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Timing of invasive fungal infections after organ transplantation
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Invasive fungal infections are infections of importance and are increasing in incidence in immunocompromised hosts such as patients who have had hematopoietic stem cell and solid organ transplants. Despite our expanded antifungal armamentarium, these infections cause considerable morbidity and mortality. Indeed, certain trends have emerged in these...
Context in source publication
Context 1
... time to development of invasive fungal infection after transplantation depends on the transplant type, the use and duration of use of antifungal prophylaxis, and the fungal pathogen. In the HSCT population, the timeline is split into three time periods from the time of transplantation: early onset (≤1 month [pre-engraftment phase]), late onset (1-6 months [post-engraftment phase]) and very late onset (>6 months) (Figure 1). In the TRANSNET report, the median time after transplanta- tion to onset of invasive fungal infection was 61, 99, 123, and 135 days for candidiasis, aspergillosis, fusariosis, and zygomycosis cases, respectively [7]. ...
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Citations
... under critical fungal pathogen category in its rst ever fungal pathogen priority list (Fisher & Denning, 2023). Invasive fungal infections associated with C. albicans, are the primary cause of the rising death rate in the immunocompromised population (Low & Rotstein, 2011;Rayens & Norris, 2022). Over the last few decades, invasive candidiasis, caused by C. albicans has become the most prevalent illness among hospitalised patients, giving rise to a critical condition known as candidemia which has been listed as the fourth most frequent cause of bloodstream infection (Bongomin et al., 2017;Pahwa et al., 2014;Weiner-Lastinger et al., 2020). ...
Candida albicans has been listed in critical priority group by the WHO in 2022 depending upon its contribution in invasive candidiasis and increased resistance to conventional drugs. Drug repurposing is an efficient and cost-effective solution to develop alternative therapeutics where alexidine dihydrochloride (AXD) and hexachlorophene (HCP) are FDA approved anti-cancer and anti-septic drugs, respectively. In this study, we have shown antifungal properties of AXD and HCP against C. albicans and clinical isolates. The minimum inhibitory concentrations (MIC 50 ) of AXD and HCP against C. albicans ranged between 0.2-0.4 µg/ml and 8-10 µg/ml, respectively. The biofilm inhibitory and eradication concentration of AXD and HCP also ranged in permissible range for C. albicans biofilm. Further investigations were performed to understand the antifungal mode of action of AXD and HCP by studying virulence features like cell surface hydrophobicity, adhesion, and yeast to hyphae transition, were also reduced upon exposure to both the drugs. Ergosterol content in cell membrane of the wild type strain was upregulated on exposure to AXD and HCP both. Biochemical analyses of the exposed biofilm indicated reduced contents of carbohydrate, protein, and e-DNA in the extracellular matrix of the biofilm when compared to the untreated control biofilm. AXD exposure downregulated activity of tissue invading enzyme, phospholipase in the reference strain. In wild type strain, ROS level, and activities of antioxidant enzymes were found elevated upon exposure to both drugs. FESEM analysis of the drug treated biofilms revealed degraded biofilm. This study has indicated mode of action of antifungal potential of alexidine dihydrochloride and hexachlorophene in C. albicans .
... AFS shares similar goals with AMS, such as promoting the scientific and rational use of antimicrobial drugs, appropriately simplifying the prescription of antifungal drugs, and preventing the spread of multidrug-resistant microorganisms [8]. However, there are several unique difficulties in implementing AFS due to the differences between bacterial infection and fungal infection [9][10][11]. (I) Patients infected with bacteria could be either inpatients or outpatients, while fungal infections mostly occur in immunosuppressed hospitalized patients. (II) Most clinicians are experienced in the treatment of bacterial infections, but there is often a knowledge gap among clinicians regarding the treatment of IFDs. ...
Background
The sharp increase in fungal infections, insufficient diagnostic and treatment capabilities for fungal infections, poor prognosis of patients with fungal infections as well as the increasing drug resistance of fungi are serious clinical problems. It is necessary to explore the implementation and evaluation methods of antifungal stewardship (AFS) to promote the standardized use of antifungal drugs.
Methods
The AFS programme was implemented at a tertiary first-class hospital in China using a plan-do-check-act (PDCA) quality management tool. A baseline investigation was carried out to determine the utilization of antifungal drugs in pilot hospitals, analyse the existing problems and causes, and propose corresponding solutions. The AFS programme was proposed and implemented beginning in 2021, and included various aspects, such as team building, establishment of regulations, information construction, prescription review and professional training. The management effectiveness was recorded from multiple perspectives, such as the consumption of antifungal drugs, the microbial inspection rate of clinical specimens, and the proportion of rational prescriptions. The PDCA management concept was used for continuous improvement to achieve closed-loop management.
Results
In the first year after the implementation of the AFS programme, the consumption cost, use intensity and utilization rate of antifungal drugs decreased significantly (P < 0.01). The proportion of rational antifungal drug prescriptions markedly increased, with the proportion of prescriptions with indications increasing from 86.4% in 2019 to 97.0% in 2022, and the proportion of prescriptions with appropriate usage and dosage increased from 51.9 to 87.1%. In addition, after the implementation of the AFS programme, physicians’ awareness of the need to complete microbial examinations improved, and the number of fungal cultures and serological examinations increased substantially. Statistics from drug susceptibility tests revealed a decrease in the resistance rate of Candida to fluconazole.
Conclusion
This study indicated that the combination of AFS and the PDCA cycle could effectively reduce antifungal consumption and promote the rational use of antifungal drugs, providing a reference for other health care systems to reduce the overuse of antifungal drugs and delay the progression of fungal resistance.
... As resistance spreads, the number of effective treatment options decreases, leaving patients with fewer alternatives for managing fungal infections [93]. Evidence has revealed that vulnerable populations, such as those with compromised immune systems (e.g., transplant recipients, HIV/AIDS patients, and cancer patients), are particularly susceptible to fungal infections [96] [111] [112]. AFR disproportionately affects these individuals, leading to increased health disparities [113]. ...
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.
... Additionally, in our opinion, such analyses are important not only because of the possibility of discovering new fungal species [7], but above all, because the underground object is a popular touristic attraction and contact with potentially pathogenic fungal matter (e.g., spores) [24] might cause serious health issues, especially in individuals with impaired immune systems [71]. ...
Soil and sediment host microorganisms are able to survive in extremely resource-limited environments. Therefore, more and more attention is being paid to cave sediments as a reservoir of microbiota. The aim of this study is the speleomycological evaluation of the culturable soil and sediment fungal communities in the Brestovská Cave. To explore the origins of fungi, speleomycological studies were conducted both inside and outside the cave under investigation. Additionally, two incubation temperatures (5 and 24 °C) were used to increase the species spectrum of isolated fungi. To achieve the most accurate species identification, we combined an assessment of morphological characteristics of the isolates with molecular sequencing (ITS, internal transcribed spacer). Twenty different species were found and the most frequent was Penicillium commune, fol-lowed by Trichosporiella cerebriformis and Pseudogymnoascus pannorum. To our knowledge, our study has enabled the first identification of fungal species such as Penicillium swiecicki, Cephalotrichum hinnuleum, Cosmpospora berkeleyana, Lecythophora hoffmannii, Ambomucor seriatoinflatus, and Mortierella minutissima in underground sites. Our data showed that the abundance and composition of the fungal community varied between the indoor and outdoor samples and thus from the entrance and less visited sites deeper in the cave.
... Rights reserved. (Low and Rotstein 2011). As its infection progresses and deepens into the membrane, yeast cells penetrate vessels, disseminate with the blood flow, and infect the host major organs viz. ...
Candida species is the causative agent in approximately 80% of invasive mycoses and drug-resistant Candida albicans is among the four strains of ‘critical priority group’ framed by WHO. Lichens are endowed with some rare phytochemicals and a plethora of therapeutics viz. antifungal capacities of Roccella montagnei. Biosynthesis of silver nanoparticles (AgNPs) using lichen could offer an eco-friendly, and cost-effective alternative against emerging ‘microbial resistance.’ Therefore, the objective was to biosynthesize silver nanoparticles (Rm-AgNPs) using a Hydro-alcoholic (1:1) extract of R. montagnei to develop a potent anticandidal agent against Fluconazole-resistant C. albicans NBC099. UV-Spectroscopy identified AgNPs specific-peak of Rm-AgNPs at 420–440 nm and FTIR revealed the presence of amines, alcohol, aromatic compounds, and acids. SEM and TEM analysis indicated that Rm-AgNPs are spherical shaped with a size range of 10–50 nm. Zetasizer analysis indicated that particles are highly stable and have a mean hydrodynamic diameter of 116 nm with a zeta potential charge of − 41 mV. XRD analysis suggested face centered cubic crystal lattice structure. Results indicated that Rm-AgNPs strongly inhibited the growth of NBC099 at a minimum inhibitory concentration (IC50) of ≤ 15 µg. C. albicans culture treated with Rm-AgNPs at concentrations below IC50, down-regulates the production of different virulence factors in NBC099, viz. hyphal formation (> 85%), biofilms production (> 80%), phospholipase, esterase, proteinase activity. The apoptosis assay demonstrated the Rm-AgNPs induced apoptosis in NBC099 cells via oxidative stress. Interestingly, Rm-AgNPs showed negligible cytotoxicity (< 6%) in murine RAW 246.7 macrophage cells at a concentration above 15 µg/mL. Therefore, Rm-AgNPs have been offered as an anti-candida alternative that can be utilized to improve the efficacy of already available medications.
Graphical abstract
... The spectrum of pathologies caused by Aspergillus species is named aspergillosis with IA as one of the most critical diseases due to its high mortality rates among immunocompromised hosts. 1,39,40 Aspergillus fumigatus is the most frequently isolated species among the Aspergillus genus in different parts of the world. 23,24,26,28,31 Similarly, in our 3-year surveillance results, out of a total of 335 Nowadays, the rise of A. fumigatus azole-resistant strains has become globally alarming, 7 representing a severe threat to a successful clinical outcome, because azole resistance is closely associated to treatment failure and a higher mortality rate. ...
Background
Surveillance studies are crucial for updating trends in Aspergillus species and antifungal susceptibility information.
Objectives
Determine the Aspergillus species distribution and azole resistance prevalence during this 3‐year prospective surveillance study in a Spanish hospital.
Materials and Methods
Three hundred thirty‐five Aspergillus spp. clinical and environmental isolates were collected during a 3‐year study. All isolates were screened for azole resistance using an agar‐based screening method and resistance was confirmed by EUCAST antifungal susceptibility testing. The azole resistance mechanism was confirmed by sequencing the cyp 51A gene and its promoter. All Aspergillus fumigatus strains were genotyped using TRESPERG analysis.
Results
Aspergillus fumigatus was the predominant species recovered with a total of 174 strains (51.94%). The rest of Aspergillus spp. were less frequent: Aspergillus niger (14.93%), Aspergillus terreus (9.55%), Aspergillus flavus (8.36%), Aspergillus nidulans (5.37%) and Aspergillus lentulus (3.28%), among other Aspergillus species (6.57%). TRESPERG analysis showed 99 different genotypes, with 72.73% of the strains being represented as a single genotype. Some genotypes were common among clinical and environmental A. fumigatus azole‐susceptible strains, even when isolated months apart. We describe the occurrence of two azole‐resistant A. fumigatus strains, one clinical and another environmental, that were genotypically different and did not share genotypes with any of the azole‐susceptible strains.
Conclusions
Aspergillus fumigatus strains showed a very diverse population although several genotypes were shared among clinical and environmental strains. The isolation of azole‐resistant strains from both settings suggest that an efficient analysis of clinical and environmental sources must be done to detect azole resistance in A. fumigatus.
... Although bacterial and viral infections are the most common causes of death in patients with hematological neoplasms and infections, IFI are also of great medical importance due to their frequency and mortality. 27 Among the causative agents of IFI in immunocompromised patients, the most common are yeasts (mainly Candida spp.) and molds (mainly Aspergillus spp.), while other fungal pathogens (e.g. Zygomycetes, Mucorales, Fusarium spp., Cryptococcus spp., and others) occur much less frequently. ...
... Zygomycetes, Mucorales, Fusarium spp., Cryptococcus spp., and others) occur much less frequently. 27 In patients with hematological neoplasms, the most common causative agent of IFI is Aspergillus spp., which results in significant mortality. 28 Fungi are opportunistic agents of infection, which can cause IFI in humans (especially in those who are immunocompromised) in the presence of certain risk factors that facilitate the onset of infection. ...
Multiple myeloma is among the most common hematological malignancies and is characterized by a strong susceptibility to infections primarily bacterial and viral and, to a much lesser extent, fungal. There appears to be a slightly increasing frequency of invasive fungal infections. This is attributed to the use of different combinations of newer drugs and patients’ exposure to increasing therapeutic lines, and thus to risk factors for invasive fungal infections, especially severe and long-term neutropenia. Novel immunotherapy modalities including bispecific antibodies and chimeric antigen receptor T-cell therapy are being introduced for the treatment of relapsing-refractory forms of the disease. Consequently, in the near future, it can be expected that myeloma patients will exhibit a significantly increased frequency of invasive fungal infections. Therefore, we must carefully monitor all epidemiological trends related to invasive fungal infections in patients with multiple myeloma, both in clinical studies and in real life. This will help us learn to prevent fungal infections, as well as quickly recognize and treat them to reduce their impact on patients’ morbidity and mortality. In this review article, we describe in detail the epidemiological characteristics of invasive fungal infections in myeloma patients, the risk factors for these infections, and the treatment and prevention options.
... [8,9]. The risk of getting a fungal disease for immunocompromised patients is many times higher and also more life-threatening than for other patients [10][11][12]. It was also noticed that the number of patients with fungal disease increased significantly during the coronavirus pandemic. ...
In addition to the rising number of patients affected by viruses and bacteria, the number of fungal infections has also been rising over the years. Due to the increase in resistance to various antimycotics, investigations into further disinfection options are important. In this study, two yeasts (Candida auris and Saccharomyces cerevisiae) and a mold (Cladosporium cladosporioides) were irradiated at 365, 400, and 450 nm individually. The resulting log 1 reduction doses were determined and compared with other studies. Furthermore, fluorescence measurements of C. auris were performed to detect possible involved photosensitizers. A roughly exponential photoinactivation was observed for all three fungi and all irradiation wavelengths with higher D90 doses for longer wavelengths. The determined log 1 reduction doses of C. auris and S. cerevisiae converged with increasing wavelength. However, S. cerevisiae was more photosensitive than C. auris for all irradiation wavelengths and is therefore not a suitable C. auris surrogate for photoinactivation experiments. For the mold C. cladosporioides, much higher D90 doses were determined than for both yeasts. Concerning potential photosensitizers, flavins and various porphyrins were detected by fluorescence measurements. By excitation at 365 nm, another, so far unreported fluorophore and potential photosensitizer was also observed. Based on its fluorescence spectrum, we assume it to be thiamine.
Graphic abstract
... The large filamentous form of fungi cannot be removed by phagocytosis. NETs play a significant role in controlling these large filamentous fungi [57][58][59]. ...
Neutrophils are the principal trouper of the innate immune system. Activated neutrophils undergo a noble cell death termed NETosis and release a mesh-like structure called neutrophil extracellular traps (NETs) as a part of their defensive strategy against microbial pathogen attack. This web-like architecture includes a DNA backbone embedded with antimicrobial proteins like myeloperoxidase (MPO), neutrophil elastase (NE), histones and deploys in the entrapment and clearance of encountered pathogens. Thus NETs play an inevitable beneficial role in the host’s protection. However, recent accumulated evidence shows that dysregulated and enhanced NET formation has various pathological aspects including the promotion of sepsis, pulmonary, cardiovascular, hepatic, nephrological, thrombotic, autoimmune, pregnancy, and cancer diseases, and the list is increasing gradually. In this review, we summarize the NET-mediated pathophysiology of different diseases and focus on some updated potential therapeutic approaches against NETs.
... In 2017, it was estimated that globally, there were approximately 750,000 cases of candidiasis, 900,000 cases of mucormycosis, and 220,000 cases of cryptococcosis (Bongomin et al., 2017). These three invasive fungal infections (IFIs) account for more than half of IFI-associated deaths annually (Banerjee et al., 2021;Bongomin et al., 2017;Brown et al., 2012;Low & Rotstein, 2011;Varshney et al., 2017). Death rates are very high even following antifungal drug treatment, and in many cases of mucormycosis, the surgical removal of infected tissue is necessary. ...
DectiSomes are anti‐infective drug‐loaded liposomes targeted to pathogenic cells by pathogen receptors including the Dectins. We have previously used C‐type lectin (CTL) pathogen receptors Dectin‐1, Dectin‐2, and DC‐SIGN to target DectiSomes to the extracellular oligoglycans surrounding diverse pathogenic fungi and kill them. Dectin‐3 (also known as MCL, CLEC4D) is a CTL pathogen receptor whose known cognate ligands are partly distinct from other CTLs. We expressed and purified a truncated Dectin‐3 polypeptide (DEC3) comprised of its carbohydrate recognition domain and stalk region. We prepared amphotericin B (AmB)‐loaded pegylated liposomes (AmB‐LLs) and coated them with this isoform of Dectin‐3 (DEC3‐AmB‐LLs), and we prepared control liposomes coated with bovine serum albumin (BSA‐AmB‐LLs). DEC3‐AmB‐LLs bound to the exopolysaccharide matrices of Candida albicans, Rhizopus delemar (formerly known as R. oryzae), and Cryptococcus neoformans from one to several orders of magnitude more strongly than untargeted AmB‐LLs or BSA‐AmB‐LLs. The data from our quantitative fluorescent binding assays were standardized using a CellProfiler program, AreaPipe, that was developed for this purpose. Consistent with enhanced binding, DEC3‐AmB‐LLs inhibited and/or killed C. albicans and R. delemar more efficiently than control liposomes and significantly reduced the effective dose of AmB. In conclusion, Dectin‐3 targeting has the potential to advance our goal of building pan‐antifungal DectiSomes.
