Advances In Antifungal Therapy Research Articles

B-Cell Epitope Mapping from Eight Antigens of Candida albicans to Design a Novel Diagnostic Kit: An Immunoinformatics Approach

Invasive candidiasis is an emerging fungal infection and a leading cause of morbidity in health care facilities. Despite advances in antifungal therapy, increased antifungal drug resistance in Candida albicans has enhanced patient fatality. The most common method for Candida albicans diagnosing is blood culture, which has low sensitivity. Therefore, there is an urgent need to establish a valid diagnostic method. Our study aimed to use the bioinformatics approach to design a diagnostic kit for detecting Candida albicans with high sensitivity and specificity. Eight antigenic proteins of Candida albicans (HYR1, HWP1, ECE1, ALS, EAP1, SAP1, BGL2, and MET6) were selected. Next, a construct containing different immunodominant B-cell epitopes was derived from the antigens and connected using a suitable linker. Different properties of the final construct, such as physicochemical properties, were evaluated. Moreover, the designed construct underwent 3D modeling, reverse translation, and codon optimization. The results confirmed that the designed construct could identify Candida albicans with high sensitivity and specificity in serum samples of patients with invasive candidiasis. However, experimental studies are needed for final confirmation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10989-022-10413-1.

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy.

Paracoccidioidomycosis (PCM) is a notable fungal infection restricted to Latin America. Since the first description of the disease by Lutz up to the present day, Brazilian researchers have contributed to the understanding of the life cycle of this pathogen and provided the possibility of new targets for antifungal therapy based on the structural and functional genomics of Paracoccidioides. In this context, in silico approaches have selected molecules that act on specific targets, such as the thioredoxin system, with promising antifungal activity against Paracoccidioides. Some of these are already in advanced development stages. In addition, the application of nanostructured systems has addressed issues related to the high toxicity of conventional PCM therapy. Thus, the contribution of molecular biology and biotechnology to the advances achieved is unquestionable. However, it is still necessary to transcend the boundaries of synthetic chemistry, pharmaco-technics, and pharmacodynamics, aiming to turn promising molecules into newly available drugs for the treatment of fungal diseases.

Beyond tissue concentrations: antifungal penetration at the site of infection.

Despite advances in antifungal therapy, invasive fungal infections remain a significant cause of morbidity and mortality worldwide. One important factor contributing to the relative ineffectiveness of existing antifungal drugs is insufficient drug exposure at the site of infection. Despite the importance of this aspect of antifungal therapy, we generally lack a full appreciation of how antifungal drugs distribute, penetrate, and interact with their target organisms in different tissue subcompartments. A better understanding of drug distribution will be critical to guide appropriate use of currently available antifungal drugs, as well as to aid development of new agents. Herein we briefly review current perspectives of antifungal drug exposure at the site of infection and describe a new technique, matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging, which has the potential to greatly expand our understanding of drug penetration.

Ethnopharmacological survey, antioxidant and antifungal activity of medicinal plants traditionally used in Baham locality (Cameroon) to treat fungal infections

Invasive fungal infections are important causes of mortality despite advances in antifungal therapy. The aim of this study was collect information on plants used by traditional healers for the treatment of fungal infections in the Baham subdivision (Western region of Cameroon) and to assess the in vitro antifungal and antioxidant potentials of the extracts from the medicinal plants surveyed. The antifungal activity was assessed by the broth micro-dilution method and the antioxidant activity was determined using the free-radical scavenging assays. The extracts for the plants Kotschya strigosa and Eryngium foetidum had potent antifungal activity with minimum inhibitory concentration value of 32 μg/mL against Cryptococcus neoformans. Eugenia gilgii extract had the highest free radical scavenging capacity in 2,2-Diphenyl-1-picrylhydrazyl assay (IC50 of 4.54μg/mL). There is a rich wealth of knowledge and usage of plants by traditional healers for the treatment of fungal infections and further studies should consider isolation of active compounds from the extracts in order to assess the potential for developing new, effective, safe and affordable phytomedicine for the treatment of fungal infections and other pharmacological applications.Keywords: Ethnomedicine; Fungal infections; Antifungal; Antioxidant; Extract

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis.

The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of efflux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the preliminary testing of new antifungal agents. In general, many years are required from discovery of a new antifungal to clinical use. However, the development of new antifungal strategies will reduce the therapeutic time and/or increase the quality of life of patients.

Oral mycoses and other opportunistic infections in HIV: therapy and emerging problems - a workshop report.

Oral mycoses and other opportunistic infections are recognized features of HIV infection even after four decades of the epidemic. The therapeutic options, challenges of therapy, and evolving patterns of opportunistic infections were evaluated by the workshop. It was observed that high Candida counts and infection are still more prevalent in HIV-positive individuals even in the era of antiretroviral therapy. Furthermore, one or more non-Candida albicans are present in some HIV-positive individuals. While Candida species are more virulent in HIV infection, similar virulence may be present in other states of immunosuppression. Consequently, the interplay between host factors and virulence ultimately determines the clinical outcomes. Adverse clinical outcomes such as candidemia and other deep fungal infections are on the increase in HIV infection. Disseminated histoplasmosis and penicilliosis have been reported, especially with low CD4 counts. Even with advances in antifungal therapy, mortality and morbidity from deep fungal infections have not changed significantly. In addition, long-term exposure to common antifungal drugs such as fluconazole has led to the development of antifungal resistance in 6% to 36%. Development of new antifungal therapeutic agents and the use of alternative therapies may offer breakthrough. In addition, effective strategies to enhance the host immune status are being explored.

Prediction of the Clinical Outcome in Invasive Candidiasis Patients Based on Molecular Fingerprints of Five Anti-Candida Antibodies in Serum

Better prognostic predictors for invasive candidiasis (IC) are needed to tailor and individualize therapeutic decision-making and minimize its high morbidity and mortality. We investigated whether molecular profiling of IgG-antibody response to the whole soluble Candida proteome could reveal a prognostic signature that may serve to devise a clinical-outcome prediction model for IC and contribute to known IC prognostic factors. By serological proteome analysis and data-mining procedures, serum 31-IgG antibody-reactivity patterns were examined in 45 IC patients randomly split into training and test sets. Within the training cohort, unsupervised two-way hierarchical clustering and principal-component analyses segregated IC patients into two antibody-reactivity subgroups with distinct prognoses that were unbiased by traditional IC prognostic factors and other patients-related variables. Supervised discriminant analysis with leave-one-out cross-validation identified a five-IgG antibody-reactivity signature as the most simplified and accurate IC clinical-outcome predictor, from which an IC prognosis score (ICPS) was derived. Its robustness was confirmed in the test set. Multivariate logistic-regression and receiver-operating-characteristic curve analyses demonstrated that the ICPS was able to accurately discriminate IC patients at high risk for death from those at low risk and outperformed conventional IC prognostic factors. Further validation of the five-IgG antibody-reactivity signature on a multiplexed immunoassay supported the serological proteome analysis results. The five IgG antibodies incorporated in the ICPS made biologic sense and were associated either with good-prognosis and protective patterns (those to Met6p, Hsp90p, and Pgk1p, putative Candida virulence factors and antiapoptotic mediators) or with poor-prognosis and risk patterns (those to Ssb1p and Gap1p/Tdh3p, potential Candida proapoptotic mediators). We conclude that the ICPS, with additional refinement in future larger prospective cohorts, could be applicable to reliably predict patient clinical-outcome for individualized therapy of IC. Our data further provide insights into molecular mechanisms that may influence clinical outcome in IC and uncover potential targets for vaccine design and immunotherapy against IC.

Recent advances in molecular and non-PCR-based platforms for the rapid diagnosis of invasive candidasis in the ICU

Invasive candidasis (IC) accounts for 15?30% of all nosocomial intensive care unit (ICU) infections. Two-thirds of infections are due to candidemia, a rate 5?10 times higher compared with that in the general hospital population. Crude mortality rates and associated health costs remain high, despite advances in antifungal therapy. Candida albicans remains the most frequently isolated species (45%) although there has been a slow but definite shift towards non-C. albicans species (especially Candida glabrata) infections, which has been attributed to the increased use of fluconazole prophylaxis in some centres. Early antifungal therapy significantly reduces IC-related mortality but is often delayed because ?gold standard? diagnosis by culture and/or histology is insensitive (for example, 50% candidemia cases not detected by blood culture) and slow (at least 48?96 hours required for species detection and identification). This article highlights a number of recent advances in molecular and non-PCR-based technologies that have enabled more rapid diagnosis of IC in the ICU (a recent review provides a comprehensive summary of molecular and serological methods in diagnostic mycology).

Dynamic duo takes down fungal villains

F ungal pathogens are notoriously difficult to treat because of antifungal drug toxicity and drug resistance, and the limited armamentarium (1). Some drug classes inhibit fungal growth but do not efficiently eliminate pathogens, and there is a pressing need for advances in antifungal therapy. The problem is especially acute in the immunocompromised. In a recent issue of PNAS, Cowen et al. (2) describe how harnessing heat shock protein 90 (Hsp90) dramatically enhances the efficacy of available antifungal drugs and provides a powerful new avenue for eradicating fungal infections.

Tratamiento actual de la candidemia. Papel de anidulafungina

Despite recent advances in antifungal therapy, the incidence of invasive Candida infections and resulting mortality have remained unchanged in the last few years. In surveillance studies published to date, the estimated incidence of candidemia differs depending on the geographic area and is significantly higher in North America than in Europe. The main predisposing conditions for candidemia are neutropenia, cellular immunity deficit, and alteration of normal microbial flora. Some independent risk factors have been identified, such as previous colonization, antibiotic therapy, central venous catheters, neutropenia, and renal dysfunction. In the last two decades, the proportion of infections due to non-albicans Candida has markedly increased. Although fluconazole use has been considered one of the main causes for the epidemiologic change in invasive candidiasis, especially in the increase of species less sensitive to this agent, this association remains unproven. These recent epidemiological changes are highly important when selecting treatment for candidemia. The echinocandins, which include anidulafungin, represent a step forward in the treatment of these infections. The clinical efficacy, tolerability and safety of anidulafungin have been demonstrated in controlled clinical trials in candidemia and invasive candidiasis. Current recommendations include this antifungal agent in the initial empirical therapy of certain patients, especially in those with a critical clinical situation, previous azole exposure, or the possibility of developing adverse events or drug interactions.

Cluster of multidrug-resistant Neisseria gonorrhoeae with reduced susceptibility to the newer cephalosporins in Northern Greece

management of cryptococcal disease. Clin Infect Dis 2000; 30: 710–8. 3. Sable CA, Strohmaier KM, Chodakewitz JA. Advances in antifungal therapy. Annu Rev Med 2008; 59: 455–73. 4. Baddley JW, Pappas PG. Antifungal combination therapy. Drugs 2005; 65: 1461–80. 5. Sionov E, Mendlovic S, Segal E. Efficacy of amphotericin B or amphotericin B-intralipid in combination with caspofungin against experimental aspergillosis. J Infect 2006; 53: 131–9. 6. Mukherjee PK, Sheehan DJ, Hitchcock CA et al. Combination treatment of invasive fungal infections. Clin Microbiol Rev 2005; 18: 163–94.

Advances in Antifungal Therapy

The prevalence of invasive fungal infections (IFIs) has increased over the past three decades owing to the increasing numbers of immunocompromised hosts. These infections are associated with significant morbidity and mortality. Recent significant advances in antifungal therapy include the broad-spectrum triazoles (voriconazole and posaconazole) and a new class of antifungals, the echinocandins (caspofungin, micafungin, and anidulafungin). New treatment strategies, such as combination therapy and pre-emptive therapy, are being investigated. There have also been significant improvements in diagnostics; the galactomannan enzyme immunoassay and the beta-glucan test are now part of the EORTC/MSG criteria for diagnosis of IFI. Despite these advances, there remain a number of unanswered questions regarding optimal management of serious fungal infections, and research continues to discover and develop new therapies and evaluate new management strategies.

Mucormycosis of the Bronchial Anastomosis: A Case of Successful Medical Treatment and Historic Review

Rhizomucor is a genus of zygomycetes that can cause pulmonary mucormycosis. In the immunocompromised host, mucormycosis was fatal until advances in anti-fungal therapy were combined with surgery. Although uncommon, fungal infection at the bronchial anastomosis is associated with a significant risk of morbidity and mortality after lung transplantation. Our patient is a middle-aged woman with end-stage chronic obstructive pulmonary disease who received a bilateral lung transplant. After discharge, she developed increasing dyspnea. Bronchoscopy revealed stenosis and Rhizomucor at the right anastomosis. Repeated endobronchial debridement, systemic lipid-soluble amphotericin, and inhaled amphotericin successfully resolved the infection. The residual stenosis was treated with a self-expandable metal stent. At 3 months, the patient continues on inhaled amphotericin suppression therapy without sequelae. Anastomosis mucormycosis is a grave complication after lung transplantation. Without combination therapy of surgery and anti-fungal drugs, mortality has been exceedingly high. We present a case wherein endobronchial debridement and anti-fungal therapy were successful without surgery.

Advances in Antifungal Therapy

Advances in Antifungal Therapy

Antifungal drugs and rational use of antifungals in treating invasive aspergillosis: the role of the hospital pharmacist

This review discusses the most common used antifungal agents in the treatment of invasive fungal infections. In addition, guidelines for the treatment of invasive aspergillosis, as used in the Ghent University Hospital, are described. Moreover, the importance of determining the effectiveness of antifungal therapy as well as the potential role of the hospital pharmacist in the management of this infection is highlighted. A review of the English-language literature was conducted using the MEDLINE database and scientific websites. Search terms including antimycotics, antifungal therapy and invasive aspergillosis were used to refine the search, and preference was given to studies published after 1992. This was completed with recent treatment guidelines. An overview of the most recent advances in antifungal therapy is described. In addition, a flowchart for treatment of invasive aspergillosis (proven, probable or possible) has been developed. Invasive fungal infections will remain a frequent and important complication of modern medicine. Considering the clinical and financial outcome of invasive fungal infections, the role of the hospital pharmacist can be a paramount to the treatment.

Evaluation and management of Fungal infections in Immunocompromised patients

As the population of chronically immunosuppressed individuals continues to grow, the prevalence of fungal infections is increasing. Fungal infections in this patient population represent challenges in diagnosis and management. This article will review the common superficial and invasive mycoses that occur in the solid organ transplant and HIV-infected populations. Disease presentations are reviewed, but emphasis is placed on cutaneous manifestations. Recent advances in antifungal therapy and their direct application to specific diseases provide important new approaches to this complex and often seriously ill patient population.

Prophylaxis and treatment of invasive candidiasis in the intensive care setting.

The term "invasive candidiasis" encompasses a group of infections of increasing relevance in the intensive care setting. Prophylaxis is an attractive strategy when dealing with diseases of high prevalence, morbidity, and mortality. The success of prophylaxis is determined by the selection of a population at high risk and the use of the safest and most effective drug. Although risk factors for this disease are known, risk assessment strategies need to be developed to predict a high likelihood of disease so that targeted prophylaxis can be offered. Recent advances in antifungal therapy, such as development of the azoles and echinocandins, have resulted in excellent prophylactic and therapeutic choices for the management of this problem.

EVALUATION OF FUNGICHROM 1 : A NEW YEAST IDENTIFICATION SYSTEM

Advances in anti-fungal therapy necessitate the need for accurate identification of fungi especially yeasts to their species level for more effective management. Unlike the time consuming conventional methods of yeast identification using fermentation and assimilation patterns of various carbohydrates, the new commercialized yeast identification systems are simpler, rapid and are particularly easy to interpret. In our study, a new colorimetric yeast identification system-Fungichrom 1(International microbio, Signes, France) was evaluated against the conventional method to identify 50 clinical isolates of yeasts belonging to the genera -Candida, Cryptococcus, Geotrichum. 96% agreement was found between the two methods.

Therapy of Candida infections: susceptibility testing, resistance, and therapeutic options.

Review the epidemiology of fungal infections, approved susceptibility testing methods, the scope of antifungal resistance, and advances in the treatment of fungal infections. MEDLINE databases (from 1966 to March 1998) were searched for literature pertaining to the epidemiology and management of fungal infections. Articles were selected to assist in providing the reader an understanding of the epidemiology and management of fungal infections. Fungi have emerged as an important class of pathogens. Even though fungi rank as the fourth most commonly encountered nosocomial bloodstream pathogen, and are associated with the highest mortality of commonly encountered pathogens, only within the past year have methods for conducting and guidelines for interpreting in vitro susceptibility tests been approved. Under the guidance of these standards, we have begun to understand important issues regarding fungi such as the scope and mechanisms of antifungal resistance. Although there has not been a significant addition to our antifungal armamentarium since 1992, advances in antifungal therapy have been realized with the reformulation of available agents and the delineation of the pharmacodynamic characteristics of several antifungals. Additionally, several new agents, including a new class of antifungals, probably will enter into clinical use within the next 5 years. We have entered an era in which our understanding of fungi is increasing tremendously. Clinicians need to familiarize themselves with the current concepts surrounding the management of fungal infections in order to provide optimal care for their patients.

Antifungal agents in the 1990s. Current status and future developments.

Significant advances in antifungal therapy have occurred in the last decade. Most of these advances have been tied to the introduction of the triazoles, itraconazole and fluconazole. Itraconazole has proved efficacious for the treatment of subacute to chronic infections with the endemic mycoses and other opportunistic filamentous fungi, including Aspergillus spp. Fluconazole is now routinely used for mucocutaneous and systemic candidiasis, and its use for coccidioidal meningitis has obviated the need for intrathecal amphotericin B in most patients. Large, well controlled trials in AIDS patients with cryptococcal meningitis have shown the benefit of induction therapy with amphotericin B and flucytosine, followed by consolidation and life-long maintenance therapy with fluconazole. Concomitant with the increased use of these well tolerated, effective oral triazole agents has come the emergence of drug resistance in AIDS patients and shifts in the species of yeasts causing infection in hospitalised patients. Amphotericin B remains the drug of choice for many fungal infections, especially those that are life-threatening. Lipid-containing formulations of amphotericin B have recently been approved: these preparations significantly reduce the risk of amphotericin B-induced nephrotoxicity. Several new fungicidal agents are currently in early trials. With the increasing number of available antifungal drugs, future studies will help define the appropriate niche for each and the possible benefit of therapy with combinations of drugs.