infections in China： review of literature

Objective To summarize the recent findings on the epidemiology of medically important, opportunistic invasive fungal infections （IFIs） in China and discuss the relevant social, economical reasons and medical factors. Data sources We performed a comprehensive search of both English and Chinese literatures of opportunistic IFIs from China up to April 2012. Study selection Relevant literatures involving researches and cases/case sedes were identified, retrieved and reviewed. Results The incidence of opportunistic IFIs in China was steadily increasing. The incidence and mortality of IFIs were different in patients with various underlying conditions/diseases, from 4.12% to 41.18% and 9.8% to 60.0%, respectively. Candida species, Aspergillus species and Cryptococcus neoformans species complex were the most frequent isolated pathogens. Other uncommon opportunistic IFIs were also been reported, including trichosporonosis, mucormycosis, hyalohyphomycosis （hyaline hyphomycetes） and phaeohyphomycosis （dematiaceous hyphomycetes）. Reports of Chinese patients differed from those of many other countries as there were a higher number of patients without identifiable underlying diseases/conditions. Conclusions Because of the rapid economic development, changing population structure and a growing number of immunocompromised hosts with risk factors, today opportunistic IFIs in China have a significant impact on public health, associated with high morbidity/mortality and higher care costs. Now information related to the epidemiology of opportunistic IFIs in China is still sparse, so we need more organized groups of clinical scientists performing related researches to help the clinicians to obtain more accurate epidemiological characteristics.

Delivery strategies of amphotericin B for invasive fungal infections

Invasive fungal infections(IFIs)represent a growing public concern for clinicians to manage in many medical settings,with substantial associated morbidities and mortalities.Among many current therapeutic options for the treatment of IFIs,amphotericin B(AmB)is the most frequently used drug.AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance.In this review,we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs.We have also discussed the mechanism of actions of AmB,rationale for treating IFIs,and recent advances in formulating AmB for clinical use.Finally,this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.

Pulmonary fungal infections after bone marrow transplantation： the value of high-resolution computed tomography in predicting their etiology

Background The correct diagnosis of etiology of fungal infection after bone marrow transplantation is very important to the choice of antifungal drugs and a premise for improvement of therapeutic efficacy. This study aimed to compare high-resolution computed tomography （HRCT） findings of the pulmonary fungal infections to determine whether the etiology of various fungal infections could be diagnosed with HRCT. Methods Eighty-five cases were enrolled. According to the pathogens responsible for fungal infections, the patients were classified into three groups including invasive aspergillosis （n=52）, candidiasis （n=19） and cryptococcosis （n=14） groups. All the patients underwent HRCT scans. Two independent radiologists retrospectively analyzed the HRCT scans regarding CT patterns and distribution of lung abnormality. Results Most fungal infections in the three groups occurred in the neutropenic phase. There was no significant difference in the constituent ratio of fungal infections at different phases after bone marrow transplantation among the three groups. Agreement between the two observers for all the CT characteristics of fungal infections was excellent （k 〉0.75）. There was a significant difference in occurrence ratio of mass among the three groups （P=-0.02）. Occurrence ratio of mass （43.3%, 13/30） in the group with invasive aspergillosis was higher than in each of other two groups （20.0%, 2/10; 14.3%, 1/7）. There was no significant difference in other CT characteristics of nodules or masses; including number, margin, halo sign, cavitation and air-crescent sign. There was no significant difference in number, margin, air bronchogram and distribution of air-space consolidation. Conclusions The HRCT appearance of various pulmonary fungal infections has a great deal of overlap and is nonspecific. Mass is more common in invasive aspergillosis, which is helpful to the diagnosis of invasive aspergillosis after bone marrow transplantation.

IL-17C is required for lethal inflammation during systemic fungal infection

Within the interleukin-17 （IL-17） family of cytokines, IL-17A is known to be critical in the host defense against fungal infections; however, the function of the other IL-17 family members in anti-fungal immunity remains largely unknown. Here, we show that IL-17C expression was highly induced in kidney epithelial cells after fungal infection. Mice that lacked IL-17C exhibited increased survival and attenuated kidney tissue damage, although they had similar fungal loads. IL-17C deficiency resulted in decreased pro-inflammatory cytokine expression compared with wild-type control mice. Additionally, IL-17C directly acted on renal epithelial cells in vitro to promote pro-inflammatory cytokine production. Taken together, our data demonstrate that IL-17C is a critical factor that potentiates inflammatory responses and causes host injury during fungal infection.

Diagnosis and treatment of fungal infection after liver transplantation

Background Liver transplantation is the most effective treatment for end-stage liver diseases; however, infections after transplantation can seriously affect the patient＇s health. The aim of this research was to investigate the diagnosis and treatment of fungal infection following liver transplantation.

Bioresponsive micro-to-nano albumin-based systems for targeted drug delivery against complex fungal infections

As a typical human pathogenic fungus,Cryptococcus neoformans is a life-threatening invasive fungal pathogen with a worldwide distribution causing w700,000 deaths annually.Cryptococcosis is not just an infection with multi-organ involvement,intracellular survival and extracellular multiplication of the fungus also play important roles in the pathogenesis of C.neoformans infections.Because adequate accumulation of drugs at target organs and cells is still difficult to achieve,an effective delivery strategy is desperately required to treat these infections.Here,we report a bioresponsive micro-to-nano(MTN)system that effectively clears the C.neoformans in vivo.This strategy is based on our in-depth study of the overexpression of matrix metalloproteinase 3(MMP-3)in infectious microenvironments(IMEs)and secreted protein acidic and rich in cysteine(SPARC)in several associated target cells.In this MTN system,bovine serum albumin(BSA,a natural ligand of SPARC)was used for the preparation of nanoparticles(NPs),and then microspheres were constructed by conjugation with a special linker,which mainly consisted of a BSA-binding peptide and an MMP-3-responsive peptide.This MTN system was mechanically captured by the smallest capillaries of the lungs after intravenous injection,and then hydrolyzed into BSA NPs by MMP-3 in the IMEs.The NPs further targeted the lung tissue,brain and infected macrophages based on the overexpression of SPARC,reaching multiple targets and achieving efficient treatment.We have developed a size-tunable strategy where microspheres"shrink"to NPs in IMEs,which effectively combines active and passive targeting and may be especially powerful in the fight against complex fungal infections.

Invasive fungal infection in allogeneic hematopoietic stem cell transplant recipients: single center experiences of 12 years

Invasive fungal infection （IFI） is a growing cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT）. We retrospectively reviewed the records of 408 patients un- dergoing alIo-HSCTs during the period November 1998 to December 2009, analyzed the incidence and risk factors of IFI, and examined the impact of IFI on overall survival. A total of 92 （22.5%） episodes suffered proven or probable IFI （4 patients were proven, 88 patients were probable）. Candida was the most common pathogen for early IFI, and mold was the most frequent causative organism for late IFI. A prior history of IFI, human leukocyte antigen （HLA） mismatch, long-time neutropenia, and acute graft-versus-host-disease （GVHD） were risk factors for early IFI. A prior history of IFI, corticosteroid therapy, cytomegalovirus （CMV） disease, and chronic GVHD were risk factors for late IFI. IFI-related mortality was 53.26%. The 12-year overall survival （OS） rate for IFI was significantly lower than that of patients without IFI （41.9% vs. 63.6%, P〈0.01）.

Guideline for diagnosis, prophylaxis and treatment of invasive fungal infection post burn injury in China 2013

Invasive fungal infection is one of the major complication of severe burns which can induce local or systemic inflammatory response and cause serious substantial damage to the patient. The incidence of fungal infection for burn victims is increasing dramatically during recent years. This guideline, organized by Chinese Society of Burn Surgeons, aims to standardize the diagnosis, prevention and treatment of burn invasive fungal infection. It can be used as one of the tools for treatment of major burn patients.

Caspofungin versus liposomal amphotericin B for treatment of invasive fungal infections or febrile neutropenia

Background Nowadays,there are published trials in regards to the comparison of caspofungin with liposomal amphotericin B （L-AmB）.However,these studies have a modest sample size and convey inconclusive results.The aim of this study was to review the efficacy and safety of caspofungin for the treatment of invasive fungal infections （IFIs）,compared with L-AmB.Methods Electronic databases （up to July 31,2013） PubMed and Embase databases,the Cochrane Library,and Google Scholar were searched to identify relevant trials of caspofungin and L-AmB.Analyses of efficacy and adverse outcomes were performed by relative risks （RRs） and 95% confidence intervals （C/s）.Heterogeneity was assessed by x2-test and the/2-statistic.Results Three trials were included in this meta-analysis with 1249 modified intention-to-treat （MITT） patients.The results showed that caspofungin produced equal efficacy in favorable overall response （RR=1.02,95% Cl 0.88-1.18; P=0.81） and mortality rate （RR=1.53,95% Cl 0.38-6.27,P=0.55）,safer in clinical adverse events （RR=0.20,95% Cl 0.08-0.54; P=0.001）,laboratory adverse events （RR=0.69,95% Cl 0.57-0.84; P=0.0002）,and discontinuation rate （RR=0.26,95% Cl 0.08-0.83,P=0.02）,compared with L-AmB in the treatment of patients with IFls.Conclusion Based on the results of this meta-analysis,it would appear that caspofungin was measured to have equal efficacy in clinical outcomes and safer in terms of adverse events.