An overview of opportunistic fungal infections associated with COVID-19.

The COVID-19 survivors and long-term steroid administered patients exhibit a variety of fungal co-infections. The lives of COVID-19 patients and survivors are hampered by fungal species of the genera Candida, Aspergillus, and Mucor. There have been cases of mucormycosis, aspergillosis, and candidiasis in COVID-19 patients. The treatments given to these opportunistic fungal infections include polyene like amphotericin B, azoles including imidazoles like ketoconazole, miconazole, and triazoles like fluconazole, voriconazole, itraconazole, Echinocandin derivatives like- caspofungin, micafungin, immunomodulatory therapy, granulocyte transfusion, etc. A successful recovery and the reduction of fatalities depend on prompt diagnosis and treatment. To reduce mortality, advanced techniques to identify such uncommon infections at a very early stage are necessary. This review's goal is to provide a summary of the systemic and superficial opportunistic fungal infections that the COVID-19 survivors were dealing with, including information on illness incidence, pathogenicity, and treatment.

The challenges of the genome-based identification of antifungal resistance in the clinical routine.

The increasing number of chronic and life-threatening infections caused by antimicrobial resistant fungal isolates is of critical concern. Low DNA sequencing cost may facilitate the identification of the genomic profile leading to resistance, the resistome, to rationally optimize the design of antifungal therapies. However, compared to bacteria, initiatives for resistome detection in eukaryotic pathogens are underdeveloped. Firstly, reported mutations in antifungal targets leading to reduced susceptibility must be extensively collected from the literature to generate comprehensive databases. This information should be complemented with specific laboratory screenings to detect the highest number possible of relevant genetic changes in primary targets and associations between resistance and other genomic markers. Strikingly, some drug resistant strains experience high-level genetic changes such as ploidy variation as much as duplications and reorganizations of specific chromosomes. Such variations involve allelic dominance, gene dosage increments and target expression regime effects that should be explicitly parameterized in antifungal resistome prediction algorithms. Clinical data indicate that predictors need to consider the precise pathogen species and drug levels of detail, instead of just genus and drug class. The concomitant needs for mutation accuracy and assembly quality assurance suggest hybrid sequencing approaches involving third-generation methods will be utilized. Moreover, fatal fast infections, like fungemia and meningitis, will further require both sequencing and analysis facilities are available in-house. Altogether, the complex nature of antifungal resistance demands extensive sequencing, data acquisition and processing, bioinformatic analysis pipelines, and standard protocols to be accomplished prior to genome-based protocols are applied in the clinical setting.

Sulfonamides with Heterocyclic Periphery as Antiviral Agents.

Sulfonamides are the basic motifs for a whole generation of drugs from a large group of antibiotics. Currently, research in the field of the new sulfonamide synthesis has received a "second wind", due to the increase in the synthetic capabilities of organic chemistry and the study of their medical and biological properties of a wide spectrum of biological activity. New reagents and new reactions make it possible to significantly increase the number of compounds with a sulfonamide fragment in combination with other important pharmacophore groups, such as, for example, a wide class of N-containing heterocycles. The result of these synthetic possibilities is the extension of the activity spectrum-along with antibacterial activity, many of them exhibit other types of biological activity. Antiviral activity is also observed in a wide range of sulfonamide derivatives. This review provides examples of the synthesis of sulfonamide compounds with antiviral properties that can be used to develop drugs against coxsackievirus B, enteroviruses, encephalomyocarditis viruses, adenoviruses, human parainfluenza viruses, Ebola virus, Marburg virus, SARS-CoV-2, HIV and others. Since over the past three years, viral infections have become a special problem for public health throughout the world, the development of new broad-spectrum antiviral drugs is an extremely important task for synthetic organic and medicinal chemistry. Sulfonamides can be both sources of nitrogen for building a nitrogen-containing heterocyclic core and the side chain substituents of a biologically active substance. The formation of the sulfonamide group is often achieved by the reaction of the N-nucleophilic center in the substrate molecule with the corresponding sulfonylchloride. Another approach involves the use of sulfonamides as the reagents for building a nitrogen-containing framework.

Combination therapy in Mucormycosis: Current evidence from the world literature, a mini review.

The emergence of Mucorales infections is an urgent global public health threat rapidly disseminating during the current COVID-19 pandemic. Invasive mucormycosis carries significant morbidity and mortality; this is further compounded by the lack of newer effective antifungals on the horizon. Liposomal Amphotericin (L-AMB) is currently considered the cornerstone of antifungals therapy against mucormycosis; However, two decades later (since the introduction of L-AMB), the outcome remains dismal. Furthermore, adverse events related to therapeutic doses of L-AMB are also a hindrance. There is an imperative need for an alternative therapeutic approach to reduce the high mortality. One such approach is to combine the amphotericin with other agents (e.g., caspofungin, posaconazole, isavuconazole, and iron chelators) that can work synergistically or help in reducing the therapeutic doses of L-AMB. This review aims to highlight the various treatment approaches by gathering the clinical evidence from the literature and considering all potential pharmacological combinations that can provide the direction for future studies.

Mucormycosis: A hidden mystery of fungal infection, possible diagnosis, treatment and development of new therapeutic agents.

Mucormycosis is a fungal infection which got worsens with time if not diagnosed and treated. The current COVID-19 pandemic has association with fungal infection specifically with mucormycosis. Already immunocompromised patients are easy target for COVID-19 and mucormycosis as well. COVID-19 infection imparts in weak immune system so chances of infection is comparatively high in COVID-19 patients. Furthermore, diabetes, corticosteroid medicines, and a weakened immune system are the most prevalent risk factors for this infection as we discussed in case studies here. The steroid therapy for COVID-19 patients sometimes have negative impact on the patient health and this state encounters many infections including mucormycosis. There are treatments available but less promising and less effective. So, researchers are focusing on the promising agents against mucormycosis. It is reported that early treatment with liposomal amphotericin B (AmB), manogepix, echinocandins isavuconazole, posacanazole and other promising therapeutic agents have overcome the burden of mucormycosis. Lipid formulations of AmB have become the standard treatment for mucormycosis due to their greater safety and efficacy. In this review article, we have discussed case studies with the infection of mucormycosis in COVID-19 patients. Furthermore, we focused on anti-mucormycosis agents with mechanism of action of various therapeutics, including coverage of new antifungal agents being investigated as part of the urgent global response to control and combat this lethal infection, especially those with established risk factors.

Emergence and Genomic Characterization of Multidrug Resistant Candida auris in Nigeria, West Africa.

Candida auris is an emerging multidrug-resistant fungal pathogen that has become a worldwide public health threat due to the limitations of treatment options, difficulty in diagnosis, and its potential for clonal transmission. Four ICU patients from three different healthcare facilities in Southern Nigeria presented features suggestive of severe sepsis and the blood cultures yielded the growth of Candida spp., which was identified using VITEK 2 as C. auris. Further confirmation was performed using whole genome sequencing (WGS). From the genomic analysis, two had mutations that conferred resistance to the antifungal azole group and other non-synonymous mutations in hotspot genes, such as ERG2, ERG11, and FKS1. From the phylogenetic analysis, cases 2 and 4 had a confirmed mutation (ERG11:Y132F) that conferred drug resistance to azoles clustered with clade 1, whilst cases 1 and 3 clustered with clade 4. Three of the patients died, and the fourth was most likely a case of colonization since he received no antifungals and was discharged home. These first cases of C. auris reported from Nigeria were most likely introduced from different sources. It is of public health importance as it highlights diagnostic gaps in our setting and the need for active disease surveillance in the region.

Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation?

Invasive fungal infections are an important cause of morbidity and mortality, especially in critically ill patients. Increasing resistance rates and inadequate antifungal exposure have been documented in these patients, due to clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) alterations, leading to treatment failure. Physiological changes such as third spacing (movement of fluid from the intravascular compartment to the interstitial space), hypoalbuminemia, renal failure and hepatic failure, as well as common interventions in the intensive care unit, such as renal replacement therapy and extracorporeal membrane oxygenation, can lead to these PK and PD alterations. Consequently, a therapeutic target concentration that may be useful for one patient may not be appropriate for another. Regular doses do not take into account the important PK variations in the critically ill, and the need to select an effective dose while minimising toxicity advocates for the use of therapeutic drug monitoring (TDM). This review aims to describe the current evidence regarding optimal PK/PD indices associated with the clinical efficacy of the most commonly used antifungal agents in critically ill patients (azoles, echinocandins, lipid complexes of amphotericin B, and flucytosine), provide a comprehensive understanding of the factors affecting the PK of each agent, document the PK parameters of critically ill patients compared to healthy volunteers, and, finally, make recommendations for therapeutic drug monitoring (TDM) of antifungals in critically ill patients.

Impact of COVID-19 on the antifungal susceptibility profiles of isolates collected in a global surveillance program that monitors invasive fungal infections.

Studies demonstrated the impact of the COVID-19 pandemic in the prevalence and susceptibility profiles of bacterial and fungal organisms. We analyzed 4821 invasive fungal isolates collected during 2018, 2019, and 2020 in 48 hospitals worldwide to evaluate the impact of this event in the occurrence and susceptibility rates of common fungal species. Isolates were tested using the CLSI broth microdilution method. While the percentage of total isolates that were C. glabrata (n = 710 isolates) or C. krusei (n = 112) slightly increased in 2020, the percentage for C. parapsilosis (n = 542), A. fumigatus (n = 416), and C. lusitaniae (n = 84) significantly decreased (P < .05). Fluconazole resistance in C. glabrata decreased from 5.8% in 2018-2019 to 2.0% in 2020, mainly due to fewer hospitals in the US having these isolates (5 vs. 1 hospital). Conversely, higher fluconazole-resistance rates were noted for C. parapsilosis (13.9 vs. 9.8%) and C. tropicalis (3.5 vs. 0.7%; P < .05) during 2020. Voriconazole resistance also increased for these species. Echinocandin resistance was unchanged among Candida spp. Voriconazole susceptibility rates in A. fumigatus were similar in these two periods (91.7% in 2018 and 2019 vs. 93.0% in 2020). Changes were also noticed in the organisms with smaller numbers of collected isolates. We observed variations in the occurrence of organisms submitted to a global surveillance and the susceptibility patterns for some organism-antifungal combinations. As the COVID-19 pandemic is still ongoing, the impact of this event must continue to be monitored to guide treatment of patients affected by bacterial and fungal infections. LAY SUMMARY: Secondary infections were documented in COVID-19 patients. We compared the prevalence of invasive fungal isolates consecutively collected in 48 worldwide hospitals and their susceptibility patterns between 2020, the year of the global COVID-19 pandemic, and the two prior years.

Design and synthesis of heterocyclic azole based bioactive compounds: Molecular structures, quantum simulation, and mechanistic studies through docking as multi-target inhibitors of SARS-CoV-2 and cytotoxicity.

Two heterocyclic azole compounds, 3-(2,3-dihydrobenzo[d]thiazol-2-yl)-4H-chromen-4-one (SVS1) and 5-(1H-indol-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (SVS2) were obtained unexpectedly from 2-aminothiophenol and 4-oxo-4H-chromene-3-carbaldehyde (for SVS1), and (E)-2-((1H-indol-3-yl)methylene)-N-methylhydrazine-1-carbothioamide in the presence of anhydrous FeCl3 (for SVS2), respectively. The compounds were well characterized by analytical and spectroscopic tools. The molecular structures of both the compounds were determined by single crystal X-ray diffraction (XRD) study. The results obtained from density functional theory (DFT) study revealed the molecular geometry and electron distribution of the compounds, which were correlated well with the three-dimensional structures obtained from the single crystal XRD. DMol3 was used to calculate quantum chemical parameters [chemical potential (µ), global hardness (η), global softness (σ), absolute electronegativity (χ) and electrophilicity index (ω)] of SVS1 and SVS2. Molecular docking study was performed to elucidate the binding ability of SVS1 and SVS2 with SARS-CoV-2 main protease and human angiotensin-converting enzyme-2 (ACE-2) molecular targets. Interestingly, the binding efficiency of the compounds with the molecular targets was comparable with that of remdesivir (SARS-CoV-2), chloroquine and hydroxychloroquine. SVS1 showed better docking energy than SVS2. The molecular docking study was complemented by molecular dynamics simulation study of SARS-CoV-2 main protease-SVS1 complex, which further exemplified the binding ability of SVS1 with the target. In addition, SVS1, SVS2 and cisplatin were assessed for their cytotoxicity against a panel of three human cancer cells such as HepG-2 (hepatic carcinoma), T24 (bladder) and EA.hy926 (endothelial), as well as Vero (kidney epithelial cells extracted from an African green monkey) normal cells using MTT assay. The results showed that SVS2 has significant cytotoxicity against HepG-2 and EA.hy926 cells with the IC50 values of 33.8 µM (IC50 = 49.9 µM-cisplatin and 8.6 µM-doxorubicin) and 29.2 (IC50 = 26.6 µM-cisplatin and 3.8 µM-doxorubicin), respectively.