The role of adjuvant agents in treating fungal diseases

Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality despite the recent introduction of new antifungal medications. In this review, the available data on the use of adjuvant agents for the treatment of IFIs are discussed. Cytokines such as interferon-γ, colony-stimulating factors, granulocyte transfusions, and the monoclonal antibody efungumab may have in a role in the management of IFIs through augmentation of the host immune response, whereas pathogen-specific vaccines may help prevent infection. Pentraxin 3, an acute phase protein, may assist in the prevention and treatment of aspergillosis. Deferasirox, an iron chelator, is being investigated as an adjunctive therapy for the treatment of zygomycosis. Lactoferrin, an ironbinding protein, appears to have activity in Candida and Aspergillus infections, and omiganan may help prevent fungal catheter-related infections. Although none of these agents are currently approved for the treatment of IFIs, they may be involved in current and/or future treatment options when used in combination with antifungal drugs.     

Update on Antifungal Resistance and its Clinical Impact

Candida and Aspergillus species are important causes of opportunistic infection in an ever-growing number of vulnerable patients, and these infections are associated with high mortality. This has partly been attributed to the emerging resistance of pathogenic fungi to antifungal therapy, which potentially compromises the management of infected patients. Multi-azole resistance of Aspergillus fumigatus is a current health problem, as well as is the co-resistance of Candida glabrata to both azoles and echinocandins. In most cases, negative clinical consequences of reduced in vitro fungal susceptibility to azoles and/or echinocandins can be traced to acquisition of particular resistance mechanisms. While strategies using antifungal combinations or adjunctive agents that maximize the efficacy of existing antifungals may limit treatment failures, new therapeutic approaches, including antifungal agents with novel mechanisms of action, are urgent. In the meantime, more efforts should be devoted to close monitoring of antifungal resistance and its evolution in the clinical setting.     

Candida Biofilm: Clinical Implications of Recent Advances in Research

Candida spp. are human commensals that can colonize devices and cause diseases associated with host tissue damage. In each lifestyle, Candida forms biofilms – communities of cells living within a protective extracellular matrix comprising proteins, polysaccharides, extracellular nucleic acids, and lipids. In vitro and in vivo models have defined basic steps in Candida biofilm formation as adhesion, initiation, maturation, and dispersal. Biofilms afford Candida cells resistance to antifungal agents, and host defenses and immune responses. In addition to “pathogenic” biofilm, Candida albicans also produces an alternative, permeable “sexual” biofilm that facilitates mating between cells. Treatment of biofilm infections consists of removing the infected device (if feasible) and antifungal therapy. Optimal antifungals are not defined, but echinocandins and lipid formulations of amphotericin B are most consistently active in model systems. Future research will shed light on how biofilm regulation allows Candida to adapt to diverse microenvironments relevant to commensalism and disease.     

Hsp21 Potentiates Antifungal Drug Tolerance in Candida albicans

Systemic infections of humans with the fungal pathogen Candida albicans are associated with a high mortality rate. Currently, efficient treatment of these infections is hampered by the relatively low number of available antifungal drugs. We recently identified the small heat shock protein Hsp21 in C. albicans and demonstrated its fundamental role for environmental stress adaptation and fungal virulence. Hsp21 was found in several pathogenic Candida species but not in humans. This prompted us to investigate the effects of a broad range of different antifungal drugs on an Hsp21-null C. albicans mutant strain. Our results indicate that combinatorial therapy targeting Hsp21, together with specific antifungal drug targets, has strong synergistic potential. In addition, we demonstrate that Hsp21 is required for tolerance to ethanol-induced stress and induction of filamentation in response to pharmacological inhibition of Hsp90. These findings might pave the way for the development of new treatment strategies against Candida infections.     

Investigation of aryl isonitrile compounds with potent,broad-spectrum antifungal activity

Invasive fungal infections present a formidable global public health challenge due to the limited number of approved antifungal agents and the emergence of resistance to the frontline treatment options, such as fluconazole. Three fungal pathogens of significant concern are Candida, Cryptococcus, and Aspergillus given their propensity to cause opportunistic infections in immunocompromised individuals. New antifungal agents composed of unique chemical scaffolds are needed to address this public health challenge. The present study examines the structure-activity relationship of a set of aryl isonitrile compounds that possess broad-spectrum antifungal activity primarily against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these key pathogens at concentrations as low as 0.5 µM. Remarkably, the most active compounds exhibit an excellent safety profile and are non-toxic to mammalian cells even at concentrations up to 256 µM. The present study lays the foundation for further investigation of aryl isonitrile compounds as a new class of antifungal agents.     

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.     

Invasive Fungal Infections in the Child with Chronic Granulomatous Disease

Invasive fungal infections (IFI) are a major threat for patients with chronic granulomatous disease (CGD) which is an inherited disorder of NADPH oxidase. The absence of a functional NADPH oxidase complex affects the display of an efficient antimicrobial effect as well as a controlled inflammatory response. Invasive aspergillosis caused by either Aspergillus fumigatus or A. nidulans is the most common IFI. Aspergillus nidulans infections seem to display a unique interaction with the CGD host and are seldom reported in other immunocompromised hosts. The occurrence of mucormycosis in the CGD host is mainly noted in the setting of treatment of inflammatory complications with immunosuppressive drugs. Candida infections are infrequently seen and show an age-dependent clinical presentation mainly affecting infants and young children. Furthermore, the child with CGD is susceptible to a wide range of fungal pathogens, indicating the need to determine the causative fungus, often by invasive diagnostic approaches, to guide optimal and rational treatment. Currently, it is becoming more and more clear that the exaggerated inflammatory response to fungal infection in the CGD host is leading in the pathogenesis, and antiinflammatory treatment might become as important as antifungal treatment in this specific host.     

Antifungal activity of substituted aurones

Novel antifungals are in high demand as there is a growing resistance to antifungals currently in use. In particular, opportunistic fungal infections caused by Candida spp. are on the rise with infections by this genus accounting for the most severe fungal infections following chemotherapy, implantation procedures, and in patients with HIV/AIDS. A series of simple aurone analogs were synthesized and screened for antifungal activity versus Candida spp. Several compounds displayed activity at 100 μM, with two having IC₅₀ values below 20 μM for three species of Candida. One of the compounds tested here also exhibits anti-biofilm activity for mid-maturation growth.     

Treatment of Invasive Candida Infections in the Neonatal Intensive Care Unit

Invasive Candida infections are a leading cause of morbidity and mortality in the neonatal intensive care unit (NICU). Extremely preterm and very low birth weight infants are at the highest risk of infection. There are currently no antifungal agents that have FDA-labeling for the treatment of invasive candidiasis in the neonatal population. Based on the current IDSA guidelines, amphotericin and fluconazole are considered first-line options for neonatal candidiasis. The newer antifungal agents (i.e., echinocandins and voriconazole) are currently considered second-line or salvage therapy; however, evidence supporting their use is emerging. This review focuses on the supporting evidence for the selection of antifungal agents for treatment of invasive Candida infections in the NICU.     

Design, synthesis, and evaluations of antifungal activity of novel phenyl(2H-tetrazol-5-yl)methanamine derivatives

Fungal infections pose a continuous and serious threat to human health and life. The intrinsic resistance has been observed in many genera of fungi. Many fungal infections are caused by opportunistic pathogens that may be endogenous (Candida infections) or acquired from the environment (Cryptococcus and Aspergillus infections). So, new therapeutic strategies are needed to combat various fungal infections. Fluconazole shows good antifungal activity with relatively low toxicity and is preferred as first line antifungal therapy, but it has suffered from severe drug resistance. So, there is a need to design novel analogues by modification of fluconazole-like structure. A novel series of phenyl(2H-tetrazol-5-yl)methanamine derivatives were synthesized by reaction of α-amino nitrile with sodium azide and ZnCl₂ in presence of isopropyl alcohol. They were evaluated for antifungal activity against Candida albicans and Aspergillus niger and subjected to docking study against 1EA1.     

In Vitro Antifungal Susceptibility of Oral <Emphasis Type="Italic">Candida</Emphasis> Isolates from Patients Suffering from Caries and Chronic Periodontitis

Caries and chronic periodontitis are common oral diseases where a higher Candida colonization is reported. Antifungal agents could be adjuvant drugs for the therapy of both clinical conditions. The aim of the current study has been to evaluate the in vitro activities of conventional and new antifungal drugs against oral Candida isolates from patients suffering from caries and/or chronic periodontitis. In vitro activities of amphotericin B, fluconazole, itraconazole, miconazole, nystatin, posaconazole and voriconazole against 126 oral Candida isolates (75 Candida albicans, 18 Candida parapsilosis, 11 Candida dubliniensis, six Candida guilliermondii, five Candida lipolytica, five Candida glabrata, four Candida tropicalis and two Candida krusei) from 61 patients were tested by the CLSI M27-A3 method. Most antifungal drugs were highly active, and resistance was observed in less than 5% of tested isolates. Miconazole was the most active antifungal drug, being more than 98% of isolates susceptible. Fluconazole, itraconazole, and the new triazoles, posaconazole and voriconazole, were also very active. Miconazole, fluconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent suitable treatment for a hypothetically adjunctive therapy of caries and chronic periodontitis.     

Understanding Vulvovaginal Candidiasis Through a Community Genomics Approach

Vulvovaginal candidiasis (VVC), predominantly caused by Candida albicans, is one of the most common types of infectious vaginitis. Extensive study has been directed toward understanding host defenses against this infection, and results remain inconclusive. While many have examined the role of innate and cell-mediated immunity, as well as Candida-specific antibodies and the anti-Candida activity of vaginal epithelial cells, little attention has been given to one of the most important players: the vaginal microbiota. Exploring changes in species composition and gene expression within the vaginal community using high-throughput genomic technologies is invaluable to fully understanding Candida pathogenesis and host response to infection. This integrative perspective of pathogenesis, host response and microbial influence are critical to our ability to improve routine gynecologic care and treatment of vaginal infections.     

Antifungal Activity of Naphthoquinoidal Compounds In Vitro against Fluconazole-Resistant Strains of Different Candida Species: A Special Emphasis on Mechanisms of Action on Candida tropicalis

In recent decades, the incidence of candidemia in tertiary hospitals worldwide has substantially increased. These infections are a major cause of morbidity and mortality; in addition, they prolong hospital stays and raise the costs associated with treatment. Studies have reported a significant increase in infections by non-albicans Candida species, especially C. tropicalis. The number of antifungal drugs on the market is small in comparison to the number of antibacterial agents available. The limited number of treatment options, coupled with the increasing frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. The objective of this study was to evaluate and compare the antifungal activities of three semisynthetic naphthofuranquinone molecules against fluconazole-resistant Candida spp. strains. These results allowed to us to evaluate the antifungal effects of three naphthofuranquinones on fluconazole-resistant C. tropicalis. The toxicity of these compounds was manifested as increased intracellular ROS, which resulted in membrane damage and changes in cell size/granularity, mitochondrial membrane depolarization, and DNA damage (including oxidation and strand breakage). In conclusion, the tested naphthofuranquinones (compounds 1–3) exhibited in vitro cytotoxicity against fluconazole-resistant Candida spp. strains.     

Candida Sepsis: a New Entity?

Despite progress in the field of biological sciences, a definitive diagnosis of Candida sepsis remains an elusive target. Candida, which is frequently found in non-immunocompromised patients in intensive care units, causes severe sepsis, septic shock, and multiple-organ failure in a similar fashion as bacteria. Despite its imprecision, the blood and/or sterile-site culture is still the gold standard for diagnosis, although new biological markers are becoming available for earlier and more accurate diagnosis of invasive candidiasis. Mortality remains high due to a number of factors, and early initiation of appropriate antifungal therapy is a critical factor in positive outcomes. Echinocandins are the drug of choice for severe Candida infections in hospitalized patients. Antifungal stewardship programs may decrease the likelihood of resistance strains, and preventive measures are becoming available to lower the rate of fungal infections in intensive care units.     

Antifungal Drug Resistance: Clinical Relevance and Impact of Antifungal Drug Use

Antifungal drug resistance significantly impacts treatment outcomes in patients with invasive fungal infections (IFIs). Although primary (intrinsic) resistance may occur independent of previous therapy, prior concomitant antifungal exposure increases the risk for secondary (acquired) resistance and subsequent colonization or infection with less-susceptible pathogens. Among various pathogen-antifungal combinations, this effect has been best studied clinically with azole exposure and the risk of Candida spp. with reduced susceptibility. The rapid development of secondary resistance to flucytosine in Candida spp. has limited its use as monotherapy. Secondary resistance to amphotericin B is infrequent. In contrast, secondary resistance in Aspergillus spp. is less of a concern. Recent reports of secondary resistance in patients receiving fluconazole for cryptococcal infections may justify susceptibility testing in the setting of prior therapy or treatment failure. Despite numerous patient-focused, drug-focused, and disease-focused strategies to improve treatment outcomes, clinical resistance (manifesting as treatment failures despite adequate antifungal therapy) continues to be problematic in patients with serious IFIs.     

A Case for Antifungal Stewardship

Purpose of Review

The expanding utilization of limited available antifungal agents has led to a pressing need to implement interventions to ensure appropriate usage. The global emergence of resistant, difficult-to-treat invasive fungal infections among the most vulnerable patient populations is a call to action to develop a multifaceted antifungal stewardship approach.

Recent Findings

Candida species demonstrating multi-drug resistance, including highly resistant Candida auris, are emerging threats. Azole-resistant Aspergillus fumigatus, likely initially originating in the environment, likewise presents a treatment challenge. Routine empiric and prophylactic antifungal use, though effective, further complicates this issue, with the emergence of breakthrough mold infections. Early evidence supports success with antifungal stewardship programs.

Summary

Broad antifungal stewardship approaches that optimize antifungal drug usage, facilitate provider education, and monitor fungal epidemiology are crucial steps to preserve the antifungal armamentarium. Future development of novel diagnostic and treatment strategies will further facilitate management of invasive fungal infections.

     

Formic Acid and Acetic Acid Induce a Programmed Cell Death in Pathogenic Candida Species

Cutaneous fungal infections are common and widespread. Antifungal agents used for the treatment of these infections often have undesirable side effects. Furthermore, increased resistance of the microorganisms to the antifungal drugs becomes the growing problem. Accordingly, the search for natural antifungal compounds continues to receive attention. Apoptosis is highly regulated programmed cell death. During yeast cell apoptosis, amino acids and peptides are released and can stimulate regeneration of human epithelium cells. Thus, detection of chemical compounds inducing apoptosis in yeast and nontoxic for humans is of great medical relevance. The aim of this study was to detect chemical compound inducing apoptosis in pathogenic Candida species with the lowest toxicity to the mammalian cells. Five chemical compounds—acetic acid, sodium bicarbonate, potassium carbonate, lithium acetate, and formic acid—were tested for evaluation of antifungal activity on C. albicans, C. guilliermondii, and C. lusitaniae. The results showed that acetic acid and formic acid at the lowest concentrations induced yeast cells death. Apoptosis analysis revealed that cells death was accompanied by activation of caspase. Minimal inhibitory concentrations of potassium carbonate and sodium bicarbonate induced Candida cells necrosis. Toxicity test with mammalian cell cultures showed that formic acid has the lowest effect on the growth of Jurkat and NIH 3T3 cells. In conclusion, our results show that a low concentration of formic acid induces apoptosis-like programmed cell death in the Candida yeast and has a minimal effect on the survivability of mammalian cells, suggesting potential applications in the treatment of these infections.     

Antifungal lock therapy: an eternal promise or an effective alternative therapeutic approach?

Each year, millions of central venous catheter insertions are performed in intensive care units worldwide. The usage of these indwelling devices is associated with a high risk of bacterial and fungal colonization, leading to the development of microbial consortia, namely biofilms. These sessile structures provide fungal cells with resistance to the majority of antifungals, environmental stress and host immune responses. Based on different guidelines, colonized/infected catheters should be removed and changed immediately in the case of Candida-related central line infections. However, catheter replacement is not feasible for all patient populations. An alternative therapeutic approach may be antifungal lock therapy, which has received high interest, especially in the last decade. This review summarizes the published Candida-related in vitro, in vivo data and case studies in terms of antifungal lock therapy. The number of clinical studies remains limited and further studies are needed for safe implementation of the antifungal lock therapy into clinical practice.     

Delivery of Antifungal Agents from Bone Cement

Fungal osteoarticular infections, including prosthetic joint infections and osteomyelitis, are rare yet present a therapeutic challenge with no guidelines to direct optimal treatment. When these infections occur, the majority are due to Candida species. In addition to systemic therapy, adjunctive antifungal-loaded bone cement has been utilized to successfully treat these infections. Amphotericin B is used most commonly, but cases utilizing voriconazole, fluconazole, and itraconazole have been reported as well. In vitro data suggest better elution of voriconazole from bone cement while there is minimal elution of amphotericin B. Unfortunately, a lack of consistency in the methods of both in vitro studies and case reports makes it difficult to determine if the addition of an antifungal agent in bone cement improves outcomes in fungal osteoarticular infections. This article provides an overview of bone cement as a delivery system for antifungal agents in vitro and in clinical reports.     

抗白念珠菌感染的疫苗及抗体研究进展

白念珠菌是与人类共生的条件致病真菌,能引起免疫力低下患者皮肤黏膜和全身系统性持续感染.系统性念珠菌病是引起免疫力低下患者死亡的主要原因之一.由于临床缺乏念珠菌病的早期诊疗手段、可用的抗真菌药物种类有限且毒副作用大、耐药菌株越来越普遍、新药研发难度大等因素,抗真菌治疗依然面临着严峻挑战.目前有较多研究者致力于阐明白念珠菌感染的宿主免疫应答机制,并试图研发抗白念珠菌感染的免疫治疗方法,使免疫治疗有望成为预防和治疗真菌感染的有效手段.该文将几种抗白念珠菌感染的疫苗和抗体研究进展作简要概述,旨在为新型抗白念珠菌感染疫苗及抗体的研究提供参考.