Adverse Drug Reaction of Antifungals in the Management of Black Fungus: A Tertiary Care Centre Experience.

In India, COVID-19 has led to a surge in cases of a potentially fatal fungal infection called mucormycosis, popularly known as "black fungus." Intravenous amphotericin B is the only available drug for salvage therapy. Efforts to improve its therapeutic efficacy and decrease its nephrotoxicity have focussed on the reformulation of AmB in three new lipid formulations such amphotericin B lipid complex (Abelcet), amphotericin B colloidal dispersion (Amphotec), and liposomal amphotericin B (AmBisome). The aim of this study is (1) to evaluate the adverse drug reaction of various formulations of amphotericin B used for the treatment of rhinooculocerebralmucormycosis in Indian population. (2) to evaluate the adverse drug reaction of injectable form of posaconazole. This prospective observational study was done on a random sample of 110 patients who got admitted for the management of rhinooculocerebral mucormycosis in a tertiary care centre of middle india… The patients were assessed for the adverse reactions following the administration of various antifungal medication and the findings were analysed. All the 110 patients had received two forms of Amphotericin B (liposomal Amphotericin B and Amphotericin B lipid complex) and Posaconazole injection. 60 patients had received all three forms of Amphotericin B. Out of the 110 patients who received Liposomal amphotericin B, only 2 patients developed adverse drug reaction while in 110 patients who received Amphotericin B Lipid complex, 7 patients had adverse drug effects. Lyophilised amphotericin B had been administered to 60 patients in which 51 patients developed adverse drug reaction and in them one patient went to congestive cardiac failure. Injection posaconazole had been administered to 110 patients in which 72 patients developed drug reaction. In spite of its proven track record of Amphotericin B, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. Lipid formulations of AmB are better tolerated than AmB deoxycholate but infusional drug reactions have been reported in lipid formulation too. So improved strategies for the management of infusion related adverse events are required.

Biological Activities of Ruthenium NHC Complexes: An Update.

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds.

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.

Impact of COVID-19 pandemic on antifungal consumption: a multicenter retrospective analysis.

BACKGROUND: In the context of COVID-19 pandemic, antifungal overuse may have occurred in our hospitals as it has been previously reported for antibacterials. METHODS: To investigate the impact of COVID-19 on antifungal consumption, a multicenter retrospective study including four medical sites and 14 intensive care units (ICU) was performed. Antifungal consumption and incidences of invasive fungal diseases before and during COVID-19 pandemic, for non-COVID-19 patients and COVID-19 patients, were described. RESULTS: An increase in voriconazole consumption was observed in 2020 compared with 2019 for both the whole hospital and the ICU (+ 40.3% and + 63.7%, respectively), whereas the incidence of invasive aspergillosis significantly increased in slightly lower proportions in the ICU (+ 46%). Caspofungin consumption also increased in 2020 compared to 2019 for both the whole hospital and the ICU (+ 34.9% and + 17.0%, respectively) with an increased incidence of invasive candidiasis in the whole hospital and the ICU but in lower proportions (+ 20.0% and + 10.9%, respectively). CONCLUSIONS: We observed an increased consumption of antifungals including voriconazole and caspofungin in our hospital during the COVID-19 pandemic and explained in part by an increased incidence of invasive fungal diseases in COVID-19 patients. These results are of utmost importance as it raises concern about the urgent need for appropriate antifungal stewardship activities to control antifungal consumption.

Clinical and mycological investigations of post-COVID-19 acute invasive fungal sinusitis.

Objectives: An increased incidence of acute invasive fungal sinusitis associated with the recent COVID-19 pandemic has been observed, which is considered a public health concern. This study aims to detect the incidence, risk factors, causative agents, clinical presentations, outcomes, and susceptibility rate of various antifungals. Methods: In this cross-sectional cohort study, a total of 30 patients showing acute invasive fungal rhinosinusitis following a COVID-19 infection were investigated. Histopathological biopsies, culture identification, and molecular confirmation of the causative agents were conducted. The demographic data, risk factors, clinical presentations, treatment regimen and its outcomes, and efficacy of antifungals were listed and analyzed. Results: A total of 30 cases with a mean age of 59.6 ± 11.9 years were included. Diabetes mellitus was the most recorded comorbidity with a rate of 86.7%, whereas most of the patients received corticosteroids. The mycological examination confirmed the existence of Mucor (Rhizopus oryzae) and Aspergillus (Aspergillus niger) in 96.7% and 3.3% of the cases, respectively. Various stages of sinonasal involvement (ethmoid, maxillary, sphenoid, and inferior turbinate) represented 100%, 83.3%, 66.7%, and 86.7% of the cases, respectively. Headache and facial pain, ophthalmoplegia, visual loss, and blindness represented 100%, 66.7%, 90%, and 53.3% of the cases, respectively. All the cases were simultaneously treated with surgical debridement and amphotericin B. Moreover, R. oryzae was susceptible to it, whereas A. niger was sensitive to voriconazole, resulting in a survival rate of 86.7% (26/30). The R. oryzae and A. niger isolates were proven to be sensitive to acetic acid, ethyl alcohol, formalin, and isopropyl alcohol. Conclusions: In patients with COVID-19, the diagnosis of acute invasive fungal sinusitis and prompt treatment with antifungal medicine and surgical debridement are important in achieving better outcomes and survival rates. Level of Evidence: 4.

Cirrhosis and fungal infections-a cocktail for catastrophe: A systematic review and meta-analysis with machine learning.

OBJECTIVES: We evaluated the magnitude and factors contributing to poor outcomes among cirrhosis patients with fungal infections (FIs). METHODS: We searched PubMed, Embase, Ovid and WOS and included articles reporting mortality in cirrhosis with FIs. We pooled the point and relative-risk (RR) estimates of mortality on random-effects meta-analysis and explored their heterogeneity (I 2 ) on subgroups, meta-regression and machine learning (ML). We assessed the study quality through New-Castle-Ottawa Scale and estimate-asymmetry through Eggers regression. (CRD42019142782). RESULTS: Of 4345, 34 studies (2134 patients) were included (good/fair/poor quality: 12/21/1). Pooled mortality of FIs was 64.1% (95% CI: 55.4-72.0, I 2 : 87%, p < .01), which was 2.1 times higher than controls (95% CI: 1.8-2.5, I 2 :89%, p < .01). Higher CTP (MD: +0.52, 95% CI: 0.27-0.77), MELD (MD: +2.75, 95% CI: 1.21-4.28), organ failures and increased hospital stay (30 vs. 19 days) were reported among cases with FIs. Patients with ACLF (76.6%, RR: 2.3) and ICU-admission (70.4%, RR: 1.6) had the highest mortality. The risk was maximum for pulmonary FIs (79.4%, RR: 1.8), followed by peritoneal FIs (68.3%, RR: 1.7) and fungemia (55%, RR: 1.7). The mortality was higher in FIs than in bacterial (RR: 1.7) or no infections (RR: 2.9). Estimate asymmetry was evident (p < 0.05). Up to 8 clusters and 5 outlier studies were identified on ML, and the estimate-heterogeneity was eliminated by excluding such studies. CONCLUSIONS: A substantially worse prognosis, poorer than bacterial infections in cirrhosis patients with FIs, indicates an unmet need for improving fungal diagnostics and therapeutics in this population. ACLF and ICU admission should be included in the host criteria for defining IFIs.

Prevalence and Antifungal Susceptibility Profile of Oral Candida spp. Isolates from a Hospital in Slovakia.

Oral fungal infections are a worldwide healthcare problem. Although Candida albicans is still the most common yeast involved in the infections of oral cavity, non-Candida&nbsp;albicans&nbsp;Candida species (NCACs) have been highly related to these infections, particularly in older, immunosuppressed or patients with long exposure to antimicrobial drugs. The goal of this work was to perform a quick epidemiological and mycological study on the oral samples collected from a laboratory of a hospital in Slovakia, for 60 days. The samples' identification was performed by Germ-tube formation test, CHROMID®&nbsp;Candida, Auxacolor 2, ID 32C automated method, and the antifungal susceptibility testing determined by E-test®. Results confirm that comparing with bacteria, yeasts still occur in the lower number, but there is a high rate of antifungal resistance (81.6%)-to, at least one drug-among the collected samples, particularly to azoles and 5'-FC, which is clinically noteworthy.

The Pandemic Response Box─Accelerating Drug Discovery Efforts after Disease Outbreaks.

The current Covid-19 pandemic has underlined the need for a more coordinated and forward-looking investment in the search for new medicines targeting emerging health care threats. Repositioning currently approved drugs is a popular approach to any new emerging disease, but it represents a first wave of response. Behind this would be a second wave of more specifically designed therapies based on activities against specific molecular targets or in phenotypic assays. Following the successful deployment and uptake of previous open access compound collections, we assembled the Pandemic Response Box, a collection of 400 compounds to facilitate drug discovery in emerging infectious disease. These are based on public domain information on chemotypes currently in discovery and early development which have been shown to have useful activities and were prioritized by medicinal chemistry experts. They are freely available to the community as a pharmacological test set with the understanding that data will be shared rapidly in the public domain.

Highlights of the Latest Developments in Radiopharmaceuticals for Infection Imaging and Future Perspectives.

COVID-19 pandemic has heightened the interest toward diagnosis and treatment of infectious diseases. Nuclear medicine with its powerful scintigraphic, single photon emission computer tomography (SPECT) and positron emission tomography (PET) imaging modalities has always played an important role in diagnosis of infections and distinguishing them from the sterile inflammation. In addition to the clinically available radiopharmaceuticals there has been a decades-long effort to develop more specific imaging agents with some examples being radiolabeled antibiotics and antimicrobial peptides for bacterial imaging, radiolabeled anti-fungals for fungal infections imaging, radiolabeled pathogen-specific antibodies and molecular engineered constructs. In this opinion piece, we would like to discuss some examples of the work published in the last decade on developing nuclear imaging agents for bacterial, fungal, and viral infections in order to generate more interest among nuclear medicine community toward conducting clinical trials of these novel probes, as well as toward developing novel radiotracers for imaging infections.

Emerging and future strategies in the management of recalcitrant Candida auris.

Candida auris is an emerging, multi drug resistant fungal pathogen that has caused infectious outbreaks in over 45 countries since its first isolation over a decade ago, leading to in-hospital crude mortality rates as high as 72%. The fungus is also acclimated to disinfection procedures and persists for weeks in nosocomial ecosystems. Alarmingly, the outbreaks of C. auris infections in Coronavirus Disease-2019 (COVID-19) patients have also been reported. The pathogenicity, drug resistance and global spread of C. auris have led to an urgent exploration of novel, candidate antifungal agents for C. auris therapeutics. This narrative review codifies the emerging data on the following new/emerging antifungal compounds and strategies: antimicrobial peptides, combinational therapy, immunotherapy, metals and nano particles, natural compounds, and repurposed drugs. Encouragingly, a vast majority of these exhibit excellent anti- C. auris properties, with promising drugs now in the pipeline in various stages of development. Nevertheless, further research on the modes of action, toxicity, and the dosage of the new formulations are warranted. Studies are needed with representation from all five C. auris clades, so as to produce data of grater relevance, and broader significance and validity. LAY SUMMARY: Elimination of Candida auris that causes deadly infections to susceptible individuals is extremely challenging due to the lack of effective treatment options. Promising, new antifungal agents and strategies are being developed and further refinement will facilitate their clinical use in the near future.

Advances in Antifungal Drug Development: An Up-To-Date Mini Review.

The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets for antifungals. Novel antifungals in clinical development include first-in-class agents, new structures for an established target, and formulation modifications to marketed antifungals, in addition to repurposed agents. Membrane interacting peptides and aromatherapy are gaining increased attention in the field. Immunotherapy is another promising treatment option, with antifungal antibodies advancing into clinical trials. Novel targets for antifungal therapy are also being discovered, allowing the design of new promising agents that may overcome the resistance issue. In this mini review, we will summarize the current status of antifungal drug pipelines in clinical stages, and the most recent advancements in preclinical antifungal drug development, with special focus on their chemistry.

Clinicomycological study of candida isolates in a tertiary care hospital: A pilot study

Background: Candida infection is on the rise with an increasing number of nonalbicans species. Therefore, the need to speciate Candida rapidly and accurately is of the utmost importance. The purpose of this study was to speciate Candida using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), to analyze the correlation of the isolates with the clinical condition, and to study the outcome of the patient. Materials and Methods: PCR-RFLP using universal primers ITS1 and ITS4 was done to speciate all isolates of Candida;patient details were collected to analyze the clinical condition and the outcome of the patient. Results: The most common species of Candida isolated was Candida tropicalis 14 (56%) followed by Candida albicans 5 (20%), Candida auris 3 (14%), Candida parapsilosis 1 (4%), Candida orthopsilosis 1 (4%), and Candida kefyr 1 (4%). Majority of the samples that were collected were urine samples 15 (60%). The average duration of hospital stay was found to be 13.8 days. A number of underlying risk factors were present such as patients with diabetes, sepsis, malignancy, covid19 infection, surgical patients, preterm patients, elderly patients, and patients on long-term steroids. Conclusion: Candidemia is on the rise nowadays with nonalbicans species responsible for the majority of the infections. Since the outcome of the patient depends on rapid diagnosis and prompt initiation of antifungal agents PCR-RFLP proves to be a rapid and reliable test to identify most of the prevailing species of Candida. © 2021 Journal of Medical Society ;Published by Wolters Kluwer-Medknow.

Antimicrobial Consumption among 66 Acute Care Hospitals in Catalonia: Impact of the COVID-19 Pandemic.

BACKGROUND: Antimicrobials have been widely used during the COVID-19 pandemic. This study aimed to analyze the impact of the COVID-19 pandemic on the antimicrobial consumption of 66 hospitals in Catalonia. METHODS: Adult antibacterial and antimycotic consumption was calculated as defined daily doses (DDD)/100 bed-days and DDD/100 discharges. Firstly, overall and ICU consumption in 2019 and 2020 were compared. Secondly, observed ICU 2020 consumptions were compared with non-COVID-19 2020 estimated consumptions (based on the trend from 2008-2019). RESULTS: Overall, antibacterial consumption increased by 2.31% and 4.15% DDD/100 bed-days and DDD/100 discharges, respectively. Azithromycin (105.4% and 109.08% DDD/100 bed-days and DDD/100 discharges, respectively) and ceftriaxone (25.72% and 27.97% DDD/100 bed-days and DDD/100 discharges, respectively) mainly accounted for this finding. Likewise, antifungal consumption increased by 10.25% DDD/100 bed-days and 12.22% DDD/100 discharges, mainly due to echinocandins or amphotericin B. ICU antibacterial and antimycotic consumption decreased by 1.28% and 4.35% DDD/100 bed-days, respectively. On the contrary, antibacterial and antifungal use, expressed in DDD/100 discharges, increased by 23.42% and 19.58%. Azithromycin (275.09%), ceftriaxone (55.11%), cefepime (106.35%), vancomycin (29.81%), linezolid (31.28%), amphotericin B (87.98%), and voriconazole (96.17%) use changed the most. Observed consumption of amphotericin B, azithromycin, caspofungin, ceftriaxone, vancomycin, and voriconazole were higher than estimated values. CONCLUSIONS: The consumption indicators for most antimicrobials deviated from the expected trend pattern. A worrisome increase in antibacterial and antifungal consumption was observed in ICUs in Catalonia.

Impact of the SARS-CoV-2 Pandemic in Candidaemia, Invasive Aspergillosis and Antifungal Consumption in a Tertiary Hospital.

In addition to the increase in fungal infections that has been observed in the last few decades, it has been reported that severe clinical COVID-19 can increase the risk of invasive fungal infections. The main objective of this study was to evaluate if there had been an increase in candidaemia and invasive pulmonary aspergillosis (IPA) cases since the onset of the SARS-CoV-2 pandemic. Data were retrospectively collected from April 2019 to March 2021, from patients admitted to Consorcio Hospital General Universitario de Valencia (Spain). A total of 152 candidaemia cases (56 of which were due to Candida auris) and 108 possible IPA cases were detected. A great increase in candidaemia cases was produced during the first and the third epidemic waves of the SARS-CoV-2 pandemic (June 2020, and January 2021, respectively), while an increase in IPA cases was produced during the third wave. The 28-day mortality rates in patients affected by candidaemia and IPA increased in 2020 and 2021. C. auris has displaced the other Candida species, becoming the most isolated Candida species in blood cultures since the onset of the SARS-CoV-2 pandemic. Antifungal consumption increased in 2020 when compared to 2019, especially echinocandins, voriconazole and isavuconazole.

Effects of Antifungal Carriers Based on Chitosan-Coated Iron Oxide Nanoparticles on Microcosm Biofilms.

Resistance of Candida species to conventional therapies has motivated the development of antifungal nanocarriers based on iron oxide nanoparticles (IONPs) coated with chitosan (CS). This study evaluates the effects of IONPs-CS as carriers of miconazole (MCZ) or fluconazole (FLZ) on microcosm biofilms. Pooled saliva from two healthy volunteers supplemented with C. albicans and C. glabrata was the inoculum for biofilm formation. Biofilms were formed for 96 h on coverslips using the Amsterdam Active Attachment model, followed by 24 h treatment with nanocarriers containing different concentrations of each antifungal (78 and 156 µg/mL). MCZ or FLZ (156 µg/mL), and untreated biofilms were considered as controls. Anti-biofilm effects were evaluated by enumeration of colony-forming units (CFUs), composition of the extracellular matrix, lactic acid production, and structure and live/dead biofilm cells (confocal laser scanning microscopy-CLSM). Data were analyzed by one-way ANOVA and Fisher LSD's test (α = 0.05). IONPs-CS carrying MCZ or FLZ were the most effective treatments in reducing CFUs compared to either an antifungal agent alone for C. albicans and MCZ for C. glabrata. Significant reductions in mutans streptococci and Lactobacillus spp. were shown, though mainly for the MCZ nanocarrier. Antifungals and their nanocarriers also showed significantly higher proportions of dead cells compared to untreated biofilm by CLSM (p < 0.001), and promoted significant reductions in lactic acid, while simultaneously showing increases in some components of the extracellular matrix. These findings reinforce the use of nanocarriers as effective alternatives to fight oral fungal infections.

An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study.

A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under in vitro as well as in vivo conditions.Communicated by Ramaswamy H. Sarma.