scholarly journals Outstanding Contributions of LAL Technology to Pharmaceutical and Medical Science: Review of Methods, Progress, Challenges, and Future Perspectives in Early Detection and Management of Bacterial Infections and Invasive Fungal Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 536
Author(s):  
Hiroshi Tamura ◽  
Johannes Reich ◽  
Isao Nagaoka
Keyword(s):  
Bacterial Infections ◽  
Horseshoe Crab ◽  
Fungal Infections ◽  
Medical Science ◽  
Fungal Diseases ◽  
Analytical Sensitivity ◽  
Pharmaceutical Drugs ◽  
Fungal Cell ◽  
Invasive Fungal Diseases ◽  
Lal Assay

The blue blood of the horseshoe crab is a natural, irreplaceable, and precious resource that is highly valued by the biomedical industry. The Limulus amebocyte lysate (LAL) obtained from horseshoe crab blood cells functions as a surprisingly sophisticated sensing system that allows for the extremely sensitive detection of bacterial and fungal cell-wall components. Notably, LAL tests have markedly contributed to the quality control of pharmaceutical drugs and medical devices as successful alternatives to the rabbit pyrogen test. Furthermore, LAL-based endotoxin and (1→3)-β-D-glucan (β-glucan) assay techniques are expected to have optimal use as effective biomarkers, serving as adjuncts in the diagnosis of bacterial sepsis and fungal infections. The innovative β-glucan assay has substantially contributed to the early diagnosis and management of invasive fungal diseases; however, the clinical significance of the endotoxin assay remains unclear and is challenging to elucidate. Many obstacles need to be overcome to enhance the analytical sensitivity and clinical performance of the LAL assay in detecting circulating levels of endotoxin in human blood. Additionally, there are complex interactions between endotoxin molecules and blood components that are attributable to the unique physicochemical properties of lipopolysaccharide (LPS). In this regard, while exploring the potential of new LPS-sensing technologies, a novel platform for the ultrasensitive detection of blood endotoxin will enable a reappraisal of the LAL assay for the highly sensitive and reliable detection of endotoxemia.

scholarly journals Diagnostic Challenge and Therapeutic Approaches in Human Sepsis Based on the Appearance of Endotoxemia and Beta-d-Glucanemia

2021 ◽  
Vol 22 (23) ◽  
pp. 12900
Author(s):  
Hiroshi Tamura ◽  
Yoshiyuki Adachi
Keyword(s):  
Cell Walls ◽  
Fungal Diseases ◽  
Therapeutic Approaches ◽  
Diagnostic Challenge ◽  
Fungal Cell ◽  
Gram Negative ◽  
Human Sepsis ◽  
Invasive Fungal Diseases ◽  
Fungal Cell Walls

Circulating endotoxin, also called lipopolysaccharide (LPS) and (1→3)-β-d-Glucan (β-d-glucan), major constituents of bacterial and fungal cell walls, respectively, are determined as biomarkers for Gram-negative sepsis and invasive fungal diseases [...]

Antifungal Therapy: New and Evolving Therapies

2020 ◽  
Vol 41 (01) ◽  
pp. 158-174 ◽  
Author(s):  
Yasmine Nivoix ◽  
Marie-Pierre Ledoux ◽  
Raoul Herbrecht
Keyword(s):  
Drug Interactions ◽  
Fungal Infections ◽  
Oral Route ◽  
Fungal Diseases ◽  
Main Concern ◽  
Novel Treatments ◽  
Invasive Fungal Diseases ◽  
First Choice ◽  
Critical Issues ◽  
Lipid Formulations

AbstractInvasive fungal diseases primarily occur in immunocompromised patients. Immunosuppression has become more prevalent due to novel treatments, and this has led to a rise in the incidence of invasive fungal diseases. The antifungal armamentarium has long been insufficient and has taken quite some time to become diverse. Antifungal spectrum, tolerability, and toxicity are critical issues. Amphotericin B and its lipid formulations still have the widest spectrum, but, in spite of the better tolerance of the lipid formulations, toxicity remains a drawback, mostly with regard to renal function. Azoles constitute a heterogeneous antifungal class, in which newer molecules have an improved spectrum of activity. The main concern for the clinician when using azoles relates to the management of their many potential drug–drug interactions in an often fragile patient population. Echinocandins are better tolerated but possess a narrower antifungal spectrum and lack an oral route of administration. Still, their fungicidal activity makes them a weapon of first choice against Candida species. For certain uncommon fungal infections, antifungals such as flucytosine and terbinafine can also be useful. This article will give an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug–drug interactions, and frequent side effects, all of which should drive the clinician's choice of agent when managing invasive fungal infections.

Organic Antifungal Drugs and Targets of Their Action

2021 ◽  
Vol 21 ◽  
Author(s):  
Alexander Yu. Maksimov ◽  
Svetlana Yu. Balandina ◽  
Pavel A. Topanov ◽  
Irina V. Mashevskaya ◽  
Sandeep Chaudhary
Keyword(s):  
Molecular Design ◽  
Fungal Infections ◽  
Wide Spectrum ◽  
Molecular Targets ◽  
Antifungal Drugs ◽  
The Body ◽  
Fungal Diseases ◽  
Fungal Cell ◽  
Genomics And Proteomics

: In recent decades, there has been a significant increase in the number of fungal diseases. This is due to a wide spectrum of action, immunosuppressants and other group drugs. In terms of frequency, rapid spread and globality, fungal infections are approaching acute respiratory infections. Antimycotics are medicinal substances endorsed with fungicidal or fungistatic properties. For the treatment of fungal diseases, several groups of compounds are used that differ in their origin (natural or synthetic), molecular targets and mechanism of action, antifungal effect (fungicidal or fungistatic), indications for use (local or systemic infections), methods of administration (parenteral, oral, outdoor). Several efforts have been made by various medicinal chemists around the world for the development of antifungal drugs with high efficacy with least toxicity and maximum selectivity in the area of antifungal chemotherapy. The pharmacokinetic properties of the new antimycotics are also important: the ability to penetrate biological barriers, be absorbed and distributed in tissues and organs, get accumulated in tissues affected by micromycetes, drug metabolism in the intestinal microflora and human organs, and in the kinetics of excretion from the body. There are several ways to search for new effective antimycotics: - Obtaining new derivatives of the already used classes of antimycotics with improved activity properties. - Screening of new chemical classes of synthetic antimycotic compounds. - Screening of natural compounds. - Identification of new unique molecular targets in the fungal cell. - Development of new compositions and dosage forms with effective delivery vehicles. The methods of informatics, bioinformatics, genomics and proteomics were extensively investigated for the development of new antimycotics. These techniques were employed in finding and identification of new molecular proteins in a fungal cell; in the determination of the selectivity of drug-protein interactions, evaluation of drug-drug interactions and synergism of drugs; determination of the structure-activity relationship (SAR) studies; determination of the molecular design of the most active, selective and safer drugs for the humans, animals and plants. In medical applications, the methods of information analysis and pharmacogenomics allows to take into account the individual phenotype of the patient, the level of expression of the targets of antifungal drugs when choosing antifungal agents and its dosage. This review article incorporates some of the most significant studies covering the basic structures and approaches for the synthesis of antifungal drugs and the directions for their further development.

scholarly journals Aiming for a bull’s-eye: Targeting antifungals to fungi with dectin-decorated liposomes

2021 ◽  
Vol 17 (7) ◽  
pp. e1009699
Author(s):  
Richard B. Meagher ◽  
Zachary A. Lewis ◽  
Suresh Ambati ◽  
Xiaorong Lin
Keyword(s):  
Organ Transplant ◽  
Drug Efficacy ◽  
The United States ◽  
Antifungal Drugs ◽  
Fungal Diseases ◽  
Antifungal Drug ◽  
Fungal Cell ◽  
Liposomal Drug ◽  
Invasive Fungal Diseases

Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.

scholarly journals Serum Glucan Levels Are Not Specific for Presence of Fungal Infections in Intensive Care Unit Patients

2003 ◽  
Vol 10 (5) ◽  
pp. 882-885 ◽  
Author(s):  
Justin Digby ◽  
John Kalbfleisch ◽  
Andy Glenn ◽  
Angie Larsen ◽  
William Browder ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Cell Wall ◽  
Intensive Care ◽  
Fungal Infection ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Critically Ill Patient ◽  
Fungal Cell ◽  
Icu Patients ◽  
Control Serum

ABSTRACT Fungal infections in the critically ill patient are difficult to diagnose and are associated with a high mortality rate. A major obstacle to managing fungal infection is the lack of a reliable clinical assay that will rapidly identify patients with fungal sepsis. Glucans are polymers of glucose that are found in the cell wall of fungi and certain bacteria. Glucans are also released from the fungal cell wall into the extracellular milieu. Several studies have reported that detection of fungal glucan in serum or plasma is useful in the diagnosis of mycoses. However, recent studies have questioned the clinical utility of this assay. In this study, we examined serum glucan levels in intensive care unit (ICU) patients and attempt to correlate serum glucan levels with the presence of fungal infection. Following attainment of informed consent, serum was harvested from 46 ICU patients with confirmed fungal infections, confirmed bacterial infections, or no evidence of infection. Sera from eight healthy volunteers served as control. Serum glucan was assayed with a glucan-specific Limulus assay. Serum glucan levels were increased (69.6 ± 17 pg/ml; P < 0.001) in ICU patients versus the normal (11.5 ± 1.3 pg/ml) and noninfected ICU (27.4 ± 17 pg/ml) controls. However, serum glucan levels were not different in patients with confirmed fungal infections versus those with confirmed bacterial infections. Thus, serum glucan levels did not show a correlation with the presence of fungal infections and do not appear to be specific for fungal infections. However, the assay may be useful as a negative predictor of infection.

scholarly journals Living Bacterial Microneedles for Fungal Infection Treatment

Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Fengyuan Wang ◽  
Xiaoxuan Zhang ◽  
Guopu Chen ◽  
Yuanjin Zhao
Keyword(s):  
Fungal Infection ◽  
Food Processing ◽  
Bacterial Infections ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Therapeutic Effects ◽  
Fungal Cell ◽  
Infection Treatment ◽  
Associated Proteins ◽  
Encapsulated Bacteria

Fungal infections are everlasting health challenges all over the world, bringing about great financial and medical burdens. Here, inspired by the natural competition law of beneficial bacteria against other microbes, we present novel living microneedles (LMNs) with functionalized bacteria encapsulation for efficient fungal infection treatment. The chosen beneficial bacterial components, Bacillus subtilis (B. subtilis), which are naturally found on the human skin and widely used for food processing, can get nutrients from the skin and escape from the immune system with the help of microneedles. Besides, the encapsulated B. subtilis can continuously produce and secrete various potential antifungal agents which can directly bind to fungal cell surface-associated proteins and destruct the cell membranes, thus avoiding drug resistance. After immobilization in the LMNs, the bacteria can stay within the LMNs without invasion and the encapsulated bacteria together with microneedles can be removed after application. Thus, the side effects, especially the risk for subsequent bacterial infections, are controlled to a minimum to ensure security. In addition, strong penetrability of the microneedles enhances penetration of antifungal agents, and their heights can be adjusted according to the infected depth to acquire better therapeutic effects. These features make the LMNs potentially valuable for clinical applications.

scholarly journals The Lymphocytic Scavenger Receptor CD5 Shows Therapeutic Potential in Mouse Models of Fungal Infection

2020 ◽  
Vol 65 (1) ◽  
pp. e01103-20 ◽  
Author(s):  
María Velasco-de Andrés ◽  
Cristina Català ◽  
Sergi Casadó-Llombart ◽  
Mario Martínez-Florensa ◽  
Inês Simões ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Spleen Cell ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Scavenger Receptor ◽  
Fungal Diseases ◽  
Fungal Cell ◽  
Content Type ◽  
Invasive Fungal Diseases

ABSTRACTInvasive fungal diseases represent an unmet clinical need that could benefit from novel immunotherapeutic approaches. Host pattern recognition receptors (e.g., Toll-like receptors, C-type lectins, or scavenger receptors) that sense conserved fungal cell wall constituents may provide suitable immunotherapeutic antifungal agents. Thus, we explored the therapeutic potential of the lymphocyte class I scavenger receptor CD5, a nonredundant component of the antifungal host immune response that binds to fungal β-glucans. Antifungal properties of the soluble ectodomain of human CD5 (shCD5) were assessed in vivo in experimental models of systemic fungal infection induced by pathogenic species (Candida albicans and Cryptococcus neoformans). In vitro mechanistic studies were performed by means of fungus-spleen cell cocultures. shCD5-induced survival of lethally infected mice was dose and time dependent and concomitant with reduced fungal load and increased leukocyte infiltration in the primary target organ. Additive effects were observed in vivo after shCD5 was combined with suboptimal doses of fluconazole. Ex vivo addition of shCD5 to fungus-spleen cell cocultures increased the release of proinflammatory cytokines involved in antifungal defense (tumor necrosis factor alpha and gamma interferon) and reduced the number of viable C. albicans organisms. The results prompt further exploration of the adjunctive therapeutic potential of shCD5 in severe invasive fungal diseases.

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