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Annual Review of Microbiology Sep 2023is a multidrug-resistant fungal pathogen that presents a serious threat to global human health. Since the first reported case in 2009 in Japan, infections have been... (Review)
Review
is a multidrug-resistant fungal pathogen that presents a serious threat to global human health. Since the first reported case in 2009 in Japan, infections have been reported in more than 40 countries, with mortality rates between 30% and 60%. In addition, has the potential to cause outbreaks in health care settings, especially in nursing homes for elderly patients, owing to its efficient transmission via skin-to-skin contact. Most importantly, is the first fungal pathogen to show pronounced and sometimes untreatable clinical drug resistance to all known antifungal classes, including azoles, amphotericin B, and echinocandins. In this review, we explore the causes of the rapid spread of . We also highlight its genome organization and drug resistance mechanisms and propose future research directions that should be undertaken to curb the spread of this multidrug-resistant pathogen.
Topics: Humans; Aged; Candida; Candida auris; Antifungal Agents; Echinocandins; Amphotericin B
PubMed: 37406342
DOI: 10.1146/annurev-micro-032521-015858 -
Molecular Aspects of Medicine Aug 2023The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp.,... (Review)
Review
The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii. In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system. In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies. Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology. The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches.
Topics: Humans; Antifungal Agents; Mycoses; Risk Factors; Immunocompromised Host
PubMed: 37207579
DOI: 10.1016/j.mam.2023.101190 -
Molecular Aspects of Medicine Dec 2023Invasive fungal diseases are common complications in critically ill patients and in those with significant underlying imbalanced immune systems. Fungal co-, and/or... (Review)
Review
Invasive fungal diseases are common complications in critically ill patients and in those with significant underlying imbalanced immune systems. Fungal co-, and/or super-infections are emerging and have become a rising concern within the last few years. In Europe, cases of candidiasis and aspergillosis dominate, followed by mucormycosis in India. Epidemiological studies show an increasing trend in the incidence of all three entities. Parallel to this, a shift within the underlying fungal pathogens is observed. More non-albicans Candida infections and aspergillosis with cryptic species are on the rise; cryptic species may cover intrinsic resistance to azoles and other antifungal drugs. The recent COVID-19 pandemic led to a significantly increasing incidence of invasive fungal diseases among hospitalized patients.
Topics: Humans; Pandemics; Mycoses; Antifungal Agents; Aspergillosis
PubMed: 37804792
DOI: 10.1016/j.mam.2023.101215 -
Nature Reviews. Immunology Jul 2023Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and... (Review)
Review
Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and following receipt of chemotherapy, immunosuppressive agents or targeted biologics for neoplastic or autoimmune diseases, or transplants for end organ failure. Furthermore, in recent years, the spread of multidrug-resistant Candida auris has caused life-threatening outbreaks in health-care facilities worldwide and raised serious concerns for global public health. Rapid progress in the discovery and functional characterization of inborn errors of immunity that predispose to fungal disease and the development of clinically relevant animal models have enhanced our understanding of fungal recognition and effector pathways and adaptive immune responses. In this Review, we synthesize our current understanding of the cellular and molecular determinants of mammalian antifungal immunity, focusing on observations that show promise for informing risk stratification, prognosis, prophylaxis and therapies to combat life-threatening fungal infections in vulnerable patient populations.
Topics: Animals; Humans; Mycoses; Fungi; Antifungal Agents; Immunity; Mammals
PubMed: 36600071
DOI: 10.1038/s41577-022-00826-w -
Mycopathologia Oct 2023Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of... (Review)
Review
Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of immunocompromised patients and hence vulnerable hosts increases, which is paralleled by the emergence of a rise in IA cases. Increased frequencies of azole-resistant strains are reported from six continents, presenting a new challenge for the therapeutic management. Treatment options for IA currently consist of three classes of antifungals (azoles, polyenes, echinocandins) with distinctive advantages and shortcomings. Especially in settings of difficult to treat IA, comprising drug tolerance/resistance, limiting drug-drug interactions, and/or severe underlying organ dysfunction, novel approaches are urgently needed. Promising new drugs for the treatment of IA are in late-stage clinical development, including olorofim (a dihydroorotate dehydrogenase inhibitor), fosmanogepix (a Gwt1 enzyme inhibitor), ibrexafungerp (a triterpenoid), opelconazole (an azole optimized for inhalation) and rezafungin (an echinocandin with long half-life time). Further, new insights in the pathophysiology of IA yielding immunotherapy as a potential add-on therapy. Current investigations show encouraging results, so far mostly in preclinical settings. In this review we discuss current treatment strategies, give an outlook on possible new pharmaceutical therapeutic options, and, lastly, provide an overview of the ongoing research in immunotherapy for IA.
Topics: Humans; Aspergillosis; Antifungal Agents; Mycoses; Invasive Fungal Infections; Azoles; Drug Resistance, Fungal
PubMed: 37100963
DOI: 10.1007/s11046-023-00727-z -
Nature Nov 2023Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model. Recently, the clinically vital...
Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids.
Topics: Animals; Humans; Mice; Amphotericin B; Antifungal Agents; Cells, Cultured; Cholesterol; Drug Resistance, Fungal; Ergosterol; Kidney; Kinetics; Microbial Sensitivity Tests; Mycoses; Polyenes; Serial Passage; Sterols; Time Factors
PubMed: 37938782
DOI: 10.1038/s41586-023-06710-4 -
The Journal of Dermatological Treatment Dec 2023Onychomycosis is difficult to treat due to long treatment durations, poor efficacy rates of treatments, high relapse rates, and safety issues when using systemic... (Review)
Review
Onychomycosis is difficult to treat due to long treatment durations, poor efficacy rates of treatments, high relapse rates, and safety issues when using systemic antifungal agents. Device-based treatments are targeted to specific regions of the nail, have favorable safely profiles, and do not interfere with systemic agents. They may be an effective alternative therapy for onychomycosis especially with increasing reports of squalene epoxidase gene mutations and potential resistance to terbinafine therapy. In this review, we discuss four devices used as antifungal treatments and three devices used as penetration enhancers for topical agents. Lasers, photodynamic therapy, microwaves, and non-thermal plasma have the capacity to inactivate fungal pathogens demonstrated through studies. Efficacy rates for these devices, however, remain relatively low pointing toward the need to further optimize device or usage parameters. Ultrasound, nail drilling, and iontophoresis aid in improving the permeability of topical agents through the nail and have been investigated as adjunctive therapies. Due to the paucity in clinical data, their efficacy in treating onychomycosis has not yet been established. While the results of clinical studies point toward the potential utility of devices for onychomycosis, further large-scale randomized clinical trials following regulatory guidelines are required to confirm current results.
Topics: Humans; Onychomycosis; Antifungal Agents; Terbinafine; Nails; Photochemotherapy; Administration, Topical
PubMed: 37807661
DOI: 10.1080/09546634.2023.2265658 -
PLoS Pathogens Aug 2023Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk...
Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.
Topics: Animals; Candida; Candida albicans; Candidiasis; Antifungal Agents; Azoles
PubMed: 37651385
DOI: 10.1371/journal.ppat.1011583 -
Probiotics and Antimicrobial Proteins Oct 2023Vaginitis is a common problem in women. Candida albicans is responsible for more than 85% of vaginal fungal infections. The aim of this study was to compare the effects... (Randomized Controlled Trial)
Randomized Controlled Trial
Vaginitis is a common problem in women. Candida albicans is responsible for more than 85% of vaginal fungal infections. The aim of this study was to compare the effects of probiotic and fluconazole on the treatment and recurrence of vulvovaginal candidiasis (VVC). This triple-blinded randomized controlled trial was conducted on 80 married women, aged 18-49 years, with VVC, as confirmed by clinical and laboratory diagnosis. The participants were allocated into two groups using blocked randomization method. The fluconazole-treated group received a single dose of fluconazole (150 mg) supplemented with 30 placebo capsules of probiotic, and the probiotic-treated group got 30 probiotic capsules containing 1 × 10 CFU/g LA-5 with 1 fluconazole placebo capsule. The samples were taken from patients to evaluate the vaginal pH and microbiological tests before, 30-35 days, and 60-65 days after starting the treatment. The signs and symptoms were assessed before the intervention and the first and second follow-ups. Chi-square, Fisher's exact, independent t, and ANCOVA tests were then used for data analysis. There was no statistically significant difference between the two groups (p = 0.127) in the frequency of negative culture 30-35 days after starting the treatment, but the frequency of negative culture 60-65 days after starting treatment in the fluconazole group was significantly higher than that of the probiotic group (p = 0.016). The abnormal discharge and vulvovaginal erythema in the first and second follow-ups and also pruritus in the second follow-up in the fluconazole group were significantly lower than those in the probiotic group (p < 0.05). There was, however, no statistically significant difference in burning, frequent urination, dysuria, and dyspareunia between the groups (p > 0.05). Lactobacillus acidophilus supplementation had an effect similar to that of fluconazole in treating most symptoms of VVC, but it was less effective than the latter in preventing recurrence. Trial Registration: Iranian Registry of Clinical Trials (IRCT): IRCT20110826007418N5. Date of registration: 3 March 2021; URL: https://en.irct.ir/trial/50819 ; Date of first registration: 10 March 2021.
Topics: Humans; Female; Fluconazole; Candidiasis, Vulvovaginal; Antifungal Agents; Capsules; Iran; Probiotics
PubMed: 36198994
DOI: 10.1007/s12602-022-09997-3 -
Biomolecules Oct 2023Invasive fungal infections present a significant risk to human health. The current arsenal of antifungal drugs is hindered by drug resistance, limited antifungal range,... (Review)
Review
Invasive fungal infections present a significant risk to human health. The current arsenal of antifungal drugs is hindered by drug resistance, limited antifungal range, inadequate safety profiles, and low oral bioavailability. Consequently, there is an urgent imperative to develop novel antifungal medications for clinical application. This comprehensive review provides a summary of the antifungal properties and mechanisms exhibited by natural polyketides, encompassing macrolide polyethers, polyether polyketides, xanthone polyketides, linear polyketides, hybrid polyketide non-ribosomal peptides, and pyridine derivatives. Investigating natural polyketide compounds and their derivatives has demonstrated their remarkable efficacy and promising clinical application as antifungal agents.
Topics: Humans; Antifungal Agents; Polyketides; Macrolides; Peptides
PubMed: 38002254
DOI: 10.3390/biom13111572